key: cord-0851374-xzpuc22p
authors: Ammirati, Enrico; Veronese, Giacomo; Bottiroli, Maurizio; Wang, Dao Wen; Cipriani, Manlio; Garascia, Andrea; Pedrotti, Patrizia; Adler, Eric D.; Frigerio, Maria
title: UPDATE ON ACUTE MYOCARDITIS
date: 2020-06-01
journal: Trends Cardiovasc Med
DOI: 10.1016/j.tcm.2020.05.008
sha: 2047be17eaa136b65df9cde38494a265410bd50b
doc_id: 851374
cord_uid: xzpuc22p

Acute myocarditis (AM), a recent-onset inflammation of the heart, has heterogeneous clinical presentations, varying from minor symptoms to high-risk cardiac conditions with severe heart failure, refractory arrhythmias, and cardiogenic shock. AM is moving from being a definitive diagnosis based on histological evidence of inflammatory infiltrates on cardiac tissue to a working diagnosis supported by high sensitivity troponin increase in association with specific cardiac magnetic resonance imaging (CMRI) findings. Though experts still diverge between those advocating for histological definition versus those supporting a mainly clinical definition of myocarditis, in the real-world practice the diagnosis of AM has undoubtedly shifted from being mainly biopsy-based to solely CMRI-based in most of clinical scenarios. It is thus important to clearly define selected settings where EMB is a must, as information derived from histology is essential for an optimal management. As in other medical conditions, a risk-based approach should be promoted in order to identify the most severe AM cases requiring appropriate bundles of care, including early recognition, transfer to tertiary centers, aggressive circulatory supports with inotropes and mechanical devices, histologic confirmation and eventual immunosuppressive therapy. Despite improvements in recognition and treatment of AM, including a broader use of promising mechanical circulatory supports, severe forms of AM are still burdened by dismal outcomes. This review is focused on recent clinical studies and registries that shed new insights on AM. Attention will be paid to contemporary outcomes and predictors of prognosis, the emerging entity of immune checkpoint inhibitors-associated myocarditis, updated CMRI diagnostic criteria, new data on the use of temporary mechanical circulatory supports in fulminant myocarditis. The role of viruses as etiologic agents will be reviewed and a brief update on pediatric AM is also provided. Finally, we summarize a risk-based approach to AM, based on available evidence and clinical experience.

Acute myocarditis (AM) is an inflammation of the heart of recent onset (less than 1 month). It may be caused by infections, exposure to drugs or toxic substances, and abnormal immunoreactivity [1] .

Its clinical spectrum varies from an asymptomatic or minor illness to high-risk cardiac conditions with severe heart failure (HF), refractory arrhythmias, cardiogenic shock and sudden cardiac death [2] . Not many years ago, with the lack of accurate noninvasive diagnostic tools, clinically suspected AM could be confirmed only by demonstration of inflammatory infiltrates in myocardial tissue.

Percutaneous endomyocardial biopsy (EMB), originally developed to monitor rejection in heart transplant (HTx) recipients [3] , gave the opportunity to characterize patterns of cell infiltrates and to identify myocyte loss and replacement fibrosis also in the AM setting [4] . However, with the exception of clinically aggressive forms, labeled as fulminant myocarditis (FM), which were generally associated with diffuse inflammation [5] , EMB had a relatively low sensitivity due to the patchy distribution of inflammatory infiltrates [6] . Furthermore, its rate of complications, reported to be low (1-2%) at experienced centers [7] , was estimated around 8.9% when including low-volume centers [8] . Considering that spontaneous resolution occurs in many patients, a definite EMB-based diagnosis was reached in a minority of patients with clinically suspected AM, primarily in mid-to high-risk subjects [9] [10] [11] . In the last decade, the measurement of high-sensitive (hs) troponin levels for identifying myocardial injury and the use of cardiac magnetic resonance imaging (CMRI) for characterizing myocardial tissue changes, allowed to diagnose AM non-invasively and with reasonable accuracy, in a wider population of patients including low-risk subjects. Therefore, the incidence of AM in the United States gradually increased from 95 to 144 cases per 1 million inhabitants from 2005 to 2014 [12] . Higher left ventricular (LV) ejection fraction (EF) [13] [14] [15] , and more favorable outcomes have been observed in recent series with a CMRI-based diagnosis than in previously published series with a biopsy-based diagnosis [9] [10] [11] . This is not surprising, considering that CMRI is hard to perform in severe acute settings (e.g. severe HF, hemodynamic instability, frequent or sustained arrhythmias). As CMRI cannot identify the subset of inflammatory cells characterizing the histologic type of AM, which has prognostic and therapeutic implications [16] , EMB is still thus recommended for optimal medical management in selected clinical scenarios [17] .

Of note, United States administrative data from 2005 to 2014 indicate that EMB was performed only in 3% of all suspected AM cases [12] . AM should not be regarded as a uniformly benign condition given the increasing rate of associated cardiogenic shock, from 6.9% in 2005 to approximately 12% in 2014, with ~4% overall in-hospital mortality, substantially stable over time [12] . These data are consistent with those reported by the largest collaborative observational registry on AM (the Lombardy registry, enrolling 443 patients from 2000 to 2017) in which the incidence of cardiogenic shock was 8.6% [13] and the rate of in-hospital mortality or need for HTx was 2.7%. Identification of patients at risk for dismal outcome that may require an EMB-based diagnosis to guide specific treatment and management is of utmost importance.

This review is focused on recent clinical studies and registries that shed new insights on AM.

Attention will be paid to contemporary outcomes and predictors of prognosis, the emerging entity of immune checkpoint inhibitors (ICI)-associated myocarditis, updated CMRI diagnostic criteria, new data on the use of temporary mechanical circulatory supports (MCS) in FM. The role of viruses as etiologic agents will be reviewed and a brief update on AM in the pediatric population is also provided. Finally, we summarize a risk-based approach to AM, based on available evidence and clinical experience.

In recent years, retrospective observational registries were launched with the aim to characterize the clinical course and clarify the outcome of patients with AM. By highlighting the differences in mortality and HTx rate among different clinical presentations, they provide rationale for the practical classification of AM that may help clinicians in guiding initial management and treatment. The Lombardy registry, an Italian multicenter registry including 443 patients hospitalized with an established diagnosis of AM based on EMB or a combination of increased troponin plus edema and late gadolinium enhancement (LGE) on CMRI, demonstrated that cardiac mortality and HTx occurred almost exclusively in patients presenting with a complicated AM, defined as presenting with LVEF<50% on the first echocardiogram, and/or sustained ventricular arrhythmias (VA), and/or hemodynamic instability on admission [13] . Specifically, patients with complicated AM had a cardiac mortality or HTx rate of 10.4% at 30 days and 14.7% at 5 year follow up, while uncomplicated AM had no cardiac mortality or HTx [13] . Of note, severe hemodynamic compromise on admission was associated with the highest probability of cardiac death and HTx, challenging the historical tenet of the excellent prognosis of FM [5, [18] [19] [20] . Furthermore, new evidence has emerged from a series of 220 cases with histologically proven AM and systolic dysfunction (LVEF<50%) collected from 16 tertiary hospitals, creating one of the largest international registries on biopsy-proven AM [20] .

Besides confirming that hemodynamic compromise at presentation is the major determinant of both short and long-term prognosis (cardiac death or HTx at 60 days, 28% in FM vs. 1.8% in non-FM and at 7 years, 47.7% in FM vs. 10.4% in non-FM), this registry provided strong evidence on the role of histological characterization in the setting of FM. Giant cell myocarditis (GCM) was burdened by the highest rate of mortality or need for HTx (81% at 3-year follow-up) (FIGURE 1) , supporting the recommendations for early implementation of a multimodal, aggressive immunosuppression regimen [21, 22] . The risk was also high in eosinophilic myocarditis, which requires specific therapeutic strategies also according to etiology [20, 23] . Impressively, lymphocytic FM was also shown to be a high-risk condition, with a death or HTx rate as high as 19.5% at 60 days, and 40% at 3 years, highlighting the need to reconsider the eventual role of immunosuppression in the acute phase also in these patients, in order to raise the probability of functional recovery. This is also supported by the fact that, despite a widespread use of temporary MCS devices, the outcomes did not improve significantly in recent years. Another independent factor associated with an increased risk of cardiac death or HTx was QRS width >120 ms on ECG (adjusted hazard ratio 2.49) [20] . Thus, simple factors such as clinical presentation, wide QRS, and reduced LVEF on admission can help identifying high-risk patients, in whom EMB is recommended to guide subsequent therapeutic strategies (e.g. search for specific etiologies or associated conditions, immunosuppressive regimen, short-term temporary MCS, and screening for HTx listing).

The role of viruses in myocarditis etiology has been historically recognized, with parvovirus (PV)-B19, adenoviruses, Human Herpes virus (HHV)-6 being the most common agents identified in the myocardium of patients with AM [10] . Nevertheless, a growing body of literature indicates that viruses, particularly PVB19 and HHV6, may be found in a large percentage of patients who do not have myocarditis [24] , questioning their direct causal role in the pathogenesis of myocarditis.

Similarly, despite initial enthusiasm, evidence regarding the role of viral genome persistence in the myocardium in influencing the outcome of patients is still contradictory and was mostly derived from patients affected by chronic inflammatory cardiomyopathy or dilated cardiomyopathy rather than AM. The majority of evidence suggests that virus-triggered immune-mediated reactions are the principle cause of cardiomyocyte injury [25] rather than actual direct virus-mediated cell injury.

Recent studies of influenza associated myocarditis, with influenza viruses only detected on nasopharyngeal swabs [26] , seems to support this hypothesis. In a recent series of hospitalized Corona virus disease (COVID-19) patients, the rate of acute cardiac injury demonstrated by elevation of hs-troponin ranged between 7 to 27%, highest in those requiring intensive care unit [27, 28] , further suggesting the potential role of viruses in triggering abnormal immune-mediated inflammatory injury [29] [30] [31] . The controversy matters, as it has been stated that the presence of specific viruses in the heart may be a contraindication to the use of immunosuppression, particularly in lymphocytic forms [32, 33] , where its role is mostly controversial. Indeed, the current European Society of Cardiology (ESC) position statement recommends that immunosuppression should be started only after ruling out active infection on EMB by polymerase chain reaction (PCR), including viruses [32] . Several algorithms based on presence/absence of inflammation and presence/absence of virus identification on EMB to guide management and treatment of AM have been released in recent years [32, 33] . However, literature on the role of a myocarditis management based on viral genome identification has been mostly derived from small studies in patients affected by chronic myocarditis or inflammatory cardiomyopathy with HF symptoms for more than 6 months [34] , and the results obtained have been inconsistent [35] . Of note, methods for identifying viral genome and quantifying their replication are not standardized, and the sensitivity of EMB for viral search is low.

Results from the international registry on AM further highlight the low prevalence of use of PCRbased viral search on EMB specimens in the real-world practice and the low rate of virus positive cases, with PVB19 being the only detected virus [36] . At present, the role of a routine viral genome search on EMB in guiding patient management and immunosuppression therapy in patients with AM remains largely to be proven. This is especially true in fulminant forms, where early immunosuppression could be crucial to hamper the inflammation process. Results from patients with inflammatory cardiomyopathy and PVB19 persistence showed that immunosuppressant drugs did not aggravate viral replication [37] , further questioning the rationale of withholding immunosuppression in the acute phase of suspected virus-triggered AM. Thus, the authors feel that the risk-benefit profile of immunosuppression should be reconsidered in patients with severe clinical presentation, in light of their high early and mid-term mortality.

ICI are new anti-cancer drugs that enhance T-cell-mediated immune response against tumor cells.

AM, alone or in combination with other manifestations of autoimmunity (e.g. lungs, liver, kidneys, thyroid) is being recognized more frequently than initially appreciated [38] . In a recently published multicenter observational registry, myocarditis was noted in 1.14% of ICI-treated patients, at a median interval of 34 days following the initiation of therapy [39] . This percentage may appear low, but given the high number of patients that are predicted to receive these drugs in the near future, a growing relevance of this subtype of myocarditis can be expected [40] . ICI-related AM poses quite different, specific challenges. Patients are by far older (median age 64 versus 34 years in non-ICIrelated forms), and besides being affected by advanced cancer, they commonly have other chronic comorbidities. These factors may contribute to the high mortality rate observed in these patients, and make LVEF at presentation less relevant for prognosis than in non-ICI-related AM [41] .

Furthermore, if severe heart dysfunction persists, MCS may be a debatable choice in patients with advanced, often metastatic, cancer. ICI withdrawal and high-dose steroids are first line-therapies.

Patients not responsive to steroids should be considered for additional treatment. The proposed regimens include plasmapheresis, immunoglobulins and anti-thymocyte globulin [42] . Promising effects of abatacept (a CTLA-4 agonist) and alemtuzumab (a CD52-binding monoclonal antibody) were recently reported for the treatment of severe, steroid-refractory cases [43, 44] . Awareness on this new entity among cardiologists, oncologists and critical care providers would promote early recognition and possibly structured surveillance of this complication [38] .

In the setting of clinically suspected AM, CMRI may characterize alterations of myocardial tissue signal, providing qualitative and quantitative information on their type and distribution, differentiating ischemic from inflammatory cardiomyopathies [45] . In uncomplicated AM, the abnormalities on CMRI are typically in a non-coronary distribution. These include patchy areas of edema with matching areas of LGE, localized to the sub-epicardium with variable intramyocardial extension [19, 46] ; on the opposite in ischemic heart disease LGE is typically subendocardial up to transmural, and follows coronary artery distribution. CMRI is not the initial diagnostic technique in patients in critical conditions, for whom EMB is crucial. In recent years, mapping techniques measuring myocardial T1 and T2 signal (T1 and T2 mapping) in milliseconds and calculating the percentage of extracellular volume (ECV) have been introduced, thus providing a quantitative approach to tissue characterization [16] . T1 and T2 mapping can be performed on native myocardium, while the quantification of ECV requires the administration of contrast medium. In light of scientific evidence on mapping technique in the assessment of myocarditis, the Lake Louise Criteria (LLC) for the diagnosis of myocarditis have been updated in 2018 [16] . According to this formulation, CMRI provides evidence of myocardial inflammation when at least one criterion for each of the following categories is positive: (1) T2 marker of myocardial edema (T2-weighted images or mapping) and (2) T1 marker of associated myocardial injury (LGE, T1 mapping or ECV; FIGURE 2) [16] . Pooled data on original 2009 LLC show a sensitivity of 80% and a specificity of 87% to detect acute inflammation [47] . Preliminary data have shown that the diagnostic performance of CMRI has improved with revised 2018 LLC, with a sensitivity of 87.5% and a specificity of 96.2% [48] . False negative scans can occur and could be related to the timing of acquisition, as the presence of edema is time dependent [49] , or to the entity of myocardial injury; nonetheless the presence of a negative scan (normal ventricular volumes and functions, no edema and no LGE) in a patient with suspect myocarditis is relevant information, as it portends a good prognosis at follow-up [50] . On the contrary, in 2017, two multicenter studies involving >1000 patients showed that septal localization of LGE can identify patients at risk of death or major cardiovascular events after discharge [15, 51] .

CMRI cannot identify the specific cause of myocardial inflammation and has limited sensitivity in chronic inflammatory cardiomyopathy and in patients with arrhythmic presentation, in whom also inflammatory infiltrates at EMB are less florid [52] . Frequent arrhythmias, difficulties in breath holding and intolerance to examination (e.g. claustrophobia) negatively affect image acquisition and quality. CMRI can be repeated during follow-up, generally after 6 to 12 months, to identify postinflammatory scars [46] , which are associated with a higher risk of death or major cardiovascular events [53] . In athletes, it is suggested to perform a follow up scan before re-starting competitive training [54] . However, currently available data are insufficient to derive evidence-based recommendations for physical activity reintroduction. Therefore, the decision is often based on expert consensus and shared decision making with the patient. In our clinical practice, we evaluate 

In patients with FM presenting with cardiogenic shock, the first step is to ensure adequate perfusion pressure and oxygenation, thus inotropes, vasopressors, and mechanical ventilation may be required [5] . However, high doses of vasoactive agents in patients with poor systolic function may increase myocardial oxygen consumption, reducing the probability of myocardial recovery [55] . In the last decades the results obtained with temporary MCS in FM refractory to medical therapy have been described [56] . The main goals for temporary MCS in FM are: (1) biventricular unloading, (2) optimal systemic and coronary perfusion, (3) venous decongestion. The achievement of these goals is fundamental to prevent multiple organ dysfunction and death and allow a safe bridge to recovery, HTx or a durable assist device implant [57] . The most commonly implanted temporary MCS devices reported in several registries are intra-aortic balloon pump (IABP) and venous-arterial extra corporeal membrane oxygenator (VA-ECMO) with peripheral cannulation [20, 58] . IABP alone provides only a small increase in cardiac output and may be insufficient to support circulation when profound cardiogenic shock is established. On the other hand, VA-ECMO guarantees a rapid and full cardio-respiratory assistance, with reported survival rates in the setting of FM ranging from 56% to 87% [58] [59] [60] [61] . Nevertheless, VA-ECMO alone might increase LV afterload, thus additional LV ventingstrategies to prevent LV distension and pulmonary edema may be required [62] . Low-dose inotropes and vasodilators and/or IABP implantation are the most common strategies for reducing afterload.

Percutaneous LV assist devices, such as the microaxial pump Impella system (2.5, 5.0 or CP), have been increasingly used in the setting of FM in recent years (TABLE 1) Impella support [64] . The use of LV-Impella alone as a bridge to recovery in FM was firstly described in 2003 [65] . The prerequisites of its efficacy are: (1) preserved right ventricle (RV) function, (2) absence of left intraventricular thrombi, that would represent a risk for systemic embolism, and (3) adequate LV-cavity size, to avoid suction phenomenon [66] . The last prerequisite is of particular concern in FM patients, as they often present with a relatively small LV cavity and thickened walls due to myocardial edema and the recent onset of myocardial damage. In patients with biventricular dysfunction without hypoxia the use of Impella for both LV and RV support has been described [67] .

This strategy may be particularly useful in those that may not be able to tolerate the degree of anticoagulation required for ECMO. It must be remembered that in the much more frequent setting of cardiogenic shock associated with acute coronary syndrome, there are no data showing the superiority of a single MCS device over another or over medical therapy alone [68] . Furthermore, large observational studies, small randomized studies, and meta-analyses have confirmed no benefit in terms of survival from pulmonary artery catheters (PACs) in critically ill patients. Though, we consider PAC useful in almost all severe patients presenting with cardiogenic shock, especially those with rapidly progressive low cardiac output syndrome, where identification of the exact timing for escalating treatment towards MCS is crucial. PAC may also provide key information during MCS treatment, i.e. LV filling pressure monitoring to guide eventual LV unloading strategies. In the absence of recommended protocols regarding temporary MCS use and escalation, their utilization should be tailored to the single case according to the experience of the center.

The diagnosis of AM in the pediatric population is often clinically based, since EMB is perceived as an high risk procedure, and CMRI usually requires adequate deep sedation, especially in young children [69] . A recent registry of all Finnish children (<16 years) hospitalized for clinically diagnosed AM from 2004 to 2014 (n=213) estimated an incidence of AM of 1.95/100,000 patients/year [70] . The median age was 14 years, 77% were boys and it was observed that the incidence of AM increased significantly after 7 years of age. A viral etiology (that means isolation of a virus during hospitalization) was identified only in 11% of patients; these were mainly upper respiratory infections with the most frequent virus identified being influenza (in 1.9% of patients). The inhospital rate of death or HTx was 1.9%, in line with the estimates derived from the adult population.

Furthermore, the rate of temporary MCS use was 1.4%, and 6.1% of the patients were treated in intensive care unit [70] . In a German registry including 195 children diagnosed with AM from 2013 to 2016, all presenting with HF, the median age was 13 years and 66.2% were male. The need for MCS was as high as 14%, in-hospital death or HTx rate was 7.7%, and the overall mortality rate was 4.6% with a median follow up of 8 months [61] . The need for MCS was more common in infants (0-2 years) compared with other ages, with the median age of patients receiving MCS being 1.5 years. Of note, in infants, enteroviruses, such as coxsackie virus, are more common than in adults [71] . These viruses are qualified as cardiotropic, i.e. able to cause direct myocardial injury [72] , thus the search for viruses in infants may guide specific antiviral therapy [73] , even if its efficacy in adults with AM remains unproven. Recent reports have also suggested that arrhythmogenic cardiomyopathies in children may present clinically as an AM and are sometimes triggered by viral infections [74] [75] [76] , highlighting the importance of an accurate diagnosis. Based on these observations, genetic tests for mutations of genes related to arrhythmogenic cardiomyopathy may be considered in patients with recurrent AM or in patients with AM and personal history of VA or family history of sudden cardiac death [74, 76] .

Traditionally, the histopathologic demonstration of myocarditis has been considered necessary for the diagnosis of AM, since the accuracy of noninvasive tools was poor [4, 32] . However, pathological diagnosis was rarely pursued in clinical practice, due to the invasiveness, low sensitivity and the perceived limited incremental value of EMB in what was considered in most cases a self-limiting and benign condition. The combination of measurement of hs-troponin levels and CMRI has made AM diagnosis possible with sufficient accuracy for non-complicated forms [13] . Contrarily, in patients with complicated AM, and especially in those presenting with FM, highly coordinated care is required to minimize morbidity and mortality, as illustrated in FIGURE 3. Critical elements of care for these patients include early recognition, temporary MCS when necessary, rapid referral to tertiary centers (hub centers), histological characterization by EMB and, when indicated, immunosuppression [2, 5, 59] . Of note, electroanatomic mapping-guided EMB is an emerging and promising technique [77] . By identifying regions corresponding to areas of diseased or replaced myocardium, it may guide a site for biopsy, finally improving the differential diagnosis with other cardiomyopathies or the sensitivity of EMB [78] [79] [80] . Due to the significant increase in cost and duration of electroanatomic mapping-guided EMB compared with traditional fluoroscopic guided EMB, it is mainly performed before ventricular ablation to differentiate the etiology of VA [78, 80] .

A stepwise, risk-based approach to the diagnosis of suspected myocarditis is represented in [5, 17, 20, 81] , i.e. high-risk forms like FM, AM with rapidly progressing overt HF due to worsening LV dysfunction and/or sustained arrhythmias [5, 17] .

Moreover, EMB should be considered when history or available data suggest specific etiologies (e.g. use of ICI, suspected autoimmune disorder, peripheral eosinophilia) that may be associated with severe forms of myocarditis that require specific treatment. Hs-troponin levels contribute to clinical suspicion and diagnosis. Absolute troponin values and their trend are only roughly related with AM severity and prognosis. While high or very high values should be looked as a marker of high risk, the opposite is not true with moderately or only mildly increased values [82] . An early rise and steep decline of hs-troponin is generally associated with the resolution or at least attenuation of the inflammatory process and with a good prognosis; while recurrently or persistently abnormal hstroponin values, even if mildly increased, may suggest relapsing or ongoing myocardial damage, as may happen in patients with AM associated with systemic inflammatory disorders or cardiac sarcoidosis. The latter scenario could lead to further investigations, including thoracic computed tomography or 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography [83] for detection of systemic sarcoidosis, or EMB to identify uncommon forms like eosinophilic myocarditis. Finally, it must be remembered that in the setting of cardiogenic shock with elevated troponin levels and decreased LVEF, other differential diagnoses beyond the acute coronary syndromes should be considered, such as septic shock, thiamine deficit [84] , systemic capillary leak syndrome [85] , antiphospholipid syndrome [86] , and pheochromocytoma [87] . EMB may be essential in clarifying the diagnosis and distinguishing myocarditis from alternative diagnoses.

Beyond supportive measures, even though not standardized, early administration of immunosuppressive agents is the cornerstone of treatment for eosinophilic and GCM [22, 23] , cardiac sarcoidosis [88] , and, regardless of the underlying histology, for myocarditis related to systemic autoimmune diseases and ICI [43] . As reported series have described spontaneous recovery with supportive therapy alone, immunosuppression is largely debated in the setting of virustriggered lymphocytic myocarditis. We consider initiation of immunosuppressive treatment (e.g. pulse steroid therapy) in all cases presenting with complicated AM (FIGURE 3 and 4) , especially those presenting with FM [19, 89] , where early immunosuppression may be crucial and where the risk of death or HTx has been demonstrated to be high regardless of the underlying histology [20] . We can consider cessation or implementation of a tailored immunosuppression after final histopathological characterization, eventual virus detection and in the evidence of systemic autoimmunity. In line with this management, the AHA recently stated that if a high suspicion for immune-mediated FM exists, 1 g methylprednisolone may be administered urgently, before biopsy-confirmed diagnosis or further diagnostic testing [5] . Intravenous immunoglobulin is also frequently used in pediatric lymphocytic myocarditis, but the experience in adults is limited. Large prospective studies are warranted to address the role of immunosuppression in acute and FM in order to provide evidence for standardized treatment regimens. (1) signs of myocardial edema (regional increase of SI on T2w images and regional increase of native T2 at T2 mapping, underpinned by head arrows in the anterolateral wall) and of (2) non-ischemic myocardial injury (regional LGE, increase native T1 at T1 mapping and ECV expansion in the anterolateral wall, underpinned by head arrows, with non-ischemic pattern). On the right: one supportive criterion is present, in fact a small pericardial effusion is evident at cine images, whereas there are neither global hypokinesis nor regional wall motion abnormalities in this case. Abbreviations: T2w, T2 weighted; SI, signal intensity; LGE, late gadolinium enhancement; ECV, extra-cellular Volume; LVEF, left ventricular ejection fraction. 

Inflammatory Cardiomyopathic Syndromes

Acute and Fulminant Myocarditis: a Pragmatic Clinical Approach to Diagnosis and Treatment

Serial transvenous biopsy of the transplanted human heart. Improved management of acute rejection episodes

Myocarditis: the Dallas criteria

Recognition and Initial Management of Fulminant Myocarditis: A Scientific Statement From the American Heart Association

Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis

Evaluation of the role of endomyocardial biopsy in 851 patients with unexplained heart failure from

Comparison of Utilization Trends, Indications, and Complications of Endomyocardial Biopsy in Native Versus Donor Hearts (from the Nationwide Inpatient Sample

Long-term evolution and prognostic stratification of biopsy-proven active myocarditis

Predictors of outcome in patients with suspected myocarditis

A prospective study of biopsyproven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis

Trends in the Incidence of In-Hospital Mortality, Cardiogenic Shock, and Utilization of Mechanical Circulatory Support Devices in Myocarditis (Analysis of National Inpatient Sample Data

Clinical Presentation and Outcome in a Contemporary Cohort of Patients With Acute Myocarditis

Natural History of Myocardial Injury and Chamber Remodeling in Acute Myocarditis

Cardiac MR With Late Gadolinium Enhancement in Acute Myocarditis With Preserved Systolic Function: ITAMY Study

Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations

Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the

Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. The New England journal of medicine

Survival and Left Ventricular Function Changes in Fulminant Versus Nonfulminant Acute Myocarditis

Fulminant Versus Acute Nonfulminant Myocarditis in Patients With Left Ventricular Systolic Dysfunction

Usefulness of immunosuppression for giant cell myocarditis

Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression

Eosinophilic Myocarditis: Characteristics, Treatment, and Outcomes

Relevance of cardiac parvovirus B19 in myocarditis and dilated cardiomyopathy: review of the literature

Fulminant myocarditis associated with pandemic H1N1 influenza A virus in children

Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA : the journal of the American Medical Association

Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19)

SARS-CoV-2: a potential novel etiology of fulminant myocarditis

Cardiac Involvement in a Patient With Coronavirus Disease 2019 (COVID-19)

Myocardial localization of coronavirus in COVID-19 cardiogenic shock. European journal of heart failure

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

Management of Myocarditis-Related Cardiomyopathy in Adults

Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study

Corticosteroids for viral myocarditis. The Cochrane database of systematic reviews

Viral genome search in myocardium of patients with fulminant myocarditis. European journal of heart failure

Immunosuppression in inflammatory cardiomyopathy and parvovirus B19 persistence

Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology

Myocarditis in Patients Treated With Immune Checkpoint Inhibitors

Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs

Differences in clinical presentation and outcome between immune checkpoint inhibitor-associated myocarditis and classical acute myocarditis: Same disease, distinct challenges to face

Autoimmune Myocarditis Caused by Immune Checkpoint Inhibitors Treated With Antithymocyte Globulin

Abatacept for Severe Immune Checkpoint Inhibitor-Associated Myocarditis. The New England journal of medicine

Alemtuzumab for Immune-Related Myocarditis Due to PD-1 Therapy. The New England journal of medicine

The role of cardiovascular magnetic resonance in patients presenting with chest pain, raised troponin, and unobstructed coronary arteries

Quantitative changes in late gadolinium enhancement at cardiac magnetic resonance in the early phase of acute myocarditis

Clinical applications of multi-parametric CMR in myocarditis and systemic inflammatory diseases

Lake Louise Criteria for Diagnosis of Acute Myocarditis: Results of a Validation Cohort

Acute myocarditis presenting as acute coronary syndrome: role of early cardiac magnetic resonance in its diagnosis

Epub 2010/11/26

Cardiovascular magnetic resonance risk stratification in patients with clinically suspected myocarditis

Prognostic Value of Cardiac Magnetic Resonance Tissue Characterization in Risk Stratifying Patients With Suspected Myocarditis

CMR sensitivity varies with clinical presentation and extent of cell necrosis in biopsy-proven acute myocarditis

Prognostic Value of Repeating Cardiac Magnetic Resonance in Patients With Acute Myocarditis

Myocarditis in Athletes Is a Challenge: Diagnosis, Risk Stratification, and Uncertainties

Current real-life use of vasopressors and inotropes in cardiogenic shock -adrenaline use is associated with excess organ injury and mortality

Favourable clinical outcome in patients with cardiogenic shock due to fulminant myocarditis supported by percutaneous extracorporeal membrane oxygenation

Acute mechanical circulatory support for cardiogenic shock: the "door to support" time

Venoarterial Extracorporeal Membrane Oxygenation for Acute Fulminant Myocarditis in Adult Patients: A 5-Year Multi-Institutional Experience. The Annals of thoracic surgery

Fulminant myocarditis: Characteristics, treatment, and outcomes

Extracorporeal membranous oxygenation support for acute fulminant myocarditis: analysis of a single center's experience. European journal of cardiothoracic surgery : official journal of the European Association for Cardio-thoracic Surgery

Severe heart failure and the need for mechanical circulatory support and heart transplantation in pediatric patients with myocarditis: Results from the prospective multicenter registry "MYKKE

Modalities and Effects of Left Ventricle Unloading on Extracorporeal Life support: a Review of the Current Literature. European journal of heart failure

Mode-of-action of the PROPELLA concept in fulminant myocarditis

First successful bridge to recovery with the Impella Recover 100 left ventricular assist device for fulminant acute myocarditis

Comparative outcomes in cardiogenic shock patients managed with Impella microaxial pump or extracorporeal life support. The Journal of thoracic and cardiovascular surgery

Mechanical Unloading by Fulminant Myocarditis

Impella Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock

Resident inflammatory cells in the myocardium of children: On the way to set histologic reference standards to differentiate normal myocardium from myocarditis. International journal of cardiology

Occurrence and Features of Childhood Myocarditis: A Nationwide Study in Finland

Clinical Features of Acute and Fulminant Myocarditis in Children-2nd Nationwide Survey by Japanese Society of Pediatric Cardiology and Cardiac Surgery

Molecular pathology and structural features of enteroviral replication. Toward understanding the pathogenesis of viral heart disease

Successful treatment of fulminant neonatal enteroviral myocarditis in monochorionic diamniotic twins with cardiopulmonary support, intravenous immunoglobulin and pocapavir

Myocardial inflammation detected by cardiac MRI in Arrhythmogenic right ventricular cardiomyopathy: A paediatric case series

Autosomal Recessive Cardiomyopathy Presenting as Acute Myocarditis

Genetics of myocarditis in arrhythmogenic right ventricular dysplasia

The efficacy and safety of electroanatomic mapping-guided endomyocardial biopsy: a systematic review

High prevalence of myocarditis mimicking arrhythmogenic right ventricular cardiomyopathy differential diagnosis by electroanatomic mapping-guided endomyocardial biopsy

Feasibility of combined unipolar and bipolar voltage maps to improve sensitivity of endomyocardial biopsy

Ventricular Arrhythmias in Myocarditis: Characterization and Relationships With Myocardial Inflammation

The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of

Lack of Relationship Between Serum Cardiac Troponin I Level and Giant Cell Myocarditis Diagnosis and Outcomes

Joint SNMMI-ASNC expert consensus document on the role of (18)F-FDG PET/CT in cardiac sarcoid detection and therapy monitoring

Shoshin beriberi mimicking a high-risk non-STsegment elevation acute coronary syndrome with cardiogenic shock: when the arteries are not guilty

Systemic Capillary Leak Syndrome Presenting With Fulminant Recurrent Cardiogenic Shock

Back from the brink: catastrophic antiphospholipid syndrome. The American journal of medicine

Differential diagnosis of a fulminant myocarditis: the pheochromocytoma crisis

Cardiac Sarcoidosis

Chinese society of cardiology expert consensus statement on the diagnosis and treatment of adult fulminant myocarditis