Europe PMC

This website requires cookies, and the limited processing of your personal data in order to function. By using the site you are agreeing to this as outlined in our privacy notice and cookie policy.

Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document.

Author information

Affiliations

  • 1. De Gasperis Cardio Center and Transplant Center, Niguarda Hospital, Milano, Italy (E.A., M.F., P.P.).
      Authors
    • Ammirati E 1
    • Frigerio M 1
    • Pedrotti P 1
    (3 authors)
  • 2. Division of Cardiology, Department of Medicine, University of California San Diego, La Jolla (E.D.A., M.B.).
      Authors
    • Adler ED 2
    • Brambatti M 2
    (2 authors)
  • 3. Cardiovascular Pathology, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Italy (C.B.).
      Authors
    • Basso C 3
    (1 author)
  • 4. University of Ottawa Heart Institute, Ontario, Canada (D.H.B.).
      Authors
    • Birnie DH 4
    (1 author)
  • 5. Department of Medicine and Diagnostic Radiology, McGill University, Montreal, Quebec, Canada (M.G.F.).
      Authors
    • Friedrich MG 5
    (1 author)
    • Show all (13)

ORCIDs linked to this article

Circulation. Heart Failure, 12 Nov 2020, 13(11):e007405
https://doi.org/10.1161/circheartfailure.120.007405 PMID: 33176455 PMCID: PMC7673642

Review

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
Free full text in Europe PMC

A comment on this article appears in "Outcomes With Peripheral Venoarterial Extracorporeal Membrane Oxygenation for Suspected Acute Myocarditis: 10-Year Experience From the Extracorporeal Life Support Organization Registry." Circ Heart Fail. 2023 Jul;16(7):e010152.

Abstract 

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.

Free full text 

Logo of lwwopenLink to Publisher's site
Circ Heart Fail. 2020 Nov; 13(11): e007405.
PMCID: PMC7673642
NIHMSID: NIHMS1628599
PMID: 33176455

Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy

An Expert Consensus Document
Enrico Ammirati, MD, PhD,corresponding author1,* Maria Frigerio, MD,1,* Eric D. Adler, MD,2 Cristina Basso, MD,3 David H. Birnie, MD,4 Michela Brambatti, MD, MS,2,5 Matthias G. Friedrich, MD,6 Karin Klingel, MD,7 Jukka Lehtonen, MD,8 Javid J. Moslehi, MD,9 Patrizia Pedrotti, MD,1 Ornella E. Rimoldi, MD,10 Heinz-Peter Schultheiss, MD,11 Carsten Tschöpe, MD,12,13 Leslie T. Cooper, Jr, MD,14,† and Paolo G. Camici, MDcorresponding author15,†
Author information Copyright and License information Disclaimer

Abstract

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.

Keywords: cardiac magnetic resonance imaging, endomyocardial biopsy, inflammatory cardiomyopathy, myocarditis, viruses

Definitions, Epidemiology, and Pathophysiology

Myocarditis is an inflammatory disease of the heart that may occur as a consequence of infections, exposure to toxic substances, and immune system activation1,2 and is included among secondary cardiomyopathies in the 1996 World Health Organization classification.3 Myocarditis has a wide spectrum of clinical presentations and trajectories, with most cases resolving spontaneously. It is also a relatively common cause of sudden cardiac death (SCD) in young people (from 6% to 10% in autopsy-based series; Table I in the Data Supplement).4,5,119–121 Furthermore, in some patients, inflammation may cause extensive scarring that triggers left ventricular (LV) remodeling, leading eventually to dilated cardiomyopathy (DCM)6 or alternatively to a predominant hypokinetic nondilated phenotype of cardiomyopathy. Myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month), while chronic inflammatory cardiomyopathy (infl-CMP) indicates myocardial inflammation with established DCM or hypokinetic nondilated phenotype generally with a longer duration of symptoms (>1 month; Figure ​Figure1).1). Based on the cell types infiltrating, myocarditis can be classified as eosinophilic, lymphocytic, giant cells, or granulomatous (Figure ​(Figure2).2). Chronic myocarditis could represent an intermediate stage between AM and chronic infl-CMP in patients with persisting myocardial inflammation (Figure I in the Data Supplement). Due to evolving diagnostic criteria and differences in the conceptual view and interpretation of myocarditis within the medical community, definitions associated with myocarditis have changed over the last decades. A list of definitions used in this document is presented in Table ​Table11.

Table 1.

Glossary of the Terms Used in this Document Regarding Myocarditis

An external file that holds a picture, illustration, etc. Object name is hhf-13-e007405-g001.jpg
An external file that holds a picture, illustration, etc. Object name is hhf-13-e007405-g002.jpg

Characteristic features of lymphocytic acute myocarditis and chronic inflammatory cardiomyopathy. Left, Imaging features of acute myocarditis: chest radiograph of a patient admitted for chest pain and suspected acute myocarditis with no enlargement of the cardiac silhouette and cardiac magnetic resonance imaging (CMRI) showing normal left ventricular (LV) volume and significantly increased cardiac mass with diffuse high signal in T2-weighted images (arrows) suggesting diffuse edema. Histology shows acute lymphocytic myocarditis with myocyte necrosis and diffuse mononuclear cell infiltrates by hematoxylin-eosin and immunohistological stain on CD3+ T cells and CD68+ macrophages, compatible with an active myocarditis based on Dallas criteria (magnitude ×200). Right, Imaging features of chronic lymphocytic cardiomyopathy: chest radiograph of a patient admitted with heart failure (HF) symptoms, showing enlargement of cardiac silhouette; at CMRI, the LV is dilated, with normal thickness and focal areas of high signal intensity at T2-weighted images suggesting localized edema (arrows). At histology, chronic inflammatory cardiomyopathy typically presents fibrosis (*) within areas with inflammatory cellular infiltrates and myocyte abnormalities (magnitude ×200). CD indicates cluster of differentiation.

An external file that holds a picture, illustration, etc. Object name is hhf-13-e007405-g003.jpg

Different patterns of myocardial inflammation demonstrated by histological and immunohistological stainings on endomyocardial biopsy. A, Immune checkpoint inhibitor (ICI)–associated acute myocarditis (AM) frequently reveals diffuse mononuclear infiltrates composed of CD3+ T cells and CD68+ macrophages. Based on hematoxylin-eosin (HE) and immunohistological stainings, ICI-associated myocarditis resembles a diffuse lymphocytic myocarditis. B, In eosinophilic myocarditis, prominent inflammatory cells are eosinophilic granulocytes (Giemsa) and macrophages. C, Giant cell myocarditis is characterized by large mononucleated infiltrates with the presence of giant cells (*) and eosinophils (Giemsa). D, Cardiac sarcoidosis can be differentiated from giant cell myocarditis by the presence of granuloma (†) and absence of necrotic myocytes (magnitude, ×200 in all pictures). CD indicates cluster of differentiation.

The disease burden of myocarditis is difficult to define. Based on hospital discharge forms between 1990 and 2013, an incidence of 22 cases of 100 000 patients annually was estimated by the Global Burden of Disease Study.10 However, this report did not distinguish between AM or chronic infl-CMP and other cardiomyopathies, with possible overestimation of myocarditis. Among patients presenting to the emergency department, AM was the second most common cardiac cause of chest pain (3%) in a French registry.11 Furthermore, ≈33% of the patients initially labeled as myocardial infarction with nonobstructed coronary arteries are later diagnosed as AM.12 According to contemporary registries, AM is a cardiac condition affecting relatively young patients (median age of onset ranges between 30 and 45 years in most of the series) and men more than women (male prevalence ranges between 60% and 80%; Table ​Table22).13–20 The absolute prevalence and relative proportion of different etiologies may vary over time and according to endemic diseases. For example, immune checkpoint inhibitor (ICI)–associated myocarditis is a recently recognized entity, whose rate of diagnosis has increased due to larger awareness and to the larger population of patients with cancer eligible for treatment with ICI.21 On the other hand, AM and chronic infl-CMP may have a different incidence in specific geographic areas according to local epidemiology (such as Chagas disease in South America). Controversies still exist regarding the mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial injury to chronic dysfunction. To date, it is not known which viruses other than enteroviruses may cause direct tissue damage in humans or act mainly as triggers for autoimmunity-mediated damage or both.22,23 It must be considered that the experimental evidences on murine models of viral myocarditis are based on infections with Coxsackie B viruses, whereas for the most common agent in virus-positive myocarditis patients, parvovirus-B19 (PVB19),24,25 no animal models are available. A possible association between genetic abnormalities and susceptibility to inflammation has been suggested. In particular, patients with mutations responsible for arrhythmogenic cardiomyopathy may be at risk for AM and share clinical and pathological aspects with chronic infl-CMP,26,27 although further studies are required to elucidate this association and understand its mechanistic underpinnings.

Table 2.

Principal Studies That Evaluated the Long-Term Outcome of Adult Patients With Myocarditis Based on Histology or Cardiac Magnetic Resonance Imaging Findings or the Combination of Both Published Since 1995

An external file that holds a picture, illustration, etc. Object name is hhf-13-e007405-g004.jpg

This review will try to summarize a shared and practical approach to patients presenting with AM or chronic infl-CMP, meanwhile pointing out the areas of controversies and uncertainties and the unmet clinical needs. Specific conditions such as pediatric myocarditis, including rheumatic carditis, Chagas disease, and HIV cardiomyopathy deserve separate discussion and are not addressed in this document.

Diagnostic Approach to AM and infl-CMP

AM: Symptoms and Signs

Patients with suspected AM are generally evaluated in the emergency room due to chest pain, dyspnea, fatigue, palpitations, or syncope.1 Based on large registries, chest pain is the most frequent symptom (85%–95% of cases),13–16,18 followed by dyspnea (19%–49% of cases),13,16,17 whereas syncope occurs in about 6%.13 Fever is common (about 65%),13,15 while other prodromal manifestations, such as flu-like symptoms, gastrointestinal disorders, sore throat, or respiratory tract infections, may have preceded the acute phase by a few days or weeks, with a prevalence ranging from 18% to 80%.13,14,18

In a recent retrospective registry of 443 AMs, 26.6% had a presentation complicated by LV systolic dysfunction, ventricular arrhythmias, or cardiogenic shock (ie, fulminant myocarditis [FM] that accounted for 8.6% of total cases). On the other hand, the majority of AMs (73.4%) had no such complications (uncomplicated AM) and presented chest pain in 97% of cases and ST-segment elevation on ECG in 62.3% of cases, and they had no deaths or heart transplantation (HTx) at 5 years.13 When collecting patient history, attention should focus on specific causes including recent exposure to drugs (eg, antibiotics, clozapine, ICI) or toxic substances (eg, cocaine or amphetamine)2 or to infectious agents (eg, ingestion of raw meat suggesting helminthic infections,39 travels to areas where viruses associated with AM, such as Dengue, are endemic). A proposed approach to AM is summarized in Figure ​Figure33.

An external file that holds a picture, illustration, etc. Object name is hhf-13-e007405-g005.jpg

Proposed risk-based approach to acute myocarditis. Left, Clinical features that characterize high (red boxes), intermediate (orange boxes), or low (green boxes) risk are summarized, according to the presence of low blood pressure (BP) and severity of acute heart failure (AHF), initial left ventricular ejection fraction (LVEF) on first echocardiogram, and ECG (presence of ventricular tachycardia [VT] or ventricular fibrillation [VF] or advanced atrioventricular block [AVB]). Right, How these risk features may influence patient management in terms of referral to expert centers, temporary mechanical circulatory support (t-MCS), need for endomyocardial biopsy (EMB) or cardiac magnetic resonance imaging (CMRI), and consideration for steroid treatment. Tag sign indicates recommended actions. No symbol indicates not recommended. *Immunosuppression with intravenous steroids may be considered and often used in patients with fulminant myocarditis; however, clinical studies that demonstrate their efficacy are lacking.

AM: ECG

The ECG is abnormal in about 85% of cases,13,15 ST-segment elevation mimicking acute myocardial infarctions is the most frequent abnormality13,15; inferior and lateral leads are commonly involved. QRS width >120 ms, atrioventricular block, symptomatic bradycardia, or tachycardia and ventricular arrhythmias should increase the suspicion of AM and suggest high-risk forms.38 Second- or third-degree atrioventricular block is rarely observed in patients with normal LV ejection fraction (LVEF) >50%, except in cardiac sarcoidosis (CS), Lyme carditis, as well as ICI-associated myocarditis.40

AM: Laboratory Tests

Recommended laboratory tests for identification of patients with suspected AM are myocardial necrosis biomarkers (high-sensitivity troponins, creatinine kinase-MB). Only a weak correlation exists between troponin release and the severity of cardiac dysfunction.41 Other laboratory tests routinely requested include markers of inflammation such as C-reactive protein that is positive in 80% to 95% in recent series.13,14 Erythrocyte sedimentation rate is also commonly increased, but it is generally not available in the emergency department. A persistently increased erythrocyte sedimentation rate can suggest an associated autoimmune disorder. Furthermore, differential white blood count can show eosinophilia, suggesting the presence of eosinophilic myocarditis (EM).39 Finally, peripheral blood serological and virological tests are rarely informative,2 with some exceptions (eg, HIV and Borrelia burgdorferi antibodies). A search for viral genomes with polymerase chain reaction in aerial tract fluids and pharyngeal swabs can identify viruses of the respiratory tract, such as influenza, and severe acute respiratory syndrome coronavirus-2, which can trigger an AM.42,43 Autoantibodies (eg, antinuclear antibody test) and other tests may be indicated in patients with known or possible history of autoimmune disorders.2

AM: Echocardiography

Echocardiography is part of the standard evaluation of patients with a suspected acute cardiac condition and may show a broad spectrum of findings. Even when LVEF is normal, the presence of increased wall thickness, mild segmental hypokinesia, in particular, in the inferior and inferolateral walls, diastolic dysfunction, abnormal tissue Doppler imaging, mild right ventricular dysfunction, pericardial effusion, and abnormal myocardial echogenicity may suggest AM. In the early phase, LV dimensions are generally normal even when LVEF is low or very low38—a condition that may result in severe stroke volume reduction and tachycardia. LVEF on admission is a powerful prognostic marker.13,15,38 Furthermore, cardiac function may evolve rapidly during AM, either spontaneously or after treatment.13,15

Suggested Indications for Cardiac Magnetic Resonance Imaging in AM and Chronic infl-CMP

Cardiac magnetic resonance imaging (CMRI) has emerged as a powerful noninvasive diagnostic tool for tissue characterization, including recognition and quantification of inflammation and replacement fibrosis in the setting of AM, and infl-CMP.44,45 Furthermore, CMRI is the gold standard for the quantification of biventricular volumes, ejection fraction, and cardiac mass (Table II in the Data Supplement).44 CMRI is recommended in patients with clinically suspected AM or in patients with chest pain, normal coronaries, and raised troponin, for the differential diagnosis of ischemic versus nonischemic origin,46 with the exception of those in critical condition or with usual contraindication for this diagnostic tool.2,44 CMRI should be performed in patients who initially presented with fulminant forms to assess the presence, extent, and localization of residual inflammation and replacement fibrosis when they are hemodynamically stable (Table ​(Table3).3). Unless recurrent flares occur, edema tends to decline 4 weeks after disease onset.47 Therefore, to rule in or rule out myocardial inflammation reliably, CMRI should be performed within 2 to 3 weeks from the onset of symptoms, although accuracy may be lower during the first days. The availability of high-sensitivity troponins and CMRI have improved the accuracy of noninvasive diagnosis of AM,44 which resulted in the identification of more low-risk patients than before, when diagnosis was mainly based on endomyocardial biopsy (EMB), which was performed more often in sicker patients. Thus, observational studies reported a more favorable prognosis of AM over the last decades (Table ​(Table22).13–20,28–38 In fact, in 5 of 6 studies with EMB-based diagnosis, the mean echocardiographic LVEF was <40%.20,28,29,31–33 In 2009, a consensus group published the original Lake Louise Criteria, which identified 3 hallmarks of myocardial inflammation with corresponding CMRI markers45: (1) hyperemia, that is, intense signal in early gadolinium enhancement images; (2) tissue edema, that is, increased myocardial T2 relaxation time or an increased signal intensity in T2-weighted images; and (3) necrosis/fibrosis based on late gadolinium enhancement (LGE) images. If 2 of these 3 criteria are positive, AM can be diagnosed with 74% sensitivity and 86% specificity.48 With mounting evidence that CMRI mapping increases the overall diagnostic accuracy, the Lake Louise Criteria have been recently updated (Figure II in the Data Supplement).44 The updated criteria include T2 mapping for edema and native T1, as well as extracellular volume for inflammatory injury.44 A study has confirmed an increased sensitivity of the updated criteria (87.5%) while keeping a high specificity in AM (96.2%).49 A single positive criterion can support diagnosis of myocardial inflammation if clinical suspicion is strong.44 CMRI cannot identify specific cause of myocardial inflammation, and the histological subtypes, although regional distribution of inflammatory changes in the tissue provide diagnostic clues (eg, basal septal involvement in CS). In patients with de novo DCM or unexplained ventricular arrhythmias, CMRI can suggest previous myocardial inflammation based on the regional distribution of LGE; however, its sensitivity is not high in chronic forms.50 The presence and location in the mid layer of the septum (mid-wall strip) of LGE and low LVEF at baseline appear to be the strongest negative predictors of outcome.17,51 CMRI is useful also in the follow-up of AM and is generally performed 6 to 12 months after the index event (Table ​(Table3).3). Disappearance of edema is frequent at follow-up (up to 84% of cases), whereas LGE generally persists (in up to 89%), although its extent is reduced from 6.2% to 4.1% of LV mass after 6 months in the Italian Multicenter Study on Acute Myocarditis registry including 187 cases.52 This finding is in keeping with other studies that analyzed the changes in LGE and edema at follow-up.16,53 The extent of LGE is a dynamic process in AM, mainly related to tissue edema in the acute phase that progressively vanishes over time, whereas in the late phase, LGE mainly reflects postinflammatory replacement fibrosis.53 Persistence of LGE and disappearance of edema are markers of unfavorable prognosis compared with complete resolution or persistence of both LGE and edema.52 A potential explanation is that persistent edema can suggest a still active process with some residual chance of recovery,52 further stressing the role of CMRI also in monitoring patients with AM and infl-CMP over time.

Table 3.

Comparison of Suggested Indications for Endomyocardial Biopsy, Viral Search, and Cardiac Magnetic Resonance Imaging Among Previous US and European Scientific Statements and Current Document

An external file that holds a picture, illustration, etc. Object name is hhf-13-e007405-g006.jpg

Suggested Indications for Positron Emission Tomography in AM and Chronic infl-CMP

Although positron emission tomography (PET) is not usually used in the setting of AM or chronic infl-CMP, it can be considered as an alternative noninvasive diagnostic tool in stable patients with contraindication to CMRI or in patients with suspected systemic autoimmune disease where other organs could be involved by the inflammatory process.56 PET is especially useful for the diagnosis and monitoring of CS.57,58 T cells, macrophages, or granulocytes that infiltrate the myocardium, either as a nonspecific response to cell injury or as primary lesion in CS, are characterized by an enhanced glucose metabolism that can be detected by the focal uptake of the glucose analogue 18F-fluorodeoxyglucose. PET can reveal hypermetabolic mediastinal and hilar lymph nodes differentiating CS from other autoimmune disease with cardiac involvement (eg, vasculitis). This technique provides a tool to monitor the progression of damage and its regression in response to immunosuppressive therapy.57 Recent development of additional immuno-PET tracers in oncology has dramatically expanded the usefulness of PET imaging to detect endogenous immune cells and may provide novel diagnostic and prognostication strategies in the myocarditis patients.

Suggested Indication for EMB in AM and Chronic infl-CMP

EMB is considered the reference standard for the diagnosis of myocarditis2,7; however, it is an invasive procedure that portends some risks. Cardiac complications have been reported in 1% to 2% of the patients at expert centers but in up to 8.9% at low-volume centers.59,60 The sensitivity of EMB is relatively low when evaluated with standard hematoxylin-eosin staining,61 since sampling sites do not always correspond to the distribution of inflammation. Sensitivity may be increased by increasing the number of collected specimens over the minimum recommended number (from 4 to 6 specimens).2 Immunohistochemistry-specific antibodies for leukocytes (CD45), macrophages (CD68), T cells (CD3) and their main subtypes, helper (CD4) and cytotoxic (CD8) cells, and B cells (CD19/CD20) can also increase the sensitivity of EMB.2 Quantitative criteria to improve the diagnostic yield of EMB in myocarditis include the Marburg criteria, based on the presence of >14 mononuclear leukocytes/mm2 on bioptic samples,62 with the presence of >7 T lymphocytes per mm2.63 These criteria were adopted in a position statement by the European Society of Cardiology experts.2 Despite relatively low sensitivity, the information derived from EMB is fundamental for identifying the mechanisms and deciding therapy in specific clinical scenarios both in AM and chronic infl-CMP (Table ​(Table33):

  1. AM presenting with severe heart failure (HF) or cardiogenic shock (ie, FM)55

  2. AM complicated by severe myocardial dysfunction, acute HF, ventricular arrhythmias, or high-degree atrioventricular block;

  3. AM or suspected chronic infl-CMP associated with peripheral eosinophilia;

  4. AM or chronic infl-CMP with persistent or relapsing release of biomarkers of myocardial necrosis, particularly if associated to a suspected/known autoimmune disorder or ventricular arrhythmias or high-degree atrioventricular block; and

  5. Myocarditis in the setting of ICI, where appropriate diagnosis has implications for patients receiving additional cancer therapy.64

Most of these recommendations were first released in the 2007 American Heart Association/American College of Cardiology (ACC)/European Society of Cardiology Scientific Statement on the role of EMB in the management of cardiovascular disease,54 which were validated by a retrospective analysis on 851 patients with unexplained HF who underwent EMB.59 The diagnostic yield of EMB in the setting of AM is considered to be higher if performed within 2 weeks since symptom onset and in case of normal sized or mildly dilated LV or in presence of markers (ventricular arrhythmias or high-degree atrioventricular blocks) of specific subsets such as giant cell myocarditis (GCM) or CS. AM is often a self-limiting disease and can be managed noninvasively in low-risk patients.60 However, at present, EMB is largely underutilized also in the recommended settings, as shown by some reports on the use of temporary mechanical circulatory supports (MCS) in FM.65 Thus far, a relationship between the extent of inflammatory infiltrates with prognosis and its therapeutic implications have not been consistently found across different settings of inflammatory cardiac disorders. In a retrospective study, patients with acute lymphocytic myocarditis who received an MCS or died during hospitalization had more inflammatory infiltrates compared with patients who survived without MCS.35

Differential Diagnosis

Invasive coronary arteriography or computed tomography angiography are often necessary to rule out an acute coronary syndrome.2 Furthermore, patients with AM and acute pericarditis can complain of similar symptoms. Elevation of high-sensitivity troponin can steer the diagnosis toward AM. AM can be also associated with signs of pericarditis (ie, pericardial effusion on echocardiogram or CMRI; evidence of inflammation of pericardial layers on CMRI). FM should be differentiated from other conditions that may cause hypotension,55 acute myocardial dysfunction, and cardiac shock (such as septic shock, Shoshin beriberi syndrome, systemic capillary leak syndrome, and pheochromocytoma).

Chronic infl-CMP

Chronic infl-CMP can be found in patients at their first evaluation for new-onset HF symptoms or in patients with subacute/chronic HF and DCM or hypokinetic nondilated phenotype. Chronic infl-CMP may represent the evolution of ≥1 AM episodes that, either diagnosed or missed in the acute phase, caused myocardial damage and systolic dysfunction. A mild elevation of troponin out of proportion compared with LVEF impairment, associated with a dilated LV with normal or mildly increased wall thickness, can suggest a chronic infl-CMP over AM.8 Accordingly, CMRI and EMB may show less florid inflammation, and replacement fibrosis may prevail. Furthermore, cardiomyocytes with morphological abnormalities may be found at histology (Figure ​(Figure1;1; Figure I in the Data Supplement). Due to progressive LV remodeling, patients presenting with a chronic infl-CMP have chronic HF symptoms (generally >1 month) but may be hemodynamically stable and are treated as patients with DCM.9 Anamnestic clues, subtle electrocardiographic alterations (such as low voltage or fragmentation of QRS in peripheral leads, minor conduction disturbances, and nonspecific ST-T abnormalities), low-grade, persistent elevation of troponin, and failure to respond to standard HF treatment should promote the search for an inflammatory cause.9 In chronic infl-CMP, the presence of high number of T lymphocytes or macrophages on EMB has a unique value in predicting an increased risk of mortality or transplantation over the next decade.66 The extent of myocardial fibrosis should be reported as it could be related to the likelihood of recovery. Finally, the additional analysis to search for cardiotropic viruses (eg, RNA enteroviruses and DNA adenoviruses), bacteria, and parasites in biopsy specimens using quantitative real-time polymerase chain reaction is recommended by the European Society of Cardiology experts to guide immunosuppressive therapy in the setting of chronic infl-CMP.2,67 Conversely, American Heart Association experts do not recommend routine viral genome analysis outside of centers with experience,9 even if they consider it as an additional option when diagnostic uncertainty exists.55

Virus-Induced and Immune-Mediated Lymphocytic AM and infl-CMP

Lymphocytic AM and chronic infl-CMP have been attributed to a variety of pathogens, mainly viruses (by direct virus-mediated or indirect immune-mediated myocardial injury), toxic effect of drugs or radiation, and autoimmune injury in the setting of systemic inflammatory disorders.

Virus-induced AM can refer to both virus-mediated myocarditis and virus-triggered myocarditis. Enteroviral (coxsackievirus) myocarditis are examples of virus-mediated AM, as viral replication can cause direct cardiomyocyte injury.68 The cases of enterovirus-mediated AM have been mainly reported in newborns and infants in recent years.69 Respiratory viruses, such as influenza and coronaviruses, are examples of common viruses that can trigger an immune-mediated lymphocytic myocarditis in the absence of viral genome in the myocardium.42,70 In virus-triggered AM, molecular mimicry between viral and cardiac antigens, which can result in autoreactive T-cell infiltration in the myocardium in predisposed individuals, is suspected to be the underlying mechanism of myocardial injury.22 The resolution of the viral syndrome with the extinction of viral antigens could explain the frequent self-resolving natural history of most AMs. Of note, PVB19 appears to cause both virus-mediated and virus-triggered myocarditis. In children in particular, PVB19 may cause a systemic infection associated with AM where PVB19 can be detected both in plasma and myocardium. In adults, PVB19 has been associated with both AM and chronic infl-CMP,71 and the viral genome has been detected with different titers in the myocardium of these subjects, while it is not generally detected in the bloodstream. PVB19 has been the only virus found in patients with lymphocytic FM in an international registry.25,38 A preliminary report showing a benefit from immunosuppression in chronic infl-CMP with PVB19 presence in the myocardium seems to support the hypothesis that the immune response plays a role in the development of myocardial inflammation after viral infection.72 Alternatively, low copy number of PVB19 DNA may reflect latent infection and should be interpreted as a bystander, since they can be found also in normal myocardium.73 These findings may suggest that immunosuppression is not contraindicated in all virus-positive myocarditis, but the involved virus (eg, it may be considered with PVB19 but not with coxsackievirus), the host (eg, infants versus adults or immunodeficient versus immunocompetent individuals), and the setting (noncomplicated versus FM) should be considered in the decision to start immunosuppressive drugs. According to several researchers, high viral loads and replicating (versus nonreplicating) viruses could stand against the use of immunosuppression and possibly in favor of treatment with antiviral drugs or with agents that reinforce native immune response, for example, interferon-β,74 even if clinical data from trials are substantially lacking in the setting of AM. Similarly to PVB19, human herpes virus-6 has been occasionally found in the myocardium of patients with AM and chronic infl-CMP, but its pathogenetic role is unclear.19

Immune-Mediated AM and Chronic infl-CMP

AM or chronic infl-CMP can be associated with systemic autoimmune disorders (eg, systemic lupus erythematosus or dermatomyositis) or organ/system-specific autoimmune/inflammatory diseases (eg, inflammatory bowel disorders). The immune system activation stimulated by an intercurrent infection could favor a flare of the underlying immune disorder involving the heart. The identification of the myocarditis-associated condition is relevant for the specific treatments, given that not infrequently AM is the first manifestation of a systemic inflammatory/autoimmune disease.39 The Lombardy registry of AM reported that 7.2% of patients had associated autoimmune or systemic disorders, and this condition was more frequent in patients with complicated presentation (15.4%).13

ICI-Associated Myocarditis

ICIs have transformed cancer treatment, with regulatory approval in ≈20 different cancer types. The percentage of patients with cancer who were eligible for ICI increased from 1.5% in 2011 to ≈50% in 2020.75 These agents include monoclonal antibodies, which block immune brakes or regulators, termed CTLA-4 (cytotoxic T-lymphocyte antigen-4), PD-1 (programmed death receptor-1), and its ligand (PD-L1 [programmed death-ligand 1]) that, when stimulated, can dampen the immune response to an immunologic stimulus. By blocking these checkpoints from binding with their partner proteins, ICIs inhibit the off signal, activating T cells and promoting killing of cancer cells. By activating the immune system, ICI can also lead to immune-mediated adverse events (such as colitis, dermatitis, and pneumonitis).76

Etiology and Pathogenesis

In 2016, Johnson et al77 described 2 cases of fatal FM after treatment with ICI. These patients presented with refractory electrophysiological disturbances and concomitant myositis, with pathology indicating T-cell and macrophage-dependent myocardial infiltration. Other case series of ICI-associated AM reported an incidence between 1% and 2% when ICIs are used in combination.21,78 Preclinical data suggest a critical role for CTLA-4 and PD-1 in the cross talk between the cardiovascular and immune systems. Inhibition of CTLA-4 and PD-1, either genetically or pharmacologically, was found to contrast ICI-associated myocarditis and other cardiovascular toxicities in mice.79

Diagnosis

The largest case series of 122 patients with ICI-associated myocarditis had an early onset of symptoms (median of 30 days after initial exposure to ICI), and up to 50% died.40 The increasing number of reports in the past few years is consistent with the growing awareness of this new clinical syndrome, as well as with the more widespread use of ICI. Patients on combination ICI treatment (eg, ipilimumab and nivolumab) should have an ECG and troponin assay at baseline. Once started on therapy, troponin should be checked weekly during the first 6 weeks. In addition, given concomitant myositis in a substantial number of cases of ICI-associated myocarditis, a defined workup for myositis (including checking for creatine kinase [CK] and possibly skeletal muscle biopsy) is recommended in suspected cases.

Treatment

High-dose intravenous corticosteroids associated with withdrawal of ICI are considered the first-line therapy, although mortality remains high. Alemtuzumab (anti-CD52 antibody), antithymocyte globulin (anti-CD3 antibody), and abatacept (a CTLA-4 agonist) have been proposed as second-line therapy (Table ​(Table33).100–102 A better mechanistic understanding of ICI-associated cardiovascular toxicity by using preclinical models could help for defining preventive and treatment strategies in patients.

Eosinophilic Myocarditis

EM is relatively uncommon, but it is often unrecognized; thus its incidence may be underestimated. The rate of death or HTx in patients with EM and a fulminant presentation was over 26% at 60 days after admission.38

Etiology and Pathogenesis

EM is generally associated with hypersensitivity reactions to chemicals (in particular, clozapine, carbamazepine, minocycline, and β-lactam antibiotics and occasionally vaccination) or with systemic conditions such as eosinophilic granulomatosis with polyangiitis (EGPA; former Churg-Strauss syndrome) or hypereosinophilic syndrome (HES; idiopathic or clonal) or with a parasitic infection, mainly due to Toxocara canis transmitted by raw meat.39 In rare circumstances, EM can be associated with solid-organ malignancy as a paraneoplastic event (ie, lung cancer). A 3-phase process of the eosinophilic injury has been proposed: an initial inflammatory/necrotic phase (observed during AM), followed by thrombotic and fibrotic remodeling of the endomyocardium (typical of Loeffler cardiomyopathy; Figure ​Figure44).

An external file that holds a picture, illustration, etc. Object name is hhf-13-e007405-g007.jpg

Eosinophilic myocardial injury: associated conditions and transition from acute myocarditis to inflammatory cardiomyopathy. A, Eosinophilic myocarditis can be idiopathic or associated with a systemic disorder. The associated conditions can be (1) eosinophilic granulomatosis with polyangiitis (EGPA), which is often associated with asthma, pulmonary nonfixed infiltrates (arrows on a chest computed tomographic scan image in the yellow inset), and paranasal sinus abnormalities; (2) hypereosinophilic syndromes (HES) characterized by persistent peripheral eosinophilia (≥1.5×109/L for over 6 mo), which can be a complex idiopathic form or a myeloproliferative variant like the clonal form associated with FIP1L1/PDGFRA fusion gene; (3) parasitic infections; (4) hypersensitivity reactions to drugs and drug reaction with eosinophilia and systemic symptoms (DRESS) that are generally characterized by fever and diffuse skin rush (like in the patient with DRESS showed in the rose inlet), with frequent delay onset after drug initiation (up to 2–6 wk); and rarely, (5) solid tumors. While in the acute phase, the eosinophilic myocarditis is the main determinant of prognosis, the associated conditions can be the major determinants of prognosis in the mid and long term. B, An acute intense exposure to eosinophilia can cause an acute eosinophilic myocarditis (left), which in some case can be described as necrotizing due to extensive areas of the cardiomyocyte necrosis (*) caused by diffuse eosinophilic infiltrates on endomyocardial biopsy histology. The acute inflammatory phase can cause subendocardial and transmural injuries, identified by late gadolinium enhancement on cardiac magnetic resonance imaging (CMRI). If the eosinophilic exposure persists, eosinophilic injury evolves to a thrombotic and fibrotic stage, with diffuse subendocardial fibrosis with apical thrombi (green arrows), as identified by CMRI; the latter are characteristic features of Loeffler cardiomyopathy (right).

Diagnosis

EM may affect middle-aged individuals, with similar prevalence in both sexes, presenting mainly with chest pain and dyspnea, with evidence of LV systolic dysfunction. The diversity of possible underlying causes may be responsible of the variety of clinical scenarios; specifically, fever and skin rash are more common in hypersensitivity-related EM and asthma in EGPA-related EM.39 Eosinophilia can be evident in the course of the disease,80 but it is absent in about 25% of the patients at admission.39 Echocardiography and CMRI provide information on cardiac function and may detect intracardiac thrombosis (particularly at the LV apex), mostly described in HES-related EM (up to 29% of cases) and EGPA-related EM (up to 19% of cases).39 In contrast with the typical subepicardial LGE pattern observed in other forms of myocarditis, EM is generally associated with subendocardial LGE.39

Treatment

A meta-analysis of 179 cases has shown a lower incidence of in-hospital mortality with the use of corticosteroids, although randomized trials are lacking.39 Identification and treatment of the underlying causes should be promptly considered. In particular, immediate withdrawal of the offending substance in combination with corticosteroid administration is recommended in hypersensitivity-related EM. Albendazole and corticosteroids should be given in EM associated with Toxocara canis infection,39 and imatinib is utilized in myeloproliferative variants of HES. Combined immunosuppressive therapy, including corticosteroids and cyclophosphamide, azathioprine, or methotrexate, may be considered in EM associated with EGPA and HES.39 The rate of recurrence is not known, but fatal recurrences have been reported.39 Patients with HES and EGPA are at increased risk of late recurrence, in particular if immunosuppressive agents are withdrawn.

Giant Cell Myocarditis

GCM is a form of rapidly progressing necrotizing myocarditis with a poor prognosis including an ≈85% rate of death or HTx at 3 years.38,81 GCM is responsible for ≈1 in 200 cases of myocarditis and ≈10% of all FM.

Etiology and Pathogenesis

GCM is characterized by myocardial destruction mediated by a large number of cytotoxic T cells, macrophages, giant cells, and eosinophils. This leads to LV dysfunction and ventricular arrhythmias. Associated autoimmune disorders, in particular, inflammatory bowel diseases and thyroid disorders, have been reported in ≈20% of cases.81

Diagnosis

GCM affects equally men and women. Median age at onset is between 43 and 53 years, higher than observed in lymphocytic myocarditis.38,81 GCM frequently presents as acute HF or cardiogenic shock and with ventricular tachycardia or complete atrioventricular block.82 EMB is generally the first diagnostic tool. GCM shares some histological features with CS; therefore, the differential diagnosis can be challenging.82

Treatment

Immunosuppressive therapy should be initiated promptly. Treatment with anti–T-lymphocyte–based (ie, antithymocyte globulin) and calcineurin inhibitor therapy can lead to clinical remission in up to two-thirds of patients, in particular, in those not requiring MCS.83 The initial approach may vary based on the clinical presentation. In case of FM, antithymocyte globulin associated with pulse high dose of corticosteroids is preferred, and cyclosporine is titrated to trough levels of 150 to 250 ng/L a few days after the administration of antithymocyte globulin (Table ​(Table44).84,94–96 There is a variable rate of LVEF recovery without transplant, among published series.38,81,83,85 Dosage of oral corticosteroids after the acute phase is 1 mg/kg in the first months with subsequent slow tapering over 1 year, while cyclosporine is generally maintained >2 years, with a target plasma through level of 80 to 100 ng/L. Azathioprine at 1 to 2 mg/kg per die divided into 2 daily doses or mycophenolate mofetil (500–1000 mg BID) can be added. There are anecdotal but consistent data suggesting that discontinuation of immunosuppression after 1 year of treatment may be followed by relapse and death.84 GCM patients have a high risk of ventricular tachycardia, and placement of an implantable cardiac defibrillator (ICD) is generally recommended in all patients including those with full recovery of LVEF.86 Compared with historical results, current combined immunosuppressive treatment suggests an improvement in transplant-free survival from 11% to 55% at 1 year.83,85 HTx is an effective therapy, with similar posttransplant survival in patients with GCM as in those with other causes. Nevertheless, recurrence of GCM on the transplanted hearts and a higher rate of early cellular rejection have been reported.87

Table 4.

Immunosuppressive Treatment Used for Fulminant myocarditis or Acute Myocarditis Complicated by Severe Heart Failure Not Supported by Evidences From Clinical Trials

An external file that holds a picture, illustration, etc. Object name is hhf-13-e007405-g008.jpg

Sarcoidotic Myocarditis

Sarcoidosis is a worldwide disease with a prevalence of about 4.7 to 64 in 100 000; the highest rates are reported in Northern European and African American individuals, particularly in women.57

Etiology and Pathogenesis

Sarcoidosis is a multisystem, granulomatous disease of unknown etiology. Accumulating evidence suggests an immunologic response to an unidentified antigenic trigger in genetically susceptible individuals. Organ involvement is variable, but most patients have pulmonary and lymph node involvement.57 Clinically manifest cardiac involvement occurs in about 5% of patients with pulmonary/systemic sarcoidosis.57 Sarcoidotic myocarditis is characterized by infiltration by activated macrophages, which in some cases can lead to chronic inflammation and fibrotic replacement with non-necrotizing granulomas. Eosinophils and necrosis are rare or absent.82 The macrophages within sarcoid granulomas tend to become epithelioid and form multinucleated giant cells.

Diagnosis

Most cases occur in patients 25 to 60 years of age. The 3 principal manifestations of CS are conduction abnormalities, ventricular arrhythmias, and HF.57 There is a growing awareness that CS can be the first manifestation of sarcoidosis in any organ.108 For example, between 16% and 35% of patients presenting with complete atrioventricular block (<60 years of age) or ventricular tachycardia of unknown etiology had previously undiagnosed CS as the underlying etiology.108 The ventricular septum and LV basal free wall are most commonly affected. EMB has only 20% to 30% sensitivity, 57 if not imaging guided.109 Experts’ position statements propose criteria to reach diagnosis of CS that are mainly based on positive histology in the heart or extracardiac histological evidence of sarcoidosis plus demonstration of cardiac involvement based on imaging (Table III in the Data Supplement).57

Treatment

Corticosteroids therapy is advocated for the treatment of CS by most experts. It is unknown whether all patients with CS should be treated or only those with clinical manifestations of the disease.57 Optimal doses of corticosteroids and how best to assess response to therapy is unknown. Methotrexate is often used as a second-line agent in refractory cases or if there are significant steroid side effects. Other therapies that have been used in CS include azathioprine, cyclophosphamide, infliximab,57 and rarely rituximab (Table ​(Table44).104–107

Patients with CS are at risk of SCD, and there are limited data to help with risk stratification (Table III in the Data Supplement). In a recent Finnish nationwide study, 10-year survival was 92.5% in 102 patients.110 Notably, CS can recur in transplanted hearts.105 Key unresolved questions related to treatment are whether we should treat clinically silent CS and which drugs should be first- and second-line therapies for CS.

Specific Treatments

Patients with AM or chronic infl-CMP associated with autoimmune disorders are treated according to indications regarding the systemic condition. Corticosteroids are generally the cornerstone of therapy, frequently in combination with another agent. During the acute phase, drugs with a rapid onset of action such as intravenous immunoglobulin, cyclophosphamide, and rituximab may be preferred, while for maintenance therapy, mycophenolate mofetil, methotrexate, and azathioprine may be used to allow tapering of corticosteroids over time. Plasmapheresis is occasionally used in the acute setting, for instance in AM associated with antiphospholipid syndromes. Excluding AM associated with systemic inflammatory conditions, no specific evidence-based treatments are available for lymphocytic AM. Only one trial is currently recruiting patients with AM (https://www.clinicaltrials.gov; unique identifier: NCT03018834), testing the efficacy of anakinra. AM is often a self-limiting disease, and spontaneous recovery of myocardial dysfunction may occur. There is a rationale for using immunosuppressive treatments in high-risk AM, but no trial has tested this hypothesis in the acute phase. Thus, there are no specific recommendations for therapy in the acute phase beyond standard therapy for LV dysfunction and acute HF. The only study that assessed the efficacy of immunosuppression in AM, the MTT (Myocarditis Treatment Trial), reported no benefit from immunosuppression.29 However, the initiation of treatment was delayed, since patients were enrolled between 2 weeks and 1 year from symptom onset. Almost all studies with corticosteroids focused on chronic infl-CMP with 6-month history of HF symptoms. An improvement of cardiac function has been observed, but most studies were inadequately powered,67 and there was no improvement in survival.111 The single-center Tailored IMmunosuppression in Inflammatory Cardiomyopathy trial that randomized 85 patients with virus-negative chronic infl-CMP at a 6-month course of prednisone plus azathioprine or standard HF medications only showed a significant improvement of symptoms and echocardiographic parameters (median LVEF from 27% to 46% after 6 months) in the prednisone and azathioprine group. Given these findings, a large randomized trial is needed to assess the benefit and risk of long-term immunosuppression. Furthermore, few data exist supporting treatments for patients with virus-positive chronic infl-CMP. Usual HF treatments are recommended in those patients with chronic inf-CMP or AM with reduced LVEF and stable hemodynamics. β-Blockers are often used after an AM also in patients with uncomplicated presentation (53.8% based on the Lombardy registry of AM),13 probably due to the perceived protection against arrhythmic events. Finally concerning the prevention of SCD at discharge, patients with infl-CMP follow the general indication for ICD, with the abovementioned exceptions concerning GCM and CS. In patients with AM, a multiparametric stratification of risk is reasonable for decision on ICD implantation. It may include family history of SCD or arrhythmogenic cardiomyopathy, ventricular tachycardia on presentation,112 presence and septal localization of LGE on CMRI,14,17 and histology compatible with CS or GCM. Currently, ICD is rarely implanted after an AM with preserved LVEF (2% in the Lombardy registry13 and 1.6% in the ITAMY registry). The cumulative percentage of SCD, resuscitated cardiac arrest, and appropriate ICD shock was 2.1% at 4.3 years of follow-up in the ITAMY registry.14

MCS and HTx

Patients with AM complicated by refractory HF or cardiogenic shock require inotropic agents or MCS.55 Myocarditis is often a reversible condition; thus temporary devices such as intra-aortic balloon pumps, venoarterial extracorporeal membrane oxygenator, rotary pumps, or intra-aortic axial pumps should be considered first. Observational studies and multicenter registries report a short-term transplant-free survival of 55% to 80% in patients with FM who received temporary MCS.113,114 An analysis of trends in myocarditis incidence and management in the United States between 2005 and 2014115 has reported a growing rate of use of any temporary MCS, from 4.5% to 8.6%, with a significant trend for all devices except intra-aortic balloon pump, which anyway was the most frequently used support (3.8% overall). In theory, the use of devices that reduce LV afterload, such as centrifugal pumps or intra-aortic axial pumps, alone or in combination with venoarterial extracorporeal membrane, could favor myocardial recovery more than venoarterial extracorporeal membrane alone, through both hemodynamic and anti-inflammatory mechanisms.116 Nonetheless, a multicenter registry on intra-aortic axial pump use for FM (34 patients from 2009 to 2016) showed a survival to discharge of 62%,117 not different from the 61% discharge rate reported among 185 patients supported with venoarterial extracorporeal membrane in Taiwan from 2001 to 2011.118 If there is no weaning from MCS after 2 to 3 weeks, long-term LV assist device or urgent HTx may be considered.

Knowledge Gaps and Perspective

Critical knowledge gaps exist regarding diagnosis, prognostication, and treatment of AM and chronic infl-CMP, which need to be addressed. Though EMB is the gold reference for diagnosis, it is not available or is underperformed in most hospitals60 and has a relatively low sensitivity using conventional histology. Hence, novel sensitive and specific biomarkers and imaging modalities are needed. The advent of novel technologies developed in the immuno-oncology space (eg, single-cell RNA sequencing, mass cytometry, high-frequency and deeper T-cell receptor sequencing, multiplex immunofluorescence, and other technologies) should become novel research strategies and further advance the usefulness of tissue analysis. Prospective large interventional trials or registries in the field of AM and chronic infl-CMP could help standardize the diagnostic and therapeutic approaches, which currently vary widely. Prospective registries aimed at identifying low- versus high-risk patients at the time of hospitalization and to refine and characterize the risk for specific events beyond death or HTx (eg, recurrence, evolution to DCM, and arrhythmias) at discharge and during follow-up are needed. Finally, a common terminology to describe cases of AM and infl-CMP, and shared clinical pathways for patient management, could increase our knowledge on this condition, potentially improving patient outcome.

Acknowledgments

Drs Ammirati and Frigerio acknowledge the Fondazione Centro Cardiologia e Cardiochirurgia A. De Gasperis, Niguarda Hospital, Milano, Italy, for its research support. Dr Basso is supported by the Registry of Cardio-Cerebral-Vascular Pathology, Veneto Region, Italy. Dr Tschöpe acknowledges the Federal Ministry of Education and Research, Germany, for the Cortisone in Parvovirus Inflammatory Cardiomyopathy program and the German Centre for Cardiovascular Research for the voltage mapping–guided and magnetic resonance imaging–guided endomyocardial biopsy in myocarditis and inflammatory dilated cardiomyopathy study.

Sources of Funding

None.

Disclosures

Dr Adler is a consultant for Abbott, Abiomed, AstraZeneca, Endotronix, Ionis, Medtronic, and Novartis, is on the board of directors of Genstem Therapeutics, and is a shareholder of Rocket Pharmaceuticals. Dr Brambatti is an employee at Ionis Pharmaceuticals. Dr Moslehi has served on advisory boards for Pfizer, Novartis, Bristol-Myers Squibb, Deciphera, Audentes Pharmaceuticals, Nektar, Takeda, Ipsen, Myokardia, AstraZeneca, GlaxoSmithKline, Intrexon, and Regeneron and has been supported by National Institutes of Health grants R56 HL141466 and R01 HL141466. Dr Tschöpe is a consultant at Cardiotropic Labs, Miami, FL. Dr Camici is a consultant at Servier. The other authors report no conflicts.

Supplemental Materials

Figures I and II

Movies I and II

Tables I–III

Supplementary Material

Nonstandard Abbreviations and Acronyms

ACC
American College of Cardiology
AM
acute myocarditis
CMRI
cardiac magnetic resonance imaging
CS
cardiac sarcoidosis
CTLA-4
cytotoxic T-lymphocyte antigen-4
DCM
dilated cardiomyopathy
EGPA
eosinophilic granulomatosis with polyangiitis
EM
eosinophilic myocarditis
EMB
endomyocardial biopsy
FM
fulminant myocarditis
GCM
giant cell myocarditis
HES
hypereosinophilic syndrome
HF
heart failure
HTx
heart transplantation
ICD
implantable cardiac defibrillator
ICI
immune checkpoint inhibitor
infl-CMP
inflammatory cardiomyopathy
LGE
late gadolinium enhancement
LV
left ventricle
LVEF
left ventricular ejection fraction
MCS
mechanical circulatory support
MTT
Myocarditis Treatment Trial
PD-1
programmed death receptor-1
PD-L1
programmed death-ligand 1
PET
positron emission tomography
PVB19
parvovirus-B19
SCD
sudden cardiac death

*Drs Ammirati and Frigerio contributed equally to this work.

†Drs Cooper and Camici contributed equally to this work as senior authors.

This manuscript was sent to Kenneth B. Margulies, MD, Senior Guest Editor, for review by expert referees, editorial decision, and final disposition.

The Data Supplement is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCHEARTFAILURE.120.007405.

For Sources of Funding and Disclosures, see page 683.

References

1. Cooper LT., Jr Myocarditis. N Engl J Med. 2009;360:1526–1538. 10.1056/NEJMra0800028 [Europe PMC free article] [Abstract] [Google Scholar]
2. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, Fu M, Heliö T, Heymans S, Jahns R, et al. ; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. 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;34:2636–48, 2648a. 10.1093/eurheartj/eht210 [Abstract] [Google Scholar]
3. Richardson P, McKenna W, Bristow M, Maisch B, Mautner B, O’Connell J, Olsen E, Thiene G, Goodwin J, Gyarfas I, et al. Report of the 1995 World Health Organization/International Society and Federation of Cardiology task force on the definition and classification of cardiomyopathies. Circulation. 1996;93:841–842. 10.1161/01.cir.93.5.841 [Abstract] [Google Scholar]
4. Corrado D, Basso C, Thiene G. Sudden cardiac death in young people with apparently normal heart. Cardiovasc Res. 2001;50:399–408. 10.1016/s0008-6363(01)00254-1 [Abstract] [Google Scholar]
5. Harmon KG, Drezner JA, Maleszewski JJ, Lopez-Anderson M, Owens D, Prutkin JM, Asif IM, Klossner D, Ackerman MJ. Pathogeneses of sudden cardiac death in national collegiate athletic association athletes. Circ Arrhythm Electrophysiol. 2014;7:198–204. 10.1161/CIRCEP.113.001376 [Abstract] [Google Scholar]
6. Towbin JA, Lowe AM, Colan SD, Sleeper LA, Orav EJ, Clunie S, Messere J, Cox GF, Lurie PR, Hsu D, et al. Incidence, causes, and outcomes of dilated cardiomyopathy in children. JAMA. 2006;296:1867–1876. 10.1001/jama.296.15.1867 [Abstract] [Google Scholar]
7. Aretz HT. Myocarditis: the Dallas criteria. Hum Pathol. 1987;18:619–624. 10.1016/s0046-8177(87)80363-5 [Abstract] [Google Scholar]
8. Ammirati E, Veronese G, Cipriani M, Moroni F, Garascia A, Brambatti M, Adler ED, Frigerio M. Acute and fulminant myocarditis: a pragmatic clinical approach to diagnosis and treatment. Curr Cardiol Rep. 2018;20:114 10.1007/s11886-018-1054-z [Abstract] [Google Scholar]
9. Bozkurt B, Colvin M, Cook J, Cooper LT, Deswal A, Fonarow GC, Francis GS, Lenihan D, Lewis EF, McNamara DM, et al. ; American Heart Association Committee on Heart Failure and Transplantation of the Council on Clinical Cardiology; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; Council on Epidemiology and Prevention; and Council on Quality of Care and Outcomes Research. Current diagnostic and treatment strategies for specific dilated cardiomyopathies: a scientific statement from the American Heart Association. Circulation. 2016;134:e579–e646. 10.1161/CIR.0000000000000455 [Abstract] [Google Scholar]
10. Global Burden of Disease Study C. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2015;386:743–800. 10.1016/S0140-6736(15)60692-4 [Europe PMC free article] [Abstract] [Google Scholar]
11. Charpentier S, Beaune S, Joly LM, Khoury A, Duchateau FX, Briot R, Renaud B, Ageron FX IRU Network. Management of chest pain in the French emergency healthcare system: the prospective observational EPIDOULTHO study. Eur J Emerg Med. 2018;25:404–410. 10.1097/MEJ.0000000000000481 [Abstract] [Google Scholar]
12. Pasupathy S, Air T, Dreyer RP, Tavella R, Beltrame JF. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation. 2015;131:861–870. 10.1161/CIRCULATIONAHA.114.011201 [Abstract] [Google Scholar]
13. Ammirati E, Cipriani M, Moro C, Raineri C, Pini D, Sormani P, Mantovani R, Varrenti M, Pedrotti P, Conca C, et al. ; Registro Lombardo delle Miocarditi. Clinical presentation and outcome in a contemporary cohort of patients with acute myocarditis: multicenter lombardy registry. Circulation. 2018;138:1088–1099. 10.1161/CIRCULATIONAHA.118.035319 [Abstract] [Google Scholar]
14. Aquaro GD, Perfetti M, Camastra G, Monti L, Dellegrottaglie S, Moro C, Pepe A, Todiere G, Lanzillo C, Scatteia A, et al. ; Cardiac Magnetic Resonance Working Group of the Italian Society of Cardiology. Cardiac MR with late gadolinium enhancement in acute myocarditis with preserved systolic function: ITAMY study. Am Coll Cardiol. 2017;70:1977–1987. 10.1016/j.jacc.2017.08.044 [Abstract] [Google Scholar]
15. Younis A, Matetzky S, Mulla W, Masalha E, Afel Y, Chernomordik F, Fardman A, Goitein O, Ben-Zekry S, Peled Y, et al. Epidemiology characteristics and outcome of patients with clinically diagnosed acute myocarditis. Am J Med. 2020;133:492–499. 10.1016/j.amjmed.2019.10.015 [Abstract] [Google Scholar]
16. White JA, Hansen R, Abdelhaleem A, Mikami Y, Peng M, Rivest S, Satriano A, Dykstra S, Flewitt J, Heydari B, et al. Natural history of myocardial injury and chamber remodeling in acute myocarditis. Circ Cardiovasc Imaging. 2019;12:e008614 10.1161/CIRCIMAGING.118.008614 [Abstract] [Google Scholar]
17. Gräni C, Eichhorn C, Bière L, Murthy VL, Agarwal V, Kaneko K, Cuddy S, Aghayev A, Steigner M, Blankstein R, et al. Prognostic value of cardiac magnetic resonance tissue characterization in risk stratifying patients with suspected myocarditis. J Am Coll Cardiol. 2017;70:1964–1976. 10.1016/j.jacc.2017.08.050 [Europe PMC free article] [Abstract] [Google Scholar]
18. Sanguineti F, Garot P, Mana M, O’h-Ici D, Hovasse T, Unterseeh T, Louvard Y, Troussier X, Morice MC, Garot J. Cardiovascular magnetic resonance predictors of clinical outcome in patients with suspected acute myocarditis. J Cardiovasc Magn Reson. 2015;17:78 10.1186/s12968-015-0185-2 [Europe PMC free article] [Abstract] [Google Scholar]
19. Grün S, Schumm J, Greulich S, Wagner A, Schneider S, Bruder O, Kispert EM, Hill S, Ong P, Klingel K, et al. Long-term follow-up of biopsy-proven viral myocarditis: predictors of mortality and incomplete recovery. J Am Coll Cardiol. 2012;59:1604–1615. 10.1016/j.jacc.2012.01.007 [Abstract] [Google Scholar]
20. Anzini M, Merlo M, Sabbadini G, Barbati G, Finocchiaro G, Pinamonti B, Salvi A, Perkan A, Di Lenarda A, Bussani R, et al. Long-term evolution and prognostic stratification of biopsy-proven active myocarditis. Circulation. 2013;128:2384–2394. 10.1161/CIRCULATIONAHA.113.003092 [Abstract] [Google Scholar]
21. Moslehi JJ, Salem JE, Sosman JA, Lebrun-Vignes B, Johnson DB. Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet. 2018;391:933 10.1016/S0140-6736(18)30533-6 [Europe PMC free article] [Abstract] [Google Scholar]
22. Rose NR. Learning from myocarditis: mimicry, chaos and black holes. F1000Prime Rep. 2014;6:25 10.12703/P6-25 [Europe PMC free article] [Abstract] [Google Scholar]
23. Trachtenberg BH, Hare JM. Inflammatory cardiomyopathic syndromes. Circ Res. 2017;121:803–818. 10.1161/CIRCRESAHA.117.310221 [Abstract] [Google Scholar]
24. Fung G, Luo H, Qiu Y, Yang D, McManus B. Myocarditis. Circ Res. 2016;118:496–514. 10.1161/CIRCRESAHA.115.306573 [Abstract] [Google Scholar]
25. Veronese G, Ammirati E, Brambatti M, Merlo M, Cipriani M, Potena L, Sormani P, Aoki T, Sugimura K, Sawamura A, et al. Viral genome search in myocardium of patients with fulminant myocarditis. Eur J Heart Fail. 2020;22:1277–1280. 10.1002/ejhf.1738 [Abstract] [Google Scholar]
26. Lopez-Ayala JM, Pastor-Quirante F, Gonzalez-Carrillo J, Lopez-Cuenca D, Sanchez-Munoz JJ, Oliva-Sandoval MJ, Gimeno JR. Genetics of myocarditis in arrhythmogenic right ventricular dysplasia. Heart Rhythm. 2015;12:766–773. 10.1016/j.hrthm.2015.01.001 [Abstract] [Google Scholar]
27. Belkaya S, Kontorovich AR, Byun M, Mulero-Navarro S, Bajolle F, Cobat A, Josowitz R, Itan Y, Quint R, Lorenzo L, et al. Autosomal recessive cardiomyopathy presenting as acute myocarditis. J Am Coll Cardiol. 2017;69:1653–1665. 10.1016/j.jacc.2017.01.043 [Europe PMC free article] [Abstract] [Google Scholar]
28. Grogan M, Redfield MM, Bailey KR, Reeder GS, Gersh BJ, Edwards WD, Rodeheffer RJ. Long-term outcome of patients with biopsy-proved myocarditis: comparison with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1995;26:80–84. 10.1016/0735-1097(95)00148-s [Abstract] [Google Scholar]
29. Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med. 1995;333:269–275. 10.1056/NEJM199508033330501 [Abstract] [Google Scholar]
30. McCarthy RE, 3rd, Boehmer JP, Hruban RH, Hutchins GM, Kasper EK, Hare JM, Baughman KL. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis. N Engl J Med. 2000;342:690–695. 10.1056/NEJM200003093421003 [Abstract] [Google Scholar]
31. Magnani JW, Danik HJ, Dec GW, Jr, DiSalvo TG. Survival in biopsy-proven myocarditis: a long-term retrospective analysis of the histopathologic, clinical, and hemodynamic predictors. Am Heart J. 2006;151:463–470. 10.1016/j.ahj.2005.03.037 [Abstract] [Google Scholar]
32. Caforio AL, Calabrese F, Angelini A, Tona F, Vinci A, Bottaro S, Ramondo A, Carturan E, Iliceto S, Thiene G, et al. A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis. Eur Heart J. 2007;28:1326–1333. 10.1093/eurheartj/ehm076 [Abstract] [Google Scholar]
33. Kindermann I, Kindermann M, Kandolf R, Klingel K, Bültmann B, Müller T, Lindinger A, Böhm M. Predictors of outcome in patients with suspected myocarditis. Circulation. 2008;118:639–648. 10.1161/CIRCULATIONAHA.108.769489 [Abstract] [Google Scholar]
34. Inaba O, Satoh Y, Isobe M, Yamamoto T, Nagao K, Takayama M. Factors and values at admission that predict a fulminant course of acute myocarditis: data from Tokyo CCU Network database. Heart Vessels. 2017;32:952–959. 10.1007/s00380-017-0960-0 [Abstract] [Google Scholar]
35. Ammirati E, Cipriani M, Lilliu M, Sormani P, Varrenti M, Raineri C, Petrella D, Garascia A, Pedrotti P, Roghi A, et al. Survival and left ventricular function changes in fulminant versus nonfulminant acute myocarditis. Circulation. 2017;136:529–545. 10.1161/CIRCULATIONAHA.117.026386 [Abstract] [Google Scholar]
36. Imazio M, Angelico G, Andriani M, Lobetti-Bodoni L, Davini O, Giustetto C, Rinaldi M. Prevalence and prognostic impact of septal late gadolinium enhancement in acute myocarditis with or without preserved left ventricular function. Am J Cardiol. 2018;122:1955–1958. 10.1016/j.amjcard.2018.08.038 [Abstract] [Google Scholar]
37. Berg J, Lovrinovic M, Baltensperger N, Kissel CK, Kottwitz J, Manka R, Patriki D, Scherff F, Schmied C, Landmesser U, et al. Non-steroidal anti-inflammatory drug use in acute myopericarditis: 12-month clinical follow-up. Open Heart. 2019;6:e000990 10.1136/openhrt-2018-000990 [Europe PMC free article] [Abstract] [Google Scholar]
38. Ammirati E, Veronese G, Brambatti M, Merlo M, Cipriani M, Potena L, Sormani P, Aoki T, Sugimura K, Sawamura A, et al. Fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2019;74:299–311. 10.1016/j.jacc.2019.04.063 [Abstract] [Google Scholar]
39. Brambatti M, Matassini MV, Adler ED, Klingel K, Camici PG, Ammirati E. Eosinophilic myocarditis: characteristics, treatment, and outcomes. J Am Coll Cardiol. 2017;70:2363–2375. 10.1016/j.jacc.2017.09.023 [Abstract] [Google Scholar]
40. Salem JE, Manouchehri A, Moey M, Lebrun-Vignes B, Bastarache L, Pariente A, Gobert A, Spano JP, Balko JM, Bonaca MP, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19:1579–1589. 10.1016/S1470-2045(18)30608-9 [Europe PMC free article] [Abstract] [Google Scholar]
41. Gilotra NA, Minkove N, Bennett MK, Tedford RJ, Steenbergen C, Judge DP, Halushka MK, Russell SD. Lack of relationship between serum cardiac troponin i level and giant cell myocarditis diagnosis and outcomes. J Card Fail. 2016;22:583–585. 10.1016/j.cardfail.2015.12.022 [Abstract] [Google Scholar]
42. Bratincsák A, El-Said HG, Bradley JS, Shayan K, Grossfeld PD, Cannavino CR. Fulminant myocarditis associated with pandemic H1N1 influenza a virus in children. J Am Coll Cardiol. 2010;55:928–929. 10.1016/j.jacc.2010.01.004 [Abstract] [Google Scholar]
43. Inciardi RM, Lupi L, Zaccone G, Italia L, Raffo M, Tomasoni D, Cani DS, Cerini M, Farina D, Gavazzi E, et al. Cardiac involvement in a patient with coronavirus disease 2019 (COVID-19). JAMA Cardiol. 2020;5:1–6. 10.1001/jamacardio.2020.1096 [Europe PMC free article] [Abstract] [Google Scholar]
44. Ferreira VM, Schulz-Menger J, Holmvang G, Kramer CM, Carbone I, Sechtem U, Kindermann I, Gutberlet M, Cooper LT, Liu P, et al. Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations. J Am Coll Cardiol. 2018;72:3158–3176. 10.1016/j.jacc.2018.09.072 [Abstract] [Google Scholar]
45. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Alakija P, Cooper LT, White JA, Abdel-Aty H, Gutberlet M, Prasad S, et al. ; International Consensus Group on Cardiovascular Magnetic Resonance in Myocarditis. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol. 2009;53:1475–1487. 10.1016/j.jacc.2009.02.007 [Europe PMC free article] [Abstract] [Google Scholar]
46. Bhatia S, Anstine C, Jaffe AS, Gersh BJ, Chandrasekaran K, Foley TA, Hodge D, Anavekar NS. Cardiac magnetic resonance in patients with elevated troponin and normal coronary angiography. Heart. 2019;105:1231–1236. 10.1136/heartjnl-2018-314631 [Abstract] [Google Scholar]
47. Luetkens JA, Homsi R, Dabir D, Kuetting DL, Marx C, Doerner J, Schlesinger-Irsch U, Andrie R, Sprinkart AM, Schmeel FC, et al. Comprehensive cardiac magnetic resonance for short-term follow-up in acute myocarditis. J American Heart Assoc. 2016;5:e003603 [Europe PMC free article] [Abstract] [Google Scholar]
48. Pan JA, Lee YJ, Salerno M. Diagnostic performance of extracellular volume, native T1, and T2 mapping versus lake louise criteria by cardiac magnetic resonance for detection of acute myocarditis: a meta-analysis. Circ Cardiovasc Imaging. 2018;11:e007598 10.1161/CIRCIMAGING.118.007598 [Europe PMC free article] [Abstract] [Google Scholar]
49. Luetkens JA, Faron A, Isaak A, Dabir D, Kuetting D, Feisst A, Schmeel FC, Sprinkart AM, Thomas D. Comparison of original and 2018 lake louise criteria for diagnosis of acute myocarditis: results of a validation cohort. Radiology: Cardiothoracic Imaging. 2019;1:e190010 [Europe PMC free article] [Abstract] [Google Scholar]
50. Lurz P, Eitel I, Adam J, Steiner J, Grothoff M, Desch S, Fuernau G, de Waha S, Sareban M, Luecke C, et al. Diagnostic performance of CMR imaging compared with EMB in patients with suspected myocarditis. JACC Cardiovasc Imaging. 2012;5:513–524. 10.1016/j.jcmg.2011.11.022 [Abstract] [Google Scholar]
51. Blissett S, Chocron Y, Kovacina B, Afilalo J. Diagnostic and prognostic value of cardiac magnetic resonance in acute myocarditis: a systematic review and meta-analysis. Int J Cardiovasc Imaging. 2019;35:2221–2229. 10.1007/s10554-019-01674-x [Abstract] [Google Scholar]
52. Aquaro GD, Ghebru Habtemicael Y, Camastra G, Monti L, Dellegrottaglie S, Moro C, Lanzillo C, Scatteia A, Di Roma M, Pontone G, et al. ; “Cardiac Magnetic Resonance” Working Group of the Italian Society of Cardiology. Prognostic value of repeating cardiac magnetic resonance in patients with acute myocarditis. J Am Coll Cardiol. 2019;74:2439–2448. 10.1016/j.jacc.2019.08.1061 [Abstract] [Google Scholar]
53. Ammirati E, Moroni F, Sormani P, Peritore A, Milazzo A, Quattrocchi G, Cipriani M, Oliva F, Giannattasio C, Frigerio M, et al. Quantitative changes in late gadolinium enhancement at cardiac magnetic resonance in the early phase of acute myocarditis. Int J Cardiol. 2017;231:216–221. 10.1016/j.ijcard.2016.11.282 [Abstract] [Google Scholar]
54. Cooper LT, Baughman KL, Feldman AM, Frustaci A, Jessup M, Kuhl U, Levine GN, Narula J, Starling RC, Towbin J, et al. ; American Heart Association; American College of Cardiology; European Society of Cardiology. 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. Circulation. 2007;116:2216–2233. 10.1161/CIRCULATIONAHA.107.186093 [Abstract] [Google Scholar]
55. Kociol RD, Cooper LT, Fang JC, Moslehi JJ, Pang PS, Sabe MA, Shah RV, Sims DB, Thiene G, Vardeny O American Heart Association Heart Failure and Transplantation Committee of the Council on Clinical Cardiology. Recognition and initial management of fulminant myocarditis: a scientific statement From the American Heart Association. Circulation. 2020;141:e69–e92. 10.1161/CIR0000000000000745 [Abstract] [Google Scholar]
56. Perel-Winkler A, Bokhari S, Perez-Recio T, Zartoshti A, Askanase A, Geraldino-Pardilla L. Myocarditis in systemic lupus erythematosus diagnosed by 18F-fluorodeoxyglucose positron emission tomography. Lupus Sci Med. 2018;5:e000265 10.1136/lupus-2018-000265 [Europe PMC free article] [Abstract] [Google Scholar]
57. Birnie DH, Nery PB, Ha AC, Beanlands RS. Cardiac sarcoidosis. J Am Coll Cardiol. 2016;68:411–421. 10.1016/j.jacc.2016.03.605 [Abstract] [Google Scholar]
58. Chareonthaitawee P, Beanlands RS, Chen W, Dorbala S, Miller EJ, Murthy VL, Birnie DH, Chen ES, Cooper LT, Tung RH, et al. Joint SNMMI-ASNC expert consensus document on the role of 18F-FDG PET/CT in cardiac sarcoid detection and therapy monitoring. J Nucl Cardiol. 2017;24:1741–1758. 10.1007/s12350-017-0978-9 [Abstract] [Google Scholar]
59. Bennett MK, Gilotra NA, Harrington C, Rao S, Dunn JM, Freitag TB, Halushka MK, Russell SD. Evaluation of the role of endomyocardial biopsy in 851 patients with unexplained heart failure from 2000-2009. Circ Heart Fail. 2013;6:676–684. 10.1161/CIRCHEARTFAILURE.112.000087 [Abstract] [Google Scholar]
60. Singh V, Mendirichaga R, Savani GT, Rodriguez A, Blumer V, Elmariah S, Inglessis-Azuaje I, Palacios I. Comparison of utilization trends, indications, and complications of endomyocardial biopsy in native versus donor hearts (from the nationwide inpatient sample 2002 to 2014). Am J Cardiol. 2018;121:356–363. 10.1016/j.amjcard.2017.10.021 [Abstract] [Google Scholar]
61. Chow LH, Radio SJ, Sears TD, McManus BM. Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis. J Am Coll Cardiol. 1989;14:915–920. 10.1016/0735-1097(89)90465-8 [Abstract] [Google Scholar]
62. Maisch B, Portig I, Ristic A, Hufnagel G, Pankuweit S. Definition of inflammatory cardiomyopathy (myocarditis): on the way to consensus. A status report. Herz. 2000;25:200–209. 10.1007/s000590050007 [Abstract] [Google Scholar]
63. Kühl U, Noutsias M, Seeberg B, Schultheiss HP. Immunohistological evidence for a chronic intramyocardial inflammatory process in dilated cardiomyopathy. Heart. 1996;75:295–300. 10.1136/hrt.75.3.295 [Europe PMC free article] [Abstract] [Google Scholar]
64. Hu JR, Florido R, Lipson EJ, Naidoo J, Ardehali R, Tocchetti CG, Lyon AR, Padera RF, Johnson DB, Moslehi J. Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res. 2019;115:854–868. 10.1093/cvr/cvz026 [Europe PMC free article] [Abstract] [Google Scholar]
65. Lorusso R, Centofanti P, Gelsomino S, Barili F, Di Mauro M, Orlando P, Botta L, Milazzo F, Actis Dato G, Casabona R, et al. ; GIROC Investigators. Venoarterial extracorporeal membrane oxygenation for acute fulminant myocarditis in adult patients: a 5-year multi-institutional experience. Ann Thorac Surg. 2016;101:919–926. 10.1016/j.athoracsur.2015.08.014 [Abstract] [Google Scholar]
66. Nakayama T, Sugano Y, Yokokawa T, Nagai T, Matsuyama TA, Ohta-Ogo K, Ikeda Y, Ishibashi-Ueda H, Nakatani T, Ohte N, et al. Clinical impact of the presence of macrophages in endomyocardial biopsies of patients with dilated cardiomyopathy. Eur J Heart Fail. 2017;19:490–498. 10.1002/ejhf.767 [Abstract] [Google Scholar]
67. Frustaci A, Russo MA, Chimenti C. Randomized study on the efficacy of immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy: the TIMIC study. Eur Heart J. 2009;30:1995–2002. 10.1093/eurheartj/ehp249 [Abstract] [Google Scholar]
68. Klingel K, Selinka HC, Huber M, Sauter M, Leube M, Kandolf R. Molecular pathology and structural features of enteroviral replication. Toward understanding the pathogenesis of viral heart disease. Herz. 2000;25:216–220. 10.1007/s000590050009 [Abstract] [Google Scholar]
69. Matsuura H, Ichida F, Saji T, Ogawa S, Waki K, Kaneko M, Tahara M, Soga T, Ono Y, Yasukochi S. Clinical features of acute and fulminant myocarditis in children- 2nd nationwide survey by japanese society of pediatric cardiology and cardiac surgery. Circ J. 2016;80:2362–2368. 10.1253/circj.CJ-16-0234 [Abstract] [Google Scholar]
70. Veronese G, Cipriani M, Bottiroli M, Garascia A, Mondino M, Pedrotti P, Pini D, Cozzi O, Messina A, Droandi G, et al. Fulminant myocarditis triggered by OC43 subtype coronavirus: a disease deserving evidence-based care bundles. J Cardiovasc Med (Hagerstown). 2020;21:529–531. 10.2459/JCM.0000000000000989 [Abstract] [Google Scholar]
71. Bock CT, Klingel K, Kandolf R. Human parvovirus B19-associated myocarditis. N Engl J Med. 2010;362:1248–1249. 10.1056/NEJMc0911362 [Abstract] [Google Scholar]
72. Tschöpe C, Elsanhoury A, Schlieker S, Van Linthout S, Kühl U. Immunosuppression in inflammatory cardiomyopathy and parvovirus B19 persistence. Eur J Heart Fail. 2019;21:1468–1469. 10.1002/ejhf.1560 [Abstract] [Google Scholar]
73. Verdonschot J, Hazebroek M, Merken J, Debing Y, Dennert R, Brunner-La Rocca HP, Heymans S. Relevance of cardiac parvovirus B19 in myocarditis and dilated cardiomyopathy: review of the literature. Eur J Heart Fail. 2016;18:1430–1441. 10.1002/ejhf.665 [Abstract] [Google Scholar]
74. Schultheiss HP, Piper C, Sowade O, Waagstein F, Kapp JF, Wegscheider K, Groetzbach G, Pauschinger M, Escher F, Arbustini E, et al. Betaferon in chronic viral cardiomyopathy (BICC) trial: effects of interferon-β treatment in patients with chronic viral cardiomyopathy. Clin Res Cardiol. 2016;105:763–773. 10.1007/s00392-016-0986-9 [Abstract] [Google Scholar]
75. Haslam A, Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open. 2019;2:e192535 10.1001/jamanetworkopen.2019.2535 [Europe PMC free article] [Abstract] [Google Scholar]
76. Bonaca MP, Olenchock BA, Salem JE, Wiviott SD, Ederhy S, Cohen A, Stewart GC, Choueiri TK, Di Carli M, Allenbach Y, et al. Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in cardio-oncology. Circulation. 2019;140:80–91. 10.1161/CIRCULATIONAHA.118.034497 [Europe PMC free article] [Abstract] [Google Scholar]
77. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, Hicks M, Puzanov I, Alexander MR, Bloomer TL, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375:1749–1755. 10.1056/NEJMoa1609214 [Europe PMC free article] [Abstract] [Google Scholar]
78. Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, Heinzerling LM, Sullivan RJ, Damrongwatanasuk R, Chen CL, Gupta D, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018;71:1755–1764. 10.1016/j.jacc.2018.02.037 [Europe PMC free article] [Abstract] [Google Scholar]
79. Grabie N, Gotsman I, DaCosta R, Pang H, Stavrakis G, Butte MJ, Keir ME, Freeman GJ, Sharpe AH, Lichtman AH. Endothelial programmed death-1 ligand 1 (PD-L1) regulates CD8+ T-cell mediated injury in the heart. Circulation. 2007;116:2062–2071. 10.1161/CIRCULATIONAHA.107.709360 [Abstract] [Google Scholar]
80. Morimoto S, Kubo N, Hiramitsu S, Uemura A, Ohtsuki M, Kato S, Kato Y, Sugiura A, Miyagishima K, Mori N, et al. Changes in the peripheral eosinophil count in patients with acute eosinophilic myocarditis. Heart Vessels. 2003;18:193–196. 10.1007/s00380-003-0721-0 [Abstract] [Google Scholar]
81. Cooper LT, Jr, Berry GJ, Shabetai R. Idiopathic giant-cell myocarditis–natural history and treatment. Multicenter giant cell myocarditis study group investigators. N Engl J Med. 1997;336:1860–1866. 10.1056/NEJM199706263362603 [Abstract] [Google Scholar]
82. Okura Y, Dec GW, Hare JM, Kodama M, Berry GJ, Tazelaar HD, Bailey KR, Cooper LT. A clinical and histopathologic comparison of cardiac sarcoidosis and idiopathic giant cell myocarditis. J Am Coll Cardiol. 2003;41:322–329. 10.1016/s0735-1097(02)02715-8 [Abstract] [Google Scholar]
83. Kandolin R, Lehtonen J, Salmenkivi K, Räisänen-Sokolowski A, Lommi J, Kupari M. Diagnosis, treatment, and outcome of giant-cell myocarditis in the era of combined immunosuppression. Circ Heart Fail. 2013;6:15–22. 10.1161/CIRCHEARTFAILURE.112.969261 [Abstract] [Google Scholar]
84. Cooper LT, Jr, Hare JM, Tazelaar HD, Edwards WD, Starling RC, Deng MC, Menon S, Mullen GM, Jaski B, Bailey KR, et al. ; Giant Cell Myocarditis Treatment Trial Investigators. Usefulness of immunosuppression for giant cell myocarditis. Am J Cardiol. 2008;102:1535–1539. 10.1016/j.amjcard.2008.07.041 [Europe PMC free article] [Abstract] [Google Scholar]
85. Ekström K, Lehtonen J, Kandolin R, Räisänen-Sokolowski A, Salmenkivi K, Kupari M. Long-term outcome and its predictors in giant cell myocarditis. Eur J Heart Fail. 2016;18:1452–1458. 10.1002/ejhf.606 [Abstract] [Google Scholar]
86. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, et al. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task force on clinical practice guidelines and the heart rhythm society. Circulation. 2018;138:e272–e391. 10.1161/CIR.0000000000000549 [Abstract] [Google Scholar]
87. Elamm CA, Al-Kindi SG, Bianco CM, Dhakal BP, Oliveira GH. Heart transplantation in giant cell myocarditis: analysis of the united network for organ sharing registry. J Card Fail. 2017;23:566–569. 10.1016/j.cardfail.2017.04.015 [Abstract] [Google Scholar]
88. Reiff C, Missov E. A Case of fulminant lymphocytic myocarditis responsive to immunosuppression. Am J Med. 2018;131:e465–e466. 10.1016/j.amjmed.2018.06.021 [Abstract] [Google Scholar]
89. Drucker NA, Colan SD, Lewis AB, Beiser AS, Wessel DL, Takahashi M, Baker AL, Perez-Atayde AR, Newburger JW. Gamma-globulin treatment of acute myocarditis in the pediatric population. Circulation. 1994;89:252–257. 10.1161/01.cir.89.1.252 [Abstract] [Google Scholar]
90. Chou HW, Wang CH, Lin LY, Chi NH, Chou NK, Yu HY, Chen YS. Prognostic factors for heart recovery in adult patients with acute fulminant myocarditis and cardiogenic shock supported with extracorporeal membrane oxygenation. J Crit Care. 2020;57:214–219. 10.1016/j.jcrc.2020.03.007 [Abstract] [Google Scholar]
91. Courand PY, Croisille P, Khouatra C, Cottin V, Kirkorian G, Bonnefoy E. Churg-strauss syndrome presenting with acute myocarditis and cardiogenic shock. Heart Lung Circ. 2012;21:178–181. 10.1016/j.hlc.2011.09.002 [Abstract] [Google Scholar]
92. Gotlib J, Cools J, Malone JM, 3rd, Schrier SL, Gilliland DG, Coutré SE. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood. 2004;103:2879–2891. 10.1182/blood-2003-06-1824 [Abstract] [Google Scholar]
93. Kuenzli E, Neumayr A, Chaney M, Blum J. Toxocariasis-associated cardiac diseases–a systematic review of the literature. Acta Trop. 2016;154:107–120. 10.1016/j.actatropica.2015.11.003 [Abstract] [Google Scholar]
94. Ammirati E, Oliva F, Belli O, Bonacina E, Pedrotti P, Turazza FM, Roghi A, Paino R, Martinelli L, Frigerio M. Giant cell myocarditis successfully treated with antithymocyte globuline and extracorporeal membrane oxygenation for 21 days. J Cardiovasc Med (Hagerstown). 2016;17suppl 2e151–e153. 10.2459/JCM.0000000000000250 [Abstract] [Google Scholar]
95. Suarez-Barrientos A, Wong J, Bell A, Lyster H, Karagiannis G, Banner NR. Usefulness of rabbit anti-thymocyte globulin in patients with giant cell myocarditis. Am J Cardiol. 2015;116:447–451. 10.1016/j.amjcard.2015.04.040 [Abstract] [Google Scholar]
96. Ma JI, Ammirati E, Brambatti M, Adler E. Biventricular intravascular microaxial blood pumps and immunosuppressio as a bridge to recovery in giant cell myocarditis. J Am Coll Cardiol Case Rep. 2020;2:1484–1488 [Europe PMC free article] [Abstract] [Google Scholar]
97. Evans JD, Pettit SJ, Goddard M, Lewis C, Parameshwar JK. Alemtuzumab as a novel treatment for refractory giant cell myocarditis after heart transplantation. J Heart Lung Transplant. 2016;35:256–258. 10.1016/j.healun.2015.10.009 [Abstract] [Google Scholar]
98. Berman H, Rodríguez-Pintó I, Cervera R, Morel N, Costedoat-Chalumeau N, Erkan D, Shoenfeld Y, Espinosa G Catastrophic Antiphospholipid Syndrome (CAPS) Registry Project Group (European Forum on Antiphospholipid Antibodies). Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab. Autoimmun Rev. 2013;12:1085–1090. 10.1016/j.autrev.2013.05.004 [Abstract] [Google Scholar]
99. Castellanos-Moreira R, Rodríguez-García S, López-Sobrino T, Capdevila A, Prieto-González S, Espinosa G. Successful extracorporeal membrane oxygenation in a patient with fulminant lupus myocarditis. Rev Esp Cardiol (Engl Ed). 2017;70:1013–1014. 10.1016/j.rec.2016.12.037 [Abstract] [Google Scholar]
100. Jain V, Mohebtash M, Rodrigo ME, Ruiz G, Atkins MB, Barac A. Autoimmune myocarditis caused by immune checkpoint inhibitors treated with antithymocyte globulin. J Immunother. 2018;41:332–335. 10.1097/CJI.0000000000000239 [Abstract] [Google Scholar]
101. Esfahani K, Buhlaiga N, Thébault P, Lapointe R, Johnson NA, Miller WH., Jr Alemtuzumab for immune-related myocarditis due to PD-1 therapy. N Engl J Med. 2019;380:2375–2376. 10.1056/NEJMc1903064 [Abstract] [Google Scholar]
102. Salem JE, Allenbach Y, Vozy A, Brechot N, Johnson DB, Moslehi JJ, Kerneis M. Abatacept for severe immune checkpoint inhibitor-associated myocarditis. N Engl J Med. 2019;380:2377–2379. 10.1056/NEJMc1901677 [Abstract] [Google Scholar]
103. Syed FF, Bleeker JS, Glockner J, Pardanani A, Cooper LT., Jr Response to alemtuzumab in FIP1L1/PDGFRA-negative hypereosinophilic myocarditis on serial cardiac magnetic resonance imaging. J Am Coll Cardiol. 2012;59:430 10.1016/j.jacc.2011.06.078 [Abstract] [Google Scholar]
104. Fussner LA, Karlstedt E, Hodge DO, Fine NM, Kalra S, Carmona EM, Utz JP, Isaac DL, Cooper LT. Management and outcomes of cardiac sarcoidosis: a 20-year experience in two tertiary care centres. Eur J Heart Fail. 2018;20:1713–1720. 10.1002/ejhf.1319 [Abstract] [Google Scholar]
105. Veronese G, Cipriani M, Petrella D, Geniere Nigra S, Pedrotti P, Garascia A, Masciocco G, Bramerio MA, Klingel K, Frigerio M, et al. Recurrent cardiac sarcoidosis after heart transplantation. Clin Res Cardiol. 2019;108:1171–1173. 10.1007/s00392-019-01485-z [Abstract] [Google Scholar]
106. Birnie D, Beanlands RSB, Nery P, Aaron SD, Culver DA, DeKemp RA, Gula L, Ha A, Healey JS, Inoue Y, et al. Cardiac sarcoidosis multi-center randomized controlled trial (CHASM CS- RCT). Am Heart J. 2020;220:246–252. 10.1016/j.ahj.2019.10.003 [Europe PMC free article] [Abstract] [Google Scholar]
107. Harper LJ, McCarthy M, Ribeiro Neto ML, Hachamovitch R, Pearson K, Bonanno B, Shaia J, Brunken R, Joyce E, Culver DA. Infliximab for refractory cardiac sarcoidosis. Am J Cardiol. 2019;124:1630–1635. 10.1016/j.amjcard.2019.07.067 [Abstract] [Google Scholar]
108. Kandolin R, Lehtonen J, Kupari M. Cardiac sarcoidosis and giant cell myocarditis as causes of atrioventricular block in young and middle-aged adults. Circ Arrhythm Electrophysiol. 2011;4:303–309. 10.1161/CIRCEP.110.959254 [Abstract] [Google Scholar]
109. Liang JJ, Hebl VB, DeSimone CV, Madhavan M, Nanda S, Kapa S, Maleszewski JJ, Edwards WD, Reeder G, Cooper LT, et al. Electrogram guidance: a method to increase the precision and diagnostic yield of endomyocardial biopsy for suspected cardiac sarcoidosis and myocarditis. JACC Heart Fail. 2014;2:466–473. 10.1016/j.jchf.2014.03.015 [Europe PMC free article] [Abstract] [Google Scholar]
110. Kandolin R, Lehtonen J, Airaksinen J, Vihinen T, Miettinen H, Ylitalo K, Kaikkonen K, Tuohinen S, Haataja P, Kerola T, et al. Cardiac sarcoidosis: epidemiology, characteristics, and outcome over 25 years in a nationwide study. Circulation. 2015;131:624–632. 10.1161/CIRCULATIONAHA.114.011522 [Abstract] [Google Scholar]
111. Chen HS, Wang W, Wu SN, Liu JP. Corticosteroids for viral myocarditis. Cochrane Database Syst Revi. 2013;10:CD004471 10.1002/14651858.CD004471.pub3 [Europe PMC free article] [Abstract] [Google Scholar]
112. Peretto G, Sala S, Rizzo S, Palmisano A, Esposito A, De Cobelli F, Campochiaro C, De Luca G, Foppoli L, Dagna L, et al. Ventricular arrhythmias in myocarditis: characterization and relationships with myocardial inflammation. J Am Coll Cardiol. 2020;75:1046–1057. 10.1016/j.jacc.2020.01.036 [Abstract] [Google Scholar]
113. Saito S, Toda K, Miyagawa S, Yoshikawa Y, Hata H, Yoshioka D, Domae K, Tsukamoto Y, Sakata Y, Sawa Y. Diagnosis, medical treatment, and stepwise mechanical circulatory support for fulminat myocarditis. J Artif Organs. 2018;21:172–179. 10.1007/s10047-017-1011-4 [Abstract] [Google Scholar]
114. Li S, Xu S, Li C, Ran X, Cui G, He M, Miao K, Zhao C, Yan J, Hui R, et al. A life support-based comprehensive treatment regimen dramatically lowers the in-hospital mortality of patients with fulminant myocarditis: a multiple center study. Sci China Life Sci. 2019;62:369–380. 10.1007/s11427-018-9501-9 [Abstract] [Google Scholar]
115. Pahuja M, Adegbala O, Mishra T, Akintoye E, Chehab O, Mony S, Singh M, Ando T, Abubaker H, Yassin A, et al. 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, 2005-2014). J Card Fail. 2019;25:457–467. 10.1016/j.cardfail.2019.04.012 [Abstract] [Google Scholar]
116. Tschöpe C, Van Linthout S, Klein O, Mairinger T, Krackhardt F, Potapov EV, Schmidt G, Burkhoff D, Pieske B, Spillmann F. Mechanical unloading by fulminant myocarditis: LV-IMPELLA, ECMELLA, BI-PELLA, and PROPELLA concepts. J Cardiovasc Transl Res. 2019;12:116–123. 10.1007/s12265-018-9820-2 [Europe PMC free article] [Abstract] [Google Scholar]
117. Annamalai SK, Esposito ML, Jorde L, Schreiber T, A Hall S, O’Neill WW, Kapur NK. The impella microaxial flow catheter is safe and effective for treatment of myocarditis complicated by cardiogenic shock: an analysis from the global cVAD registry. J Card Fail. 2018;24:706–710. 10.1016/j.cardfail.2018.09.007 [Abstract] [Google Scholar]
118. Chang JJ, Lin MS, Chen TH, Chen DY, Chen SW, Hsu JT, Wang PC, Lin YS. Heart failure and mortality of adult survivors from acute myocarditis requiring intensive care treatment - a nationwide cohort study. Int J Med Sci. 2017;14:1241–1250. 10.7150/ijms.20618 [Europe PMC free article] [Abstract] [Google Scholar]
119. Eckart RE, Shry EA, Burke AP, McNear JA, Appel DA, Castillo-Rojas LM, Avedissian L, Pearse LA, Potter RN, Tremaine L, et al. ; Department of Defense Cardiovascular Death Registry Group. Sudden death in young adults: an autopsy-based series of a population undergoing active surveillance. J Am Coll Cardiol. 2011;58:1254–1261. 10.1016/j.jacc.2011.01.049 [Abstract] [Google Scholar]
120. Maron BJ, Haas TS, Ahluwalia A, Murphy CJ, Garberich RF. Demographics and epidemiology of sudden deaths in young competitive athletes: from the United States National Registry. Am J Med. 2016;129:1170–1177. 10.1016/j.amjmed.2016.02.031 [Abstract] [Google Scholar]
121. Lynge TH, Nielsen TS, Gregers Winkel B, Tfelt-Hansen J, Banner J. Sudden cardiac death caused by myocarditis in persons aged 1-49 years: a nationwide study of 14 294 deaths in Denmark. Forensic Sci Res. 2019;4:247–256. 10.1080/20961790.2019.1595352 [Europe PMC free article] [Abstract] [Google Scholar]

Full text links 

Read article at publisher's site: https://doi.org/10.1161/circheartfailure.120.007405

Read article for free, from open access legal sources, via Unpaywall: https://www.ahajournals.org/doi/pdf/10.1161/CIRCHEARTFAILURE.120.007405Unpaywall

Citations & impact 

Impact metrics

251
Citations
Jump to Citations

Citations of article over time

Alternative metrics

Altmetric item for https://www.altmetric.com/details/94191990
Altmetric
Discover the attention surrounding your research
https://www.altmetric.com/details/94191990

Smart citations by scite.ai
Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles.
Explore citation contexts and check if this article has been supported or disputed.
https://scite.ai/reports/10.1161/circheartfailure.120.007405

Supporting
Mentioning
Contrasting
7
601
3

Article citations

Go to all (251) article citations

Data 

Data behind the article

This data has been text mined from the article, or deposited into data resources.

BioStudies: supplemental material and supporting data

Clinical Trials

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Funding 

Funders who supported this work.

NHLBI NIH HHS (2)