The new england journal of medicine Review Article Dan L. Longo, M.D., Editor Myocarditis Cristina Basso, M.D., Ph.D. A From the Cardiovascular Pathology Unit, ccording to the 1995 World Health Organization task force on Azienda Ospedaliera, Department of cardiomyopathies, myocarditis is an inflammatory disease of the myocar- Cardiac, Thoracic, and Vascular Sciences dium that is diagnosed on the basis of established histologic, immuno- and Public Health, University of Padua, Padua, Italy. Dr. Basso can be contacted logic, and immunohistochemical criteria.1 Since the introduction of the Dallas at cristina . basso@ unipd . it or at Cardio- criteria in 1987,2 endomyocardial biopsy has been considered the standard method vascular Pathology, via Gabelli, 61, 35121 of diagnosis.3-7 Over the past two decades, however, the diagnostic workup has Padua, Italy. changed with the introduction of new tools, mainly highly sensitive troponin and N Engl J Med 2022;387:1488-500. cardiac magnetic resonance imaging (MRI)8,9; in routine clinical practice, a com- DOI: 10.1056/NEJMra2114478 Copyright © 2022 Massachusetts Medical Society. bination of symptoms and signs, laboratory testing, and imaging studies is often sufficient to establish the diagnosis. CME The definition and diagnosis of myocarditis vary widely. For myocarditis associ- at NEJM.org ated with coronavirus disease 2019 (Covid-19) or with Covid-19 vaccination, the diagnostic criteria have been adapted from those established by the Centers for Disease Control and Prevention and the Brighton Collaboration.10,11 Epidemiology Before the Covid-19 pandemic, the estimated global incidence of myocarditis was 1 to 10 cases per 100,000 persons per year.12 The highest risk was among people between 20 and 40 years of age and among men. In the 35-to-39-year-old age group, the rate was 6.1 cases per 100,000 men and 4.4 cases per 100,000 women, with similar rates in the 20-to-44-year-old age group.13 The increased use of car- diac MRI has led to a gradual rise in the reported incidence of myocarditis in the United States, from 9.5 to 14.4 cases per 100,000 persons.14 Precise data on the burden of myocarditis are available only for selected clinical settings. For instance, the incidence of myocarditis among patients with heart failure varies from 0.5% to 4.0% according to age and region.15 Among patients with chest pain who were seen in the emergency department, 3% had acute myo- carditis and pericarditis.16 A diagnosis of myocarditis was made on the basis of cardiac MRI in one third of patients with a previous diagnosis of acute myocar- dial infarction and nonobstructed coronary arteries.17 Autopsy studies in young people who died suddenly have shown a variable incidence of myocarditis. The incidence was 12% in the prospective registry of northeastern Italy.18 Among pa- tients with advanced cancers who were treated with immune checkpoint inhibi- tors, the incidence was 1.14%.19 During the Covid-19 pandemic, 2.4 cases of defi- nite or probable myocarditis and 4.1 cases of definite, probable, or possible myocarditis have been reported per 1000 patients hospitalized for Covid-19.20 Fi- nally, analysis of currently available data on Covid-19 messenger RNA (mRNA) vaccine–related myocarditis suggests an overall incidence of 0.3 to 5.0 cases per 100,000 people in the United States and Israel.21-24 The Food and Drug Administra- tion and the European Medicines Agency have recently estimated that the risk of 1488 n engl j med 387;16 nejm.org October 20, 2022 The New England Journal of Medicine Downloaded from nejm.org by Dr. Rex Hardbody on October 21, 2022. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved. Myocarditis myocarditis is about 1 case in 100,000 people with three temporal phases: viral entry into vaccinated against Covid-19, with a higher risk cardiac myocytes through a transmembrane re- among young males.25 ceptor, with necrosis, apoptosis, and activation of innate immunity (1 to 7 days); viral replica- tion and activation of acquired immune respons- Causes and Pathogenesis es, with T-cell infiltration and autoantibodies Myocarditis can result from a wide range of in- (1 to 4 weeks); and either viral clearance or fectious or noninfectious causes, such as viruses, evolution toward dilated cardiomyopathy (months immune-system activation (autoimmunity [e.g., to years).30 Whether other, nonprimary cardio- in sarcoidosis] or immune stimulation [e.g., vac- tropic viruses cause direct tissue damage or act cines or cancer therapies]), or exposure to toxins as triggers for immune-mediated damage is still and drugs, including endogenous biochemical uncertain; the latter mechanism is probably in- compounds, as seen in amyloidosis and in thy- volved in myocarditis associated with SARS- rotoxicosis. Among infectious forms of myocar- CoV-2 and other respiratory viruses.20,31 Further- ditis, viruses are the most common cause. In more, the pathways that determine the transition selected populations, however, infections with from myocardial inflammation to chronic ven- nonviral pathogens (e.g., bacteria [Corynebacteri- tricular dysfunction are not fully elucidated, and um diphtheriae and Borrelia burgdorferi] and para- it is not clear why some patients recover and sites [Trypanosoma cruzi]) and poststreptococcal others do not. autoimmune rheumatic carditis are still major In the context of Covid-19, the mechanisms of causes.26 cardiac injury are likely to be multifactorial and Data on the real prevalence of viral myocardi- may include not only endothelialitis or myocardi- tis are not available, since endomyocardial biopsy tis but also myocardial injury due to a mismatch and viral genome searches are rarely performed between oxygen supply and demand, microvascu- in routine practice. Seasonal, geographic, and lar thrombosis, a systemic hyperinflammatory socioeconomic differences and different atti- response, and myocardial ischemia.32 tudes toward vaccination must also be consid- Multiple pharmacologic agents have been as- ered. Virus-mediated myocarditis can be due to sociated with myocarditis, mainly antipsychotic primary cardiotropic viruses, such as adenovi- agents, cytotoxic drugs, immunotherapies, vac- ruses and enteroviruses (e.g., coxsackievirus), cines, and salicylates.33 A sharp increase in vac- vasculotropic viruses (e.g., parvovirus B19 cine-related myocarditis was reported in 2010, [PVB19]), lymphotropic viruses (e.g., cytomega- mainly related to smallpox, anthrax, and influ- lovirus, Epstein–Barr virus, and herpesvirus 6 enza vaccines.33 Vaccine-induced myocarditis is [HHV-6]), cardiotoxic viruses (e.g., hepatitis C often an eosinophilic myocarditis, as has been virus, human immunodeficiency virus [HIV], shown for myocarditis associated with the small- and influenza virus), and possibly angiotensin- pox vaccine. More recently, myocarditis has been converting enzyme 2–tropic cardiotoxic viruses recognized as a rare complication of Covid-19 (e.g., coronaviruses, including severe acute respi- mRNA vaccinations.21-25 A temporal association ratory syndrome coronavirus 2 [SARS-CoV-2]).26 does not necessarily suggest that the vaccine is An epidemiologic shift from traditional cardio- the sole cause. Myocarditis could be due to pro- tropic viruses to PVB19 and HHV-6 has become motion, reactivation, or acceleration of naturally apparent in the past 30 years.27 However, since occurring myocarditis through viral or immune- PVB19 and HHV-6 can also be seen in normal mediated mechanisms. hearts or in association with other diseases (in- Immune checkpoint inhibitor therapy repre- nocent bystanders), a viral DNA copy number sents a new approach to the treatment of ad- that exceeds a threshold of 500 copies per mi- vanced cancers in which antibodies targeting crogram has been proposed for establishing a cytotoxic T-lymphocyte antigen 4 (CTLA-4), pro- virus as the cause of myocarditis.28,29 grammed cell death 1 (PD-1), or programmed Our understanding of the pathophysiology of death ligand 1 (PD-L1) are used to enhance the viral myocarditis is mainly derived from experi- T-cell–mediated immune response against tu- mental murine studies of cardiotropic viruses, mor cells. However, systemic immune-mediated n engl j med 387;16 nejm.org October 20, 2022 1489 The New England Journal of Medicine Downloaded from nejm.org by Dr. Rex Hardbody on October 21, 2022. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved. The new england journal of medicine adverse events, including potentially life-threat- studies. A precise correlation between the char- ening myocarditis, have been increasingly recog- acteristics of ventricular arrhythmias and the nized, particularly with the use of combination stage of myocarditis has been reported, with ir- immune checkpoint inhibitor therapy.19,34,35 regular, polymorphic ventricular arrhythmias in The role of genetics as a contributing factor active myocarditis and regular, monomorphic in myocarditis is now documented, with puta- arrhythmias in chronic myocarditis.41,42 tively deleterious variants in genes related to The clinical presentation can be a predictor of cardiomyocyte structure and function detected the outcome. Patients with reduced LVEF, heart in up to 16% of cases.36 According to the “two- failure, advanced atrioventricular block, sus- hit” hypothesis, the genetic substrate may play a tained ventricular arrhythmias, or cardiogenic critical role in the phenotypic outcome among shock are at increased risk for death or heart patients exposed to infective or toxic factors. transplantation.43-45 An analysis of data from a Patients with pathogenic gene variants associ- collaborative registry of cases of acute myocardi- ated with inherited cardiomyopathies seldom tis showed that most patients had an uncompli- present with clinical and histopathological fea- cated course, with chest pain in 97% of patients tures of myocarditis.37,38 Gene testing could be and ST-segment elevation on electrocardiogra- considered in all familial forms of myocarditis, phy (ECG) in 62%, with no deaths or transplan- not just in familial cardiomyopathy. tations at 5 years.43 Heart transplantation or The gut microbiome has recently been identi- death from cardiac causes occurred almost ex- fied as a potential risk-modifying factor in myo- clusively in patients presenting with an LVEF of carditis. Mimetic peptides from commensal bac- less than 50%, sustained ventricular arrhyth- teria may promote inflammatory cardiomyopathy mias, hemodynamic instability on admission, or in genetically susceptible persons.39 a combination of these findings (rate of death or transplantation, 10.4% at 30 days and 14.7% at 5 years).43 Analysis of data from a multicenter Clinical Presentation registry of endomyocardial biopsy–confirmed Myocarditis has a variety of clinical manifesta- acute myocarditis with systolic dysfunction tions according to the degree of organ involve- (LVEF, <50%) showed the prognostic effect of ment5,31 (Figs. 1, 2, and 3). The main clinical hemodynamic compromise at presentation, with manifestations are chest pain with an otherwise a 27.8% rate of death or transplantation at 60 uncomplicated clinical picture (preserved left days among patients with cardiogenic shock, as ventricular ejection fraction [LVEF] and no ven- compared with 1.8% among those without tricular arrhythmias), new or worsening heart shock. The prognostic significance of the histo- failure, chronic heart failure, life-threatening logic characterization of inflammation was also hemodynamic compromise (i.e., fulminant myo- confirmed, with giant-cell myocarditis carrying carditis, with cardiogenic shock and severely the highest risk.46 impaired left ventricular function), and life- Giant-cell myocarditis should always be sus- threatening arrhythmia or conduction distur- pected in patients presenting with rapidly pro- bances (e.g., sustained ventricular arrhythmias, gressive heart failure or cardiogenic shock, with atrioventricular block, and sudden death). or without conduction disturbances, that does In the past, the diagnosis of myocarditis was not respond to usual therapy. The prognosis is based on endomyocardial biopsy, which was poor, with an 85% rate of death or transplanta- performed mostly in patients at moderate or tion at 3 years.47-49 However, early diagnosis and high risk for complications. New tools allowing prompt initiation of aggressive immunosuppres- for a noninvasive diagnosis led to the identifica- sive therapy or advanced mechanical support tion of a wider population of patients with may reduce the risk of death or need for trans- clinically suspected myocarditis, including those plantation.49,50 with a more favorable prognosis.31 The rate of death or transplantation among Although arrhythmias or conduction distur- patients with eosinophilic myocarditis and a fulmi- bances may occur at any stage, patients present- nant presentation is more than 26% at 60 days.46 ing with conduction abnormalities as the first The use of glucocorticoids has been shown to manifestation of myocarditis40-42 have not been reduce in-hospital mortality, but data from ran- independently evaluated in international referral domized trials are lacking.51 1490 n engl j med 387;16 nejm.org October 20, 2022 The New England Journal of Medicine Downloaded from nejm.org by Dr. Rex Hardbody on October 21, 2022. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved. Myocarditis A B V 1 I V 2 II V 3 III aVR V 4 aVL V 5 V 6 aVF C D Figure 1. Infarct-like Presentation with Preserved Left Ventricular Ejection Fraction (LVEF) in an 18-Year-Old Man with Chest Pain and Gastroenteritis. A basal 12-lead electrocardiogram (ECG) obtained at admission shows an ST-segment elevation in the inferior leads (Panel A). A cardiac MRI scan shows late gadolinium enhancement with a noncoronary pattern in the orthogonal short-axis view (T1-weighted inversion recovery) (Panel B). A four-chamber view shows myocardial edema as a midwall stria on T2 mapping (Panel C, encircled). Late gadolinium enhancement, with a noncoronary pattern in the same region as the stria in Panel C, is evident on a four-chamber view (T1-weighted inversion recovery) (Panel D, encircled). Patients who have cardiac sarcoidosis may definite or probable diagnosis.20 Hemodynamic present with conduction abnormalities and heart instability, a need for temporary mechanical failure. Such patients are considered to be at risk circulatory support, and death are more likely for sudden death and may require an implant- in patients with concomitant pneumonia than in able cardioverter–defibrillator.52 Studies have those without pneumonia. shown that up to 35% of patients with complete atrioventricular block who are younger than 60 Myocarditis Associated with Covid-19 years of age and 28% of patients with ventricular Vaccines tachycardia of unknown cause may have undiag- Analyses of retrospective data in large popula- nosed cardiac sarcoidosis.53,54 tions have shown that after eligible persons have received the mRNA vaccine BNT162b2 (Pfizer– Myocarditis Associated with Covid-19 BioNTech), myocarditis is very rare, is most com- Myocarditis is uncommon, but a fulminant pre- mon in young men and within a few days after sentation is reported in 38.9% of patients with a the second dose, and is usually self-limited.21,22,55 n engl j med 387;16 nejm.org October 20, 2022 1491 The New England Journal of Medicine Downloaded from nejm.org by Dr. Rex Hardbody on October 21, 2022. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved. The new england journal of medicine A B Figure 2. Cardiogenic Shock with Severely Depressed LVEF in a 48-Year-Old Man with Dyspnea and Hypotension. In Panel A, a two-dimensional echocardiogram, four-chamber view, obtained in the intensive care unit (ICU), shows a severely dilated left ventricular chamber with depressed LVEF. In Panel B, an endomyocardial biopsy specimen shows diffuse lymphocytic myocarditis (hematoxylin and eosin). A viral genome search with polymerase-chain-reaction (PCR) and reverse-transcriptase PCR analysis was negative. More recently, on the basis of passive surveil- ety of Cardiology (ESC) task force,5 a noninvasive lance reporting in the United States, an increased diagnostic workup helps to establish a diagnosis risk of myocarditis after receipt of an mRNA- of “clinically suspected myocarditis,” on the ba- based Covid-19 vaccine (e.g., BNT162b2 or sis of the clinical presentation and criteria in mRNA-1273 [Moderna]) was reported across four categories: laboratory testing; electrocardi- multiple age and sex strata and was highest after ography, Holter monitoring, and stress testing; the second vaccine dose in adolescent boys and functional and structural assessment on cardiac young men.56 In 87% of the cases, the presenting imaging (echocardiography, angiography, and symptoms had resolved by the time of hospital MRI); and tissue characterization on cardiac MRI. discharge. Although the ESC recommends selective coro- nary angiography and endomyocardial biopsy in Myocarditis Associated with Immune all patients who meet the diagnostic criteria for Checkpoint Inhibitor Therapy clinically suspected myocarditis,5 recommenda- Analysis of data from the largest series of pa- tions for endomyocardial biopsy vary in the sci- tients with immune checkpoint inhibitor–related entific community.3,6,31 The 2007 American Heart myocarditis showed an early onset of symptoms Association (AHA)–American College of Cardiol- (median interval after the initiation of therapy, ogy (ACC)–ESC report provided the original 34 days) and high mortality (50%).57 With the recommendations on the role of endomyocardial growing awareness of this complication, as well biopsy in various clinical scenarios.3 More re- as the increasing number of patients receiving cently, a risk-based approach to the use of endo- combination immune checkpoint inhibitor ther- myocardial biopsy has been proposed on the apy, ECG and troponin measurement at baseline basis of expert consensus (Fig. 4).31 and weekly in the first 6 weeks of treatment have Endomyocardial biopsy can be reserved for been recommended,31 although there is no clear patients with clinically suspected myocarditis evidence of the efficacy or value of these routine and the following findings: cardiogenic shock or baseline or serial assessments.35 acute heart failure requiring inotropic or me- chanical circulatory support; ventricular arrhyth- mias or Mobitz type II second-degree or higher Diagnosis atrioventricular block, particularly when symp- The diagnosis of myocarditis relies on multiple tom onset is recent, with mild or no left ven- sources of data. According to the European Soci- tricular dilatation; peripheral eosinophilia or an 1492 n engl j med 387;16 nejm.org October 20, 2022 The New England Journal of Medicine Downloaded from nejm.org by Dr. Rex Hardbody on October 21, 2022. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved. Myocarditis A N V VVN VVV? VV N VVV B C 1 mV VR1 mV N V V N S S N N N 1 mV aVR 1 mV D E F Figure 3. Refractory Ventricular Arrhythmias and Preserved LVEF in a 42-Year-Old Woman with Syncope. An ECG obtained during monitoring in the ICU shows nonsustained ventricular tachycardia (Panel A). N denotes normal QRS complex, S supraventricular premature beat, and V ventricular premature beat. Coronary disease was ruled out on angiography. A cardiac MRI scan shows no evidence of myocardial edema on T2 mapping (short-axis view) (Panel B). A cardiac MRI scan obtained after the admin- istration of contrast material shows epicardial and midmural late gadolinium enhancement, with a noncoronary pattern (short-axis view) (Panel C). Mild focal, replacement-type fibrosis is present (blue) in an endomyocardial biopsy specimen (trichrome stain) (Panel D). Interstitial edema and scarce inflammatory cells are also visible (hematoxylin and eosin) (Panel E). Immunohistochemical staining with CD3 antibody reveals the presence of CD3-positive T lymphocytes (>7 per square millimeter), a finding that is consistent with chronic active myocarditis (Panel F). associated systemic inflammatory disorder; per- 12 months to monitor the evolution of the dis- sistent or recurrent release of necrosis markers, ease. The 2009 consensus conference on cardiac particularly when an autoimmune condition is MRI for the diagnosis of myocarditis identified likely or ventricular arrhythmias and high- the following markers (known as the Lake Louise degree atrioventricular block are present; or criteria): an intense signal on imaging shortly cardiac dysfunction in a patient receiving im- after gadolinium enhancement, indicating hy- mune checkpoint inhibitor therapy. In other peremia; an increased myocardial T2 relaxation clinical scenarios, cardiac MRI should be consid- time or increased signal intensity on T2-weight- ered as the initial diagnostic test to detect in- ed images, reflecting tissue edema; and late flammation, and endomyocardial biopsy may be gadolinium enhancement, indicating necrosis or considered on a case-by-case basis, according to fibrosis.8 These criteria were updated in 2018,9 the likelihood of detecting a treatable disorder. with the addition of T2 mapping to detect myo- cardial edema and increases in native T1-weight- Cardiac MRI ed signal intensity and extracellular volume as In cases of clinically suspected myocarditis, car- markers of myocardial injury. The sensitivity diac MRI is a valuable tool and has the highest and specificity of the original criteria were 74% sensitivity if performed within 2 to 3 weeks after and 86%, respectively, as compared with 88% and the initial clinical presentation. Cardiac MRI is 96%, respectively, with the updated criteria.58 also useful as a follow-up assessment after 6 to The type of inflammation is not identifiable n engl j med 387;16 nejm.org October 20, 2022 1493 The New England Journal of Medicine Downloaded from nejm.org by Dr. Rex Hardbody on October 21, 2022. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved. The new england journal of medicine Presentation High-risk profile Intermediate-risk profile Low-risk profile Symptoms Cardiogenic shock Symptoms or mild No symptoms of acute HF Symptoms of acute HF symptoms of acute HF Left ventricular <30% (severely low) or 30–40% (low) or ≥50% (mildly low or normal) ejection fraction 30–40% (low) 41–49% (moderately low) Arrhythmias VT, VF, or AVB VT, VF, or AVB VT, VF, and absent or present absent or present AVB absent Immediate management Referral to expert Yes Consider No center Mechanical circulatory Consider No No support Temporary Consider Consider No pacing Immunosuppression Consider Consider No Diagnostic workup Cardiac MRI After stabilization Yes Yes Coronary angiography If needed If needed If needed to rule out CAD Endomyocardial Yes Consider No biopsy Figure 4. Risk-Based Approach to Immediate Management and Diagnostic Workup for Clinically Suspected Myocarditis. The information is modified from Ammirati et al.31 Patients with low-risk acute myocarditis should be admitted to the hospital for cardiac MRI–based diagnosis and treatment of symptoms. Patients with acute myocarditis with high-risk features require admission to centers that have expertise in endomyocardial biopsy–based diagnosis, where they should be considered for mechanical circulatory support and immunosuppression. AVB denotes atrioventricular block, CAD coronary artery disease, HF heart failure, VF ventricular fibrillation, and VT ventricular tachycardia. on cardiac MRI, although the regional distribu- clinically suspected myocarditis is associated tion can be a red flag, such as involvement of the with a good prognosis.59,60 In contrast, late gado- basal septum in sarcoidosis. Cardiac MRI fea- linium enhancement in the midlayer of the sep- tures have also been used for risk stratification, tum and a low LVEF at baseline have been since a negative MRI scan in a patient with identified as the strongest predictors of an 1494 n engl j med 387;16 nejm.org October 20, 2022 The New England Journal of Medicine Downloaded from nejm.org by Dr. Rex Hardbody on October 21, 2022. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved. Myocarditis unfavorable outcome. The persistence of late A B gadolinium enhancement and the disappearance of edema on follow-up imaging are negative predictors, as compared not only with complete resolution but also with the persistence of both late gadolinium enhancement and edema, prob- ably because the latter findings indicate a pro- cess that is still active, with the potential for C D recovery.59 Endomyocardial Biopsy Myocarditis is diagnosed when histologic assess- ment of a specimen from an endomyocardial biopsy reveals an inflammatory infiltrate, with E F necrosis or degeneration of adjacent myocytes.2,4,7 Subtypes can be identified, such as lymphocytic, eosinophilic, and giant-cell myocarditis and car- diac sarcoidosis, which have specific prognostic and therapeutic implications7,61 (Fig. 5). The presence and extent of fibrosis should also be reported and described as interstitial, endocar- G H dial, or replacement-type fibrosis. The availabil- ity of immunohistochemical staining to charac- terize inflammatory cells has led to an increase in positive findings on endomyocardial biopsy.4,7 Quantitative criteria for inflammation were specified in the 2013 ESC report,5 but they have not been validated in any population of persons I J with non-European ancestry. The diagnostic yield of endomyocardial biopsy is highest if the biopsy is performed within 2 weeks after the onset of symptoms. Sensitivity may increase by increasing the number of specimens and by guiding the endomyocardial biopsy through im- K L aging or electroanatomical mapping.4,40-42 In addition to histologic and immunohisto- chemical assessment of biopsy specimens, a poly- merase-chain-reaction assay or in situ hybridiza- tion is recommended to screen for viruses, even though the clinical significance of viral infec- tion and the causal link between such infection Figure 5. Histologic Types of Myocarditis Diagnosed and cardiac injury are still under investiga- by Means of Endomyocardial Biopsy. tion.4,5,7 Standardization of methods for viral Shown with hematoxylin and eosin staining are histo- logic samples of cardiac sarcoidosis (Panel A, with a close- genome identification and quantification is up view in Panel B), giant-cell myocarditis (Panel C, needed.26 The presence of the viral genome in with a close-up view in Panel D), eosinophilic myocar- the absence of inflammatory cells is not diag- ditis (Panel E, with a close-up view in Panel F), lympho- nostic of myocarditis. cytic diffuse myocarditis (Panel G, with a close-up view in Panel H), and lymphocytic focal myocarditis (Panel I, with a close-up view in Panel J [CD3 antibody]). Trichrome Other Tests staining of a histologic sample shows chronic active Markers of myocyte injury and inflammation myocarditis (Panel K, with a close-up view in Panel L such as the erythrocyte sedimentation rate and [hematoxylin and eosin]). C-reactive protein level are usually assessed, al- n engl j med 387;16 nejm.org October 20, 2022 1495 The New England Journal of Medicine Downloaded from nejm.org by Dr. Rex Hardbody on October 21, 2022. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved. The new england journal of medicine though they are not specific and not necessarily tensin-receptor blockade and beta-adrenergic increased in myocarditis.5,31 Troponin is a more blockade. Additional treatment with aldosterone sensitive marker than creatine kinase (creatine antagonists should be considered in patients kinase and creatine kinase MB),5 but an elevated with persistent heart failure despite adequate creatine kinase level could suggest the asso- management. Whether early initiation of treat- ciation of myocarditis with skeletal myositis. ment should also be offered to patients with A high-sensitivity troponin assay is a valuable preserved LVEF in order to reduce inflammation, tool that can detect myocarditis more accurately remodeling, and scarring remains uncertain. than a conventional troponin test.62 Measurement Patients with hemodynamically unstable heart of brain natriuretic peptides, such as N-terminal failure require inotropic agents. Treatment should pro–B-type natriuretic peptide (NT-proBNP), can be provided in an intensive care unit with respi- also be useful but is not specific, and normal ratory and mechanical cardiopulmonary support results do not rule out myocarditis.5 facilities, and referral to a tertiary care center Screening for autoimmune disease is recom- should be considered. In patients with cardio- mended in patients with clinically suspected genic shock who present with severe ventricular myocarditis. Routine viral serologic testing is dysfunction that is refractory to medical therapy, not indicated, since a positive test does not sug- mechanical circulatory support with ventricular gest myocardial infection but indicates only the assist devices or extracorporeal membrane oxy- interaction of the peripheral immune system genation (ECMO) may be needed.46,69,70 with an infectious agent.5 There are a few excep- Since myocarditis can be a reversible disease, tions, such as suspected hepatitis C and rickett- the main goals of treatment are biventricular sial, HIV, B. burgdorferi, and T. cruzi infections. unloading, adequate systemic and coronary per- Serum cardiac autoantibodies could be evaluat- fusion, and venous decongestion, in an effort ed, but such an assessment requires special ex- to prevent multiorgan dysfunction and provide a pertise, and validated cardiac autoantibody tests bridge to recovery, transplantation, or use of a are not commercially available.5,31 durable assist device. Temporary devices, such as MicroRNA profiling in blood and endomyo- an intraaortic balloon pump, venoarterial ECMO, cardial biopsy samples and transcriptome-based a rotary pump, or an intraaortic axial pump, biomarkers in endomyocardial biopsy samples should be considered. The use of devices that have been investigated, with promising results, reduce left ventricular afterload, such as a cen- but correlation between levels in tissue and trifugal or an intraaortic axial pump, alone or in blood is lacking.26,63,64 A recent study showed combination with ECMO, is more likely to pro- that a novel circulating RNA synthesized by type mote myocardial recovery than ECMO alone.71 In 17 helper T cells (hsa-miR-Chr8:96) could be recent years, left ventricular unloading through used to distinguish patients with myocarditis a transcutaneously placed axial flow pump (Im- from patients with myocardial infarction and pella; Abiomed) has been shown to be a viable healthy controls.65 These data need to be evalu- treatment option for patients with cardiogenic ated in other conditions before clinical transla- shock, both as the sole left ventricular support tion is feasible. when right ventricular function is preserved and in combination with extracorporeal life support or with a right-sided Impella pump. In the ab- Therapy sence of protocols for temporary mechanical Treatment for myocarditis comprises manage- circulatory support, the choice of device depends ment of arrhythmias and heart failure according on local experience and on right ventricular to conventional guidelines and cause-targeted function.71 If the patient cannot be weaned from therapy.5,31,53,66-68 mechanical circulatory support after 2 to 3 weeks, a durable left ventricular assist device or trans- Conventional Therapy plantation should be considered.31 Patients with hemodynamically stable heart fail- There are no specific recommendations for ure should be treated with diuretic agents, angio- the treatment of arrhythmias and conduction tensin-converting–enzyme inhibitors, or angio- disturbances in patients with myocarditis. After 1496 n engl j med 387;16 nejm.org October 20, 2022 The New England Journal of Medicine Downloaded from nejm.org by Dr. Rex Hardbody on October 21, 2022. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved. Myocarditis the acute phase, management should be in line ples.5 The recent AHA document concerning with current guidelines on arrhythmia and de- treatment for fulminant myocarditis70 calls for vice implantation.52,68 Since myocarditis is poten- immediate administration of 1 g of solumedrol tially reversible, a step-by-step approach is sug- when an immune-mediated form of myocarditis gested during the acute phase. Pacing may be is strongly suspected, before endomyocardial needed for complete atrioventricular block. Use biopsy or other tests are performed. If the diag- of an implantable cardioverter–defibrillator nosis of giant-cell myocarditis is confirmed, other should be deferred until the acute episode has immunosuppressive agents should be added. resolved, generally 3 to 6 months after the ini- Recently, empirical treatment with intrave- tiation of the acute phase, and a wearable car- nous glucocorticoids in patients with cardio- dioverter–defibrillator can be considered as a genic shock or acute myocarditis complicated by bridge. heart failure, ventricular arrhythmias, or high- In competitive athletes, physical activity should degree atrioventricular block has been pro- be restricted during the acute phase of myocar- posed.31 Maintenance therapy is then useful in ditis and for a period of 3 to 6 months subse- patients with eosinophilic or giant-cell myocar- quently, according to the clinical severity and ditis, cardiac sarcoidosis, or a confirmed auto- duration of the acute phase.72,73 After resolution, immune disorder. In rare cases, a virus, such as clinical reassessment is indicated before the enterovirus, cytomegalovirus, or adenovirus, is athlete resumes competitive sport. Prepartici- identified, and immunosuppressive therapy can pation screening should be performed every be withdrawn.80 In patients who are positive for 6 months during follow-up.5 PVB19 or HHV-6, maintenance of immunosup- pression depends on the initial response to Condition-Specific Therapy therapy and the viral load.29,31 Once the treatable causes of eosinophilia such as Alternative condition-specific therapies for drugs and parasites have been ruled out, early patients with virus-negative or autoimmune in- administration of immunosuppressive drugs (i.e., flammatory cardiomyopathies include removal glucocorticoids alone or together with azathio- of autoantibodies (i.e., immunoadsorption) with prine, cyclosporine, or both) is the key therapy subsequent intravenous immune globulin ther- for eosinophilic myocarditis, as well as for giant- apy,81 and a large, multicenter study involving cell myocarditis and cardiac sarcoidosis.51,54,74 No patients with dilated cardiomyopathy is ongo- specific therapy is available for lymphocytic ing. Intravenous immune globulin therapy is acute myocarditis, except for the forms associ- commonly used in pediatric patients,82 but the ated with systemic diseases and immune check- use of such treatment in adults with lympho- point inhibitors.5,75 cytic myocarditis has been limited. Although there is a rationale for immuno- Data are insufficient to support antiviral suppressive therapy in the acute phase of high- therapy for acute myocarditis. The beneficial ef- risk myocarditis, no data are yet available from fects of interferon treatment on viral clearance prospective trials. The early Myocarditis Treat- and New York Heart Association functional class ment Trial showed no benefit of immunosup- were shown only for adenovirus- and enterovirus- pression in patients with endomyocardial biopsy– related, endomyocardial biopsy–proven, chronic proven myocarditis, although the cause was inflammatory cardiomyopathy.83,84 Treatment unspecified and the initiation of therapy after with anti-herpesvirus drugs might be considered disease onset was delayed.76 Some studies of in patients with Epstein–Barr virus, cytomegalo- treatment with prednisone and azathioprine virus, or HHV-6 infection.5 Whether a combina- showed favorable results in patients with endo- tion of antiviral and immunosuppressive therapy myocardial biopsy–proven, virus-negative, chron- could be used in some patients with virus-posi- ic inflammatory cardiomyopathy, with an im- tive inflammatory cardiomyopathy at some stage provement in LVEF.77-79 of the disease remains to be established. For the safe use of immunosuppressive treat- Ongoing clinical trials are assessing the role ment, the ESC guidelines recommend viral ge- of high-dose methylprednisolone in patients nome analysis on endomyocardial biopsy sam- with acute myocarditis complicated by heart n engl j med 387;16 nejm.org October 20, 2022 1497 The New England Journal of Medicine Downloaded from nejm.org by Dr. Rex Hardbody on October 21, 2022. For personal use only. No other uses without permission. Copyright © 2022 Massachusetts Medical Society. All rights reserved.