2024 ACC专家共识决策路径：心肌炎诊断和管理的策略与标准

共识心血管内科· 心力衰竭 · 2024

Authors

(eg, presyncope or syncope). In a young person, the history of an antecedent viral infection, or other risk factors that define stage A at-risk for myocarditis, followed by any of these cardiovascular symptoms should raise the suspicion of this diagnosis.

2. High-sensitivity cardiac troponin (hs-cTn) is a common diagnostic test in patients with suspected myocarditis; however, some patients with myocarditis will not have an elevated hs-cTn. Further research is needed to determine whether a normal level below the limits of detection of current fifthgeneration assays can serve as an effective rule-out strategy for this diagnosis, and the prognostic utility of serial measurements. 8. Given the increasing recognition of genetic predisposition to myocarditis, genetic counseling and testing is advised for all consenting patients. Discovery of a pathogenic variant should be followed by cascade screening of family members, thereby affording undiagnosed relatives the opportunity for clinical surveillance and, when appropriate, guideline-directed management and therapy.

9. Safety for return to strenuous physical activity is guided by a follow-up CMR, 24-hour monitoring for arrhythmia, and exercise testing, typically at 6 months after diagnosis. In some athletes, these assessments can be made as early as 3 months after the initial episode of myocarditis for consideration of return to competitive sports.

10. Further research on a wide range of factors is needed.

These include how social determinants of health impact the development and progression of myocarditis; a need for international registries with diverse stakeholder involvement; improved phenotyping by novel biomarkers, imaging strategies, and refined pathological interpretation of EMB specimens, including the role of viral polymerase chain reaction (PCR) testing; the benefits of immunosuppression in lymphocytic myocarditis assessed in large prospective randomized clinical trials; whether unloading of the left ventricle for those on extracorporeal membrane oxygenation (ECMO) improves outcomes; and a greater understanding of the psychological burden on patients and caregivers following an episode of myocarditis.

1. INTRODUCTION

The definition, diagnostic strategies, prognosis, and 4. This ECDP is not intended to supersede good clinical judgment as, especially for myocarditis care, many questions remain unanswered. Given the complexity of this condition, team-based care is optimal and, depending upon the severity of the presentation, may include a broad array of specialists.

5. This ECDP is based on the best clinical and scientific data currently available. As new discoveries emerge (eg, trials of additional agents, diagnostic strategies, and devices including other populations), these data will affect the recommendations made here. Clinicians should be careful to incorporate relevant information published after this ECDP.

6. Relevant portions of these recommendations are applicable to management in the ambulatory setting or the acute inpatient hospital setting.

2.2. Definitions

Acute myocarditis: An episode of clinically suspected myocarditis presenting within a short period of time ( < 1 month).

### Guideline-directed management and therapy (GDMT):

Guideline-directed management and therapy (GDMT):

Treatment options supported for use by clinical practice guidelines. HF with mildly reduced ejection fraction (HFmrEF):

HF

clinical diagnosis of HF and LVEF 41% to 49%. 2, 5 with preserved ejection fraction (HFpEF): clinical diagnosis of HF and LVEF $50% not attributable to an underlying cause, such as an infiltrative cardiomyopathy, hypertrophic cardiomyopathy, valvular disease, pericardial disease, or high-output HF.

4.2.2. Echo and Strain Echocardiography

Transthoracic echocardiography is widely available and often serves as a screening tool to detect impaired left ventricular (LV) function in patients with suspected myocarditis 15 ; however, its sensitivity is not adequate to rule out the diagnosis of myocarditis. LV dilatation, decreased LV function, increased wall thickness associated with myocardial edema, regional wall motion abnormalities, diastolic dysfunction, increased sphericity index, and signs of associated pericardial involvement can be seen in patients with myocarditis. 15, 16 Fulminant myocarditis often presents with smaller cavity size and mildly increased wall thickness due to myocardial edema. 15 Abnormal myocardial mechanics, particularly LV global strain, may serve as a powerful diagnostic tool and add incremental value beyond ejection fraction. 12, 17 longitudinal strain alterations and 2-dimensional echocardiographic features, however, are not specific for myocarditis and are commonly seen in other forms of HF.

4.2.3. Circulating Cardiac Troponin

Elevation of circulating cardiac troponin (cTn) in combination with other diagnostic tests can help with the diagnosis of myocarditis. Early studies demonstrated cTn had enhanced sensitivity compared with creatine kinase-MB to diagnose myocarditis. 18 Nevertheless, before modern high-sensitivity assays, elevated cTn only had a sensitivity of 34% to 71% and specificity of 86% to 94% for diagnosis of myocarditis. 19 Using less-sensitive assays, normal cTn values were reported even in those with fulminant 20 or GCM. 21 Cardiac enzymes can normalize despite ongoing disease activity and progression of late gadolinium enhancement (LGE) on CMR. 22 e initial report of measurement of cTn via a highsensitivity assay was in 70 patients with clinically suspected myocarditis and reported high-sensitivity TnT was associated with myocarditis with an area under the curve of 0.878. 18 The upper reference range corresponding with the 99th percentile of a normal population for the highsensitivity TnT assay used in this study was 14 ng/L with a limit of detection of 5 ng/L. In acute myocardial infarction, single-value, rapid rule-out strategies often use lower threshold values at time zero near the limit of detection or limit of quantitation (eg, w1-5 ng/L depending upon the assay used) 19 but to date, there are no published studies testing this strategy to exclude myocarditis.

There remain several challenges that impact interpretation of clinical hs-cTn immunoassays, especially at low elevation or borderline levels. First is the impact of sex (and age) on the circulating levels of cTn.

Sex can influence the reference levels of hs-cTn [20] [21] [22] [23] [24] due to differences in heart size, hormonal state, structural differences in diseases and maladaptive processes (such as occurrence of macroscopic coronary plaque, development of fibrosis), 25, 26 27 and that the modified products could be found in the circulation. 28, 29 Unfortunately, it remains unclear whether cTnI or cTnT are modified with myocarditis.

Autoantibodies against cTnI 30 can induce myocarditis 31, 32 in animal models 33 and in patients with dilated cardiomyopathy (DCM), 34 although the extent to which this may occur in patients with myocarditis remains unknown.

4.2.4. Cardiac Magnetic Resonance Imaging

Myocarditis can lead to various pathophysiological changes in the myocardium that may be noninvasively detected using CMR. 6] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] CMR strain imaging can detect subtler impairment in cardiac function and can be undertaken commonly using CMR myocardial tissue tagging, or feature-tracking of cine images. Strain parameters can be assessed in the longitudinal, circumferential, and radial directions. [54] [55] LGE is a strong independent predictor of mortality in clinically suspected, CMR-proven myocarditis, with a hazard ratio 8.4 for all-cause mortality and 12.8 for cardiac mortality. 55 In contrast, diffuse LGE was not an independent adverse prognostic factor in 2 recent European studies of persons with biopsy-proven myocarditis. 56, 57 9] [60] [61] Undoubtedly, this high accuracy depends upon the CMR being performed in centers with appropriate expertise in this imaging technique. The Updated Lake Louise Criteria allow the use of both Overall, CMR provides an attractive noninvasive diagnostic tool in evaluating patients with myocarditis. In patients with cardiovascular risk factors, it may be reasonable to include stress perfusion into the CMR protocol in the appropriate clinical setting and, when safe to do so, to assess for signs of myocarditis and to rule out significant ischemic heart disease in a single examination.

A CMR scan that has normal findings on edema imaging as well as on LGE and stress perfusion imaging can potentially avoid the need for further coronary imaging (such as coronary computed tomography [CT] angiogram or invasive coronary angiography), to rule out ischemic heart disease as a potential cause of the patient's presentation.

4.2.5. Other Imaging Tests

##### 4.2.5.1. Nuclear Perfusion and Metabolic Imaging

4.2.5.1. Nuclear Perfusion and Metabolic Imaging

Myocardial scintigraphy using inflammation-sensitive radiotracers may demonstrate focal patchy myocardial uptake in patients with myocarditis. Gallium scanning has a sensitivity of 36% and specificity of 98% for detection of biopsy-proven myocarditis in patients with DCM. 71 rthermore, patients with viral myocarditis may also exhibit areas of decreased perfusion, detected by technetium-99m single-photon emission computed tomography (SPECT) imaging. 72 milar to SPECT imaging, focal 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake with positron emission tomography (PET) imaging is often seen in patients with myocarditis, reflecting metabolically active immune cells and presence of active myocardial inflammation. 73 18 F-FDG PET allows imaging of myocardial inflammation due to increased uptake of 18 F-FDG in macrophage-dense regions of the myocardium. Macrophages are more metabolically active and more reliant on glucose as a metabolic substrate compared to normal myocytes. 74 Adequate preparation is essential to suppress physiologic myocardial 18 F-FDG uptake and improve assessment of myocardial inflammation on PET imaging. This may include prolonged (12-18 hours) fasting; 12 hours of a high-fat, low-carbohydrate diet; or intravenous heparin, often in combination. 74 The dietary manipulation facilitates switching of myocardial metabolism from glucose to fatty acid, and generally was found to be superior to prolonged fasting alone; however, optimal dosage and duration of this preparation is not well standardized across institutions. 74 Despite adequate dietary preparation, approximately 20% of patients may still experience nonspecific myocardial 18 F-FDG uptake. 75 spite these issues related to dietary preparation, 18 F-FDG PET has been shown to be beneficial in diagnosing myocarditis with arrhythmic presentation, with a specificity of 67% compared with that of EMB. Further, it may be a useful diagnostic strategy when CMR is not feasible due to arrhythmia or an implanted device that is not CMR compatible. 76 18 F-FDG PET also offer incremental diagnostic capabilities to CMR by improving sensitivity for detection of myocarditis in cases of mild severity or longer duration than acute myocarditis. 77 is recommended to combine resting PET (ideally) or SPECT perfusion imaging with 18 F-FDG PET imaging to evaluate the full spectrum of myocardial inflammation. A normal PET examination demonstrates complete suppression of myocardial 18 F-FDG and normal resting myocardial perfusion. In contrast, patients with myocarditis typically have focal 18 F-FDG uptake with a corresponding perfusion defect. 18 F-FDG uptake without a resting perfusion defect may represent early inflammation without scarring. Caution should be exercised in the event of homogenous 18 F-FDG uptake typically due to failure to suppress physiologic myocardial 18 F-FDG uptake. Further, increased 18 F-FDG uptake is not specific to myocarditis and is seen in other states of myocardial inflammation, including myocardial ischemia.

##### 4.2.5.2. Hybrid Imaging: PET/CT, PET/CMR

4.2.5.2. Hybrid Imaging: PET/CT, PET/CMR

Hybrid PET/CMR imaging may offer incremental value vs either modality alone by simultaneously providing inflammatory, perfusion, and structural information. 78 A prospective, observational, multicenter cohort study to study the diagnostic and prognostic feasibility of 18 the European, American, and Japanese heart failure societies. 80 The intent of the EMB is to achieve a diagnosis of certainty, thereby affording the opportunity for etiology-specific therapy (ie, antiviral or immunosuppressive/immunomodulatory) as well as excluding other disease entities that may mimic myocarditis. 80 In a propensity-matched, multicenter, retrospective cohort study, an EMB within 2 days of admission to the intensive care unit was associated with improved survival free of heart transplantation or LVAD implantation at 1 year. 81 rther details regarding indications for EMB are discussed in Section 4.4.6. The writing committee recognizes that many centers do not have the capability of performing an EMB or processing the biopsy samples, further underscoring the need to transfer patients who might need this procedure to an advanced HF team with multidisciplinary myocarditis capabilities.

EMB can suffer from sampling errors such that, when negative, it does not necessarily rule out the presence of myocarditis; this is especially true when there are clear imaging signs of myocarditis in areas that may be difficult to access using EMB and when only the Dallas criteria are used. 82, 83 Technical aspects to improve the diagnostic yield of the EMB include earlier timing after symptom onset (eg, within 2-4 weeks), 84 obtaining an adequate number ($3) of samples, each 1 to 2 mm in size, and using voltage guidance to select myocardial sites for biopsy.

The latter led to a sensitivity of 83% in a systematic review. 85 The myocardial tissue obtained should have samples immediately fixed in 10% buffered formalin at room temperature for light microscopy and other samples snap frozen in liquid nitrogen and stored at À80 C or stored in RNAlater tubes at room temperature for viral PCR analysis. EMB sensitivity is higher when current immunological, immunohistochemical, and molecular tools are used, as will be described in the following text. 80, 86, 87 ere are risks of EMB. 80 The major complication rate Given these parallels between the 2 patient populations, the writing committee believed there would be value in applying a similar 4-stage approach to patients with myocarditis (Figure 5 ). We recognize that considerable work is needed to better define the natural history and therapeutic approaches for the 2 stages ("at-risk" and "asymptomatic") not typically described in patients with myocarditis. Nevertheless, this initial step of defining these stages should be an impetus for research in the coming years to fill these gaps in knowledge and thereby lead to advances in the field.

(

4.4.1. Stage A

Risk factors to define stage A at-risk for myocarditis are

shown in Table 1 .

The risk of developing myocarditis varies with genetic background. 92 Recent studies in patients with myocarditis showed a significant fraction carry pathogenic genes variants linked with dilated and arrhythmogenic cardiomyopathy, suggesting that a gene-environment interaction may predispose to clinical myocarditis. 93, 94 In contrast, whereas the major histocompatibility complex plays an important role in experimental models of immune-mediated/autoimmune myocarditis, 95 or methamphetamine). 98 Numerous infectious agents, particularly viral, 99 and some vaccines, 100 Although male sex is associated with a higher frequency of clinically suspected and biopsy-proven myocarditis, suggesting the role of testosterone in proinflammatory pathways, myocarditis in women with autoimmune features, in particular those with high titer antiheart autoantibodies and antinuclear autoantibodies, has a higher risk of death/heart transplantation. 101 Male sex was not listed as a risk factor defining stage A at-risk for myocarditis because the absolute risk of myocarditis among all men in the population remains low.

Symptom-free, healthy relatives of both familial and nonfamilial immune-mediated DCM who have antiheart autoantibodies are at increased risk of DCM development at 5 years, similar to other organ-specific autoimmune diseases like type 1 insulin-dependent diabetes mellitus. 102 Further work is needed to define whether patients harboring antiheart autoantibodies are also at increased risk of myocarditis.

The relationship between physical activity, sports, and myocarditis is complex. Vigorous exercise during infection can heighten the immune response and increase inflammation in the heart muscle due to immune suppression, cardiac stress, altered blood flow, and potential viral persistence. 103 A retrospective analysis of 82 physically active individuals revealed an association between high-static component sports and complicated myocarditis, whereas endurance activities were linked with uncomplicated disease. 104 Exercise-induced immunomodulation, particularly in endurance sports, might play a protective role, reducing myocardial inflammation and necrosis. Future studies are needed to assess these parameters as well as explore additional factors affecting myocarditis in athletes, such as psychological stress, travel, nutrition, and performance-enhancement medications. There is inadequate evidence to include physical inactivity or high levels of exercise as a risk factor for myocarditis.

##### 4.4.1.1. Focus on Genetic Risk Factors

4.4.1.1. Focus on Genetic Risk Factors

Host genetics have long been understood to determine myocarditis outcomes in animal models 105 ; yet, only in the last decade have important human genetic factors been elucidated. Since the 1990s, myocarditis has been reported as a frequent histopathological finding in arrhythmogenic cardiomyopathy. 106 In 2015, myocarditis was described as the clinical presentation of arrhythmogenic cardiomyopathy, including in 5 individuals found to harbor predicted disease-causing variants in DSP or LDB3. 107 Shortly thereafter, rare, predicted causative variants in desmosomal genes (PKP2, DSP, or DSC2) were identified in 3 fatal cases of myocarditis suggesting that genetically mediated structural alterations impart myocardial vulnerability to pathogenic infection. 108 ditional case series have reported frequent (up to 92%) findings of pathogenic desmosomal gene variants in patients initially presenting with myocarditis 109 and later meeting task force criteria for arrhythmogenic RV cardiomyopathy. 110 More recently, there is an emerging concept termed "hot phases" of arrhythmogenic cardiomyopathy in which patients with at-risk genotypes present with findings consistent with stage B myocarditis on imaging and laboratory testing or a clinical syndrome of stage C or D myocarditis. 111 Further research is needed to understand whether such "hot phases" are clinically distinguishable from myocarditis as defined in this document.

The reports above formed the basis for formal genetic association studies in myocarditis. Although mice that lack genes encoding proteins related to immune pathways are more susceptible to myocardial coxsackievirus infection 112 and an adult patient with enteroviral myocarditis was reported to carry a rare, dominant-negative variant in a toll-like receptor gene (TLR3), 113 variations in BAG3, DSP, PKP2, RYR2, SCN5A, or TNNI3. 114 6] [117] [118] [119] In one such series, patients with myocarditis with relevant genotypes had significantly lower LVEF at follow-up (median: 71 months) than genotype-negative patients. 119 terestingly, familial studies (cases and series) have repeatedly implicated DSP as a causal gene, including in cases of recurrent myocarditis or families with both myocarditis and DCM or sudden cardiac death. LGE patterns (ring-like or septal) on CMR compared with those with negative genetic testing, suggesting that these features may be "red flags" for genetic forms of myocarditis. 120 More recent studies performing burden analyses for putatively damaging variants in patients with exclusively biopsy-confirmed myocarditis 123, 124 or either biopsy-or CMR-confirmed myocarditis 125

4.4.5. Myocarditis With Associated Pericarditis

In some patients, pericarditis is associated with myocarditis. Pericarditis may contribute to symptoms of chest pain and signs of pericardial rub on physical examination.

On imaging studies, pericardial effusion may be noted, which is usually small or moderate in size, unless associated with systemic inflammatory disorders such as lupus, which may be associated with large pericardial effusions. Pericardial LGE may also be detected on CMR.

There are inadequate data on the prognostic value of the coexistence of pericarditis with myocarditis compared with that of myocarditis alone. Myocarditis with associated pericarditis may reflect the extent of cardiac and systemic inflammation and imply causes beyond etiologies with cardiac myocyte tropism alone. Similar to that of viral myocarditis, viral myocarditis with associated pericarditis is usually self-limited and resolves without major complications or adverse outcomes. In the setting of systemic inflammatory disorders, myocarditis with associated pericarditis can be recurrent. In cardiooncology, radiation therapy can result in pericardial inflammation in addition to myocardial injury.

4.4.6. Endomyocardial Biopsy

Indications for EMB, previously described in Section Contrary to the common perception of good long-term prognosis in patients with acute myocarditis, there is an overall increased risk of mortality, life-threatening ventricular arrhythmias, HF, and disease recurrence rate of 11.5% over a mean follow-up of 2 years. 133 In particular, the presence of LGE and LGE in the anteroseptal location heralded a 3-and 2-fold increased risk, respectively, of mortality and major adverse cardiac events during a mean 2-year follow-up. In another study, LGE was the strongest independent predictor of mortality in myocarditis among clinical and imaging parameters (all-cause mortality hazard ratio [HR]: 8.4; cardiac mortality HR: 12.8). 136 In contrast, diffuse LGE was not an independent adverse prognostic marker in 2 recent studies. 56, 57 Reduced LVEF is another important adverse prognostic marker in myocarditis.

4.5.2. Trajectories of Myocarditis

There remains much to be learned about the trajectories of those individuals with stage A and B myocarditis (see In stage C myocarditis, the risk of recurrence varies from 3% to approximately 10% per year and may be influenced by the presence of desmosomal gene variants. 101, 120 Remission, defined as symptomatic and ventricular functional improvement, is common in HF patients with myocarditis treated with GDMT. After clinical and functional recovery in acute nonischemic DCM, the risk of recurrent heart failure after standardized withdrawal of GDMT is substantial. 137 Defining the risks of short-term major adverse cardiac events after similar medication withdrawal in patients with myocarditis and of delayed ventricular stiffening leading to HFpEF 138 will require long-term studies in diverse cohorts with specific causes of myocarditis.

The trajectory of stage D myocarditis can be variable.

Patients can progress to cardiac standstill but also can fully recover their ventricular function. Whereas previous studies suggested those with fulminant myocarditis (comparable with stage D) often recovered more dramatically than those with a nonfulminant presentation, more recent data caution that may not be the case. In an Italian study of 187 patients with acute myocarditis, of which 55

were characterized as fulminant, the rate of in-hospital death or transplantation was 25.5% in the advanced myocarditis group vs 0% in those with less severe presentations. 139 Additionally, after a median follow-up of 22 months, 29% of patients with fulminant myocarditis still had an LVEF < 55%.

Overall, further research is needed to determine how frequently stages B, C, and D myocarditis progress to HF and its subtypes of HFrEF, HFmrEF, or HFpEF.

4.6. Treatment of Myocarditis

1] [142] [143] [144] as well as antiviral therapies when appropriate 80, 86, 87 ; treatment of HFmrEF, HFrEF

Index Admission

Step 2 in the 5-step care pathway for myocarditis (see Figure 1 ) requires the clinician to make the critical

4.6.2. Pharmacological Treatment of Myocarditis

There is not a robust database guiding the treatment of chest pain in myocarditis or myocarditis with associated pericarditis. Pericardial-type chest pain with normal or low normal LVEF can be treated with nonsteroidal antiinflammatory drugs and weight-adjusted colchicine. 38 though murine models raised concern about the use of nonsteroidal anti-inflammatory drugs in myocarditis, observational studies suggest that aspirin or ibuprofen are complicate myocarditis with associated pericarditis, 147, 148 and, when suspected, addition of a dihydropyridine calcium channel blocker would be reasonable based on extrapolation from other clinical settings. 149 0] [151] [152] Beyond GDMT for HF and antiarrhythmia therapy, distinct etiology-directed therapeutic options 36, 86, 87, 140, 153 should be considered.

A particularly common question in the care of patients with acute myocarditis is when to implement immunosuppressive therapy. Key points regarding their use are summarized (see Figure 10 ). Immunosuppression is indicated in select patients with stage B (eg, in setting of ICI therapy) or stage C myocarditis and more with stage D myocarditis, particularly those with histologically confirmed, noninfectious immune-mediated forms such as eosinophilic myocarditis, GCM, and cardiac sarcoidosis, or with an associated systemic immune-mediated disease. 86, 87, 142, 153 The writing committee did not reach uniform consensus, but some members felt the available evidence base, which includes the TIMIC (Tailored IMmunosuppression in virus-negative Inflammatory Cardiomyopathy) trial with chronic inflammatory cardiomyopathy, 141, 142 single-center studies, 140, 143, 144, 154, 155 and one systematic review and meta-analysis, 156 supports the use of immunosuppression of select patients with lymphocytic myocarditis if the EMB sample has a negative viral PCR. Larger prospective randomized clinical trials would provide additional support for this approach.

Generally, a multidisciplinary team including a clinical immunologist or rheumatologist will provide essential expertise in management of multiorgan system inflammation and mitigation of drug-related adverse event risk.

Intravenous methylprednisolone boluses 7 to 14 mg/kg/ d for 3 days, followed by prednisone 1 mg/kg/d orally, with subsequent tapering with steroid-sparing immunosuppressive drugs, have been associated with clinical benefit in case series. 36, 86, 87, 142, 153 In a recent large, propensityweighted study, participants with biopsy-proven autoimmune myocarditis who received vs those who did not receive a long-term individualized immunosuppressive regimen tailored to their comorbid conditions (eg, presence of systemic immune-mediated disease) and their disease (eg, severity of illness, histological type, and contraindication to immunosuppression), had a comparable 5-year rate of the composite outcome of death or heart transplant despite a baseline higher risk profile (including lower LVEF). 140 Patients with GCM require higher levels of immunosuppression, typically also including calcineurin inhibitors, in addition to steroids.

Immunosuppression for myocarditis with coexistent inflammation in other organs may need to be adjusted to manage other organ involvement.

An ESC position statement 86 recommended that, prior to immunosuppressive therapy, PCR testing of the endomyocardial sample be negative for presence of viral DNA to avoid the possibility of exacerbating an active infection. 86, 87, 142 Indeed, studies to date [141] [142] [143] [144] 154, 155 showing efficacy and safety of immunosuppression in biopsy-proven myocarditis have been done in patients with negative viral PCR on EMB. The wri g committee recognizes that many centers currently do not have established protocols for viral PCR testing of endomyocardial samples; in such cases, referral to a multidisciplinary myocarditis team with this capability would be reasonable.

Antiviral therapies for viral myocarditis are evolving.

Therefore, it is helpful to consult an infectious diseases or similar expert specialist for management. Antiviral therapies are an accepted alternative therapeutic approach when delivered in the context of such expert input.

Intravenous immunoglobulin may be considered in the setting of inflammatory, antibody-mediated, or autoimmune disorders. Finally, a pharmacological agent that is thought to be the trigger of the episode of acute myocarditis (eg, clozapine, ICI therapy) should be discontinued.

4.6.3. Restriction of Strenuous Physical Activity

In Fortunately, in the acute phase, this is relatively uncommon. In the National Inpatient Sample from 2005 to 2014, there was an increase in the presence of cardiogenic shock from 7% to 12% of patients with acute myocarditis.

Although there was a parallel increase in the use of TCS from 0.16% to 1.6% of patients, the absolute rates remained low. 157 In a more recent multicenter registry of 443 patients with acute myocarditis, 4.1% required venoarterial extracorporeal membrane oxygenation (VA-ECMO), 1.1% underwent implantation of a VAD, and 0.9% heart transplantation, with overall in-hospital mortality being 2.3%. 158 Further, all of the patients who required In the setting of myocarditis complicated by cardiogenic shock, there is a paucity of data suggesting which TCS device is preferential, a knowledge gap also present for cardiogenic shock due to other clinical conditions.

Although VA-ECMO is preferentially used in patients with fulminant myocarditis for its ease of insertion and ability to provide biventricular support, short-term outcomes of patients receiving this therapy remain suboptimal. In a multicenter registry, approximately one-third of patients with fulminant myocarditis supported by VA-ECMO required a durable LVAD, transplant, or died at 90 days. 160 Likewise, a systematic review and meta-analysis of 54 observational studies involving 2,388 patients with fulminant myocarditis supported by VA-ECMO reported a short-term mortality of 35%. 161 Conversion from peripheral to central cannulation for VA-ECMO does not seem to improve outcome. 162 Prognostic factors for patients with fulminant myocarditis supported with VA-ECMO include those favorable: early administration of IVIG 163 or performance of an EMB 160 ; and those unfavorable: ventricular tachycardia/fibrillation at admission, an elevated CRP, and higher peak creatine kinase-MB levels. 160, 163 loading of the LV via axial flow devices, such as the IMPELLA, may contribute to myocardial recovery. 164, 165 loading is felt to reduce activation of cardiac mechano-transduction pathways, thereby reducing activation of the inflammatory cascade. Indeed, serial EMBs

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demonstrated a reduction of multiple markers of inflammation, including inflammatory cellular infiltrates in the heart, in the setting LV unloading with an IMPELLA, in addition to immunosuppressive therapy. 166 Further, in that report, removal of the IMPELLA was associated with a subsequent rebound increase in markers of myocardial inflammation; however, further data, including randomized trials, if possible, are needed to confirm this intriguing hypothesis.

If patients with fulminant myocarditis supported on TCS do not recover, conversion to a durable LVAD and/or evaluation for heart transplantation should be considered. 167 In the International Society for Heart and Lung Some patients with myocarditis who receive a durable VAD will subsequently recover ventricular function, even allowing explanation of the VAD. In the IMACS registry, patients with myocarditis vs nonischemic cardiomyopathy were more likely to have recovered or had their VAD explanted by 12 months though the absolute rates of such recovery were low (5% vs 1.7%). 168 The time course for VAD explanation in those with myocarditis was 6 months (0.6% of cohort), 1 year (4.4%), 2 years (11.2%), and 3 years (11.2%). Similarly, in the European Registry for Patients with Mechanical Circulatory Support (EUROMACS), of 45 adults who had their VAD explanted after a median duration of 410 days, 36% had a DCM, 32% myocarditis, 14% ischemic, and 18% miscellaneous etiologies. 169 Thus, the frequency of recovery among those with myocarditis was much higher compared with the other underlying etiologies. Specifically, 12 of 137 (9%) patients with myocarditis were explanted vs 14 of 1,009 (1.4%) with DCM and 9 of 1,294 (0.7%) with ischemic cardiomyopathy.

Cardiac transplantation is another option for patients with myocarditis who do not stabilize in the acute setting or subsequently develop progressive HF. In the United Network for Organ Sharing database of patients listed for heart transplantation, those with myocarditis were sicker as compared with those with a nonischemic or ischemic cardiomyopathy, including a higher frequency of mechanical ventilation, biventricular mechanical circulatory support and VA-ECMO use, and allosensitization.

Nevertheless, their post-transplant outcomes, including rates of rejection or retransplantation and overall survival, were comparable with patients without myocarditis. 170 Likewise, a systematic review and meta-analysis showed that while a small percentage (8%) of patients with GCM were at risk of recurrence post-heart transplantation, the one and 5-year post-transplant survival rates of patients with or without GCM were comparable. 171 6. LGE) was present in only 11% at 6-month follow-up. 174 The subset of patients with LGE and no edema on follow-up CMR at 6 months had the worst prognosis (19 of 22 patients had cardiac events during the 7-year follow-up period), whereas patients with no LGE and no edema had the best prognosis (no cardiac events in this group). In multivariable analysis, the only independent predictors of cardiac events were a midwall septal LGE pattern on follow-up CMR (HR: 2.8; 95% CI: 1.1-7.2; P ¼ 0.028) and persistence of LGE without edema on follow-up CMR (HR: 4.5; 95% CI: 1.3-14.5; P ¼ 008). Others have demonstrated the prognostic value of serial changes of

LGE. 173, 175, 176 Myocardial T 1 and T 2 relaxation times may remain elevated on follow-up CMR after normalization of other parameters, such as T 2 ratio, EGE ratio, and ECV fraction; however, the prognostic significance of such findings remains unclear. 175 Among patients with nonfulminant acute myocarditis and normal LVEF on initial CMR, reduction in LVEF on follow-up CMR is uncommon 139, 158 but should prompt further evaluation if present.

Although the role of serial 18

sk, and social determinants of health in myocarditis outcomes.

|follow-up of myocarditis with repeat assessment of FIGURE 1 Drazner et al circulating biomarker levels, echocardiography, and usu-|J A C C V O L . -, NO. -, 2024 changes, and elevated high-sensitivity troponin (Tn) levels are common, many patients with suspected|| |---|---|---|

|is intended for cardiologists of all subspecialties and|diagnostic capabilities and better risk-stratify patients|diagnostic capabilities and better risk-stratify patients|

|frontline clinicians, including those in the emergency|with myocarditis. 14 ECG should be performed in cases of|with myocarditis. 14 ECG should be performed in cases of|

|department and primary care settings.|suspected myocarditis, but a normal ECG would not rule|suspected myocarditis, but a normal ECG would not rule|

|4.1. Diagnosis of Myocarditis|out presence of myocarditis.|out presence of myocarditis.|

|4.1.1. Clinical Symptoms|||

|The initial step for a clinician in the assessment of a pa-|||

|tient with possible myocarditis is to recognize that a|||

|clinical scenario is consistent with this diagnosis.|||

|Although patients with myocarditis can be asymptomatic|||

|or have vague, nondescript symptoms, clinicians should|||

|be aware of 3 classic presentations as being consistent|3. PATHWAY SUMMARY GRAPHIC|3. PATHWAY SUMMARY GRAPHIC|

|with this diagnosis: chest pain, arrhythmia, or HF/|||

|cardiogenic shock (Figure 2). The history of an antecedent|Figure 1 provides a summary graphic outlining the 5-step|Figure 1 provides a summary graphic outlining the 5-step|

|viral infection (upper respiratory or gastrointestinal) in a|process for evaluation and management of clinically|process for evaluation and management of clinically|

|young person, a prior diagnosis of myocarditis or auto-|suspected myocarditis. The initial step is to recognize that|suspected myocarditis. The initial step is to recognize that|

|a patient's clinical presentation might be consistent with as clinically appropriate. Triage decisions should be made tious agents. Pharmacological treatment of myocarditis is immune disease, a family history of cardiomyopathy or|a patient's clinical presentation might be consistent with as clinically appropriate. Triage decisions should be made tious agents. Pharmacological treatment of myocarditis is immune disease, a family history of cardiomyopathy or|a patient's clinical presentation might be consistent with as clinically appropriate. Triage decisions should be made tious agents. Pharmacological treatment of myocarditis is immune disease, a family history of cardiomyopathy or|

|the diagnosis of myocarditis. Given the numerous ways at this initial evaluation based on the acuity of the pa-initiated (Section 4.6.2) once the diagnosis is established, unexplained sudden death, or exposure to known car-|the diagnosis of myocarditis. Given the numerous ways at this initial evaluation based on the acuity of the pa-initiated (Section 4.6.2) once the diagnosis is established, unexplained sudden death, or exposure to known car-|the diagnosis of myocarditis. Given the numerous ways at this initial evaluation based on the acuity of the pa-initiated (Section 4.6.2) once the diagnosis is established, unexplained sudden death, or exposure to known car-|

|that myocarditis can manifest (Figure 2 and Section 4.1.1), tient's condition. Considerations include whether the and, in some cases with clinical instability, when highly diotoxin, followed by any symptoms potentially related to|that myocarditis can manifest (Figure 2 and Section 4.1.1), tient's condition. Considerations include whether the and, in some cases with clinical instability, when highly diotoxin, followed by any symptoms potentially related to|that myocarditis can manifest (Figure 2 and Section 4.1.1), tient's condition. Considerations include whether the and, in some cases with clinical instability, when highly diotoxin, followed by any symptoms potentially related to|

|clinicians in a variety of healthcare settings need to be patient needs to be hospitalized or referred to an suspected. Further, if the patient's condition has deteri-these 3 presentations should raise the suspicion for this|clinicians in a variety of healthcare settings need to be patient needs to be hospitalized or referred to an suspected. Further, if the patient's condition has deteri-these 3 presentations should raise the suspicion for this|clinicians in a variety of healthcare settings need to be patient needs to be hospitalized or referred to an suspected. Further, if the patient's condition has deteri-these 3 presentations should raise the suspicion for this|

|aware of this diagnosis. Examples include primary care advanced heart failure center with a multidisciplinary orated, the need for temporary circulatory support should condition.|aware of this diagnosis. Examples include primary care advanced heart failure center with a multidisciplinary orated, the need for temporary circulatory support should condition.|aware of this diagnosis. Examples include primary care advanced heart failure center with a multidisciplinary orated, the need for temporary circulatory support should condition.|

|myocarditis team (Section 4.6.1), and whether emergent|be considered, if not previously implemented. A small||

|4.2. Diagnostic Testing||minority of patients will not recover and require transi-|

|Detailed below are some of the tests available to evaluate||tion to a durable LVAD or heart transplantation. Patients|

|a patient with clinically suspected myocarditis. Two of||in the outpatient setting should be educated to refrain|

|these, specifically CMR with T 1 and T 2 parametric map-||from strenuous physical activity and competitive sports|

|ping and EMB with pathological analysis of the myocar-||until cleared to return to such activities (Section 4.8).|

|dial tissue, are considered pivotal in the diagnostic||Required care does not end even if symptoms resolve|

|process. Because chest pain, electrocardiographic||after 2-3 weeks. Rather, patients need longitudinal|

|Genetic variants|n Pathogenic gene variants linked to dilated and| |---|---|

||arrhythmogenic cardiomyopathy and neuromus-|

||cular disorders|

||n Disease-causing variants in DSP and TTN are|

||consistently associated with myocarditis|

|History of myocarditis|n Personal history of prior episode of myocarditis|

||n Family history of myocarditis|

|Cardiotoxins|n Prescribed medications, including immune|

||checkpoint inhibitors, doxorubicin, trastuzumab,|

||clozapine|

||n Illicit substances: cocaine, methamphetamine|

|Thymoma||

|Systemic immune-mediated/|Sarcoidosis, systemic lupus, rheumatoid arthritis,|

|connective tissue disease|scleroderma, myositis, or vasculitis|

|Hypereosinophilia||

|Infectious agents|Particularly viruses (eg, adenovirus, enterovirus,|

||parvovirus, human herpes virus 6, influenza, HIV,|

||SARS-CoV-2) but also other organisms, including|

||bacteria, fungi, and parasites|

|Vaccines|Including smallpox, mRNA COVID-19|

|TA BLE 2|Key Risk Factors for Adverse Prognosis in Patients With Myocarditis|||| |---|---|---|---|---|

|Clinical Presentation|Echocardiography|CMR|Histology||

|Symptomatic HF|Biventricular reduced|Biventricular|GCM||

|||EF|reduced EF||

|Cardiogenic shock||Presence of LGE|||

|Electrical instability|||||

|n Recurrent ventricular|||||

|arrhythmia|||||

|n Advanced AV block|||||

|||||Those in stage A|

|||||should be monitored for onset of symptoms, have the|

|||||inciting agent removed (eg, cocaine or methamphet-|

|||||amine, or in those with a prior history of myocarditis,|

|||||consideration of discontinuation of pharmacological|

|||||therapies known to cause myocarditis, when feasible),|

|CMR at 6 months would be suggested to assess for its|| |---|---|

|resolution. In those with a normal LVEF and no LGE at||

|baseline, a repeat echocardiogram, ideally with strain||

|assessment, would be reasonable.||

|Patients with symptomatic myocarditis also require||

|longitudinal follow-up of their condition. Care should||

|not stop even if symptoms resolve in 1 to 2 weeks. Such||

|longitudinal diagnostic studies afford the opportunity||

|to detect persistence of myocardial inflammation and||

|deterioration of ventricular function as well as to||

|provide important prognostic information. Currently,||

|there are no available evidence-based guidelines as to||

|which tests should be acquired, and at what frequency.|With Myocarditis|

|The following recommendations (see Table 3) were|Genetic predisposition is now firmly established to|

|determined via the deliberations of the writing committee|explain a subset of myocarditis cases and therefore ge-|

|to provide needed guidance for healthcare clinicians and|netic testing, much as is recommended for patients with|

|payers involved in the care of patients with symptomatic|peripartum cardiomyopathy where similar (w15%) ge-|

|myocarditis.|netic associations are known, 172 should be part of the|

|Repeat cardiac imaging was felt appropriate at 2 time|standard workup for new diagnoses. In settings of limited|

|points. First, at an early interval (eg, 2-4 weeks), echo-|resources, genetic testing could be prioritized to those|

|cardiography can determine whether there is new or|with recurrent myocarditis or other risk factors for|

|progressive deterioration of LV function, findings that|inherited cardiomyopathy (eg, as ascertained by family|

|would signal the possibility of a condition such as GCM. A|history) until wider capabilities are available. The genetic|

|second follow-up imaging study is advised at 6 months|evaluation is ideally overseen by specialists in genetics|

|with the modality (echocardiography or multiparametric|(ie, clinical geneticist or genetic counselor) and should|

|CMR) being based on the risk profile of the clinical pre-|include collection of a 3-generation family history and|

|sentation (low or medium/high risk). In those who are not|molecular testing, primarily as targeted panel sequencing,|

|low risk, a CMR will allow reassessment of LV function|including validated genes associated with cardiomyopa-|

|and resolution of myocardial inflammation. Further|thies and inherited arrhythmia disorders. Pretest genetic|

|research is needed regarding treatment for patients with|counseling requires a somewhat lengthy and detailed|

|persistence or progression of inflammation. This|conversation with patients or parents and is best suited to|

|approach will allow for implementation of GDMT if a|the ambulatory setting. Because genetic results are un-|

|reduced LVEF is newly documented and provide esti-|likely to alter immediate management, the genetic eval-|

|mates of prognosis. In athletes wanting to return to|uation can be performed following resolution of the acute|

|competitive sports, the CMR can be repeated as soon as 3|phase (ie, posthospitalization). A positive genetic test|

|months after resolution of symptoms.|should prompt cascade genetic testing in first-degree|

||relatives and clinical screening for cardiomyopathy and|

|4.7.1. Longitudinal Surveillance With Imaging|arrhythmia in any relatives found to harbor a familial|

|In a study of 24 patients with acute myocarditis, a repeat|variant. This approach may afford the opportunity to|

|CMR at 3 months after diagnosis was more sensitive at|deliver GDMT and thereby improve clinical outcomes in|

|detecting persistent myocardial inflammation than was|previously undiagnosed relatives. In cases when the in-|

|serial echocardiography or repeated measurement of|dex patient with myocarditis is found to carry a patho-|

|biomarkers, including high-sensitivity Tn, CRP, and|genic or likely pathogenic variant, it is not known|

|natriuretic peptides. 173 Moreover, surveillance CMR at 3|whether clinical surveillance is still needed in those rel-|

|to 12 months after the acute presentation provided valu-|atives who test negative genetically.|

|able long-term prognostic information. Most patients||

|showed improvement in myocardial edema and reduction|4.7. Longitudinal Follow-Up of Stage B, C, and D Myocarditis|

|in LGE on follow-up CMR, but persistent or worsening|Patients with stage B myocarditis should have repeat|

|LGE was an adverse prognostic indicator. In another|cardiac imaging with the caveat being there are no data|

|study of 187 patients with acute myocarditis who were|yet available on its utility in this newly classified stage.|

|hemodynamically stable in the ITAMY (ITAlian Study in|We advise that the follow-up imaging modality (echo-|

|Myocarditis) Registry, healing (absence of edema and|cardiography or CMR) be based upon the clinical context|

||at the time of diagnosis. For example, in those with|

||demonstrated myocardial inflammation on CMR, a repeat|

||Severity of Risk|Severity of Risk| |---|---|---|

|Timing of Postdischarge||Stage D or Medium-/High-|

|Follow-Up and Testing|Low-Risk Stage C|Risk Stage C|

||All the following:|Any of the following:|

||n Normal LVEF|n Reduced LVEF|

||n No LGE|n NSVT or higher-grade|

||n Hemodynamic and|ventricular ectopy|

||electrical stability|n Significant|

|||bradyarrhythmias|

|||n LGE on CMR|

|||n Increased myocardial 18 F-|

|||FDG uptake on PET scan|

|||n Hemodynamic instability/|

|||clinical heart failure|

|By 2-4 weeks*|n Office visit|n Office visit|

||n Echocardiogram †|n Biomarkers ‡|

|||n ECG|

|||n Echocardiogram †|

|Interval visits||n Uptitration of GDMT for|

|||HFrEF as appropriate|

|6 months|n Echocardiogram †|n CMR §|

|APPENDIX 3. ABBREVIATIONS|APPENDIX 3. ABBREVIATIONS||||||||| |---|---|---|---|---|---|---|---|---|---|

|MYOCARDITIS||||||||||

|ACC ¼ American College of Cardiology|ACC ¼ American College of Cardiology|||GDMT ¼ guideline-directed management and therapy||||||

|AHA ¼ American Heart Association|AHA ¼ American Heart Association|||HF ¼ heart failure|HF ¼ heart failure||Institutional, Organizational, or|||

|Committee AV ¼ atrioventricular|||Speakers HR ¼ hazard ratio Ownership/Partnership/||Personal|Other Financial|Expert|||

|Member CD ¼ cluster of differentiation Employment|Consultant|Bureau HFrEF ¼ heart failure with reduced ejection fraction Principal Research Benefit|Witness|||||||

|Mark H. Drazner (Chair) CMR ¼ cardiac magnetic resonance UT Southwestern Medical CenterdClinical Chief of Cardiology; James M. Wooten Chair in Cardiology CRP ¼ C-reactive protein||None|None hs-cTn ¼ high-sensitivity cardiac troponin None None ICI ¼ immune checkpoint inhibitor|None|None|||||

|(Vice Chair) cTn ¼ cardiac troponin DeBakey VA Medical CenterdSenior Dean of Faculty, Medical Care Line Executive, Gordon Cain Chair, Professor cTnI ¼ cardiac troponin I|n Johnson & Johnson n Roche|LGE ¼ late gadolinium enhancement LV ¼ left ventricle|LGE ¼ late gadolinium enhancement LV ¼ left ventricle|LGE ¼ late gadolinium enhancement LV ¼ left ventricle|LGE ¼ late gadolinium enhancement LV ¼ left ventricle|Laboratories* n AstraZeneca Pharmaceuticals||||

|of Medicine cTnT ¼ cardiac troponin T|||LVAD ¼ left ventricular assist device|LVAD ¼ left ventricular assist device|LVAD ¼ left ventricular assist device|LVAD ¼ left ventricular assist device|n Respicardia/Zoll|||

|(Vice Chair) ECDP ¼ expert consensus decision pathway|Myers Squibb|miRNA ¼ microRNA||(DSMB)|Therapeutics* n The Myocarditis|||||

|ECG ¼ electrocardiogram|ECG ¼ electrocardiogram|Company*|MRI ¼ magnetic resonance imaging|MRI ¼ magnetic resonance imaging|MRI ¼ magnetic resonance imaging|MRI ¼ magnetic resonance imaging|Foundation †|||

|ECV ¼ extracellular volume|ECV ¼ extracellular volume|n Cantargia n Cardiol*|PCR ¼ polymerase chain reaction|||||||

|EGE ¼ early gadolinium enhancement|EGE ¼ early gadolinium enhancement|n Kiniksa|n Kiniksa|n Kiniksa|n Kiniksa|PET ¼ positron emission tomography||||

|Niti R. Aggarwal ECMO ¼ extracorporeal membrane oxygenation Mayo Clinicd|None|None TCS ¼ temporary circulatory support None None|None|None||||||

|Assistant Professor of Medicine Consultant, Department of Cardiovascular EMB ¼ endomyocardial biopsy|Assistant Professor of Medicine Consultant, Department of Cardiovascular EMB ¼ endomyocardial biopsy|||Tn ¼ troponin||||||

|Disease ESC ¼ European Society of Cardiology||||||||||

|Cristina Basso 18 F-FDG ¼ 18 F-fluorodeoxyglucose University of PaduadProfessor of||None|None|None||None|None|None||

|Pathology GCM ¼ giant cell myocarditis||||||||||

|Nicole M. Bhave|University of Michigan Medical||None|None|None||None|None|None|

||SchooldAssociate Professor of|||||||||

||Cardiovascular Medicine|||||||||

|Alida L.P. Caforio|University of PaduadDepartment of||None|None|None||None|None|None|

||Cardiac, Thoracic, Vascular Sciences and|||||||||

||Public Health Associate Professor of|||||||||

||Cardiology|||||||||

|Vanessa M.|University of OxforddProfessor of||None|None|n Patent-Method and|n GE|None|None||

|Ferreira|Cardiovascular Medicine||||apparatus for enhancing||Healthcare*|||

||||||medical images †|||||

||||||n Patent-Method and|||||

||||||apparatus for quality|||||

||||||prediction †|prediction †|prediction †|prediction †|prediction †|

||||||n Patent-Method for|||||

||||||identity validation and|||||

||||||quality assurance of|||||

||||||quantitative magnetic|||||

||||||resonance imaging|||||

||||||protocols †|protocols †|protocols †|protocols †|protocols †|

|Heidecker|Berlin, Universitätsmedizin dHead of|n Pfizer|n Pfizer|n Pfizer|n Pfizer||patents that use RNA|||

||Heart Failure and Cardiomyopathy||||for diagnosis of|||||

||||||myocarditis †|myocarditis †|myocarditis †|myocarditis †|myocarditis †|

|Amy R.|Icahn School of Medicine at Mount|n Alexion|n Alexion|n Alexion|n Alexion|None|None||None|

|Kontorovich|SinaidAssociate Professor of Medicine|n AstraZeneca||||||||

||in Cardiology and Genomic Medicine|||||||||

|Pilar Martín|National Cardiovascular Research||None|None|None||None|None|None|

||CenterdAssistant Professor|||||||||

|Gregory A. Roth|University of Washington School of||None|None|None||None|None|None|

||MedicinedAssociate Professor|||||||||

|Jennifer E. Van|Cedar Sinai Medical CenterdProfessor||None|None|None|n Abbott*|n Abbott*|n Abbott*|n Abbott*|

|Eyk||||||||||

Previous Diagnostic Criteria . . . . . . . . . . . . . . . . . . 13 4.3.1. World Health Organization . . . . . . . . . . . . . . 13 4.3.2. European Society of Cardiology . . . . . . . . . . 13 4.3.3. Centers for Disease Control and Prevention and Brighton Collaboration . . . . . . . . . . . . . . 14 4.4. A New Classification of Myocarditis . . . . . . . . . . . . 14 Figure 5. Proposed Stages of Myocarditis . . . . . . . . 15 4.4.1. Stage A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 Risk Factors to Define Stage A At-Risk for Myocarditis Endomyocardial Biopsy . . . . . . . . . . . . . . . . 18 Figure 6. When to Perform EMB in Patients With Suspected Myocarditis . . . . . . . . . . . . . . 19 4.5. Prognosis and Trajectories of Myocarditis . . . . . . . 19 4.5.1. Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Table 2. Key Risk Factors for Adverse Prognosis in Patients With Myocarditis . . . . . . . . . . . . . . 20 4.5.2. Trajectories of Myocarditis . . . . . . . . . . . . . . 20 Figure 7. Key Unanswered Questions Regarding Trajectories Across Stages of Myocarditis . . . . . . . . . . . . . . . . . . . . . . . . . 21 4.6. Treatment of Myocarditis . . . . . . . . . . . . . . . . . . . . 20 Figure 8. Surveillance and Treatment by Stage of Myocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4.6.1. Triage for Need of Referral to Advanced HF Center During Index Admission . . . . . . . . . . 22 Figure 9. Triage Factors When Considering Referral to an Advanced HF Center With a Multidisciplinary Myocarditis Team During Index Admission

Longitudinal Surveillance of Stage C and D Myocarditis . . . . . . . . . . . . . . . . . . . . . . . . . .2 4.7.1. Longitudinal Surveillance With Imaging . . . 27 4.7.2. Longitudinal Surveillance With Biomarkers . . . . . . . . . . . . . . . . . . . . . . 28 4.8. Return to Strenuous Physical Activity, Including Competitive Sports . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Figure 11. Recommendations for Abstinence From Strenuous Physical Activity and Return to Competitive Sports Following Diagnosis of Myocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 4.9. Knowledge Gaps and Future Directions . . . . . . . . Need for Improved Phenotyping: Biopsy . . . 31 4.9.5. Need to Be Aware of Racial Differences . . . 32 Figure 12. State-Level Age-Standardized Mortality Rates for Myocarditis in 2019 . . . . . 30 4.9.6. Needs for Consideration of Social Determinants of Health . . . . . . . . . . . . . . . . . 32 Figure 13. Social Determinants of Health Related to Myocarditis . . . . . . . . . . . . . . . . . . . 31 4.9.7. Need for Access and Coverage for Screening, Diagnostic Evaluation, and Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

The Evaluation and Management of Clinically Suspected Myocarditis Described as a 5-Step Care Pathway

BLE 1 Risk Factors to Define Stage A At-Risk for Myocarditis

¼ atrioventricular; CMR ¼ cardiac magnetic resonance; EF ¼ ejection fraction; GCM ¼ giant cell myocarditis; HF ¼ heart failure; LGE ¼ late gadolinium enhancement.

5. Genetic Counseling and Testing of Patients

Longitudinal Surveillance of Stage C and D MyocarditisThose with symptomatic HFrEF ideally should be seen within 1 week of hospital discharge. †When feasible, include assessment of strain. ‡Biomarkers include hs-troponin and natriuretic peptide level (if elevated at baseline or clinical deterioration) and CRP (if elevated at baseline, especially in context of connective tissue disease). Further biomarker testing can be based on the results at first follow-up. §A CMR at 3 months may be preferable in athletes considering return to competitive sports. CMR ¼ cardiac magnetic resonance; CRP ¼ C-reactive protein; ECG ¼ electrocardiogram; 18 F-FDG ¼ 18 F-fluorodeoxyglucose; GDMT ¼ guideline-directed management and therapy; HFrEF ¼ heart failure with reduced ejection fraction; hs ¼ high sensitivity; LGE ¼ late gadolinium enhancement; LVEF ¼ left ventricular ejection fraction; NSVT ¼ nonsustained ventricular tachycardia; PET ¼ positron emission tomography.

4.9.7. Need for Access and Coverage for Screening, Diagnostic Evaluation, and Care There is inadequate healthcare coverage for myocarditis care. Many patients are not covered for repeat imaging and/or testing following myocarditis diagnosis or initial testing with advanced imaging in the outpatient setting. Patients may require repeat diagnostic evaluation to ascertain resolution of abnormal cardiac involvement and/or for consideration of additional therapies, such as GDMT for cardiomyopathy or HF if they have persistent symptoms and or cardiac dysfunction. There also is a great need for advocacy, health policy, and interventions for equity for a disease such as myocarditis, that requires advanced therapies when severe. 179. Maron BJ, Udelson JE, Bonow RO, et al. Eligibility and disqualification recommendations for competitive athletes with cardiovascular abnormalities: task force 3: hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and other cardiomyopathies, and myocarditis: a scientific statement from the American Heart Association and American College of Cardiology. J Am Coll Cardiol. 2015;66:2362-2371. 180. Patriki D, Baltensperger N, Berg J, et al. A prospective pilot study to identify a myocarditis cohort who may safely resume sports activities 3 months after diagnosis. J Cardiovasc Transl Res. 2021;14:670-673. 181. Pelliccia A, Solberg EE, Papadakis M, et al. Recommendations for participation in competitive and leisure time sport in athletes with cardiomyopathies, myocarditis, and pericarditis: position statement of the Sport Cardiology Section of the European Association of Preventive Cardiology (EAPC). Eur Heart J. 2019;40: 19-33. 182. Escandon R, Heidecker B. The need for ethical and pragmatic strategies for sample and data collection during public health emergencies-minimizing missed opportunities. Eur Heart J. 2021;42:3114-3116. 183. Salem JE, Manouchehri A, Moey M, et al. Cardiovascular toxicities associated with immune checkpoint inhibitors: an observational, retrospective, pharmacovigilance study. Lancet Oncol. 2018;19:1579-1589. 184. Birnie D, Beanlands RSB, Nery P, et al. Cardiac sarcoidosis multi-center randomized controlled trial (CHASM CS-RCT). Am Heart J. 2020;220:246-252. 185. Cooper LTJ, Hare JM, Tazelaar HD, et al. Usefulness of immunosuppression for giant cell myocarditis. Am J Cardiol. 2008;102:1535-1539. Alix School of Medicine at Mayo ClinicdElizabeth C. Lane, PhD, and M. Nadine Zimmerman, PhD, Professor of Medicine Mayo Clinic, Division of Cardiovascular Disease table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of $5% of the voting stock or share of the business entity or ownership of $$5,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. According to the ACC, a person has a relevant relationship IF: a) the relationship or interest relates to the same or similar subject matter, intellectual property or asset, topic, or issue addressed in the document; b) the company/ APPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES (RELEVANT)-2024 ACC EXPERT CONSENSUS DECISION PATHWAY ON STRATEGIES AND CRITERIA FOR THE DIAGNOSIS AND MANAGEMENT OF

This table represents all reported relationships of reviewers with industry and other entities as disclosed by the reviewers, including those not deemed to be relevant to this document, at the time it was being reviewed. The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest represents ownership of $5% of the voting stock or share of the business entity, or ownership of $$5,000 of the fair market value of the business entity; or if funds received by the person from the business entity exceed 5% of the person's gross income for the previous year. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted. Please refer to https://www.acc.org/Guidelines/About-Guidelines-and-Clinical-Documents/Relationships-with-Industry-Policy for definitions of disclosure categories or additional information about the ACC Disclosure Policy for Writing Committees. *This disclosure was entered under the Clinical Trial Enroller category in the ACC's disclosure system. To appear in this category, the reviewer acknowledges that there is no direct or institutional relationship with the trial sponsor as defined in the ACC Disclosure Policy for Writing Committees.

References

Circulating hs-cTn levels should be followed sequentially in a patient with symptomatic myocarditis. For those with elevated natriuretic peptide levels at baseline, serial measurement to document improvement is reasonable. As described previously, CMR has greater utility for monitoring myocardial inflammation than does biomarkers. Nevertheless, the significantly lower cost and ease in obtaining biomarkers, particularly hs-cTn, is such that they can be obtained more frequently and could alert clinicians to subclinical deterioration, which would prompt reassessment of ventricular function by echocardiography or even an early CMR to reassess the degree of myocardial inflammation and injury. In a very small study of patients with myocarditis related to ICIs, higher cTnI and creatine kinase-MB at presentation correlated with progression to severe myocarditis. 177 Delineating potential autoantigens that could be used as circulating biomarkers would be useful mechanistically and potentially helpful for tracking severity or changes in status.

4.8. Return to Strenuous Physical Activity, Including Competitive Sports

9] [180] [181] At that time, it is advisable to obtain either a CMR (stage D or $ medium-risk stage C myocarditis) or transthoracic echocardiography (low-risk stage C myocarditis), a 24-hour ECG, and an exercise stress test to evaluate for stress-induced arrhythmias. 180 [180] [181] Due to an increased risk for recurrence and silent clinical progression of the disease, athletes with previous myocarditis should undergo a periodic reassessment, particularly within the first 2 years. 181 International registries for myocarditis are necessary to gather data on a larger scale that enables detection of characteristics and patterns of myocarditis that would not be recognized in single-center studies. A shared international definition of myocarditis with similar diagnostic standards will be paramount to allow for comparability of data. 35 gistry data will help to obtain in-depth understanding of common patterns in pathophysiology, to discover risk predictors, to learn about the clinical course based on various treatment approaches, and to identify novel trends earlydfor example, if a novel virus is spreading in a population, 182 or if myocarditis develops as a side effect of a novel therapy. 183 least as important as establishing international registries will be multicenter clinical trials, when novel therapies are tested. Because of the heterogeneity of the patient population, innovative trial methods, including adaptive design or precision medicine approaches, should be considered. 5] [186] [187] [188] Due to the absence of standardized therapy guidelines, myocarditis treatment varies significantly among national and international centers. To enhance patient care, it is essential to establish uniform treatment protocols, enabling the collection of large-scale therapy response data for further refinement and optimization of treatment options.

Partnerships with industry, academic centers, and patient advocacy groups are needed to successfully complete multicenter, international registries for the study of There is also a critical need to capture myocarditis as a diagnosis. The International Classification of Diseases-Tenth Revision code may not be used in cases that are missed or not hospitalized; thus, there may be gross under-reporting. Furthermore, proximate causes such as severe COVID-19 infection, cancer that requires ICI therapy, or systemic lupus may be the primary diagnosis and myocarditis may or may not be captured as a secondary diagnosis. Therefore, defining the epidemiology of myocarditis, including the true incidence and prevalence, geographic, and secular variation of myocarditis, mortality, and outcomes related to myocarditis, needs further study.

The psychosocial, socioeconomic, and healthcare burden of the diagnosis of myocarditis, including depression and anxiety, are considerable in both patients and their caregivers, particularly because young and often previously active individuals are affected. Long-term follow-up found that up to one-third of patients with fulminant myocarditis requiring mechanical circulatory support had severe anxiety or depressive symptoms and were at risk for post-traumatic stress disorder. 189 This burden has not been systematically measured or consistently addressed in current practice. Individuals may not be able to resume physical activity, sports, or return to work that may entail physical labor. Economic burden at the individual or healthcare level has not been studied and requires further research.

4.9.2. Need for Improved Phenotyping: Immuno-Metabolic Imaging

The ability to directly image the immune system and cellular activity would vastly improve the phenotyping of myocarditis. Advanced cardiac imaging modalities, such as PET and CMR, to image the molecular inflammatory response, immune cell types, and metabolic activity for phenotypic signatures, 190, 191 offers promise to enhance diagnostic testing and risk stratification as well as allowing more targeted therapy. Emerging PET radiotracers and molecular targets for imaging myocarditis include 68 Ga-DOTATATE (targeting somatostatin receptors expressed on proinflammatory macrophages), and 18 F-and 68 Gabased tracers (targeting the folate receptor beta-isoform expressed on activated macrophages). 190, 192 In MRI, tissue-resident macrophage activity and cellular inflammation can be detected by ultrasmall superparamagnetic particles of iron oxide, 193 neutrophil and monocyte activity by myeloperoxidase-activated gadolinium chelate in preclinical studies, 194 and monocytes by intravenous 19 F-enhanced CMR-perfluorocarbon-containing nanoparticles. 195 Clinical hyperpolarized MRI can image key metabolites of inflammation, such as hyperpolarized carbon-13 pyruvate and carbon-13 lactate. These biomarkers are evident in both organ-specific myocarditis and myocarditis in the context of systemic immune-mediated diseases, serving as predictors of a worse prognosis, especially at high titers. 101, 196, 197 Cellular immune-phenotype biomarkers have also been reported. 198, 199 Others are being studied; galectin-3, soluble suppression of tumorigenicity 2 (sST2), and specific microRNAs (miRNAs) have shown promise in their association with myocarditis. Galectin-3 has been associated

with cardiac remodeling and poor prognosis in HF. 200 A study in chronic Chagas disease cardiomyopathy caused by Trypanosoma cruzi infection suggests that galectin-3 plays a significant role in inflammation and fibrosis, and its expression in human hearts associates with myocarditis in Chagas cardiomyopathy. 201, 202 Adapted with permission from Johnson et al. 221 Drazner et al

to be associated with myocarditis. Importantly, care is required to carry out experiments in humans and ensure that the miRNA homologs are feasible in human (eg, miR-721 213 with its putative human homolog). 214, 215 It is also important to ensure disease specificity, as many micro-RNAs are also expressed in other cardiomyopathies. 216, 217 nally, although some may distinguish, 210 all have yet to be validated in a large, well-defined clinical cohort. Thus, to date, there is no validated miRNA alone or a set of miRNAs that is specific and reliable to distinguish myocarditis, limiting their present diagnostic value.

In summary, to achieve a more accurate and etiologyspecific diagnosis of myocarditis, it is essential to ensure disease-specificity and carry out validation alone or as part of a combination of multiple biomarkers (with cTn)

and incorporate them into comprehensive diagnostic algorithms that consider clinical evaluation, imaging studies, and other relevant parameters. Although no major issues are present in the setting of eosinophilic, polymorphous, granulomatous, and GCM, the real diagnostic challenge is with lymphocytic myocarditis. The existing cutoff of $14 leukocytes/mm 2 including up to 4 monocytes/mm 2 with the presence of $7

CD3 T-lymphocytes/mm 2 , without any specification of distribution, should be revised. A recent survey on EMB practice for myocarditis highlighted the clinically unmet need to update and standardize the current diagnostic criteria. 88, 219, 220 The following crucial issues include: 1) the histopathological diagnosis (the extent/grading and type of inflammation; whether myocyte injury is always required; and the role of fibrosis); 2) the need of IHC (when and which panel, especially when the infiltrates are of mononuclear cells, such as lymphocytes and macrophages, which cannot be distinguished clearly by histology); and 3) the use of molecular pathology for infectious agents.

4.9.5. Need to Be Aware of Racial Differences

The age-standardized mortality rates for myocarditis in the United States are higher in Black people than White people, both in women and men (Figure 12 ). 221 Efforts to increase awareness of this condition in those at higher risk from myocarditis are needed.

4.9.6. Needs for Consideration of Social Determinants of Health

There is inequity in access to screening, evaluation, and treatment of myocarditis. Underinsured/not insured patients, patients with low income, people of color, and patients living in rural areas may not be referred for screening, imaging, testing, and or advanced therapies.

Contemporary diagnoses of myocarditis rely heavily on the use of CMR; however, uptake of this technology is heterogeneous and variation in use as well as wait times present concerns for equity of provision. 222 More widespread and equitable genetic testing in myocarditis is desired, given that currently there appears to be lower clinical testing rates in Black populations as well as higher genetic diversity in individuals of African ancestry. 223 nomic studies in diverse and inclusive populations should be a priority for further myocarditis research.

Because social determinants of health have been implicated in altered immunity and inflammation, 224 it stands to reason that these variables may impact the course and outcome of myocarditis (Figure 13 ). Further research is needed to understand the intersection between clinical variables, genetic risk, and social determinants of health in myocarditis outcomes.

|ally a follow-up CMR (Section 4.7). A reassessment for|myocarditis will have undergone coronary angiography|myocarditis will have undergone coronary angiography|

|return to strenuous physical activity, including competi-|(invasive or via computed tomography) to exclude an|(invasive or via computed tomography) to exclude an|

|tive sports, can be performed at 3-6 months after initial|acute coronary syndrome.|acute coronary syndrome.|

|diagnosis. Finally, outpatient genetic counseling and|||

|testing should be provided to consenting patients.|4.2.1. Electrocardiogram|4.2.1. Electrocardiogram|

||Electrocardiogram (ECG) is widely used as an initial|Electrocardiogram (ECG) is widely used as an initial|

|4. DESCRIPTION, RATIONALE, AND IMPLICATION|screening tool for diagnosis of myocarditis, despite its low|screening tool for diagnosis of myocarditis, despite its low|

|OF PATHWAY|sensitivity of 47%. 9 ECGs of patients with myocarditis|sensitivity of 47%. 9 ECGs of patients with myocarditis|

||often display a myriad of nonspecific findings, including|often display a myriad of nonspecific findings, including|

|Based upon a comprehensive literature review and expert|sinus tachycardia, nonspecific ST/T-wave changes, low|sinus tachycardia, nonspecific ST/T-wave changes, low|

|opinion, this ECDP aims to inform clinicians regarding the|voltage, and PR-segment depression, none of which are|voltage, and PR-segment depression, none of which are|

|following: 1) the current diagnostic algorithm to follow in|pathognomonic for myocarditis. 10 A normal ECG or ECG|pathognomonic for myocarditis. 10 A normal ECG or ECG|

|the setting of suspected myocarditis; 2) the pivotal role of|with nonspecific changes do not rule out myocarditis but|with nonspecific changes do not rule out myocarditis but|

|advanced imaging and EMB in the confirmation of|presence of pathological Q waves, left bundle branch|presence of pathological Q waves, left bundle branch|

|myocarditis; 3) when to refer patients to an advanced HF|block, wide complex QRS $120 ms, prolonged QT interval,|block, wide complex QRS $120 ms, prolonged QT interval,|

|center and potential therapies for those with advanced|high-grade atrioventricular (AV) block, malignant tachy-|high-grade atrioventricular (AV) block, malignant tachy-|

|myocarditis; 4) a new 4-stage classification of myocarditis,|arrhythmias, fragmented QRS, and T-wave inversion are|arrhythmias, fragmented QRS, and T-wave inversion are|

|now including those "at-risk" for myocarditis and those|often associated with decreased left ventricular function,|often associated with decreased left ventricular function,|

|with "asymptomatic myocarditis"; 5) recommendations|presence of left ventricular scar and overall poor clinical|presence of left ventricular scar and overall poor clinical|

|for pharmacological treatment of myocarditis; 6) the need|prognosis in patients with myocarditis. 10-13 Involvement|prognosis in patients with myocarditis. 10-13 Involvement|

|for longitudinal surveillance of patients with myocarditis,|of the conduction system also raises the suspicion for|of the conduction system also raises the suspicion for|

|including a follow-up CMR; and 7) the growing importance|sarcoidosis, GCM, or Lyme disease. Ongoing research,|sarcoidosis, GCM, or Lyme disease. Ongoing research,|

|of genetic predisposition for myocarditis. This document|particularly by artificial intelligence, may improve our|particularly by artificial intelligence, may improve our|

4.7.2. Longitudinal Surveillance With Biomarkers

引用 / 出处

2024 ACC专家共识决策路径：心肌炎诊断和管理的策略与标准. 2024.