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INTRODUCTION (CONT.)

Recent (2021 HF, 2022 cardio-oncology, 2022 prevention of SCD) guidelines of ESC are the first official documents updating the knowledge on the management of myocarditis since the 2013 ESC expert consensus statement.
These guidelines and new research allow standardization and improvements to the diagnosis and treatment of myocarditis.

G Ital Cardiol (Rome) . 2022 Apr;23(4 Suppl 1):e1-e127. doi: 10.1714/3777.37630.

Eur Heart J. 2013;34(33):2636–2648. doi: 10.1093/eurheartj/eht210.

Eur Heart J. 2022;43(40):3997–4126. doi: 10.1093/eurheartj/ehac262.

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Personalized diagnostics and treatment of myocarditis; CMR — cardiac magnetic resonance; ECHO — echocardiography; EMB — endomyocardial biopsy; HLA — human leukocyte antigen; PET — positron emission tomography.

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Etiologies	Examples
Infections	Viral: adenoviruses, echoviruses, enteroviruses (e.g., Coxsackieviruses), herpes viruses (human cytomegalovirus, Epstein-Barr virus, human herpesvirus 6), hepatitis C virus, human immunodeficiency virus (HIV), influenza A virus, parvovirus B19, SARS-CoV-2�Bacterial, fungal, protozoal, rickettsial, spirochetal, helminthic.
Autoimmune	Hypereosinophilic syndrome, Kawasaki disease, lupus erythematous, rheumatoid arthritis, scleroderma, ulcerative colitis, celiac disease, Churg-Strauss syndrome, Crohn’s disease, dermatomyositis.
Hypersensitivity reactions to drugs	Penicillin, ampicillin, cephalosporins, tetracyclines, sulfonamids, antiphlogistics, benzodiazepines, clozapine, loop and thiazide diuretics, methyldopa, smallpox vaccine, tetanus toxoid, tricyclic antidepressants.
Toxic reactions to drugs	Immune checkpoint inhibitors, amphetamines, anthracyclines, catecholamines, cocaine, cyclophosphamide, 5-fluorouracil, phenytoin, trastuzumab.
Others	Arsenic, copper, iron, radiotherapy, thyreotoxicosis.

Viruses. 2021;13(10):1924. doi: 10.3390/v13101924

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Clinical manifestation	Chest pain, dyspnea, signs of left and/or right heart failure, and/or arrhythmias or sudden cardiac death
Diagnostic tests
ECG	Novel ST-T abnormalities, atrial or ventricular arrhythmias, atrio-ventricular blocks, QRS abnormalities
Laboratory tests	Increased troponins with dynamic fluctuations�C-reactive protein or erythrocyte sedimentation rate often increased but non-specific�Raised concentrations of brain natriuretic peptides and circulating cytokines�Diagnostic tests for specific infective factor�Viral serology — low efficacy due to high rate of IgG antibodies against cardiotropic viruses in the general population�Anti-heart autoantibodies — may help personalize diagnosis, treatment, and therapy monitoring. So far, it has been used in a limited number of centers
Echocardiography	New regional wall motion abnormalities or global ventricular dysfunction�Elevated wall thickness caused by myocardial edema, pericardial effusion, intracardiac thrombi
CMR	Inflammation, edema, and fibrosis detection through T1 and T2 mapping, extracellular volume assessment and LGE
ICA or CTCA	To rule out significant coronary artery disease
EMB	Necessary for definite diagnosis and personalized treatment. May be useful in treatment monitoring
Cardiac PET	May be useful in patients with suspected systemic autoimmune disease or cardiac sarcoidosis and with contraindications to CMR

Recommended diagnostic tests in patients with suspected myocarditis

Definition of suspected myocarditis: clinical manifestation + ≥ 1 obligatory positive test and no coronary artery disease, valvular, congenital heart disease or other disease that could explain the symptoms; CMR — cardiac magnetic resonance; CTCA — computed tomography coronary angiography; ECG — electrocardiography; EMB — endomyocardial biopsy; ICA — invasive coronary angiography; LGE — late gadolinium enhancement; PET — positron emission tomography

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RECOMMENDATIONS FOR ENDOMYOCARDIAL BIOPSY IN PATIENTS WITH SUSPECTED MYOCARDITIS

Recommendations for endomyocardial biopsy	Class of recommendation
In case of acute/fulminant myocarditis with progression or persistent cardiac dysfunction and/or malignant ventricular arrhythmias and/or atrioventricular block without expected response to standard treatment during first < 1–2 weeks	I
In patients with exacerbation of heart failure despite optimal treatment when there is a suspicion of specific diagnosis which can be confirmed in myocardial samples	IIa
Endomyocardial biopsy is especially recommended in patients with acute and/or chronic heart failure and suspected giant cell-, eosinophilic-, immune checkpoint inhibitor-related and/or lymphocytic myocarditis, vasculitis, sarcoidosis, systemic lupus erythematosus, and other auto-immune conditions	I

Kardiol Pol. 2020;78(12):1297–1298. doi: 10.33963/KP.15647.

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TREATMENT OPTIONS

For the first time, the latest ESC HF guidelines offer a detailed approach to patients with myocarditis.
Treatment of myocarditis should be based on clinical presentation, disease stage and if known — disease etiology.
Around 50% of cases resolve spontaneously in weeks after onset, 25% of cases transform into permanent heart dysfunction, app. 25% deteriorate or progress to DCM with a need for heart transplantation or other form of ventricular support.
Factors such as symptomatic HF, ventricular arrhythmias, atrioventricular and/or bundle branch block, low LVEF at baseline, and fulminant course of the disease predict a worse prognosis.
As highlighted by the current guidelines, individual therapy of myocarditis should be based on EMB findings. This applies to immunosuppressive or anti-infective treatment, as well as to the monitoring of therapy.

Circulation. 2013;128(14):1531–1541. doi: 10.1161/CIRCULATIONAHA.13.001414.

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SUPPORTIVE TREATMENT

The main goal of treatment: optimal management of HF and arrhythmias according to standard recommendations.
Standard HF therapy: angiotensin converting enzyme inhibitors or angiotensin receptor neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists and sodium glucose co-transporter type 2 inhibitors (SLGT2i) should be initiated when baseline LVEF is decreased.
Patients after myocarditis with improved ejection fraction (EF): previous HF with reduced EF and now an EF > 40% should continue HF therapy.

J Am Coll Cardiol. 2022;79(17):e263–e421. doi: 10.1016/j.jacc.2021.12.012.

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SUPPORTIVE TREATMENT (CONT.)

Hemodynamically unstable patients: CICU + mechanical circulatory support, if necessary.
Patients with FM and deteriorating cardiac function: diuretics, inotropes, and vasopressors.
In case of cardiogenic shock unresponsive to initial treatment: temporary mechanical ventilation, veno-arterial extracorporeal membrane oxygenation or the Impella heart pump should be considered.
Heart transplant or left ventricular assist device implantation should be under consideration when transient mechanical circulatory support must be continued for more than 2 or 3 weeks.

Mayo Clin Proc. 2016;91(9):1256–1266. doi: 10.1016/j.mayocp.2016.05.013.

J Geriatr Cardiol. 2022;19(2):137–151. doi: 10.11909/j.issn.1671-5411.2022.02.006.

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PREVENTION OF SCD

In patients with myocarditis, it is recommended to assess individually the indications for ICD or cardiac resynchronization therapy (CRT).
ICD implantation in primary SCD prevention:

Not advised in the acute phase of myocarditis
The decision should be delayed for 3 to 6 months.
In patients with a high risk of arrhythmias and/or serious left ventricular dysfunction: may be beneficial as a bridge to an implanted device, cardiac transplantation, or resolution after immunosuppressive treatment.

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If sustained ventricular tachycardia or ventricular fibrillation is hemodynamically not tolerated: ICD implantation should be considered even in the acute phase of myocarditis.
In patients with chronic myocarditis or post-myocarditis if ventricular tachycardia is recurrent, the administration of amiodarone or catheter ablation (when amiodaron is not effective or not tolerated) and/or ICD implantation should be considered.

J Shock Hemodynamics. 2022;1(2):E2022123.

Eur Heart J. 2021;42(35):3427–3520. doi: 10.1093/eurheartj/ehab364.

Eur Heart J. 2022;43(40):3997–4126. doi: 10.1093/eurheartj/ehac262.

PREVENTION OF SCD

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ANTI-CANCER TREATMENT RELATED MYOCARDITIS

In patients with suspected immune checkpoint inhibitor-associated myocarditis: methylprednisolone intravenously for 3–5 days, then orally (clinical, ECG, ECHO and cardiac troponin surveillance).
Complete recovery is defined:

total resolution of acute symptoms,
normalization of biomarkers,
or decrease in cardiac troponin by 50% from the highest level, and improvement of LVEF after the end of immunosuppressive therapy.
CMR: absence of acute edema.

Immunother Cancer. 2021;9(6) doi: 10.1136/jitc-2021-002435.

Circulation. 2020;141(24):2031–2034. doi: 10.1161/CIRCULATIONAHA.119.044703.

Eur Heart J. 2022;43(41):4229–4361. doi: 10.1093/eurheartj/ehac244.

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IMMUNOSUPPRESSION

Immunosuppressive treatment (IST) (usually for at least 6–12 months) is recommended in:

EMB-proven myocarditis, particularly giant cell or eosinophilic myocarditis, cardiac sarcoidosis,
and myocarditis (especially FM) triggered by systemic autoimmune diseases.

In case of acute HF and/or life-threatening arrhythmias during FM: corticosteroids IV may be considered without delay (ruling out a virus in EMB) when immune etiology is suspected.

Circulation. 2020;141(6):e69–e92. doi: 10.1161/CIR.0000000000000745.

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Drug	Action	Treatment dose and duration
		Giant cell myocarditis	Fulminant lymphocytic myocarditis	Chronic lymphocytic myocarditis	Eosinophilic myocarditis	Sarcoidosis	ICI-mediated myocarditis
Corticosteroids	Suppresses leukocyte migration	Methylprednisolone IV or 500-1000 mg for 3 d; then, 1 mg/kg/24 h with gradual tapering	*Methylprednisolone IV, 7-14 mg/kg or 500-1000 mg for 3 d; then, 1 mg/kg/24 h with gradual tapering	*Methylprednisolone IV, 1 mg/kg/24 h for the first 4 wk followed by gradual tapering	*Methylprednisolone IV, 1 mg/kg/24 h for the first 4 wk followed by gradual tapering	*Prednisone 0.5 mg/kg for 1 mo; then gradual tapering over at least 12 mo	*Methylprednisolone IV 1000 mg for 3 d; then, 1 mg/kg/24 h with gradual tapering
Cyclosporine	Inhibits T-cell activation induced by interleukin 2	Duration: indefinite. Target concentrations:0-3 mo: 150-250 ng/mL4-12 mo: 100-150 ng/mL>12 mo: 80-100 ng/mL
Azathioprine	Inhibits purine synthesis, affecting DNA production in T and B cells	Duration: 1 y² 1-2 mg/kg/d divided into 2 doses		Duration: 6 mo1-2 mg/kg/d divided into 2 doses³⁰	Duration: 6 mo1-2 mg/kg/d divided into 2 doses

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Drug	Action	Treatment dose and duration
		Giant cell myocarditis	Fulminant lymphocytic myocarditis	Chronic lymphocytic myocarditis	Eosinophilic myocarditis	Sarcoidosis	ICI-mediated myocarditis
Immunoglobulins	Antigen-specific activity, multiple immunomodulatory activity		2 g/kg in continuous infusion over 24-48 h or divided over 4 d. More experience in children
Interferon beta	Antiviral and immunomodulatory activity mediated by cell receptors		4×10⁶ IU SC/48 h wk 18×10⁶ IU from wk 2 to >6 mo
Rituximab	Cytotoxicity due to antibodies against CD20⁺ B cells	375 mg/m²/wk IV for 4 wk		375 mg/m²/wk for 4 wk
Infliximab/adalimumab	Tissue necrosis factor inhibitors					Third-line treatment if no response to corticosteroids or other immunosuppressive agents
Imatinib	Inhibits tyrosine kinase activity of BCR-ABL, c-kit, and PDGFR proteins

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Drug	Action	Treatment dose and duration
		Giant cell myocarditis	Fulminant lymphocytic myocarditis	Chronic lymphocytic myocarditis	Eosinophilic myocarditis	Sarcoidosis	ICI-mediated myocarditis
Immunoglobulins	Antigen-specific activity, multiple immunomodulatory activity		2 g/kg in continuous infusion over 24-48 h or divided over 4 d. More experience in children
Interferon beta	Antiviral and immunomodulatory activity mediated by cell receptors		4×10⁶ IU SC/48 h wk 18×10⁶ IU from wk 2 to >6 mo
Rituximab	Cytotoxicity due to antibodies against CD20⁺ B cells	375 mg/m²/wk IV for 4 wk		375 mg/m²/wk for 4 wk
Infliximab/adalimumab	Tissue necrosis factor inhibitors					Third-line treatment if no response to corticosteroids or other immunosuppressive agents
Imatinib	Inhibits tyrosine kinase activity of BCR-ABL, c-kit, and PDGFR proteins

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ANTI-INFECTION THERAPY

Antiviral therapy is recommended in confirmed cases of HIV, cytomegalovirus, or human herpes virus 6 based on viral load and replication activity.

treatments with interferon beta in EMB-diagnosed viral myocarditis improved LVEF, quality of life and symptoms based on NYHA.
Viral serology has low efficacy in the diagnosis of myocarditis (presence of circulatory IgG antibodies).
lack of a correlation between virus serology and EMB results.

Other curable infectious diseases (i.e., Lyme disease): specific treatment should be administered.

Clin Res Cardiol. 2016;105(9):763–773. doi: 10.1007/s00392-016-0986-9.

J Am Coll Cardiol. 2012;60(14):1295–1296. doi: 10.1016/j.jacc.2012.06.026.

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SPECIFIC FORMS OF MYOCARDITIS AND TREATMENT

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IMMUNOMODULATION

The intravenous immunoglobulin (IVIG) treatment is non-established in myocarditis although it has been linked to improvement of LV function in DCM.
A recently published meta-analysis of the pediatric population has shown that IVIG treatment improved LVEF and decreased in-hospital mortality with fine tolerance.
Another meta-analysis did not prove an increase in LVEF. Based on current data, IVIG is not routinely recommended as a treatment option in myocarditis or DCM.

Int Heart J. 2019;60(2):359–365. doi: 10.1536/ihj.18-299.

Sci Rep. 2019;9(1):10459. doi: 10.1038/s41598-019-46888-0.

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RETURN TO PHYSICAL ACTIVITY AND LONG-TERM MONITORING

Assessment of exercise related SCD risk (ECG, imaging studies, exercise stress test and Holter monitoring): 3–6 months after the acute phase, then annually for at least 4 years.
Moderate to high-intensity training: abandoned for at least 6 months till symptoms, increased troponins, or clinically significant ECG/CMR/ECHO abnormalities are persistent. Patients with vast LGE areas (> 20%) and decreased LVEF should not participate in training of a moderate to high intensity.
A follow-up EMB to reveal evidence of the resolution of inflammation and healed myocarditis may be considered. Patients with previous myocarditis are at an increased risk for the recurrence of the disease.

Eur Heart J. 2021;42(1):17–96. doi: 10.1093/eurheartj/ehaa605.

J Pers Med. 2022;12(2):183. doi: 10.3390/jpm12020183.

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Recommendations on sports and exercise after myocarditis. CMR, cardiac magnetic resonance imaging; CK, creatine kinase; ICD, implantable cardioverter-defibrillator; LGE, late gadolinium enhancement; LV, left ventricle; LVEF, left ventricular ejection fraction.

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CÂU HỎI LƯỢNG GIÁ

1/ Sinh thiết cơ tim được chỉ định với những bệnh nhân nghi ngờ viêm cơ tim cấp mà:
A - Tiến triển rất cấp, ác tính (fulminant myocarditis)
B – Viêm cơ tim cấp, tiến triển suy tim ngày một nặng, mặc dù đã điều trị tối ưu
C – Viêm cơ tim cấp gây suy tim cấp/mạn tính nghi do bệnh lý tự miễn hoặc tế bào khổng lồ, bạch cầu ái toan
D – Các ý trên đều đúng.
E – Tất cả các ý trên đều sai, cần làm cho mọi bệnh nhân nghi ngờ để chẩn đoán xác định viêm cơ tim cấp.

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