Myocarditis: Clinical Guidelines

List of Abbreviations

BP – blood pressure in peripheral arteries

Td** – tetanus-diphtheria toxoid**

MRA – mineralocorticoid receptor antagonists (ATC: aldosterone antagonists)

AHA – American Heart Association

ACE – angiotensin-converting enzyme

ARB – angiotensin II receptor blockers (ATC: angiotensin II receptor blockers)

ARNI – angiotensin receptor-neprilysin inhibitor (ATC: angiotensin II receptor blockers in combination with other drugs)

ACC – American College of Cardiology

HIV – human immunodeficiency virus

Vasodilators – Vasodilators for cardiac diseases

GCS – Glucocorticoids

DCM – dilated cardiomyopathy

DNA – deoxyribonucleic acid

CHD – coronary heart disease

IMV – invasive mechanical ventilation

ICD – Implantable single-chamber cardioverter-defibrillator***, Implantable three-chamber (biventricular) cardioverter-defibrillator***, Implantable dual-chamber cardioverter-defibrillator***

CHD – coronary heart disease

CMP – cardiomyopathy

ESD – end-systolic dimension

LV – left ventricle

CK-MB – creatine kinase MB fraction

ICD-10 – International Classification of Diseases

MRI – magnetic resonance imaging (Magnetic resonance imaging of the heart and great vessels, Contrast-enhanced cardiac magnetic resonance imaging)

NSAIDs – non-steroidal anti-inflammatory drugs (ATC: non-steroidal anti-inflammatory and antirheumatic products)

ACS – acute coronary syndrome

PMC – paramagnetic contrast agents

DOACs – direct oral anticoagulants (Antithrombotic agents)

PCR – polymerase chain reaction (Determination of Human Herpes virus 6 DNA in a biological material sample, other or unspecified by polymerase chain reaction, qualitative; Quantitative determination of Epstein-Barr virus DNA in biopsies and punctates from organ and tissue lesions by PCR; Qualitative determination of Cytomegalovirus DNA in biopsies and punctates from organ and tissue lesions by PCR; Qualitative determination of Parvovirus B19 DNA in autopsy material by polymerase chain reaction)

RNA – ribonucleic acid

RF – Russian Federation

HF – heart failure

ESR – erythrocyte sedimentation rate

CRP – C-reactive protein

LCE – level of confidence of evidence

GRS – grade of recommendation strength

EF – ejection fraction

FC – functional class

CHF – chronic heart failure

HR – heart rate

ECG – electrocardiography (recording of electrocardiogram)

ECMO – extracorporeal membrane oxygenation

Pacemaker – Implantable dual-chamber pacemaker, without rate response***, Implantable dual-chamber pacemaker, rate-responsive***, Implantable single-chamber pacemaker, without rate response***, Implantable single-chamber pacemaker, rate-responsive***, Implantable three-chamber (biventricular) pacemaker***

EMB – endomyocardial biopsy (Myocardial biopsy)

EchoCG – echocardiography

AV block – atrioventricular block

CAR receptor – chimeric antigen receptor

ESC – European Society of Cardiology

HFA – Heart Failure Association of the ESC

ESMO – European Society for Medical Oncology

NT-proBNP – N-terminal pro-brain natriuretic peptide

Top2b – topoisomerase 2b

Top2a – topoisomerase 2a

** – the drug is included in the list of vital and essential drugs

*** – medical device implanted when providing medical care under the state guarantee program for free medical care to citizens

# – off-label prescription of a medicinal product not approved by state regulatory bodies and not mentioned in the instructions for use.

Terms and Definitions

Myocarditis is a umbrella term (a group of independent nosological entities or a manifestation of other diseases), an inflammatory myocardial disease of infectious, toxic (including drug-induced), allergic, autoimmune, or unclear etiology, with a wide spectrum of clinical symptoms: from asymptomatic course, mild shortness of breath, and mild chest pain resolving spontaneously, to heart failure, cardiogenic shock, life-threatening arrhythmias, and sudden cardiac death.

Inflammatory cardiomyopathy is a clinical umbrella term denoting myocarditis associated with myocardial dysfunction, where the histological and immunohistochemical criteria for the disease are identical to those of myocarditis. However, the clinical phenotype must include left ventricular systolic and/or diastolic dysfunction.

Dilated cardiomyopathy (DCM) is an umbrella term, a clinical phenotype characterized by the development of dilation and impaired contractile function of the left or both ventricles, which cannot be explained by coronary heart disease or volume overload.

Fulminant myocarditis – a severe form of inflammatory myocardial injury that develops rapidly as acute heart failure, cardiogenic shock, or life-threatening cardiac arrhythmias. The onset of the disease is always sudden. It is characterized by the rapid development of circulatory failure symptoms and fever with a body temperature above 38°C.

Subacute myocarditis – the onset of the disease is typically insidious. The patient struggles with the chronology of disease onset and its connection to a preceding acute infectious (respiratory or intestinal) disease, but always clearly reports that the disease manifested with symptoms of heart failure or pain syndrome («mask» of acute coronary syndrome). Histological analysis of endomyocardial biopsy (EMB, myocardial biopsy) reveals moderately pronounced inflammatory infiltrates. Echocardiography shows marked enlargement of the heart chambers and a decrease in myocardial contractility. Progression to DCM is characteristic of the subacute form of myocarditis.

Chronic active myocarditis – the onset of the disease goes unnoticed by the patient; even careful questioning fails to establish the duration of the disease. Symptoms typical of chronic heart failure (CHF) predominate. Histological analysis of EMB reveals a combination of inflammatory infiltrates of varying severity with areas of marked fibrosis. Echocardiography shows a moderate decrease in myocardial contractility. CHF functional class (FC) II–III dominates the clinical picture. Progression to dilated cardiomyopathy is frequent. Recurrences of myocarditis are characteristic of the typical clinical picture.

Chronic persistent myocarditis – the onset of the disease goes unnoticed by the patient, and it is difficult to determine the duration of the disease. The clinical picture is dominated by prolonged pain syndrome or clinical manifestations of myocardial remodeling with a dilated or restrictive phenotype. Histological analysis of EMB (pathological anatomical examination of biopsy (surgical) materials) reveals a combination of inflammatory infiltrates of varying severity with necrotic changes and areas of fibrosis. Long-term coexistence of such changes is typical. Echocardiography shows a moderate decrease in myocardial contractility. Significant dilation of the heart chambers and a decrease in left ventricular (LV) ejection fraction (EF) are absent. The outcome of the disease is favorable.

Giant-cell myocarditis has an acute onset. It is typically characterized by the rapid development of severe circulatory failure, predominantly followed by progressive refractory heart failure. The second distinctive feature of the clinical presentation is persistent ventricular rhythm disturbances and cardiac conduction disorders. When taking the medical history, special attention should be paid to identifying autoimmune diseases. The prognosis of the disease is extremely poor. The most effective treatment method is heart transplantation. Histological analysis of myocardial biopsy specimens (pathological-anatomic examination of myocardial tissue biopsy/surgical material) reveals giant multinucleated cells in the inflammatory infiltrate—resulting from macrophage transformation—containing phagocytized fragments of destroyed cardiomyocytes. Zones of inflammatory infiltrates with signs of active inflammation and foci of cardiomyocyte necrosis are identified. The detection of scar tissue is characteristic. Echocardiography reveals a marked decrease in myocardial contractility.

Eosinophilic myocarditis has an acute onset. Manifestations of circulatory failure predominate. When taking the medical history, special attention must be paid to analyzing the allergy history, drug therapy, history of vaccination, and helminthic infestation; in a number of cases, a connection with the intake of a new drug or food product can be suspected. Most often, acute eosinophilic allergic myocarditis develops against the background of sulfonamide intake (Sulfonamides and trimethoprim), anticonvulsants (antiepileptic drugs), and psychotropic drugs (Psycholeptics).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Myocarditis is a collective term (a group of independent nosological entities or a manifestation of other diseases), representing myocardial damage of an inflammatory nature—infectious, toxic (including drug-induced), allergic, autoimmune, or of unclear etiology—with a wide spectrum of clinical symptoms: ranging from an asymptomatic course, mild dyspnea, and mild chest pain that resolves spontaneously, to heart failure, cardiogenic shock, life-threatening arrhythmias, and sudden cardiac death.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

In clinical practice, the etiological cause of myocarditis in the vast majority of cases remains at the level of the most probable medical assumption.

Viral etiology

The introduction of molecular technologies into clinical practice—reverse transcription polymerase chain reaction (RT-PCR)—makes it possible not only to detect the presence of the viral genome but also to determine the clinical threshold for differentiating active viral infection from latent infection. The detection rate of various viral genomes varies across geographic regions of the world. In the Marburg Registry [1], the largest analysis of biopsy material over the past decade, the most frequent cause of myocarditis in Europe and North America is viral infection. Endomyocardial biopsy (EMB) identified the genomes of enteroviruses, adenoviruses, influenza viruses, human herpesvirus type 6 (HHV-6), Epstein-Barr virus, cytomegalovirus, hepatitis C virus, and parvovirus. The detection rate of various viral genomes varies across geographic regions of the world. In the European population, the most frequent viral genome was parvovirus B19 and human herpesvirus type 6, while the incidence of cytomegalovirus, herpes simplex virus, and Epstein-Barr virus as causes of myocarditis has decreased. Importantly, against this background, the detection rate of genomes of two or more viruses has increased. Viral associations occurred in 25% of cases [2–9].

The possibility of myocarditis developing during the acute period of novel coronavirus infection has been proven both by autopsy studies [1–3] and by intravital endomyocardial biopsy [4, 5]. In most cases, acute coronavirus myocarditis is diagnosed without morphological verification of the diagnosis, and frequently even without cardiac MRI data, based solely on the clinical presentation, ECG, and echocardiography findings.

Bacterial etiology

The bacterial etiology of myocarditis in the modern world is much less common than in the first half of the 20th century. However, even today, any bacterial agent can cause myocarditis. Most commonly identified are various Chlamydia species, Corynebacterium diphtheriae, Haemophilus influenzae, Legionella pneumophila, Mycobacterium tuberculosis, and Streptococcus group A. A feature of bacterial myocarditis is that it is merely one of the manifestations of the disease—its "secondary" nature—with the development of a clinical picture specific to myocarditis against the background of the underlying disease [10].

Direct toxic effect of drugs on the myocardium

Hypersensitivity reactions to certain drugs (hydrochlorothiazide** [C03AA03], furosemide**, broad-spectrum penicillins [J01CA], ampicillin**, azithromycin**, sulfonamides, tetracycline, methyldopa**, aminophylline**, phenytoin**, benzodiazepine derivatives [anxiolytics N05B]) manifest as eosinophilic myocarditis. The frequency of such myocarditis is low. The disease onset occurs within the first hours or days after starting therapy, but can also be delayed (as described for clozapine). Tetanus and smallpox vaccinations lead to myocarditis in 6 cases per 10⁴ vaccinations. Drug-induced myocarditis is characterized by a rapid increase in eosinophil levels combined with a picture of myocardial damage.

In modern internal medicine practice, a large number of cases of cardiac complications (with toxic myocardial damage or the development of myocarditis) have been described, developing during the administration of anthracycline antibiotics (antineoplastic antibiotics and related compounds L01D) doxorubicin** (including pegylated liposomal doxorubicin hydrochloride), daunorubicin**, and idarubicin** (a dose-dependent adverse effect of antineoplastic drugs from the anthracycline and related compounds group), due to their wide application in various chemotherapeutic treatment regimens, given their high antineoplastic activity [11]. It is believed that the cause of myocardial damage is the binding of the drug to cardiolipin and other membrane molecules, resulting in damage to the cardiomyocyte cell membrane. The key mediator of anthracycline-induced (L01D Antineoplastic antibiotics and related compounds) cardiotoxicity is topoisomerase 2b.

Type II topoisomerase unwinds DNA chains during replication, transcription, or recombination. Humans have 2 types of type 2 isomerase: topoisomerase 2a (Top2a) and topoisomerase 2b (Top2b). Top2a is thought to be located predominantly in proliferating cells, is involved in DNA replication, and is the primary molecular target of the antineoplastic activity of anthracyclines (L01D Antineoplastic antibiotics and related compounds). Top2b is located in resting cells, including cardiomyocytes. Inhibition of topoisomerase 2 by anthracyclines leads to double-stranded DNA breaks, which causes myocardial cell death and frequently the development of inflammation. The effect of anthracyclines (L01D Antineoplastic antibiotics and related compounds) on Top2b is a key factor in the development of cardiotoxicity.

Anthracycline cardiotoxicity is conventionally divided according to the time of its onset into acute, subacute, chronic, and late chronic. The 2012 ESMO guidelines (European Society for Medical Oncology) present the following classification of cardiotoxicity arising from treatment with anthracycline antibiotics (L01D Antineoplastic antibiotics and related compounds):

• acute – occurs in less than 1% of patients immediately after drug administration, reversible;

• acute-onset chronic progressive – occurs in 1.6–2.1% of cases during chemotherapy or within the first year after it;

• late-onset chronic progressive – occurs in 1.6–5.0% of cases 1 year after the end of chemotherapy;

• delayed (late-onset) – occurs 20–30 years after the end of chemotherapy [12].

Cardiotoxicity associated with the use of doxorubicin** and other drugs from the anthracycline and related compounds group is dose-dependent: with a cumulative doxorubicin** dose of 300 mg/m², the probability of developing chronic heart failure (CHF) is 1.7%; at a dose of up to 400 mg/m², it is 4.7%; at 500 mg/m², it is 15.7%; and at 650 mg/m², it is 48% [13].

Non-infectious causes of myocarditis include:

• myocarditis in systemic connective tissue diseases with immune disorders and systemic vasculitides (systemic lupus erythematosus, dermatomyositis, polymyositis, systemic sclerosis [systemic scleroderma], rheumatoid arthritis, granulomatosis with polyangiitis [Wegener's granulomatosis], etc.) [14];

• hypereosinophilic syndrome, helminthic infestation, and parasitic infections leading to the development of eosinophilic myocarditis.

Rare autoimmune and idiopathic myocarditides include:

• necrotizing eosinophilic myocarditis, which can be caused by hypersensitivity syndrome and Churg-Strauss systemic vasculitis. The role of human herpesvirus type 6 infection as a cause of the fulminant course of the disease with a rapid increase in symptoms of heart failure and high early mortality cannot be ruled out;

• idiopathic giant cell myocarditis, characterized by an extremely severe prognosis. Adolescents are most commonly affected. 20% of patients with verified giant cell myocarditis also have another autoimmune disease and allergic reactions, including to medications;

• cardiac sarcoidosis (a type of granulomatous myocarditis) can develop as part of an idiopathic systemic disease or be isolated. The isolated variant is extremely rare in clinical practice. However, myocardial remodeling with the development of heart failure clinical presentation is the second leading cause of death in systemic sarcoidosis (25%). Rare cases of isolated cardiac sarcoidosis require differential diagnosis with arrhythmogenic cardiomyopathy or primary cardiomyopathies presenting with dilated or hypertrophic phenotypes. An infarction-like course of cardiac sarcoidosis is also encountered, as well as involvement of the pericardium in the process.

Table 1. Main etiological factors in the development of myocarditis / inflammatory cardiomyopathies

^[1] Meadow saffron seed extract – source of the alkaloid colchicine

Pathogenesis of Myocarditis

Current concepts of the pathogenesis of myocarditis development can be schematically represented as a three-phase model [15], established through experimental studies on laboratory mice infected with Coxsackie B virus [16]. The Coxsackie B virus enters the human body via the gastrointestinal tract or respiratory system. The triggering mechanism of the inflammatory process is the binding of the virus to the endothelial receptor (CAR receptor – coxsackie-adenovirus receptor) [17]. To enter the cell, viruses utilize various biological factors, including viral adhesion molecules to the cardiomyocyte cell membrane, which accelerate cell membrane damage and facilitate viral entry into the cell. Once inside cardiomyocytes, viruses replicate and cause myocytolysis and activation of microRNA synthesis, which in turn leads to apoptosis and necrosis. These processes in the myocardium are conventionally described as the first phase of myocarditis development [15]. Altered cardiomyocytes trigger immune responses leading to inflammation in the myocardium and the formation of inflammatory cellular infiltration. Analysis of the inflammatory infiltrate showed that it consists of 70% mononuclear cells: monocytes, macrophages, and T lymphocytes. The first phase of the disease may end either with viral elimination upon an adequate immune response or progression to the second phase – secondary autoimmune damage to cardiomyocytes [15]. The autoimmune process, characterized by the production of antibodies against cardiomyocyte membranes, plays a leading role in the second stage of the disease [15].

Thus, the role of the virus that has invaded the cell is obvious: replication – cardiomyocyte damage, its death, and the initiation of an autoimmune response.

The second phase of autoimmune myocardial damage is accompanied by the development of autoimmune reactions. This process is mediated through several mechanisms: 1) release of autoantigenic proteins due to cell necrosis; 2) polyclonal activation of lymphocytes; 3) activation of T lymphocytes due to the action of a number of factors, including cytokines; 4) the phenomenon of molecular mimicry [18, 19]. The realization of the autoimmune process also occurs with the participation of a number of humoral factors, namely immunoglobulins, complement components, and autoreactive antibodies [20].

The third phase is characterized by the development of myocardial remodeling. Such a division is conventional; it is not possible to clearly divide the process into 3 phases, as the described processes may occur synchronously.

1.3 Epidemiology of the Disease or Condition

Current concepts regarding the epidemiology of myocarditis are fragmented and do not allow for a comprehensive picture. The variability of clinical manifestations at disease onset, numerous mild or subclinical forms that go unnoticed by physician and patient [2], and the high rate of spontaneous recovery (averaging 57%) [21] make recording this disease in routine clinical practice a challenging task [22–24]. The extremely rare practical application of the "gold standard of diagnostics" [22] – EMB – also complicates diagnostic verification.

It is known that during the analysis of post-mortem and biopsy material from patients initially followed up for DCM, morphological signs of myocarditis were absent in only 9–16% of adult patients and 46% of children [24–26].

Despite the heterogeneity of the analyzed groups, the main phenomenon of the modern stage of studying this problem is the undeniable increase in the number of new cases. The frequency of myocarditis ranges from 20 to 30% of all non-coronary heart diseases [27].

In a large population-based study conducted between 1990 and 2013 across 188 countries, an analysis of 301 nosological units determined that the incidence of myocarditis is approximately 22 cases per 100,000 population per year [28]. This suggests that approximately 1.5 × 10⁶ cases of acute myocarditis are diagnosed worldwide annually.

In the professional athlete population, sudden cardiac death is registered at a frequency of approximately 1 case per 80,000–200,000 athletes, with myocarditis occurring in every third case [29].

A 20-year follow-up of military recruits, which collectively analyzed > 670,000 men with signs of possible myocarditis, revealed 98 cases of acute myocarditis, 1 case of sudden cardiac death, and 9 cases of DCM onset [30].

According to the Pavlovsk Registry [31], myocarditis as a cause of circulatory decompensation requiring hospitalization was noted in 3 cases out of 1,000 hospitalizations/year.

In a Japanese autopsy study of the same duration, it was determined that myocarditis occurs with a frequency of 0.11% of all autopsies, regardless of the underlying disease and primary cause of death [32].

According to post-mortem examinations in Europe, inflammatory myocardial lesions are identified in 3–5% of cases [22], and among individuals dying suddenly under the age of 35, myocarditis is detected at autopsy in approximately 42% of cases.

Analysis of post-mortem study results revealed a significant clinical problem – pre-mortem underdiagnosis of myocarditis. Out of 17,162 autopsies, 91 cases revealed undiagnosed myocarditis during life, most frequently in the age group of 20 to 39 years [33]. The underdiagnosis of myocarditis is largely explained by the multifaceted clinical onset and subsequent manifestations. Analysis of the clinical picture in 3,055 patients with suspected myocarditis enrolled in the European Study of Epidemiology and Treatment of Inflammatory Heart Disease showed that in 72% of cases the dominant complaint was dyspnea, in 32% – diffuse substernal chest pain, and in 18% – palpitations. Such a disease manifestation in routine clinical practice significantly complicated the diagnosis of myocarditis [34], since in the absolute majority of cases, physicians attributed the clinical picture to ischemic heart disease (IHD). Thus, the prevalence of myocarditis is seriously underestimated due to its nonspecific presentation and frequently asymptomatic course.

The prevalence of myocarditis among men and women was studied in hospitalized patients admitted to the inpatient department for verified myocarditis. Out of 3,274 hospitalized patients, myocarditis was significantly more common in men, while a more severe course of the disease was characteristic of women [36, 37].

Young men develop myocarditis more frequently than women, which is explained by the influence of sex hormones on the severity of the immune response in women [9, 38].

In children, including newborns, the fulminant form of viral myocarditis is more common [37]. Pathomorphological analysis of biopsy material has shown that in the European population, parvovirus B19 is most frequently detected [38], in the USA — adenovirus 9 [19], and in Japan — hepatitis C virus [20]. This trend has been consistently observed in the European population over the past 20 years. A significantly higher frequency of parvovirus B19 identification in myocardial biopsies of myocarditis patients, reaching 60–80%, is reported in [38–42].

On the other hand, based on the fact that parvovirus B19 is quite frequently detected in myocardial biopsies of patients with preserved LVEF, the diagnostic significance of this fact has become a subject of discussion [43]. It must be agreed that, in addition to the presence of the virus in the myocardial tissue, the viral load, the severity of the replication process, and the baseline status of the patient are of importance [44], and epidemiological data focusing solely on the frequency of virus detection in the myocardium do not allow for true epidemiological perceptions. However, an analysis of data from the Marburg Registry [45] (12,500 patients) showed that PV B19 is detected twice as often in the myocardial tissue of patients with signs of myocardial inflammation and reduced LVEF compared to patients without signs of myocardial inflammation and reduced LVEF (33.3% versus 17.6%, respectively) [1].

Due to the difficulties in verifying the diagnosis, the true incidence of acute coronavirus myocarditis is unknown and, according to various authors, ranges from 0.011 to 0.2% of all PCR-positive patients [46], and up to 14% according to autopsy data [6]. Based on an analysis of data from nearly 57,000 hospitalized patients with COVID-19, myocarditis was diagnosed (based on biopsy in 17 patients, and in the rest based on MRI and elevated troponin levels) in 112 patients, which accounted for less than 1%; mortality among patients with myocarditis over 120 days reached 6.6% [47].

Thus, the analysis of epidemiological studies suggests that the actual number of acute myocarditis cases in real clinical practice is much higher than the rate of diagnosed cases.

1.4 Features of Coding the Disease or Condition

In the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) (in both the 1996 and 2019 Russian-language versions), myocarditis corresponds to categories I40, I41*, and I51.4.

I40 Acute myocarditis

I40.0 Infectious myocarditis

Included: septic myocarditis. If necessary to identify the infectious agent, additional codes B95-B98 are used (note: in the Russian Federation (RF), in cases of fatal outcomes, when formulating the diagnosis and issuing the medical death certificate, such second additional codes are not used).

I40.1 Isolated myocarditis

I40.8 Other acute myocarditis

I40.9 Acute myocarditis, unspecified

I41* Myocarditis in diseases classified elsewhere

(note: ICD-10 for special tabulations, but not for formulating the diagnosis and medical death certificate, allows dual coding of certain conditions, in particular using the dagger (†) and asterisk (*) symbols. In the RF, the use of subcategories [codes] with an asterisk (*) as independent categories in diagnoses and medical death certificates is strictly prohibited).

I41.0* Myocarditis in bacterial diseases classified elsewhere.

Myocarditis:

• diphtheritic (A36.8†)

• gonococcal (A54.8†)

• meningococcal (A39.5†)

• syphilitic (A52.0†)

• tuberculous (A18.8†)

I41.1* Myocarditis in viral diseases classified elsewhere.

Influenza myocarditis (acute):

• seasonal virus identified (J10.8†)

• virus not identified (J11.8†)

• zoonotic or pandemic virus identified (J09†)

• mumps myocarditis (B26.8†)

I41.2* Myocarditis in other infectious and parasitic diseases classified elsewhere.

Myocarditis in:

• Chagas disease, chronic (B57.2†)

• Chagas disease, acute (B57.0†)

• toxoplasmosis (B58.8†)

I41.8* Myocarditis in other diseases classified elsewhere.

• Rheumatoid myocarditis (M05.3†)

• Sarcoid myocarditis (D86.8†)

I51.4 Myocarditis, unspecified

Included: myocardial fibrosis, myocarditis (unspecified) chronic (interstitial).

In this regard, any classification available to the medical institution may be used in parallel with ICD-10. However, when formulating the diagnosis or medical death certificate and coding myocarditis, it is required to use ICD-10 terms and codes (in the diagnosis, followed by decryption according to the applied classification).

For the convenience of formulating a diagnosis in a therapeutic, cardiological, or other non-surgical inpatient setting, preference should be given to the Mayo Clinic classification.

1.5 Classification of the disease or condition

In the clinical and morphological classification by E.B. Lieberman (1991), along with the Dallas morphological criteria, the specific features of the course of inflammatory myocardial diseases are taken into account. The author's version of the classification identifies the following clinical variants of myocarditis: fulminant, subacute, chronic active, and chronic persistent myocarditis (Table PA3-1, Appendix A3).

Subsequent variants of this classification, supplemented by other experts, introduced 2 additional clinical variants: giant cell and eosinophilic myocarditis. In modern clinical practice, this classification is used more frequently than others.

Fulminant myocarditis — a severe form of inflammatory myocardial injury that develops rapidly in the form of acute heart failure, cardiogenic shock, or life-threatening cardiac arrhythmias. The onset of the disease is always sudden. It is characterized by the rapid development of circulatory failure symptoms and a fever with body temperature above 38°C. During patient questioning, a clear temporal link with a preceding common cold/acute viral infection occurring approximately 2 weeks prior to the onset of myocarditis can be established. Echocardiography reveals a marked decrease in contractility, no significant dilation of the heart chambers, and myocardial edema. Pathomorphological analysis of the myocardial biopsy (surgical) material reveals multiple foci of inflammatory infiltration, and necrosis foci may be present. Within 2 weeks, this form of myocarditis can result either in complete recovery and restoration of LV function or (much less frequently) in rapid progression of heart failure, persistent hypotension, and a fatal outcome. With this variant of the disease course, the earliest possible use of mechanical circulatory support in intensive care units is required.

Subacute myocarditis — the onset of the disease is typically insidious. The patient has difficulty with the chronology of the disease onset and its connection with a preceding acute infectious (respiratory or intestinal) disease, but always clearly reports that the disease manifested with symptoms of heart failure or pain syndrome («mask» of acute coronary syndrome). Pathomorphological analysis of the myocardial biopsy (surgical) material reveals moderately severe inflammatory infiltrates. Echocardiography reveals marked dilation of the heart chambers and a decrease in myocardial contractility. Transition to DCM is characteristic of the subacute form of myocarditis.

Chronic active myocarditis — the onset of the disease remains unnoticed by the patient; even a thorough patient interview does not allow determining the duration of the disease. Symptoms typical of CHF dominate. Histological analysis of endomyocardial biopsy (EMB) of the heart reveals a combination of inflammatory infiltrates of varying severity with areas of pronounced fibrosis. Echocardiography reveals a moderate decrease in myocardial contractility. The clinical picture is dominated by CHF NYHA functional class II-III. Transition to dilated cardiomyopathy frequently occurs. Recurrences of myocarditis are characteristic of the typical clinical picture.

Chronic persistent myocarditis – the onset of the disease remains unnoticed by the patient, and the duration of the disease is difficult to determine. The clinical picture is dominated by prolonged pain syndrome or clinical manifestations of myocardial remodeling with a dilated or restrictive phenotype. Analysis of the post-mortem or biopsy (surgical) myocardial tissue material reveals a combination of inflammatory infiltrates of varying severity with necrotic changes and areas of fibrosis. Long-term coexistence of such changes is typical. Echocardiography determines a moderate decrease in myocardial contractility. Significant dilation of the heart chambers and decrease in LVEF are not observed. The outcome of the disease is favorable.

Giant cell myocarditis – the onset of the disease is acute. Rapid development of pronounced circulatory failure is typical, subsequently dominated by progressive refractory heart failure. The second feature of the clinical picture is persistent ventricular rhythm disturbances and cardiac conduction disorders. When taking the anamnesis, special attention must be paid to identifying autoimmune diseases. The prognosis of the disease is extremely severe. The most effective treatment method is heart transplantation. Analysis of the post-mortem or biopsy (surgical) myocardial tissue material reveals giant multinucleated cells in the inflammatory infiltrate – the result of macrophage transformation, containing phagocytosed fragments of destroyed cardiomyocytes. Zones of inflammatory infiltrates with signs of active inflammation and foci of cardiomyocyte necrosis are determined. The detection of scar tissue is characteristic. Echocardiography determines a pronounced decrease in myocardial contractility.

Eosinophilic myocarditis – the onset of the disease is acute. Manifestations of circulatory failure dominate. When taking the anamnesis, special attention must be paid to the analysis of allergic history, drug therapy, indications of vaccination, helminthic invasion; in a number of situations, a connection with the intake of a new drug or food product can be suggested. Most often, acute eosinophilic allergic myocarditis develops against the background of taking sulfonamides (sulfonamides and trimethoprim), anticonvulsants (antiepileptic drugs), and psychotropic drugs (psycholeptics).[48].

Echocardiography reveals a slight decrease in cardiac contractility and mural thrombi in the heart cavities. Thus, eosinophilic myocarditis is characterized by the formation of thrombi leading to thromboembolic complications. Analysis of the post-mortem or biopsy (surgical) myocardial tissue material reveals, along with foci of necrosis, eosinophilic dominance in the inflammatory infiltrate and involvement of the endocardium in the pathological process, which leads to the formation of mural thrombi. A general (clinical) blood test may reveal eosinophilia. In rare cases, the final stage of the disease may be the formation of endomyocardial fibrosis leading to severe, refractory CHF.

The main criterion of the Lieberman clinical-morphological classification is the histological picture of the myocardial biopsy specimen. It is important to remember that class I recommendation for myocardial biopsy (ACC/AHA and ESC guidelines) applies only to patients with the following clinical phenotypes.

Table 3. Absolute indications for endomyocardial biopsy [49]

In all other situations, EMB can only be discussed, including in the differential diagnosis of the causes of heart failure that developed more than 3 months ago with a reasonable suspicion of a granulomatous process (Table 3).

Attempts to put clinical-morphological classifications into practice run into the need to have the tools, highly qualified specialists to perform EMB, qualified pathologists to evaluate the histological material, as well as to conduct and evaluate the results of immunohistochemical examination (pathological and anatomical examination of biopsy [surgical] material using immunohistochemical methods), and a molecular biological laboratory to detect the viral genome, which makes the practical application of these classifications unlikely (if EMB cannot be performed in a specific hospital, the patient should be referred to a higher-level hospital). The question of using EMB in patients with a subclinical course of the disease remains unclear, when the risk of developing DCM is very high, and the transition to this clinical form remains unnoticed.

Therefore, in the interests of real clinical practice, along with morphological and clinical-morphological classifications, clinical classifications based on the etiopathogenetic principle continue to be developed.

In 2016, a simple and convenient classification of myocarditis based on the assessment of the initial condition of patients was proposed – the Mayo Clinic classification [39], which allows determining the prognosis and choosing treatment tactics. Based on three leading symptoms: chest pain, arrhythmia, manifestations of heart failure, high-risk, moderate-risk, and low-risk patients are distinguished (Table AP3-2, Appendix A3).

• Low-risk patients: the prognosis for such patients is favorable. The disease begins with typical chest pain and supraventricular arrhythmias. LV contractile function is preserved. A rapid response to therapy and normalization of ECG and echocardiography (EchoCG) within 1-4 weeks are typical.

• High-risk patients: the prognosis is severe, but largely depends on the early response to ongoing therapy, the dynamics of clinical symptoms (symptoms of circulatory failure, life-threatening arrhythmias, atrioventricular blocks, syncopal states) and EchoCG parameters (LVEF).

• Intermediate risk: the prognosis is uncertain. Patients show moderately pronounced structural and functional changes determined during the decoding, description, and interpretation of the ECG (decoding, description, and interpretation of electrocardiographic data) and EchoCG. Life-threatening rhythm and conduction disorders are not recorded. There are no syncopal states. Non-sustained ventricular arrhythmias are characteristic. The recording of late gadolinium enhancement in the myocardium in the absence of remodeling of the heart chambers and a pronounced decrease in LV contractility is typical.

For the convenience of formulating a diagnosis in a therapeutic, cardiological, or other non-specialized hospital, the Mayo Clinic classification appears to be the most convenient and simple (Table AP3-2, Appendix A3).

Myocarditis can be classified by etiological factor into infectious and non-infectious.

Infectious myocarditis includes:

– viral (enteroviruses, Coxsackie viruses, ECHO viruses, influenza viruses, parvovirus B-19, herpes viruses, adenoviruses, rubella, measles, hepatitis B and C viruses, cytomegalovirus, human immunodeficiency virus (HIV);

– bacterial (Chlamydia, Corynebacterium diphtheriae, Legionella, Mycobacterium tuberculosis, Mycoplasma, Staphylococcus, Streptococcus A, Streptococcus pneumoniae);

– myocarditis caused by:

• fungi (Actinomyces, Aspergillus, Candida, Cryptococcus);

• helminthic invasion (Echinococcus granulosus, Trichinella spiralis);

• protozoa (Toxoplasma gondii, Trypanosoma cruzi – Chagas disease);

• rickettsiae (Coxiella burnetii, Rickettsia typhi);

• spirochetes (Borrelia burgdorferi, Leptospira, Treponema pallidum).

Non-infectious myocarditis includes:

– myocarditis in systemic connective tissue diseases with immune disorders (systemic lupus erythematosus, dermatomyositis, polymyositis, systemic sclerosis [systemic scleroderma], rheumatoid arthritis);

– myocarditis in systemic diseases (sarcoidosis, granulomatosis with polyangiitis [Wegener's granulomatosis], Kawasaki disease, Crohn's disease, ulcerative colitis, polyarteritis nodosa);

– myocarditis caused by hypersensitivity to certain drugs (broad-spectrum penicillins [J01CA], sulfonamides [sulfonamides and trimethoprim], tetracycline, methyldopa**);

– myocarditis caused by the use of agents with cardiotoxic effects (amphetamine and its derivatives, catechols [adrenergic and dopaminergic agents], cocaine, streptomycin**, antineoplastic drugs);

– myocarditis caused by exposure to various poisons (arsenic, iron, lead, cobalt, thallium);

– myocarditis associated with thyrotoxicosis, radiotherapy courses, and ionizing radiation.

1.6 Clinical presentation of the disease or condition

The analysis of the clinical picture and the initial clinical suspicion of myocarditis onset are established by a general practitioner or family physician at the primary care level. Timely initiation of treatment and determination of the required volume of specialized care depend on the correct interpretation of complaints and symptoms.

Myocarditis primarily affects young and middle-aged individuals.

The outcome of acute myocarditis is largely determined by the etiology of the disease, the severity of circulatory failure, and the rate of symptom progression [2, 50, 51]. Disease onset with biventricular failure is always prognostically unfavorable and indicates a high risk of a fatal outcome [2, 22, 24, 25, 50, 52, 53].

The clinical presentation at disease manifestation varies widely: from mild malaise, minor chest pain, and mild dyspnea to a fulminant course resulting in acute heart failure and death. The initial manifestation of myocarditis may be sudden death caused by ventricular tachycardia or ventricular fibrillation secondary to focal inflammatory myocardial lesions.

Myocarditis frequently debuts with thromboembolism in the pulmonary (more commonly) and (less commonly) systemic circulation.

Disease onset with rapid progression of heart failure is always due to severe diffuse myocarditis and indicates a high risk of a fatal outcome.

In some cases, at early stages, clinical manifestation is completely absent, and the diagnosis is established retrospectively. Deterioration caused by the onset of myocarditis in patients with pre-existing cardiovascular disease and symptoms of chronic heart failure is often misdiagnosed as decompensation of the underlying condition.

When analyzing the onset of the disease, it is important to remember that the initial clinical manifestations of myocarditis—complaints of palpitations, skipped heartbeats, and dyspnea upon mild exertion or at rest—are reported by patients either during or 1–2 weeks after the onset of an acute respiratory viral infection.

Almost all patients develop prolonged, diffuse pain in the left hemithorax and the precordial region, dull, aching, or stabbing in nature, unrelated to physical exertion and not relieved by organic nitrates. Chest pain is most frequently caused by concomitant pericarditis, and less commonly by myocardial ischemia resulting from direct injury to cardiomyocytes by an infectious or toxic agent, as well as endothelial dysfunction of the coronary arteries.

Myalgia is characteristic, representing a manifestation of myositis caused by myotropic Coxsackie A viruses.

The clinical picture of myocarditis onset is complemented by fever, weakness, rapid fatigue (the severity of which does not change despite reduced physical activity), arthralgia, and gastroenteritis.

Data from observational and epidemiological studies [35, 54] have established that at disease onset, 68.6% of patients experience dyspnea, 34.1% chest pain, 32.8% palpitations, 29.8% fever, 16.4% arrhythmias, 11.9% hemoptysis, 8.9% cough, 5.97% asthma attacks, 2.9% dizziness, 1.5% syncopal episodes, and 1.5% arthralgia.

The interpretation of newly emerged symptoms characteristic of myocarditis onset requires a thorough patient history regarding preceding events, such as acute respiratory viral infections, vaccination, initiation of a new medication, or any toxic exposure.

The severity of the clinical course of myocarditis depends on the intensity of the inflammatory process and whether the inflammation predominantly involves the left, the right, or both ventricles simultaneously.

At the stage of full-blown manifestation, the clinical picture of myocarditis is characterized primarily by manifestations of heart failure, either newly developed or as an exacerbation/decompensation of pre-existing failure. This period is typically characterized by a combination of heart failure symptoms with rhythm and conduction disorders, most commonly against the background of sinus tachycardia.

The recovery period is characterized by the alleviation of circulatory failure symptoms. In most cases, they resolve completely. In moderate myocarditis, complete recovery may occur within 1–6 months from disease onset. In one-third of cases, symptoms of circulatory failure persist and tend to progress, subsequently becoming dominant.

During the recovery period, varying degrees of asthenia are characteristic of all patients.

Table 5. Diagnostically significant criteria in suspected myocarditis

Clinical scenarios of myocarditis onset

Myocarditis onset mimicking acute coronary syndrome (ACS)

The differential diagnosis between acute coronary syndrome and acute myocarditis is one of the challenging issues in internal medicine. The difficulty in making a diagnostic decision is due to the fact that ST-segment elevation in 2 contiguous leads is recorded in 54% of cases; negative T wave in 27% of cases; ST-segment depression in 18% of cases; pathological Q wave in 27% of cases [55, 56]; and elevated troponin levels to some degree in the vast majority of cases. In situations where the ST segment is above the baseline, the patient routinely undergoes coronary angiography or cardiac magnetic resonance imaging (contrast-enhanced CMR), and a diagnostic decision is made based on the results [57–59]. In the absence of coronary pathology, the likelihood of myocarditis, pericarditis, or—considering the duration, severity, and localization of the pain syndrome—aortic dissection increases sharply [60, 61].

When diagnosing acute myocarditis, it is important to remember that a clinical picture dominated by chest pain is typical for parvovirus B19. This virus is characterized by infection of coronary artery endothelial cells, leading to coronary spasm and myocardial ischemia. A clinical feature of such myocarditis is the lack of parallelism between the severity of the pain syndrome and the severity of circulatory failure [62, 63].

It must be acknowledged that in various combinations of pronounced pain syndrome, varying degrees of troponin elevation, presence or absence of regional wall motion abnormalities on echocardiography, and absence of ST-segment elevation, the diagnosis of myocarditis can be considered in the differential diagnosis as merely probable. Prompt performance of coronary angiography or CMR will undoubtedly resolve this issue.

If these diagnostic procedures cannot be performed, a number of authors [60] suggest evaluating the rate of troponin level decline. In most cases, unlike ACS, myocarditis is characterized by a delayed decrease in troponin levels, which allows for a retrospective assessment of the probability of myocarditis. In complex cases, endomyocardial biopsy is a subject of discussion.

Table 6. Diagnostically significant criteria for myocarditis onset mimicking ACS

Note: ACS – acute coronary syndrome, CAD – coronary artery disease, ECG – electrocardiography, EchoCG – echocardiography, CMR – cardiac magnetic resonance imaging

Myocarditis onset mimicking heart failure

The most frequent clinical symptom at the onset of myocarditis is circulatory failure. In situations where the patient has no coronary insufficiency and/or other known causes of heart failure, myocarditis comes to the forefront of the differential diagnostic series. To simplify the diagnostic search, it is customary to distinguish 2 clinical situations:

1) the onset or progression of heart failure within 2 weeks to 3 months from the onset of the disease;

2) the manifestation of CHF more than 3 months from the onset of the disease.

For the first situation, an in-depth analysis of the patient's medical history is important, since the possible appearance of symptoms after a respiratory or gastrointestinal infection, or during pregnancy, is of crucial diagnostic importance. It should be remembered that the clinical presentation may develop against the background of impaired systolic function of the left and/or right ventricle with/without wall thickening, with/without ventricular dilatation on echocardiography, as well as against the background of nonspecific ECG changes. The lack of response to the ongoing recommended therapy for myocarditis over a short period, recurrent ventricular arrhythmias, and second- to third-degree AV blocks raise the question of re-analyzing the patient's coronary angiogram and performing EMB (Table 7).

In the second situation (Table 8), it is important to note that an out-patient presenting with severe fatigue, palpitations, dyspnea, prolonged atypical chest pain, and arrhythmias for more than 3 months exhibits frequent episodes of circulatory decompensation and repeated hospitalizations despite standard CHF therapy. In this situation as well, the diagnostic hypothesis requires morphological confirmation.

Despite the conventional nature of this division, it must be acknowledged that this approach allows the internist to focus on two diagnostically important aspects: the cause-and-effect relationship between myocarditis and a preceding infection, and the lack of response to the administered recommended treatment.

Table 7. Diagnostically significant clinical signs of myocarditis onset masked as the onset or progression of heart failure in the absence of CAD or other causes of circulatory failure (manifestation period – from 2 weeks to 3 months)

Note: HF – heart failure, CAD – coronary artery disease, ECG – electrocardiography, echocardiography – echocardiography, MRI – magnetic resonance imaging

Table 8. Diagnostically significant clinical signs of myocarditis onset masked as chronic heart failure in the absence of coronary insufficiency and other known causes of heart failure (manifestation period – more than 3 months) [38]

Note: HF – heart failure, DCM – dilated cardiomyopathy, ECG – electrocardiography, ECHO-CG – echocardiography, MRI – magnetic resonance imaging

Onset of myocarditis disguised as life-threatening rhythm and conduction disorders

Viral myocarditis is characterized by arrhythmias, which is explained by the direct damaging effect of the virus on cardiomyocytes and conduction system cells, the development of myocardial edema, and inflammatory myocardial infiltration. These processes lead to repolarization heterogeneity, transmembrane potential instability, and the formation of ectopic foci of abnormal automaticity, clinically manifested as ventricular tachyarrhythmias. In rare cases, tachyarrhythmias lead to sudden death. The onset of myocarditis with torsades de pointes is a clinical rarity. A key factor for the clinician is the development of arrhythmias without preceding ischemic myocardial changes and in the absence of overt coronary artery disease.

Atrial fibrillation – persistent form or paroxysms in the absence of verified CAD, valvular pathology, and thyroid disease – strongly suggests myocarditis. Rare manifestations of myocarditis onset include cardiogenic shock.

Table 9. Diagnostically significant clinical signs of myocarditis onset masked as life-threatening rhythm and conduction disorders [38]

Onset of myocarditis in diphtheria

Myocarditis of varying severity develops in every tenth patient with diphtheria [64, 65]. Simultaneous involvement of the pharynx and myocardium is characteristic. Myocarditis develops either in the first days of the disease or several weeks later. Myocarditis in diphtheria patients occurs due to the effect of Corynebacterium diphtheriae exotoxin, which has a high tropism for the cardiac conduction system. Various conduction disorders are quite common in patients with diphtheritic myocarditis. Clinically and prognostically unfavorable are bifascicular block and complete AV block, which require temporary pacemaker implantation***, although the impact of this procedure on long-term prognosis has not been studied [65, 66]. In addition to conduction disorders, clinically significant circulatory failure develops. A high mortality rate is characteristic of unvaccinated children. A decrease in vaccination coverage within scheduled timeframes has led to an increase in the number of new cases. Only 95% coverage of the child population with diphtheria immunization prevents the epidemic spread of diphtheria. In cases of developed disease in adults, ECG monitoring (electrocardiogram recording) is mandatory during treatment of the underlying condition.

Onset of myocarditis in streptococcal infection

Streptococcal toxin has a high tropism for cardiomyocyte membranes, leads to necrosis and pain syndrome, and plays a key role in the clinical manifestation of the disease. It is important to note the clinical feature of this disease: the simultaneous development of tonsillitis and myocarditis. Another feature is the discrepancy between pronounced complaints and a benign clinical course. A key feature of this myocarditis is rapid and complete recovery.

Rheumatic myocarditis

The main feature of this myocarditis course is the involvement of the endocardium, myocardium, and pericardium in the pathological process. Rheumatic myocarditis is a component of rheumatic carditis, which is rare in clinical practice and occurs predominantly in young people. Analysis of endomyocardial biopsy (EMB) results reveals inflammatory infiltrates and Aschoff-Talalaev bodies. Pronounced necrosis is generally absent. Valvular involvement is present in virtually every clinical case, making isolated myocardial dysfunction without valvular involvement uncharacteristic of this process.

Typical clinical phenotypes of myocarditis onset

• Acute diffuse, prolonged chest pain (identical in characteristics to pericarditic pain) of varying intensity, frequently retrosternal in localization, accompanied by fever (subfebrile/febrile), rhythm disorders, dyspnea, tachycardia, and arrhythmias, predominantly in young individuals without overt signs of coronary artery disease. In this situation, ruling out coronary pathology is an urgent measure.

• Dyspnea, fatigue, diffuse, prolonged chest pain, arrhythmias, or other signs of circulatory failure present in the patient within days to a month after suffering, or with an anamnestic history of, a respiratory or gastrointestinal infection, or reports of chills, headache, myalgia, general malaise, or pregnancy.

• Newly onset (from several days to 3 months from disease onset) dyspnea at rest or upon exertion, and/or fatigue, with/without signs of left- and/or right-ventricular failure in a situation where coronary insufficiency and/or other known causes of heart failure are absent.

• Worsening of previously existing dyspnea at rest or upon exertion, or chronic (> 3 months) presence of dyspnea, and/or increased fatigue, or chronic (> 3 months) presence of edema and other signs of HFrEF/HFpEF in a situation where decompensation of coronary insufficiency and/or other known causes of heart failure progression are absent.

• Persistent tachycardia and/or arrhythmias of unclear genesis, and/or syncopal states, and/or successful cardiopulmonary resuscitation within several days to 3 months from disease onset, in a situation where coronary insufficiency is absent.

• Cardiogenic shock in a situation where coronary insufficiency and/or other known causes of acute LV failure are absent.

• In the differential diagnostic series, the probability of myocarditis must be analyzed in all situations where the history includes indications of bronchial asthma or other allergic diseases, autoimmune diseases, DCM, prior myocarditis, exposure to toxic agents, including medicinal ones.

Myocarditis in patients with acute coronavirus infection

Characteristic features of coronavirus myocarditis are its combination with pericarditis, the development of coronaritis and endothelitis with microvascular thrombosis and secondary ischemic damage to cardiomyocytes, and mural endocardial thrombosis. Histological examination (pathological and anatomical examination of biopsy material) predominantly reveals lymphocytic infiltration in the myocardium, endocardium, and pericardium, as well as increased expression of innate antiviral immunity markers (toll-like receptors types 4 and 9), which confirms the viral-immune nature of the inflammation [67, 68]. The detection of macrophages [69] and an increased CD4/CD8 ratio are also considered typical.

Differential diagnostics must be performed with other variants of myocardial injury: Takotsubo syndrome [70], acute myocardial ischemia due to microvascular thrombosis [71], and type 2 myocardial infarction. Acute coronavirus myocarditis, which most frequently presents in an infarction-like form (with anginal pain, ischemic ECG changes, and a significant increase in troponin levels), may be accompanied by severe systolic dysfunction, life-threatening rhythm and conduction disorders, and become one of the causes of death [72–74]. Fulminant forms have been described [75–77]. The development of coronavirus myocarditis is possible in patients without pneumonia [78, 79], as well as with negative PCR results of nasopharyngeal swabs (detection of coronavirus RNA 229E, OC43, NL63, HKUI (Human Coronavirus) in nasopharyngeal mucosa swabs by PCR) [68].

Post-COVID myocarditis

By June 2021, 1,226 suspected cases of vaccine-associated pericarditis and myocarditis were reported to VAERS (Vaccine Adverse Event Reporting System), with 40% of the cases occurring in individuals under 30 years of age [VAERS—Guide to Interpreting VAERS Data. (accessed on 21 May 2023)]. Of these, 323 reports were confirmed by the Centers for Disease Control and Prevention. The estimated incidence of myocarditis/pericarditis in individuals aged < 30 years after receiving the second dose of an mRNA vaccine was approximately 40 cases per million among males and 4.2 cases per million among females. When considering the age group ≥ 30 years, these rates were significantly lower: 2.4 and 1.0 per million in males and females, respectively [80]. The true incidence of vaccination-associated myocarditis is unknown, since available reports refer only to symptomatic patients. Reports of myocarditis following SARS-CoV-2 vaccination are heterogeneous due to different inclusion criteria in studies, different characteristics (age, sex, etc.) of subjects, different diagnostic criteria for post-vaccination myocarditis, different vaccine types and doses, as well as various follow-up periods after vaccination. According to several authors, post-vaccination myocarditis is a rather rare phenomenon: 0.58 per 100,000 people vaccinated with the second dose [81]. In the majority of subjects, myocarditis occurred after the administration of the second dose, with a median interval from the last dose administration to symptom onset of 3 days. These findings suggest the presence of an immune-mediated reaction to vaccine administration. Among the proposed mechanisms by which the COVID-19 vaccine** may induce myocarditis, activation of both innate and adaptive immune responses against the SARS-CoV-2 spike glycoprotein, as well as recognition of the mRNA itself as an antigen by the immune system, should be mentioned first. Like other viral myocarditides, post-vaccination myocarditis occurs predominantly in genetically predisposed young males, pointing to a potential role of sex hormones [82, 83, 84].

Post-vaccination myocarditis (induced by SARS-CoV-2 vaccines)

The first description of post-vaccination myocarditis appeared in April 2021. Cases of pericarditis following vaccination were soon described [85]. Myocarditis is listed among the 4 main causes of death following vaccination, along with thrombotic thrombocytopenia, myocardial infarction, and rhabdomyolysis [86]. There are reports on the use of mechanical circulatory support and heart transplantation for fulminant post-vaccination myocarditis [87, 88]. The consolidated Vaccine Adverse Event Reporting System (VAERS, USA, Europe, and UK) included 18,204 cases of myo- and pericarditis, 40% of patients were older than 40 years [89]. Overall, the incidence of post-vaccination myocarditis is estimated at 7.64 per million vaccine doses, and for pericarditis at 5.32 per million; case fatality is estimated at 0.102 per million vaccine doses and 0.017 per million, respectively [90].

The majority of post-vaccination myocarditis cases developed after the administration of mRNA-containing vaccines (Pfizer-BioNTech and Moderna). However, myocarditis is also possible after the administration of vector-based vaccines [91], which include products created in Russia. The mechanism of post-vaccination myocarditis may be associated with the active component of the vaccine, the mRNA sequence encoding the SARS-CoV-2 Spike protein, or with the immune response following vaccination. The disease is registered more frequently in men after the administration of the second dose of the vaccine. Risk factors include a history of autoimmune diseases (e.g., bronchial asthma).

Cases of post-vaccination myocarditis development (arrhythmic, decompensated) both in the first hours and 2–4 weeks after the administration of domestic vaccines are also known to us; more frequently, such a reaction to the vaccine developed in patients who had previously suffered from coronavirus infection, which is confirmed by literature data [96–98]. Severe post-COVID myocarditis requires the prescription of corticosteroids (systemic corticosteroids) according to regimens similar to the treatment of acute COVID or post-COVID myocarditis. Re-vaccination is contraindicated in such patients.

Novel coronavirus infection in patients with chronic myocarditis of another etiology

SARS-CoV-2 infection can affect the course of chronic non-COVID myocarditis, which depends on the extent of baseline myocarditis therapy. Maintenance immunosuppressive therapy to a certain extent helps avoid SARS-CoV-2-induced exacerbations; however, during the infection period, the cytostatic drug (antineoplastic agent) must be discontinued. The absence of baseline therapy is a risk factor for myocarditis exacerbation, for the relief of which systemic corticosteroids should be used primarily.

Baseline immunosuppressive therapy does not significantly alter the serological response to coronavirus infection/vaccination; statistics regarding the safety of vaccination in patients with chronic myocarditis are currently lacking. There is also no evidence supporting the advisability of coronavirus vaccination in patients with myocarditis who have previously had the infection. Given the risk of myocarditis exacerbation and the unproven benefit of vaccination in such patients, it is better to refrain from it.

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for diagnosing myocarditis:

• Acute chest pain, including pericarditis-like or pseudo-ischemic pain. Newly onset (from several days to 3 months) or worsening of previously existing dyspnea at rest or upon exertion, and/or fatigue, with/without signs of left- and/or right-ventricular failure

• Subacute/chronic (> 3 months) presence of dyspnea at rest or upon exertion, and/or fatigue, with/without signs of left- and/or right-ventricular failure, or worsening of these symptoms

• Palpitations and/or arrhythmia of unclear genesis, and/or syncopal states, and/or aborted sudden death (successful resuscitation)

• Cardiogenic shock of unclear etiology

2.1 Complaints and Anamnesis

Currently, there are no prospective clinical studies proving the importance and mandatory nature of a specific list of questions during the initial examination. Nevertheless, years of clinical experience [15, 35, 54, 67, 68] have helped identify essential questions that have diagnostic value.

Given that myocarditis should be suspected in all cases of unexplained heart failure (where routine cardiac diagnostic methods fail to identify the cause), unexplained tachycardia, and arrhythmias (especially ventricular), it is necessary to check if the patient presents with [15, 35, 54, 67, 68]:

— complaints of dyspnea, palpitations, episodes of syncope, fatigue, paroxysmal nocturnal dyspnea;

— a history of a recent respiratory or gastrointestinal infection;

— episodes of chills, headache, myalgia, general malaise (it should be remembered that symptoms of myocarditis typically develop 1–2 weeks after the onset of a viral illness);

— pregnancy.

A number of conditions increase the likelihood of developing myocarditis [101].

When taking the medical history, it is necessary to clarify whether there is a history of:

— bronchial asthma or other allergic conditions, autoimmune diseases;

— dilated cardiomyopathy (DCM);

— previous myocarditis;

— exposure to toxic agents, including medications.

During the physical examination, it is necessary to determine:

— the patient's position in bed (orthopnea);

— the presence of lower extremity edema;

— the presence of acrocyanosis, jugular venous distension.

2.2 Physical Examination

The key aspect of the physical examination is the search for signs of circulatory failure. There are no pathognomonic signs of myocarditis; in some cases, physical examination reveals no abnormalities, while in others, the detected changes are minimal. In approximately one-third of patients, the manifestations of the disease are overt.

• Measurement of body temperature: fever of varying severity may be recorded, but low-grade fever is most common.

• An elevated temperature is not characteristic of myocarditis. Febrile or low-grade fever is a manifestation of the infectious disease underlying the development of myocarditis or its complications, such as pulmonary embolism or acute pneumonia.

• Measurement of heart rate (HR): persistent tachycardia is typical, the severity of which does not correlate with the elevation of body temperature. Bradycardia or bradiarrhythmias may occur if conduction disorders develop.

• Blood pressure (BP) measurement (on peripheral arteries): arterial hypotension is considered an absolute indication for admission to the intensive care unit [100]. It is rare at disease onset and is a sign of a poor prognosis.

• To correctly interpret the obtained data, it is necessary to find out whether the patient is taking medications that affect these hemodynamic parameters.

• Palpation and percussion of the heart (percussion in heart and pericardial pathology): the position of the apex beat depends on the degree of LV chamber remodeling. Percussion may reveal an expansion of the borders of relative and absolute cardiac dullness.

• Abdominal palpation (palpation in abdominal wall pathology): hepatomegaly may occur as a manifestation of developing severe heart failure. Ascites typically develops in severe cases with treatment-refractory heart failure (the same applies to the development of hydrothorax).

• Auscultation of the lungs and heart (auscultation in heart and pericardial pathology, auscultation in pulmonary and bronchial diseases): tachypnea is a very frequent symptom. Fine moist symmetrical rales may be auscultated in the lungs as a manifestation of pulmonary congestion.

• During cardiac auscultation (auscultation in heart and pericardial pathology), the key point is determining the amplitude of the first heart sound. The amplitude of the first sound is always inversely proportional to the blood volume in the left ventricle. Consequently, a decrease in the amplitude of the first sound indicates the onset of LV remodeling. The appearance of a gallop rhythm (S3) is a sign of severe circulatory failure. A systolic murmur at the apex radiating to the axilla indicates the development of relative mitral regurgitation [27, 67, 68].

2.3 Laboratory Diagnostics

Nonspecific inflammatory markers and peripheral blood eosinophil counts

An elevated erythrocyte sedimentation rate (ESR) and an increased C-reactive protein (CRP) level are frequently recorded in acute myocarditis. These changes are not specific to myocarditis and reflect the severity of the systemic inflammatory response. An elevated ESR and increased CRP level allow the physician only to suspect myocarditis, but cannot confirm the diagnosis. The normalization of altered values is individual. A prolonged lack of positive dynamics may indicate chronic progression of the process. Circulating cytokine levels are not specific to myocarditis and indicate the severity of the systemic inflammatory response [102]. In acute myocarditis, determining the eosinophil count in a complete blood count (CBC) is diagnostically significant. High baseline eosinophilia suggests eosinophilic myocarditis.

ESC IC (RR S, ELD 5)

Necrosis biomarkers

There are no necrosis markers specific solely to myocarditis. When acute myocarditis is suspected, it is more appropriate to determine the serum concentration of troponin T or I (troponin I and T blood test) [38], as these markers are more sensitive to cardiomyocyte injury than changes in the MB fraction of creatine kinase (CK-MB). Normal troponin T and I levels do not rule out myocarditis. High troponin T levels also carry a negative prognostic value [71, 72, 105]. In recent years, new myocardial injury markers have been described that can also be used as adjuncts in the diagnosis of myocarditis: markers associated with extracellular matrix degradation [106], pentraxin 3, galectin-3, and growth differentiation factor 15 [107].

ESC I C (LoE C, GoR 4)

Serum cardiac autoantibodies

More than 20 serum cardiac autoantibodies against various cardiac and muscle antigens have been identified in patients with myocarditis [2, 40, 52, 76, 77]: AFA, anti-fibrillary Ab; AHA, organ-specific and partially organ-specific anti-heart aabs; AIDA, anti-intercalated disks-aabs; Anti B-1-AR; Anti B-2-AR; Anti Alpha-MNC; Anti-non-myofibrillar; Anti ANT, adenine nucleotide translocator; AMLA, anti-myolemmal aabs; AR, adrenergic receptor; ASA, anti-sarcolemmal aabs; IFA, anti-interfibrillary aabs; BCKD, branched chain alpha-ketoacid dehydrogenase dihydrolipoyl transacylase; HSP, heat shock protein.

An elevated titer of cardiac autoantibodies indicates an autoimmune nature of the process; however, the absence of an elevated titer does not rule out myocarditis, as the inflammatory process in the myocardium may develop without autoantibody formation. The dynamics of autoantibody titers help assess the efficacy of ongoing immunosuppressive or immunomodulatory therapy.

In situations where:

• endomyocardial biopsy (EMB) data show histological and immunohistochemical criteria for myocarditis, the viral genome is absent in the myocardial biopsy tissue, and cardiac autoantibodies are detected in the blood serum, it can be assumed that viral elimination has occurred, but autoimmune myocarditis persists [2, 52, 78, 79].

• a patient lacks an infectious etiology for myocarditis, baseline levels of IgG antibodies highly specific for myocarditis should be used as autoimmune markers of disease prognosis and the efficacy of immunosuppressive therapy or immunomodulation [2, 52, 76, 78, 79].

• cardiodepressive antibodies are detected in the serum of a patient suffering from myocarditis, immunoadsorption makes it possible to achieve stabilization and improvement of hemodynamic parameters [111].

Modern clinical practice recognizes serum cardiac autoantibodies, which are considered predictors of the development of myocarditis or DCM [81, 82]; the clinical significance of these data is currently being refined.

Currently, in real-world clinical practice, there are no inexpensive and readily available tests to detect cardiac autoantibodies. Such studies are conducted only in diagnostic centers, controlled trials, and research laboratories [114].

No ESC guideline (LoE C, GoR 5)

Viral antibodies

Serological markers of viral infection verified in the patient's peripheral blood do not constitute a basis for a diagnostic conclusion regarding the presence of viral myocarditis. The diagnostic significance of serological methods is limited due to the high prevalence in the population of viruses that cause myocarditis, while reactivation, viral reinfection, or cross-reactivity with Epstein-Barr virus/enteroviruses makes the interpretation of laboratory data extremely difficult and ambiguous. In the general population, including healthy individuals, the circulation of IgG antibodies against cardiotropic viruses is common and is not accompanied by clinical manifestations of viral myocarditis.

In clinical practice, infection with non-cardiotropic enteroviruses can trigger the appearance of antibodies that are laboratory-indistinguishable from the response to cardiotropic viruses. Consequently, determining the titer of viral antibodies has limited value in the diagnosis of viral myocarditis [22, 43, 52, 115, 116, 117, 118].

Comparison of EMB analysis results with the titer levels of circulating IgG antibodies against cardiotropic viruses revealed no correlation between them [2, 3, 7, 88, 89]. Persistence of the virus in the myocardium was associated with ventricular dysfunction, whereas elimination of the viral genome from myocardial tissue was associated with improved cardiac contractility and a better 10-year prognosis [7]. Other results contradicting the above are also known; for instance, it was established that immunohistochemically verified inflammation in the myocardial biopsy specimen, rather than the fact of viral persistence in the myocardial tissue, was an independent predictor of life prognosis [3]. Unfortunately, to date, it remains unclear what percentage of spontaneously recovered patients had a viral etiology of myocarditis. The mechanisms responsible for the reactivation of latent viral infection and viral replication processes in chronic myocarditis also remain unclear [5].

The feasibility of virological studies is high when myocarditis is suspected in a patient with hepatitis C, rickettsiosis, Lyme disease (only in endemic areas), and HIV.

ESC III B (CGR C, LER 2)

Heart failure markers

An elevated natriuretic peptide level is not specific to myocarditis, but it allows the physician to assess the severity of intracardiac hemodynamics changes and the degree of left ventricular filling pressure alteration. An elevated natriuretic peptide level indicates the onset of heart failure and makes it possible to assess its severity in patients with myocarditis.

Normal NT-proBNP values do not rule out the presence of myocarditis. Changes in NT-proBNP levels over time provide insight into treatment efficacy and patient prognosis. Persistence of high levels suggests active inflammation and chronization of the process.

ESC IC (RR S, ELD 5)

ESC IC (RR S, ELD 5)

2.4 Instrumental Diagnostics

Electrocardiography

When myocarditis is suspected, ECG changes exhibit low sensitivity and specificity. The sensitivity of the method is only 47% [121]. There are no specific electrocardiographic changes characteristic exclusively of myocarditis. The most frequent ECG changes are sinus tachycardia, negative T wave, ST-segment changes, AV blocks, and left bundle branch block. In some cases, an infarction-like ECG is recorded (ST-segment elevation or depression and pathological Q wave [73, 91]), which indicates a poor prognosis [2, 27]. Thus, the most valuable electrocardiographic parameter in patients suffering from myocarditis is the QRS complex duration.

ESC I C (LoE C, GoR 4)

Chest X-ray

ESC IC (RR S, ELD 5)

Transthoracic echocardiography

At the very first stage of the diagnostic workup, this method allows for identifying the causes leading to the development of heart failure while ruling out valvular heart disease, hypertrophic and restrictive cardiomyopathies, and pericardial effusion [122]. The detection of a regional wall motion abnormality zone requires mandatory differential diagnosis with coronary artery disease [123]. In 25% of cases, intracavitary thrombi are verified in patients with myocarditis, which requires assessing the risks and benefits of initiating therapy with direct oral anticoagulants (DOACs).

Analysis of the baseline state and subsequent dynamics of systolic and diastolic ventricular functions, ejection fraction (EF) values, left and right ventricular dimensions, wall thicknesses, left atrial dimensions, left ventricular filling pressure, and pulmonary artery pressure makes it possible to assess the disease prognosis and the effect of ongoing treatment with high probability [123].

In typical situations of acute myocarditis, there may be minimal left ventricular dilation, wall thickening due to myocardial edema, and global or regional contractility impairments. In patients with acute myocarditis, additional assessment of left ventricular longitudinal myocardial strain using speckle-tracking echocardiography enables the detection of left ventricular dysfunction and its severity, especially in patients with preserved ejection fraction [124, 125], and helps predict the risk of non-sustained ventricular tachycardias [126] and supraventricular arrhythmias [127].

Fulminant myocarditis is characterized by a marked decrease in EF, but normal heart chamber dimensions. At the same time, global longitudinal left ventricular strain assessed via speckle-tracking echocardiography can be a very important indicator of myocardial inflammation, and its initially low values do not indicate poor recovery of myocardial function during hospitalization in patients with fulminant myocarditis [128].

As the process becomes chronic, significant chamber dilation and reduced EF are more characteristic.

In patients with suspected myocarditis, the Tei index (Appendix G1) can serve as an additional echocardiographic parameter of left ventricular dysfunction, especially when traditional echocardiographic parameters are within normal limits (Table PA3-3, Appendix A3) [129, 130].

Performing an echocardiogram is mandatory prior to the EMB procedure.

ESC I C (CGR A, LER 5)

Radionuclide diagnostics

For the diagnosis of myocardial inflammation in myocarditis, radionuclide diagnostic methods are inappropriate for initial disease detection due to low specificity [40, 92].

Radionuclide imaging methods may be justified in cases of suspected sarcoid myositis (if cardiac MRI data are inconclusive). In suspected myocarditis in a patient with sarcoidosis, myocardial scintigraphy using thallium chloride 199Tl and technetium [99mTc] sestamibi may be used [94, 95, 133].

Whole-body positron emission tomography with fluorodeoxyglucose [18F] can rarely be used to diagnose cardiac sarcoidosis and systemic sarcoidosis (in ambiguous cases) [134].

• Radionuclide diagnostic methods are not recommended for the primary diagnosis of myocarditis due to their low specificity and lower availability, unlike cardiac MRI [38, 95, 226].

ESC III C (LoR C, LoE 5)

ESC not specified (LoE C, GoR 4)

Magnetic resonance imaging

In modern practice, contrast-enhanced cardiac MRI (magnetic resonance imaging) using paramagnetic contrast agents (gadolinium-based agents) with myocardial mapping is widely used and significantly improves the diagnosis of acute myocarditis. To date, it is the most informative tomographic imaging method for identifying foci of myocardial inflammation, myocyte injury and necrosis, as well as a tool for the differential diagnosis of myocarditis from other myocardial diseases.

Late gadolinium enhancement (LGE) cardiac MRI using a paramagnetic contrast agent (PCA) identifies myocardial regions from which EMB should be targeted [55, 98]. Healthy myocardium in the delayed enhancement phase (15–20 minutes after PCA administration) no longer accumulates the contrast agent and shows a low-intensity signal on specialized MR pulse sequences that null the MR signal from normal heart muscle. Foci of acute inflammation, necrosis, and myocardial fibrosis in myocarditis accumulate and retain PCA for a prolonged period [136]. In this case, they appear on MRI as areas with high signal intensity. An important feature of these lesions is their specific distribution pattern in the myocardium: they are typically subepicardial, intramyocardial, or multiple in localization. In acute myocarditis, contrast-enhanced cardiac MRI may also reveal signs of hyperemia in affected myocardial areas, edema, or alterations in T1 and T2 magnetic relaxation times, which can be evaluated using MRI mapping techniques.

Special Lake Louise Criteria have been proposed for the diagnosis of myocarditis by MRI [4, 100]. These include:

• Regional or global myocardial edema visible on T2-weighted images (signal intensity is considered increased if the myocardial-to-skeletal muscle signal intensity ratio is ≥ 2.0) [99, 101, 102].

• Prolonged myocardial T2 relaxation time (based on myocardial T2 relaxation time mapping)

• Early myocardial enhancement visualized on T1-weighted images following intravenous PCA administration. This is assessed based on the ratio of signal intensity from myocardial segments to that of skeletal muscle. A ratio ≥ 4 or an increase in myocardial signal intensity by ≥ 45% indicates hyperemia and edema of the affected myocardial area during the acute inflammatory phase, pointing to myocarditis.

• At least one late gadolinium enhancement (LGE) focus in the myocardium visible on T1-weighted images with normal myocardium signal suppression 15–20 minutes after PCA administration. Typically, in myocarditis, LGE foci are multiple and have a subepicardial or intramural localization. Subepicardial and transmural enhancement foci are more characteristic of acute myocardial infarction and scar lesions, corresponding to affected coronary artery territories. In myocarditis, the distribution and extent of LGE foci do not correspond to coronary artery vascular territories.

• Prolonged myocardial T1 relaxation time or increased extracellular volume (ECV) fraction calculated from myocardial relaxation time mapping.

Additional criteria include signs of myocardial dysfunction and the presence of exudative pericarditis.

The presence of ≥ 2 criteria on MRI indicates the presence of inflammation characteristic of myocarditis.

When 2 positive criteria are present, the sensitivity and specificity of the method are 67% and 91%, respectively.

When only late gadolinium enhancement with PCA is present, the sensitivity and specificity of the method are 59% and 86%, respectively [98, 100, 103, 104, 105].

The sensitivity of the method decreases in patients with a long disease duration and chronic myocarditis, especially outside of exacerbations [59, 106, 107].

Late gadolinium enhancement on MRI usually does not differentiate between the acute and chronic phases of inflammation; data interpretation depends largely on the patient's clinical status [137]. However, acute myocarditis is characterized by signs of myocardial edema and hypervascularization (see above).

MRI allows for highly accurate quantitative assessment of heart chamber dilatation, as well as regional or global myocardial dysfunction.

A direct comparison of EMB and cardiac MRI results in 82 patients with a positive troponin test (blood troponin I, T levels) but no coronary artery abnormalities showed that late gadolinium enhancement corresponded to histologically verified active myocarditis. EMB was more informative in cases of mild or subclinical myocarditis. The combination of both methods (EMB and contrast-enhanced cardiac MRI) has greater diagnostic significance than each method individually.

Thus, contrast-enhanced MRI is a highly informative imaging modality in myocarditis [55]. A repeat contrast-enhanced cardiac MRI is justified in cases where the clinical presentation is consistent with myocarditis, but the initial MRI either reveals no pathological changes or shows only a single pathological sign. MRI is also useful for evaluating treatment efficacy in myocarditis as it allows simultaneous assessment of myocardial status, global and regional contractility, and the dynamics of pericardial effusion.

ESC IIaC (LoE C, GoR 3)

Comments: Contrast-enhanced cardiac MRI helps optimize the diagnosis of acute myocarditis and identifies myocardial regions from which EMB should be targeted (if this procedure is technically unavailable at the current medical facility, the possibility of transferring the patient to another medical facility to perform this study should be discussed) [51, 94].

ESC I C LoR C, LoE 5

ESC IIb C (LoR C, LoE 5)

Contrast-enhanced cardiac MRI does not replace the diagnostic value of EMB, especially in critically ill patients. Performing contrast-enhanced cardiac MRI should generally precede EMB [99, 100, 104, 105, 107].

Computed tomography angiography (CTA) of the heart and coronary arteries

Cardiac CTA is inferior to MRI in detecting myocardial lesions in myocarditis. Currently, advanced CT techniques for diagnosing inflammatory myocardial diseases (dual-energy CT, delayed iodine enhancement CT) are being investigated, but their use is still limited to expert centers with experience in performing and interpreting them.

At the same time, CTA can be used as an alternative to invasive coronary angiography to rule out coronary artery disease and acute coronary syndrome [94], if necessary. CTA allows for the assessment of heart chamber volumes, global and regional myocardial contractility.

Coronary angiography

ESC IIaC (LoE C, GoR 5)

2.5 Other Procedures

Endomyocardial biopsy of the myocardium

Endomyocardial biopsy of the myocardium is considered the gold standard for diagnosing myocarditis [49]. The introduction of the Dallas criteria for the morphological diagnosis of myocarditis into clinical practice has standardized diagnostic criteria and made it possible to determine the etiological cause of myocarditis—specifically, identifying giant cell and necrotizing eosinophilic myocarditis [22, 50, 51]. Diagnostic accuracy depends on the number and size of biopsy specimens; however, the inability in most cases to perform targeted myocardial biopsy due to the initial mosaic pattern of myocardial lesions reduces the sensitivity and value of this method. The sensitivity of the method is 50% when obtaining and subsequently analyzing 4–5 samples, and 79% when analyzing 17 biopsy specimens [144]. The recommended size of biopsy specimens is 1–2 mm. The minimum number of biopsy specimens required to formulate a diagnostic conclusion is 3 [123]. EMB is performed via access through the right or left jugular veins, subclavian vein, or right or left femoral arteries and veins. The site for obtaining EMB from the left or right ventricles is determined by MRI data, which provides the physician with more accurate information on the localization of the pathological process than decisions based on clinical presentation, which only allow for presumptive localization of the inflammatory process based on the severity of circulatory congestion. In addition to hematoxylin and eosin staining of histological sections and light microscopy tissue structure analysis (pathological-anatomical examination of biopsy material), immunohistochemical analysis of myocardial biopsy specimens (pathological-anatomical examination of biopsy (surgical) material using immunohistochemical methods) using antibodies against T-lymphocyte markers (CD3), monocytic lineage cells (CD68), HLA-DR (Determination of HLA antigens), etc., is mandatory. This approach allows for a comprehensive characterization of the inflammatory infiltrate. Detection of HLA-DR expression (Determination of HLA antigens) is a marker of non-infectious myocarditis etiology and allows autoimmune genesis to be considered primary. These data provide a rationale for initiating immunosuppressive therapy [22, 78]. The detection of complement fraction C3d and C4d deposits in myocardial biopsy specimens is used to identify rejection reactions in heart transplantation. Currently, this is used to verify immune system activation in patients with inflammatory cardiomyopathy [52, 108].

The diagnostic value of EMB was previously based solely on morphological criteria. Dallas morphological criteria are based on three pathomorphological changes in myocardial tissue: infiltration, myocytolysis, and edema. The infiltrate contains T-lymphocytes and helper T-lymphocytes (≥ 7 CD3+ per mm² or 2 per high-power field, CD4+), suppressor T-lymphocytes (CD8+), activated T-lymphocytes (CD45RO), monocytes, and macrophages (CD68+).

The presence of more than 14 lymphocytes and monocytes/macrophages per mm² indicates an active inflammatory process in the myocardium. Myocarditis is considered ruled out if the number of myocardial infiltrating cells is < 14 per mm². Acute myocarditis is considered verified in the presence of ≥ 14 infiltrating cells per mm² of myocardial biopsy specimen combined with signs of cardiomyocyte necrosis and degeneration; chronic myocarditis is verified in the presence of ≥ 14 infiltrating cells per mm² of biopsy specimen, presence of fibrosis, but absence of signs of cardiomyocyte necrosis and degeneration [141, 142]. There are typically 4 degrees of myocardial fibrosis (sclerosis) severity: 0 – no fibrosis, grade 1 – mild, grade 2 – moderate, grade 3 – severe fibrosis [141]. The severity of fibrosis is a prognostic criterion for the development of circulatory failure.

The Dallas criteria did not require immunohistochemical study (pathological and anatomical examination of biopsy (surgical) material using immunohistochemical methods) and virus genome determination. Currently, molecular analysis (with DNA (deoxyribonucleic acid)-RNA extraction and PCR amplification of the viral genome, quantitative determination of viral load and viral replication rate, allowing to determine the etiology of myocarditis) is mandatory [2, 5, 22, 52, 108].

Previously, EMB complications occurred in 6% of cases, including perforation and cardiac tamponade in 0.1-0.5% of cases [109, 110]. Performing the procedure by experienced specialists currently reduces this rate to 0-0.8% [2, 3, 107, 111].

Determining the patient's clinical phenotype helps the physician decide on the indications for EMB.

Table 10. Indications for endomyocardial biopsy

Repeat EMB procedures are not routine practice. Their appropriateness should be discussed if there are reasonable assumptions of non-compliance with EMB requirements, lack of consensus among pathologists, lack of response to etiological therapy, or lack of response to treatment in a patient with progressive heart failure of unknown etiology.

ESC not specified (LoE C, GoR 4)

ESC I C (LoE C, GoR 4)

No ESC guideline (LoE C, GoR 5)

For the diagnosis of post-COVID myocarditis, contrast-enhanced cardiac MRI and, in cases of persistent myocardial systolic dysfunction, EMB in expert centers should be used.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Prospective, controlled, full-scale studies evaluating the efficacy of myocarditis treatment and its impact on prognosis have not been conducted. Existing guidelines are based solely on expert opinion [40, 112, 113]. The modern fundamental principle in the treatment of myocarditis: "myocarditis treatment must be carried out in accordance with current guidelines for the management of acute and chronic HF" [146]. Treatment of myocarditis aims at:

— emergency correction of life-threatening conditions (refractory circulatory failure, cardiac rhythm and conduction disorders);

— correction of chronic manifestations of circulatory failure caused by myocardial dysfunction and neurohumoral activation;

— specific etiopathogenetic effects on viral infection and immune inflammation.

3.1 Conservative Treatment of Myocarditis

Treatment of myocarditis in patients with unstable hemodynamics

Hospitalization of such patients should be carried out in major hospitals with intensive care unit monitoring capabilities equipped with cardiopulmonary resuscitation devices (LUCAS 2 mechanical chest compression device with accessories) and mechanical ventilation equipment (Mechanical ventilator). At the onset of myocarditis, unstable hemodynamics can develop in any of its forms, but most often a sharp deterioration in hemodynamic parameters and the development of cardiogenic shock, despite ongoing symptomatic medical therapy, accompanies fulminant myocarditis. Making the correct decision regarding the monitoring location for such a patient (primarily taking into account the equipment of the department) becomes life-saving, as connecting a circulatory support device or performing ECMO (extracorporeal membrane oxygenation) can save a life or buy time needed to address issues related to heart transplantation [114, 115].

Mortality in fulminant myocarditis ranges from 20-40% across various clinical groups. The majority of patients who survive the acute phase of fulminant myocarditis experience recovery of ventricular contractility. Therefore, the combination of symptomatic medical therapy and mechanical hemodynamic support devices (Intra-aortic balloon counterpulsation device) (when medical therapy alone is ineffective) is the basic principle of treatment for patients at the onset of acute myocarditis with unstable hemodynamics or cardiogenic shock [114, 115].

Organization of medical care for patients with fulminant acute myocarditis and unstable hemodynamic parameters – see Section 6.

General principles and management tactics for patients with acute myocarditis hospitalized with unstable hemodynamics

• If signs of cardiogenic shock or respiratory failure are verified in patients with acute myocarditis, hemodynamic or respiratory support measures must be initiated immediately to stabilize hemodynamic parameters or ensure adequate ventilation, thereby preventing further deterioration and the development of complications [116, 117].

  Further treatment tactics and drug selection are based on determining the patient's hemodynamic profile (J. S. Forrester and L. W. Stevenson classification) as "wet – cold" / "dry – warm" (Appendix B) [116, 117].

• Catheterization of major vessels (subclavian and other central vein catheterization) and invasive hemodynamic monitoring are indicated for patients with acute myocarditis only in cases of cardiogenic shock or therapy-refractory circulatory failure and the inability to relieve symptoms [116, 117].

Determination of natriuretic peptide levels (testing for N-terminal pro-B-type natriuretic peptide) and analysis of subsequent dynamics are mandatory. With an NT-proBNP level < 300 pg/ml, circulatory failure due to acute myocarditis is virtually unlikely. However, it should be remembered that a low NT-proBNP level may indicate an extremely severe (terminal) condition in a patient with acute myocarditis or the development of right ventricular failure, for example, following pulmonary embolism.

ESC not specified (LoE C, GoR 4)

No ESC guideline (LoE C, GoR 5)

No ESC guideline (LoE C, GoR 5)

No ESC guideline (LoE C, GoR 5)

No ESC guideline (LoE C, GoR 5)

Principles of diuretic therapy in a patient with acute myocarditis and unstable hemodynamics

No ESC guideline (LoE C, GoR 5)

Diuretic therapy involves choosing one of two loop diuretic administration tactics: bolus or continuous intravenous infusion. The DOSE study [153] compared the efficacy of these two tactics using high (200 mg) and low (80 mg) doses of loop diuretics. High-dose furosemide** compared to low doses was more effective and allowed for a faster increase in diuresis and reduction of respiratory failure, but was significantly more likely to cause transient renal injury. No clinical difference was found between the bolus and continuous intravenous infusion tactics of loop diuretics. In the ROSE-AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure) study [154], an analysis of the dynamics of renal tubular injury markers (N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1) in 283 patients with circulatory decompensation over 72 hours treated with high-dose furosemide** (median dose 560 mg IV, individual range 300 to 815 mg) revealed no impairment in tubular filtration, although renal function worsening occurred in 21.2% of patients. This study demonstrated that short and aggressive diuretic therapy does not lead to irreversible tubular damage.

The use of torasemide is preferred over furosemide** in patients with decompensated chronic heart failure [124, 125, 155], since torasemide use was associated with significantly fewer episodes of creatinine elevation and reduced renal filtration function. Long-term outcome analysis showed that therapy with torasemide, but not furosemide**, led to a reduced risk of rehospitalization due to decompensated chronic heart failure [124, 125, 155]. Clinical experience gained from the analysis of diuretic regimens [150], data from the ASCEND-HF trial subanalysis [151], and long-term prognosis evaluation [150] indicate that a "smooth and prolonged" diuretic regimen compared to an "intensive and short" regimen leads to a reduction in long-term rehospitalizations [167] and less renal function impairment.

The development of loop diuretic resistance is a frequent phenomenon upon the initiation of diuretic therapy.

ESC: none (LoE C, GoR II)

No ESC guideline (LoE C, GoR 5)

• в) It is recommended to use blood ultrafiltration in patients with acute myocarditis when drug-based methods are ineffective [184, 160].

No ESC guideline (LoE C, GoR 5)

Principles of vasodilator administration for heart disease in a patient with acute myocarditis and unstable hemodynamics

Venodilation reduces preload and pulmonary capillary wedge pressure, relieving symptoms of pulmonary edema. Arteriolar dilation reduces afterload. Vasodilators for cardiac diseases (C01D) (hereinafter referred to as vasodilators) allow for a simultaneous effect on veins and arterioles, improving the contractility of the inflammation-damaged myocardium.

The following dosages and administration regimens should be adhered to:

— Nitroglycerin**: starting dose of 8–16 mcg/min with subsequent titration up to 166 mcg/min

— Isosorbide dinitrate**: starting dose of 1 mg/hour with subsequent titration up to 10 mg/hour

— Sodium nitroprusside dihydrate: starting dose of 0.3 mcg/kg/min with subsequent titration up to 5 mcg/kg/min.

No ESC guideline (LoE C, GoR 5)

Principles of positive inotropic drug administration in a patient with acute myocarditis and unstable hemodynamics

In routine clinical practice for unstable hemodynamics, the following are used: adrenergic and dopaminergic agents (catecholamines) (C01CA) (dopamine** (C01CA04), dobutamine** (C01CA07)); inotropic agents with vasodilatory effects (levosimendan** (other cardiotonic agents), cardiac glycosides).

ESC none (LoE B, GoR 2)

The duration of positive inotropic therapy is strictly limited to the period of hypoperfusion and persistent hypotension (with the exception of digoxin**), as prolonged use of positive inotropic agents worsens the prognosis in patients with circulatory failure [139, 140].

Not addressed in ESC guidelines (Level of Evidence B, Grade of Recommendation 2)

Comments: In domestic practice, dopamine** and epinephrine** (adrenergic and dopaminergic agents C01CA) are prescribed more often than others; the use of epinephrine** is frequently necessitated by hypotension and shock in patients with myocarditis. The strategy for selecting dopamine** doses is as follows: low-dose dopamine** (1–3 mcg/kg/min) exerts a dopaminergic effect and stimulates diuresis, whereas high-dose dopamine** (> 5 mcg/kg/min) stimulates beta- and alpha-adrenoceptors, leading to tachycardia and vasoconstriction. Dobutamine** shares the same indications and is used in the following dosages: 2–20 mcg/kg/min. Epinephrine** shares the same indications and is used in the following dosages: 0.2–1.0 mcg/kg/min. Administration of a 1 mg dose of epinephrine** is appropriate during resuscitation measures. Repeated injections are possible every 3–5 minutes. In routine situations, the drug is administered at a dose of 0.05–0.5 mcg/kg/min.

An analysis of long-term outcomes in patients receiving prolonged dopamine** therapy for refractory hypotension and hypervolemia demonstrated that low-dose dopamine** does not improve renal function, but neither does it worsen the long-term prognosis of survivors of the acute period [142, 143, 167].

During the acute phase of viral myocarditis, the use of digoxin** is discouraged [50], as digoxin** therapy increases the myocardial synthesis of pro-inflammatory cytokines, potentially exacerbating myocardial inflammation (data obtained from a murine model) [168].

Therapy with the inodilator levosimendan** (other cardiotonic agents) in the SURVIVE trial [169] showed no superiority over dobutamine**, while in the REVIVE I and II trials, the clinical effect of the drug evaluated by mortality risk did not differ from placebo. Furthermore, a subgroup analysis revealed an increased risk of death with levosimendan** therapy in patients with a baseline systolic blood pressure below 100 mm Hg. These findings necessitate an exceptionally cautious approach when selecting a drug to correct hypoperfusion in patients with hemodynamic instability [170].

Rationale for glucocorticoid (GC) therapy in the acute phase of myocarditis with hemodynamic instability

In routine clinical practice, erroneous GC therapy (glucocorticoids H02AB) in patients with hemodynamic instability occurs frequently and can be life-threatening.

Two clinical phenotypes of patients with acute myocarditis should be distinguished:

• virus-negative – virus-negative inflammatory cardiomyopathy (eosinophilic, granulomatous, giant cell myocarditis, and lymphocytic myocarditis associated with systemic connective tissue diseases, as well as myocarditis during heart transplant rejection);

• virus-positive – virus-associated inflammatory cardiomyopathy.

The administration of GCs (H02AB) is not indicated in patients with acute myocarditis, with the exception of autoimmune, eosinophilic, granulomatous, and giant cell variants.

In a randomized, prospective, double-blind, single-center trial (TIMIC) [171], the administration of prednisolone** and azathioprine** in patients with virus-negative inflammatory cardiomyopathy resulted in an increased left ventricular ejection fraction (LVEF) and a reduction in left ventricular end-diastolic and end-systolic dimensions (LVESD) in 88% of patients (38 of 43 treated) compared to a deterioration in cardiac contractility in 83% of patients receiving placebo (35 of 42 treated with placebo). The lack of response in 100% of cases can be attributed either to undetected viruses or to mechanisms of injury and inflammation refractory to immunosuppression.

These findings are supported by a systematic review (Cochrane Database of Systematic Reviews 2013) [172]. The administration of GCs in 719 patients with viral myocarditis (only 38% with verified viral infection) did not lead to a significant reduction in mortality compared with patients not receiving this treatment (RR = 0.93, 95% CI 0.70–1.24); however, CK-MB levels were 10 U/L lower (MD = 10.35 U/L, 95% CI 8.92–11.78). At 3 months, LVEF was 7% higher in the GC-treated group (MD = 7.36%, 95% CI 4.94–9.79). The functional class of heart failure and LVESD did not differ between patients with and without GC (H02AB) treatment. The greatest therapeutic benefit was observed in pediatric patients.

These data illustrate the difficulty of deciding to initiate GC (H02AB) therapy during disease onset when the etiology of myocarditis remains unclear.

GCs (H02AB) may be prescribed to a patient with acute myocarditis and hemodynamic instability in the presence of morphologically confirmed giant cell, eosinophilic, or granulomatous myocarditis, as well as criteria-proven autoimmune myocarditis in mixed connective tissue disease [172].

In all other cases, the decision to initiate immunosuppressive therapy should be made only in the event of standard therapy failure in patients with moderate or severe heart failure, life-threatening rhythm and/or conduction disturbances, and strictly upon histological and immunohistochemical confirmation of inflammatory myocardial disease, alongside the absence of viral genomes in myocardial biopsy specimens.

Absolute evidence can only be provided by the results of histochemical analysis of biopsy material (pathomorphological examination of renal biopsy/surgical material using histochemical methods).

In the absence of such data, only a medical board (consilium) can weigh anamnestic or other clinical findings (eosinophil counts, fulminant onset of symptoms, etc.) to decide on the initiation of GC therapy (H02AB).

Management of rhythm and conduction disturbances in the acute phase of myocarditis

The poor prognosis in patients with myocarditis, both in the acute and long-term phases of the disease, is largely driven by the development of refractory, malignant ventricular tachyarrhythmias (Lown-Wolf grade III or higher).

There are no dedicated clinical trials on the treatment of life-threatening arrhythmias in myocarditis. Expert consensus on this issue is based on experimental studies.

In everyday clinical practice, it is appropriate to follow current European Society of Cardiology (ESC) guidelines for the management of arrhythmias and the prevention of sudden cardiac death [173]. Real-world clinical experience has helped identify the following prognostic markers of high risk, typical of myocarditis presentation and preceding the onset of malignant arrhythmias:

• sinus bradycardia,

• prolongation of the QRS complex,

• enlargement of left ventricular hypokinetic zones,

• persistently elevated or fluctuating troponin levels [173].

It is important to remember that the improvement of hemodynamic parameters does not rule out a high probability of life-threatening arrhythmias due to established and irreversible myocardial fibrosis. The risk of arrhythmias in patients with myocarditis, both during the acute phase and in subsequent periods, remains very high and requires specialized treatment.

No ESC guideline (LoE C, GoR 5)

Not addressed in ESC guidelines (Level of Evidence C, Grade of Recommendation 5)

The administration of antiarrhythmic therapy in patients with acute myocarditis has several distinct features and is primarily indicated for patients with symptomatic nonsustained ventricular tachycardia in the acute phase of myocarditis [91, 145].

The administration of beta-blockers, which are the drug of choice in the treatment of patients with chronic heart failure (CHF), to patients at the onset of acute myocarditis with ventricular heart rhythm disorders is associated with an unfavorable prognosis [3, 176, 177].

ESC not specified (LoE C, GoR 4)

No ESC guideline (LoE C, GoR 5)

Comments: It is known that amiodarone** is a first-line drug in the treatment of life-threatening cardiac arrhythmias, leading to a reduced risk of sudden death in the post-infarction period in patients with obvious symptoms of circulatory failure. An analysis of the efficacy of amiodarone** in patients during the period of circulatory decompensation showed that the risk of sudden death in patients with sustained ventricular arrhythmias decreased by 28.4%, and the risk of cardiovascular mortality by 18.2%, while amiodarone** had no effect on overall mortality [178]. Regarding the treatment of patients with acute myocarditis, it is important to remember that amiodarone** has demonstrated its effect on reducing the risk of sudden death only in combination with beta-blockers [179]. For long-term therapy, the maintenance dose of amiodarone** is 100-200 mg/day per os, and monitoring of the QT interval duration and thyroid function is mandatory. In the acute period of myocarditis, an individual benefit-risk assessment must precede the initiation of therapy:

• prescribing the drug to a patient without a life-threatening arrhythmia for the purpose of primary prevention of sudden death is pointless;

• with the progression of symptoms of circulatory failure, amiodarone** may increase the risk of a fatal outcome, which requires continuous ECG monitoring (continuous bedside monitoring of vital functions and parameters) of the patient, i.e., observation in an intensive care unit setting [174].

In case of intolerance to amiodarone** or the impossibility of its administration, sotalol** is considered as an alternative. Sotalol** is a class III antiarrhythmic drug (Antiarrhythmic drugs, class III C01BD) with beta-blocking properties (to be remembered when starting treatment for myocarditis) [180], which is practically identical in clinical efficacy to amiodarone**, but has a greater proarrhythmic effect in patients with reduced myocardial contractility [181]. Initiating sotalol** therapy requires knowledge of the glomerular filtration rate, as the drug is contraindicated at a creatinine clearance < 40 ml/min. The starting dose of sotalol** is 40 mg twice daily. The maximum dose is 160 mg twice daily. With an increase in the dose of the drug and the severity of circulatory failure, the proarrhythmic risk increases [181]. Currently, there are no controlled prospective clinical studies evaluating the safety and efficacy of sotalol** in patients with CHF, which equates these recommendations to the "expert opinion" level.

In fulminant myocarditis, the use of permanent artificial pacemakers***, implantable cardioverter-defibrillators (ICDs)***, and cardiac resynchronization therapy should not be performed until the acute situation resolves and the need for these procedures and their application is reassessed [173].

No ESC guideline (LoE C, GoR 5)

• The use of wearable defibrillators is recommended to be maintained either until the complete disappearance of arrhythmias and restoration of myocardial contractility, or until the implantation of a permanent ICD*** 1-3 months after the end of the acute period of myocarditis [173].

No ESC guideline (LoE C, GoR 5)

Comments: The implantation of a permanent ICD*** is advisable only if hemodynamic disturbances and sustained life-threatening ventricular arrhythmias persist, and the patient's expected life expectancy is greater than one year. It is important to consider that the procedure should preserve or improve the patient's quality of life [173].

• The implantation of an ICD*** or artificial pacemaker*** in patients with inflammatory cardiomyopathy is recommended after the resolution of the acute stage of myocarditis [146].

No ESC guideline (LoE C, GoR 5)

Comments: The life prognosis in patients with giant cell myocarditis and cardiac sarcoidosis is always poor due to the high probability of developing a refractory electrical storm with sustained ventricular tachycardia and ventricular fibrillation. This fact requires ongoing aggressive antiarrhythmic therapy and early ICD*** implantation [182].

In patients with giant cell myocarditis and sarcoidosis who have documented hemodynamically significant sustained ventricular arrhythmias or successful resuscitation for cardiac arrest, ICD*** implantation is possible at an earlier date if the patient's expected life expectancy is greater than one year.

When deciding on the implantation of a permanent ICD***, it is important to take into account that in a patient who has undergone the acute phase of myocarditis, if persistent inflammatory infiltrates in the myocardium are detected by endomyocardial biopsy (EMB), or large areas of fibrosis and "abnormally" located fibrosis fields in conduction system areas are detected by cardiac MRI, the risk of sudden death remains high [183].

Implantation of a cardiac resynchronization therapy defibrillator is indicated for heart failure > NYHA functional class II NYHA with an LVEF ≤ 35% in combination with left bundle branch block and should be performed in accordance with the guidelines for the management of chronic heart failure [184].

Use of nonsteroidal anti-inflammatory and antirheumatic drugs in patients with acute myocarditis

There are no specific studies on the use of NSAIDs in the treatment of myocarditis. Expert opinion on this issue is based on experimental studies [185]. The question of using NSAIDs becomes relevant only when pericarditis accompanied by pain is present. In such a situation, in the absence of severe myocardial contractility impairment, the use of minimal doses for the shortest possible course may be considered.

• The use of NSAIDs is not recommended for the treatment of myocarditis, except for cases of acute myocarditis combined with dry/effusive pericarditis: in this case, the administration of NSAIDs (ibuprofen** per os 1200 mg/day for 2-4 weeks) may be indicated [185].

No ESC guideline (LoE C, GoR 5)

Tactics of anticoagulant (antithrombotic agent) use in the acute period of myocarditis

In acute myocarditis, due to ventricular dilatation, forced sharp restriction of exertion volume, mandatory bed rest, and intensive decongestion therapy, blood stasis develops in the heart cavities and peripheral veins, increasing the risk of both peripheral venous and intracardiac thrombosis. Formed thrombi become a source of numerous venous and arterial thromboembolisms. No special studies have been conducted to investigate the incidence of thrombosis in patients with acute myocarditis, but it is known that approximately one-third of patients with pronounced symptoms of circulatory failure have signs of deep vein thrombosis of the lower leg, and every twentieth has a pulmonary embolism. Everyday clinical practice suggests that the lower the EF and the more severe the circulatory failure, the more likely thrombosis and embolism are. Therefore, acute myocarditis with unstable hemodynamics should be considered a condition in which the risk of thrombosis and thromboembolism increases, and the use of anticoagulants (antithrombotic agents) should be an obligatory component of patient treatment [158, 159].

Data from the MEDINOX study suggest that in patients on bed rest, the risk of thrombosis and embolism is significantly reduced with low-molecular-weight heparin therapy—Enoxaparin sodium** (heparin group B01AB) at a dose of 40 mg daily subcutaneously for 2 weeks [160, 161]. Observation of patients for 4 months showed that their risk of thrombosis and embolism was 60% lower compared to the untreated group of patients. A positive effect, though less pronounced than that of Enoxaparin sodium** (B01AB05), has been described for dalteparin sodium [160, 162].

In patients with acute myocarditis complicated by circulatory failure and the development of low LVEF (< 35%) who are receiving intensive diuretic therapy, it is advisable to consider: the possibility of adhering to bed rest for at least 3 days, as well as therapy with the heparin group (low-molecular-weight heparins) (B01AB) for 1-2 weeks [160, 162].

• Patients with deep vein thrombosis of the lower leg developing in the acute phase of myocarditis are recommended to be switched to warfarin** therapy for up to 3 months, and in case of recurrent venous thrombosis, such therapy should be continued indefinitely [186].

No ESC guideline (LoE C, GoR 5)

Due to the high risk of bleeding in modern clinical practice, instead of the regimen "low-molecular-weight heparin (heparin group) followed by switching to warfarin**", alternative regimens are used that exclude both low-molecular-weight heparin (heparin group) and warfarin**. This involves therapy with one of the factor Xa inhibitors (direct factor Xa inhibitors B01AF): either rivaroxaban** (15 mg twice daily for 21 days, followed by 20 mg once daily for up to 3 months) or apixaban** (10 mg twice daily for 7 days, followed by 5 mg twice daily for up to 3 months).

The described approach achieves the same clinical efficacy in the treatment of thrombosis with a significantly lower risk of bleeding [164, 165, 187].

Every fifth patient with severe clinical manifestations of heart failure has thrombi in the left ventricular cavity. The number of patients with thrombi in the heart ventricular cavities significantly increases (approximately 2-fold) when the left ventricular ejection fraction drops below 40% [186]. Such patients are indicated for warfarin** therapy. Although these studies were performed in patients with sinus rhythm, post-infarction cardiosclerosis, and left ventricular aneurysm, they can be extrapolated to patients with acute myocarditis and a formed thrombus in the ventricular cavitys.

No ESC guideline (LoE C, GoR 5)

Comments: The prescription of warfarin** for prophylactic purposes in patients with sinus rhythm, symptoms of heart failure, and low left ventricular ejection fraction, but without detected intracardiac thrombi, is a complex issue that has no unambiguous answer regarding the efficacy of reducing the risk of thrombus formation in the heart cavities. In the WARCEF study [188], warfarin** had no advantage in reducing the risk of death in patients with chronic heart failure and sinus rhythm compared to acetylsalicylic acid**, but led to a 48% reduction in the risk of stroke and a proportional increase in the risk of major bleeding. The analysis of warfarin** efficacy in various age groups showed that the effect of warfarin** therapy depends on the patient's age. In the age group under 60 years, warfarin** compared to acetylsalicylic acid** significantly reduced the risk of the combined primary endpoint (risk of death or ischemic stroke) by 37%. These data can be taken into account when deciding on the appropriateness of initiating warfarin** therapy in patients under 60 years of age with acute myocarditis, severe circulatory insufficiency symptoms, and a high risk of ventricular thrombus formation [188].

ESC none (LoE B, GoR 2)

Comments: The development of any form of atrial fibrillation in a patient with acute myocarditis—permanent, persistent, or paroxysmal—implies the calculation of the risk of thromboembolic events using the CHA2DS2VASc scale (Appendix G3) and, at a risk score of ≥ 2 points, the automatic initiation of DOAC therapy.

3.2 Treatment of a Patient with Acute Myocarditis and Stable Hemodynamics

First-line drugs in the treatment of acute myocarditis in a patient with stable hemodynamics

In patients with stable circulatory insufficiency in the acute phase of myocarditis, it is advisable to conduct therapy in accordance with the clinical guidelines for the treatment of chronic heart failure [184].

Basic, mandatory drugs include: angiotensin-converting enzyme (ACE) inhibitors; angiotensin II receptor blockers (ARBs) (losartan**, valsartan, candesartan) in case of ACE inhibitor intolerance; angiotensin II receptor blockers in combination with other agents—(angiotensin receptor-neprilysin inhibitor, ARNI) may be considered as a starting drug for initial heart failure therapy, as the drug of choice when switching from ACE inhibitors upon stabilization of a patient with stage II–III NYHA functional class heart failure with systolic BP > 100 mmHg, as a drug superior in clinical efficacy to ACE inhibitors in reducing the risk of death in patients with heart failure; beta-blockers immediately upon normalization of inflammatory markers under heart rate control (Pulse test); ivabradine** in case of beta-blocker intolerance or sinus rhythm with a heart rate > 70 bpm in a patient with titrated, maximally tolerated doses of beta-blockers; mineralocorticoid receptor antagonists (aldosterone antagonists, MRAs).

No ESC guideline (LoE C, GoR 5)

Physical activity level in a patient with acute myocarditis

Physical activity in the acute phase of myocarditis is radically restricted. Restrictions remain in effect until complete recovery or normalization of inflammatory marker levels [166, 167]. The increase in workload should occur gradually over a long period. Verified myocarditis requires the categorical disqualification of athletes from any type of competition for at least 6 months, followed by a gradual increase in workload. The question of resuming physical activity is resolved based on the results of Holter monitoring (Holter heart rhythm monitoring) (exclusion of high-grade arrhythmias), analysis of the dynamics of heart chamber sizes, and the state of myocardial contractility [166, 167].

In patients with stable chronic heart failure following a previous myocarditis, the resumption of physical activity at a moderate level, not requiring excessive exertion, should be recommended as part of the patient's routine chronic heart failure rehabilitation program.

It is advisable to restrict physical activity during the acute phase of myocarditis for at least 6 months in both athletes and non-athletes [166, 167].

Antiviral therapy in the treatment of acute myocarditis

Currently, there are no large prospective clinical trials evaluating the effect of antiviral therapy on hard endpoints. Our understanding of the problem is shaped by small-scale studies.

In a randomized, double-blind, placebo-controlled BICC study (Betaferon in patients with chronic viral cardiomyopathy; ClinicalTrials.gov identifier: NCT001185250) [189], 143 patients with severe clinical symptoms of circulatory insufficiency and PCR-verified presence of enterovirus, adenovirus, and/or parvovirus B19 genomes in myocardial biopsies were randomized into 3 groups: placebo for 24 weeks (n = 48); interferon beta-1b** 4×10⁶ IU therapy for 24 weeks (n = 49); interferon beta-1b** 8×10⁶ IU therapy for 24 weeks (n = 46). Both doses of interferon beta-1b** led to either a reduction in viral load or complete elimination of the viral genome compared to the placebo group (OR = 2.33, p = 0.048), although 100% elimination of the viral genome was not achieved. Persistence of parvovirus B19 mainly continued. Interferon beta-1b** therapy resulted in a decrease in the functional class of circulatory insufficiency during 12 weeks of follow-up (p = 0.013), an improvement in quality of life according to the Minnesota Living with Heart Failure Questionnaire (Appendix G2) in patients with heart failure during 24 weeks of follow-up (p = 0.032), and an improvement in global self-assessment (p = 0.039). Thus, interferon beta-1b** therapy had a positive effect on the course of viral myocarditis.

Viral persistence is considered an independent negative prognostic factor that increases the risk of death. A 5-year follow-up [190] of patients with viral persistence in the myocardium (confirmed by PCR of an endomyocardial biopsy) and patients with 100% viral elimination from myocardial tissue after acute viral myocarditis showed that:

• after 60 months of follow-up, 92% of patients with 100% viral elimination were alive, and their left ventricular ejection fraction significantly increased over 5 years (baseline 53 ± 16%, at 60 months 58 ± 1%, p = 0.001);

• after 60 months of follow-up, only 69% of patients with viral persistence were alive, and their left ventricular ejection fraction did not change significantly (baseline 39 ± 18%, at 60 months in survivors 41 ± 16%, p = 0.37).

An evaluation of the efficacy of long-term interferon beta-1b** therapy in eliminating the virus from myocardial tissue was performed in a long-term study (120 months of follow-up). Treatment results were compared with survival in a group with 100% viral elimination immediately after the acute period of myocarditis. A total of 96 patients with verified viral invasion and symptoms of circulatory failure were included in the study. At 9.5 ± 7.6 months after repeat endomyocardial biopsy, viral persistence was verified in 49 patients. In 28 of them, 4 months after repeat endomyocardial biopsy, therapy with interferon beta-1b** 8×10⁶ IU every other day for 6 months was initiated against the background of baseline heart failure therapy. At 95.8 ± 36 months, 52.5% of patients with viral persistence in the control group who did not receive interferon beta-1b** treatment died, whereas in the group treated with interferon beta-1b**, mortality was identical to that in the 100% viral elimination group. Thus, long-term interferon beta-1b** therapy significantly improves the long-term outcomes of acute myocarditis.

In clinical practice, where obtaining data on the presence of the viral genome in the myocardium is unlikely, a multidisciplinary team conference involving infectious disease specialists will help optimize diagnostic decision-making and determine the feasibility of initiating antiviral therapy.

ESC none (LoE B, GoR 2)

3.3 Use of Immunoglobulins and Immunoadsorption in the Treatment of Acute Myocarditis

Intravenous administration of high-dose immunoglobulins

Intravenously administered immunoglobulins (J06B) have antiviral and immunomodulatory effects, which suggested a positive effect in the treatment of acute myocarditis when using immunoglobulins [191]. In the only placebo-controlled study evaluating the effect of immunoglobulins on the course of heart failure, 40 patients with dilated cardiomyopathy or ischemic heart failure and an LVEF of less than 40% received intravenous immunoglobulins for 26 weeks [192]. The treatment group showed a significant increase in the levels of IL-10, soluble IL-1 receptors, and soluble TNF-α receptors. Against the background of a pronounced anti-inflammatory effect, the treatment group showed a significant increase in LVEF from 26 ± 2% to 31 ± 3% and a decrease in NT-proBNP levels. These data raised hopes for success in the treatment of myocarditis, but the results obtained in clinical trials were contradictory.

Thus, the use of immunoglobulins for the treatment of myocarditis in children in a non-randomized study led to improved myocardial contractility and reduced mortality during 12 months of follow-up [193]. Conversely, the results of using immunoglobulins at a dose of 2 g/kg of body weight intravenously for the treatment of circulatory failure in 62 patients with dilated cardiomyopathy aged 43 ± 12 years and an LVEF of less than 40% (according to a randomized placebo-controlled study) did not confirm the hypothesis regarding the effect of immunoglobulins on disease outcome. It should be noted that all patients underwent endomyocardial biopsy, but only 16% of them showed inflammatory myocardial infiltration. Left ventricular contractility in the active treatment group and the placebo group did not differ. Over 12 months, LVEF increased by 16 ± 12% in the treatment group and by 15 ± 0.16% in the placebo group. After 2 years of follow-up, there were no indications for heart transplantation in 92% of patients in the treatment group and 88% in the placebo group [230].

No ESC guideline (LoE C, GoR 5)

Use of immunoadsorption

The method is based on the removal of anticardiac antibodies, the titers of which are elevated in patients with autoimmune diseases and acute autoimmune myocarditis. Currently, there are no large prospective clinical studies evaluating the effect of this method on hard clinical endpoints. In small controlled studies, immunoadsorption led to an improvement in hemodynamic parameters and the severity of the inflammatory response in patients with dilated cardiomyopathy [172, 173].

60 patients with dilated cardiomyopathy, NYHA functional class II–III, and an LVEF of less than 45% were included in a single-center case-control study [195]. 30 patients underwent immunoadsorption followed by IgG replacement, and the effect of this procedure on exercise capacity using a stress system with gas analysis (cardiological stress system for ECG exercise testing) and echocardiography results at baseline and after 3 months was evaluated, comparing the data obtained with the results of the control group without immunoadsorption. In the treatment group, LVEF increased from 33.0% ± 1.2% to 40.1% ± 1.5% (p < 0.001). Exercise duration increased from 812 ± 29 to 919 ± 30 seconds (p < 0.05), and peak oxygen consumption increased from 17.3 ± 0.9 to 21.8 ± 1.0 mL/(min × kg) (p < 0.01).

The effect of immunoadsorption of cardiotoxic antibodies on hemodynamic parameters and T-cell activation was studied in 10 patients with dilated cardiomyopathy, marked inflammatory reaction in the myocardium according to endomyocardial biopsy, and an LVEF of less than 35% during 6 months of follow-up [196]. Six months after immunoadsorption of cardiotoxic antibodies, LVEF increased from 25.6 ± 4.9 to 37.3 ± 10.1% (p < 0.05), the end-diastolic dimension decreased from 63.3 ± 3.1 to 57.1 ± 4.1 mm (p < 0.05), and the activity of CD4(+), CD25(+), and CD127 T-cells increased.

The effect of immunoadsorption followed by IgG replacement (0.5 g/kg of polyclonal IgG) on hemodynamic parameters determined invasively via a Swan-Ganz catheter (Swan-Ganz medical catheter) was evaluated in a small study of 9 patients with NYHA functional class III–IV dilated cardiomyopathy and an LVEF < 30% [197]. After the first immunoadsorption procedure and throughout 3 months, it was noted that the cardiac index increased from 2.1 ± 0.1 to 2.8 ± 0.1 L/min/m² (p < 0.01); the stroke volume index increased from 27.8 ± 2.3 to 36.2 ± 2.5 mL/m² (p < 0.01); total vascular resistance decreased from 1,428 ± 74 to 997 ± 55 dyn × sec × cm^-5 (p < 0.01). Immunoadsorption of antibodies to β₁-receptors in 22 patients with NYHA functional class III–IV dilated cardiomyopathy and an LVEF < 30% [198] showed no effect on hemodynamic parameters. The ejection fraction after immunoadsorption in patients with elevated titers of antibodies to β₁-receptors did not differ from the LVEF in patients who initially had no elevated antibody titers.

In clinical practice, determining circulating autoantibodies is a challenging task, which dictates the use of this technology only in large centers capable of identifying autoantibodies and tracking their levels over time. The current state of knowledge, formed in the absence of large prospective studies, does not allow recommending immunoadsorption as a standard baseline method in the treatment of acute myocarditis.

ESC not specified (LoE C, GoR 4)

Immunosuppressive therapy for acute myocarditis

Currently known clinical experience with immunosuppressive therapy in patients with acute myocarditis is based on the following drug regimens: systemic glucocorticoids as monotherapy or in combination with cytostatics (antineoplastic agents and immunomodulators) [177]. These guidelines emphasize studies that used immunohistochemical methods for analyzing endomyocardial biopsy specimens (pathological anatomical examination of biopsy (surgical) material using immunohistochemical methods) to verify the etiology of myocarditis. The lack of immunohistochemical and molecular genetic verification methods for biopsy material (pathological anatomical examination of biopsy (surgical) material using immunohistochemical methods) or a study design lacking a control group (high probability of spontaneous recovery in a patient with myocarditis) makes the interpretation of results unacceptable for practical healthcare needs. For instance, the Myocarditis Treatment Trial (MTT) (involving 111 patients with myocarditis of undetermined etiology) evaluated the efficacy of immunosuppressive therapy (prednisolone** combined with #azathioprine** or #ciclosporin** vs. placebo) on patient mortality and myocardial contractile function. The addition of immunosuppressive therapy to standard treatment after 1 year of follow-up did not lead to reduced mortality or improved cardiac contractile function, which is presumably explained by the heterogeneity of the included patients. A beneficial effect from immunosuppressive therapy was expected only in cases of autoimmune myocarditis, whereas patients with a potential baseline viral myocardial injury experienced enhanced viral replication during immunosuppressive therapy, resulting in greater myocardial damage and a worse prognosis.

These flaws in study design were avoided in the TIMIC (Immunosuppressive Therapy in Patients With Virus Negative Inflammatory Cardiomyopathy) trial [199], which was designed as a randomized, double-blind, placebo-controlled study. Upon enrollment (85 patients included), an endomyocardial biopsy was performed with histological and immunohistochemical analysis of the myocardial tissue (pathological anatomical examination of biopsy (surgical) material using immunohistochemical methods). This approach made it possible to exclude viral myocarditis and form a homogeneous group of patients with virus-negative inflammatory cardiomyopathy. All 85 patients had pronounced signs of circulatory failure for 6 months that could not be managed by guideline-directed medical therapy for chronic heart failure [171].

In the ESETCID (European Study of Epidemiology and Treatment of Inflammatory Heart Disease, a multicenter, double-blind, placebo-controlled, randomized trial), 3 treatment arms were formed: treatment with prednisolone** and azathioprine** for virus-negative inflammatory cardiomyopathy in patients with left ventricular ejection fraction (LVEF) below 45%; treatment with interferon alfa-2b** for enteroviral myocarditis; and treatment with intravenous immunoglobulins for cytomegalovirus, adenoviral, and parvovirus B19 myocarditis. Treatment efficacy in each group was compared with placebo and assessed by the drug's ability to increase baseline LVEF by 5% and affect the severity of myocardial inflammation. A total of 3055 endomyocardial biopsy specimens were analyzed in the study. Immunosuppressive therapy led to the disappearance of inflammatory signs at 6 months in 59% of patients compared to 40% in the placebo group. Data on changes in LVEF were not reported [200]. These findings further confirm the efficacy of targeted immunosuppressive therapy.

A personalized approach to the treatment of myocarditis helps identify a specific group of patients with proven autoimmune forms of myocarditis, for whom immunosuppression is mandatory:

1. Giant cell myocarditis – the use of combined immunosuppressive therapy (dual – #methylprednisolone** and #ciclosporin**, or triple – #methylprednisolone**, #ciclosporin**, and #azathioprine**) has a proven positive impact on life expectancy [151, 177, 222, 223]. The dose of #methylprednisolone** is 1 mg/kg/day (up to 1000 mg/day is permissible in severe patient conditions), followed by a gradual taper to a maintenance dose (5–10 mg) over several months of therapy for an indefinite period; the dose of #azathioprine** is 2 mg/kg/day; the dose of #ciclosporin** is determined by its blood concentration, and the duration of therapy is not strictly defined but is at least 1 year. The decision to discontinue immunosuppressive therapy is complex and requires a multidisciplinary consensus. Discontinuation of therapy can lead to a relapse of myocarditis, quite frequently in a more severe form and with a worse prognosis for survival.

2. Cardiac sarcoidosis – the use of high-dose glucocorticoids is associated with improved cardiac contractile function. The prognosis for survival remains poor over 5 years, with mortality observed in every 6th patient. The starting dose of #prednisolone** ranges from 30–60 mg/day, and it must be gradually tapered over 8–12 weeks to a dose of 10–20 mg/day, which the patient continues for at least 6–12 months [177, 222, 223]. Despite the lack of conclusive evidence demonstrating the superiority of high-dose glucocorticoids over moderate doses, the duration of immunosuppressive therapy is unquestionably an important prognostic factor. Therefore, steroid-sparing regimens are employed to minimize risks associated with glucocorticoid administration.

3. Eosinophilic myocarditis – most commonly develops at 30–40 years of age and is associated with hypersensitivity reactions, eosinophilic granulomatosis with polyangiitis in 34.1% of cases. Concomitant conditions can be identified in 65% of cases. Idiopathic eosinophilic myocarditis develops in 35.7% of cases. Treatment is initiated with glucocorticoids (H02AB) in 77.7% of cases [201]. Eosinophilia always warrants diagnostic workup to rule out paraneoplastic syndrome. The prognosis of eosinophilic myocarditis is consistently severe due to life-threatening ventricular arrhythmias and progressive circulatory failure, with a high risk of mortality during the acute phase of myocarditis [201, 202].

Eosinophilic myocarditis can be a manifestation of a heterogeneous group of hematological disorders collectively known as idiopathic hypereosinophilic syndrome. This rare condition should be suspected in the presence of unexplained peripheral blood eosinophilia exceeding 1500 cells per 1 mm³ for at least 6 months. Every 5th patient with this condition will develop eosinophilic myocarditis, which in the vast majority of cases is combined with skin, lung, and intestinal involvement [203, 204].

Treatment of eosinophilic myocarditis depends on the underlying etiology. In cases of hypersensitivity, the causative agent should be eliminated first; if parasitic infestation is suspected, specific therapy must be initiated (initial appointment (examination, consultation) with an infectious disease physician is mandatory); in myeloproliferative disorders, specific therapy (tyrosine kinase inhibitors (ATC: L01E protein kinase inhibitors)) is determined by a hematologist; patients with Churg-Strauss syndrome require glucocorticoid therapy. The absolute majority of patients with eosinophilic myocarditis receive immunosuppressive therapy. Our perspective on the methods and duration of such therapy is based on small-scale studies or individual clinical case reports [204]. The starting dose of #prednisolone** is 1 mg/kg/day for 4 weeks, followed by a gradual taper to a maintenance dose (5–10 mg) over several months of therapy [177, 205, 222, 223]. The duration of therapy is 6–9 months. In severe disease courses, it is advisable to use combination therapy consisting of "#prednisolone** plus #ciclosporin**/#azathioprine**". Such therapy leads to a significant reduction in the risk of heart failure progression. The greatest prospects in the treatment of eosinophilic myocarditis are associated with the use of #mepolizumab** at a single dose of 300 mg, which inhibits the bioactivity of IL-5 on eosinophils [177, 206, 222, 223, 224, 225, 229].

4. Myocarditis associated with extracardiac autoimmune diseases – combined immunosuppressive therapy is indicated according to the protocols established for the underlying disease.

No ESC guideline (LoE C, GoR 5)

• Immunosuppressive therapy (with glucocorticoids (H02AB) and/or immunosuppressants (L04A)) is recommended for proven autoimmune (virus-negative) forms of myocarditis, including giant cell, eosinophilic, and toxic myocarditis, cardiac sarcoidosis, and myocarditis associated with extracardiac autoimmune diseases, provided there are no contraindications to immunosuppression [38].

No ESC guideline (LoE C, GoR 5)

Immunosuppressive therapy may be considered in patients with moderate or severe heart failure, life-threatening rhythm and/or conduction disturbances unresponsive to standard therapy, only if there is histological and immunohistochemical confirmation of inflammatory myocardial disease and no viral genome is detected in myocardial biopsy specimens.

No ESC guideline (LoE C, GoR 5)

Management of patients with stable circulatory failure resulting from myocarditis

Currently, there are no prospective controlled trials on the treatment of HFrEF/HFpEF specifically in patients who have suffered from myocarditis.

In patients with stable circulatory failure resulting from prior myocarditis, therapy may be administered in accordance with clinical guidelines for the management of heart failure [184]. These guidelines do not aim to analyze the treatment of patients with preserved, mildly reduced, and reduced LVEF after myocarditis. The expert panel emphasizes that the prescription of core drugs proven to reduce the risk of death, repeat hospitalizations, and morbidity specifically in heart failure is mandatory for patients who have had myocarditis and present with signs of heart failure.

No ESC guideline (LoE C, GoR 5)

Treatment of myocarditis in patients with acute coronavirus infection.

• All patients with probable coronavirus-induced myocarditis should be initiated on or continued with standard heart failure therapy [76] [207, 208].

Comments: The clinical benefit of glucocorticoids in hospitalized patients with COVID-19 has now been demonstrated in several studies, but data in the specific context of acute myocarditis are lacking [46]. Certain immunosuppressive drugs, such as interleukin-1 antagonists (L04AC Interleukin inhibitors) (anakinra** and canakinumab**) and interleukin-6 antagonists (L04AC Interleukin inhibitors) (tocilizumab**, levilimab**), have shown promising results in patients hospitalized for COVID-19 [76] [207, 208]. However, none of these drugs has been specifically investigated for the treatment of COVID-19-associated myocarditis. Therefore, glucocorticoids may be considered as the drug of choice in severe patients with myocarditis and COVID-19, regardless of pneumonia and hypoxemia, but should be avoided in less severe forms.

Treatment of post-COVID myocarditis

The scope and duration of immunosuppressive therapy are regulated in accordance with the evidence base for classical myocarditis. A significant increase in LVEF, reduction in cardiac chamber dimensions, and improvement in functional status have been demonstrated as a result of such therapy combined with comprehensive heart failure management [209]. In the context of the pandemic, any unexplained myocardial dysfunction requires serodiagnosis of coronavirus infection (detection of coronavirus RNA 229E, OC43, NL63, HKU1 (Human Coronavirus) in nasopharyngeal swabs by PCR) and assessment of the anamnestic link between symptoms and prior COVID-19. Isolated (asymptomatic) elevation of anticardiac antibody titers and/or detection of "post-inflammatory" changes on cardiac MRI is not a basis for diagnosing post-COVID myocarditis and initiating its treatment. Patients with high anticardiac antibody titers may develop symptoms at later stages, which warrants active surveillance.

Surgical treatment

The issue of heart transplantation in the acute period of myocarditis in a patient with connected hemodynamic mechanical support equipment (intra-aortic balloon counterpulsation device) or extracorporeal membrane oxygenation can be considered only in a situation where, despite optimal pharmacological therapy and mechanical support, it is not possible to stabilize hemodynamic parameters [38].

It is important to remember that the majority of patients who have recovered from the acute phase of myocarditis will experience spontaneous recovery of cardiac contractility.

No ESC guideline (LoE C, GoR 5)

Pain Management

Patients with myocarditis do not require special pain management.

Medical Nutrition Therapy

Patients with myocarditis do not require special diet therapy.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Physical rehabilitation methods have not been developed for patients with myocarditis. Acute myocarditis is an absolute contraindication for physical training. Apparently, this can only apply to the rehabilitation of patients with stable circulatory failure resulting from myocarditis. Rehabilitation measures are based on the principles of physical rehabilitation for patients with CHF.

When CHF manifests, morphological and functional disorders develop in skeletal muscles and the diaphragm, the number of type II muscle fibers increases, and exercise tolerance decreases, making physical exercise a difficult task in everyday practice [210]. Respiratory muscles play a special role in disease progression, exacerbating rapid fatigue and dyspnea [211]. In patients with reduced LVEF, moderate-intensity aerobic exercise improves quality of life and significantly reduces the risk of recurrent hospitalizations, while in patients with preserved LVEF, it leads to symptom reduction and an improved NYHA functional class for CHF [212, 213].

No ESC recommendation (Level of Evidence A, Grade of Recommendation 1)

ESC none (LoE B, GoR 2)

Comments: A distance of less than 150 meters in 6 minutes excludes any exercise other than respiratory muscle training [216], while a distance of more than 300 meters in 6 minutes allows for walking to be prescribed. Regular physical exercise in the form of breathing exercises with prolonged expiration exerts a systemic effect on the body, increasing exercise tolerance and improving quality of life [217].

Methods for prescribing training, ways to improve patient adherence, prescription of physical training in various clinical situations, and other aspects of physical rehabilitation in patients with CHF are described in detail in the document "Guidelines for the Prescription of Physical Training in Patients with Chronic Heart Failure" [11]. To date, the most studied types of exercise in patients with CHF are walking and breathing exercises; the search for new types (such as swimming) has not yet led to their inclusion in the guidelines [218]. Ensuring a safe start to training requires the physician to know:

— relative contraindications (weight gain > 1.8 kg in the preceding 1–3 days; decrease in systolic blood pressure during exercise; stage IV CHF; ventricular arrhythmias at rest or occurring during physical exertion; severe comorbidities);

— absolute contraindications (progressive deterioration of exercise tolerance or dyspnea at rest in the preceding few days; ischemia during low-intensity physical exertion (< 2 METs); uncontrolled diabetes mellitus; acute systemic illness or fever; recent thrombosis/embolism; thrombophlebitis; acute pericarditis or myocarditis; moderate-to-severe aortic stenosis; other valvular heart diseases requiring surgery; myocardial infarction in the preceding 3 weeks; newly onset atrial fibrillation).

The data presented above refer to patients who did not engage in sports. Resuming sports activities is possible only after 6 months, provided that the LV cavity volume normalizes and there are no life-threatening arrhythmias on Holter monitoring.

No ESC guideline (LoE C, GoR 5)

Medical rehabilitation and sanatorium-resort treatment

Medical rehabilitation includes a set of measures aimed at restoring the functional capabilities of patients after illnesses, including myocarditis. Rehabilitation programs help improve the state of the cardiovascular system, reduce the risk of recurrent cardiovascular events, and enhance patients' quality of life. To achieve this, methods of physical rehabilitation, psychosocial interventions, and individually tailored physical activity programs are used.

Cardiopulmonary rehabilitation for patients with myocarditis is a sequential process carried out under the supervision of a multidisciplinary team of specialists, including cardiologists, physical and rehabilitation medicine physicians, exercise therapy specialists, and dietitians. The main goal of cardiac rehabilitation is the safe increase of physical activity levels, improvement of cardiovascular parameters, and overall physical recovery.

At the beginning of rehabilitation, especially for patients with subacute myocarditis or a history of myocarditis, it is recommended to start with low-intensity physical exercise (BORG scale 6-8/20). This helps avoid cardiac overexertion and gradually improves overall exercise tolerance. As recovery progresses, the physical impact is increased, and training becomes more structured, transitioning to moderate intensity (BORG scale 10-12/20). This approach effectively adapts the heart to increasing loads without causing excessive stress.

Psychosocial interventions are an important component of medical rehabilitation for patients with myocarditis. Cognitive behavioral therapy, stress management, and relaxation help reduce psychological distress, which in turn improves the body's overall response to treatment. The inclusion of such methods helps strengthen the psycho-emotional state and improve the quality of life.

Sanatorium-resort treatment is an important stage in the recovery of patients with myocarditis. It is recommended for patients without signs of congestive heart failure and severe heart rhythm disturbances, usually 6 months after the acute period. Climatotherapy at seaside and mountain resorts, thalassotherapy, and therapeutic walking make it possible to use natural factors to strengthen the cardiovascular system. Terrain cures (therapeutic walks along specially designed routes) are carried out in picturesque, wind-sheltered areas with clean air saturated with natural aeroions and phytoncides.

Under resort conditions, therapeutic walking is carried out in the morning and evening hours, in a sparing regimen with individual dosage of exertion (by distance, climb angle, pace, and duration of stops), which promotes the safe adaptation of the cardiovascular system to physical activity. In addition, sanatorium-resort treatment includes aeroionotherapy, heliotherapy, and terrain cure walks in low-mountain, flat, and seaside resort environments.

At cardiological resorts, patients with myocarditis can undergo comprehensive cardiac rehabilitation programs that include counseling on nutrition, weight and body composition management, correction of cardiovascular risk factors, psychosocial interventions, and aerobic training. This allows for a significant improvement in the clinical and functional state of patients, stabilization of blood pressure, normalization of lipid and carbohydrate metabolism, and an increase in exercise tolerance.

5. Prevention and Dispensary Observation

Follow-up of a patient who has suffered acute myocarditis. General provisions.

— Acute myocarditis may end either in complete recovery and the disappearance of circulatory insufficiency symptoms, or in the development of stable circulatory insufficiency of various NYHA functional classes, or in the progression of circulatory insufficiency severity and transition to DCM.

— Satisfactory well-being and the absence of symptoms of circulatory insufficiency do not exclude the occurrence of relapses.

— A persistently elevated level of blood troponin T for weeks/months after the normalization of acute myocarditis symptoms requires ruling out laboratory error (interaction of cardiac autoantibodies with laboratory test kits is possible; in this situation, it is necessary to determine the level of blood troponin I), re-examination of the coronary arteries (coronary angiography), and, if coronary artery disease is definitively ruled out, addressing the issue of EMB.

— All patients who have undergone acute myocarditis must be under clinical dispensary observation. The duration of observation and frequency of visits depend on the outcome of myocarditis. Complete recovery after acute myocarditis also requires dispensary observation for at least 1 year.

— The scope of examination during a dispensary visit includes ECG, echocardiography, Holter heart rhythm monitoring, a multi-stage fixed-intensity exercise test (6-minute walk test), complete blood count, serum C-reactive protein level test, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) level testing. The conducted examination should assess the dynamics of circulatory insufficiency and the severity of cardiac remodeling.

— In the event of a relapse, the patient must be hospitalized. The scope of treatment is the same as in the first episode of acute myocarditis. The issue of performing an EMB should always be discussed.

— Vaccination against measles, rubella, mumps, influenza, and poliomyelitis is mandatory.

— Vaccination against pneumococcus (using a vaccine for the prevention of pneumococcal infections**) is mandatory.

6. Organization of Medical Care

The condition of a patient suffering from myocarditis at disease onset, regardless of symptom severity, should be assessed as severe and unstable.

In real-world practice, even with initially preserved LV systolic function, fulminant and unpredictable deterioration can occur due to the development of life-threatening arrhythmias and AV blocks.

— Therefore, in all cases of suspected acute myocarditis, the question of hospitalization must be resolved positively. Preference should be given to multidisciplinary hospitals with a fully equipped intensive care unit.

Indications for hospitalization in a medical organization

Absolute indications for hospitalization:

— suspected myocarditis in a hemodynamically unstable patient [38].

— suspected myocarditis in a hemodynamically stable patient presenting with clinical manifestations of heart failure at NYHA functional class II–IV and documented LV systolic dysfunction on echocardiography [38, 228].

Indications for admission to the intensive care unit include: life-threatening arrhythmia, thromboembolic syndrome, signs of peripheral organ hypoperfusion, cardiogenic shock, and pulmonary edema.

• Patients with heart failure and confirmed/high risk of a novel coronavirus infection require hospitalization regardless of the severity of the infectious process course.

Patients with fulminant acute myocarditis and unstable hemodynamic parameters must be monitored in intensive care units equipped with the necessary equipment for mechanical ventilation, extracorporeal membrane oxygenation (ECMO), circulatory support, and EMB. Equipment for mechanical circulatory support or ECMO must be used either until the patient's condition stabilizes or until heart transplantation [114, 115]. Connecting a circulatory support device or performing ECMO can save a life or buy time needed to resolve issues related to heart transplantation [114, 115].

When identifying a patient with suspected myocarditis, regardless of symptom severity, including the absence of myocarditis symptoms, a primary care physician must refer the patient for hospitalization to a hospital for dynamic observation, monitoring of hemodynamic parameters, and diagnostic procedures [38].

7. Additional Information

The patient's prognosis always depends on a number of factors: the etiological cause of myocarditis, the histological picture of EMB, the results of histochemical examination of biopsy tissue (pathological and anatomical examination of biopsy (surgical) material using immunohistochemical methods), the level of cardiac autoantibodies, the severity of circulatory failure, the presence or absence of viral persistence in the myocardial tissue, and a number of other parameters.

As a rule, the prognosis is favorable in hospitalized patients with acute fulminant myocarditis.

The prognosis of myocarditis developed within the framework of infectious diseases depends on early diagnosis and the timing of pathogenetic therapy and monitoring of rhythm and conduction disturbances, especially in diphtheritic myocarditis. Provided these conditions are met, the prognosis is favorable.

The prognosis is extremely unfavorable in giant cell myocarditis.

Life expectancy in giant cell myocarditis is approximately 5.5 months from the onset of the first symptoms.

The prognosis is always severe in eosinophilic myocarditis and cardiac sarcoidosis.

Chronization of the inflammatory process and persistence of the virus in the myocardium make the prognosis unfavorable, since every fifth patient will develop DCM and the risk of needing a heart transplantation will increase.

Significant factors of an unfavorable prognosis include persistent life-threatening rhythm disorders, QRS complex widening of more than 120 ms, and syncopal states. Syncopal states in patients with acute myocarditis should be regarded as precursors of a severe prognosis and, first of all, as a risk factor for sudden cardiac death. Timely identification of these risk factors and their correction, including the implantation of an ICD*** or cardiac resynchronization therapy devices, can radically improve the prognosis.

During the follow-up period of dispensary observation of the patient, factors of an unfavorable prognosis should include the progression of circulatory failure symptoms, a persistent decrease in systolic blood pressure, and progressive pulmonary hypertension. These conditions require correction of baseline treatment. Selection of new doses should be performed only in a hospital setting, and a collegial discussion regarding the advisability of EMB is necessary, since one of the possible causes of the rapid progression of circulatory failure may be viral persistence in the myocardium. Patients with an unfavorable prognosis always have a high risk of needing a heart transplantation. It should be remembered that the risk of donor heart rejection is always high in patients with baseline giant cell myocarditis. In patients with stable circulatory failure, the prognosis depends on adherence to the prescribed comprehensive guideline-directed medical therapy for CHF.

Criteria for Evaluating the Quality of Medical Care

Criteria for assessing the quality of primary health care provided to adults with myocarditis (ICD-10 codes: I40, I41, I51.4)

Criteria for assessing the quality of specialized medical care provided to adults with myocarditis (ICD-10 codes: I40, I41, I51.4)

References

Appendix A1. Working Group Composition

Steering Committee of the Working Group:

• Arutyunov G.P. – MD, Professor, Corresponding Member of the Russian Academy of Sciences, Chief General Practitioner of the Moscow Healthcare Department, Honored Doctor of the Russian Federation, Head of the Department at the Pirogov Russian National Research Medical University.

• Dragunov D.O. – PhD, Associate Professor at the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

• Zhirov I.V. – MD, Leading Researcher at the Myasnikov Institute of Clinical Cardiology.

Working Group:

• Moiseeva O.M. – MD, Head of the Research Department of Non-Coronary Heart Diseases at the Almazov National Medical Research Centre of the Russian Ministry of Health.

• Paleev F.N. – MD, Professor, Corresponding Member of the Russian Academy of Sciences, Deputy General Director for Scientific and Analytical Work at the Myasnikov Institute of Clinical Cardiology.

• Sokolova A.V. – PhD, Associate Professor at the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

• Apkhanova Tatyana Valerievna – MD, Chief Researcher at the Department of Physiotherapy and Reflexotherapy at the National Medical Research Center for Rehabilitation and Balneology of the Russian Ministry of Health

• Arutyunov A.G. – MD, Professor at the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

• Blagova O.V. – MD, Professor at the Department of Faculty Therapy No. 1, Faculty of General Medicine; Privalova E.V. – MD, Professor at the Department of Hospital Therapy No. 1, Faculty of General Medicine, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health.

• Gabrusenko S.A. – MD, Senior Researcher at the National Medical Research Center of Cardiology of the Russian Ministry of Health.

• Garganeeva A.A. – MD, Professor, Head of the Department of General Clinical Cardiology and Cardiovascular Disease Epidemiology at the Cardiology Research Institute.

• Gendlin G.E. – MD, Professor, Professor at the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

• Gilyarevsky S.R. – MD, Professor at the Department of Clinical Pharmacology and Therapy of the Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health.

• Duplyakov D.V. – MD, Deputy Chief Medical Officer for Medical Affairs at the Samara Regional Clinical Cardiology Dispensary, Chief Cardiologist of Samara Region, Professor at the Department of Cardiology and Cardiosurgery of the Institute of Professional Education, Samara State Medical University.

• Zairatyants O.V. – MD, Professor, Head of the Department at the A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health.

• Karateev D.E. – Deputy Director for Scientific Work, Head of the Department of Early Arthritis at the V.A. Nasonova Research Institute of Rheumatology.

• Koziolova N.A. – MD, Professor, Head of the Department of Propaedeutics of Internal Diseases No. 2 at the E.A. Vagner Perm State Medical University of the Russian Ministry of Health.

• Kosmacheva E.D. – Head of the Department of Therapy, MD, Chief Cardiologist of the Southern Federal District, Chief Cardiologist of Krasnodar Krai.

• Kochetov A.G. – MD, Professor at the Department of Hospital Therapy with a Course of Clinical Laboratory Diagnostics, RUDN University.

• Lopatin Yu.M. – MD, Professor, Head of the Department of Cardiology with Functional Diagnostics of the Faculty of Advanced Medical Training, Volgograd State Medical University.

• Melekhov A.V. – MD, Associate Professor at the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

• Mitrofanova L.B. – MD, Head of the Research Laboratory of Pathomorphology at the Almazov National Medical Research Centre of the Russian Ministry of Health.

• Narusov O.Yu. – PhD, Senior Researcher at the Myasnikov Institute of Clinical Cardiology.

• Nasonova S.N. – PhD, Senior Researcher at the Myasnikov Institute of Clinical Cardiology.

• Nedostup A.V. – MD, Professor at the Department of Faculty Therapy No. 1, Faculty of General Medicine, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health.

• Nikulina S.Yu. – MD, Professor, Vice-Rector of Krasnoyarsk State Medical University.

• Orlova Ya.A. – MD, Professor, Head of the Department of Age-Associated Diseases at the Medical Research and Educational Centre of Lomonosov Moscow State University.

• Poteshkina N.G. – MD, Professor, Head of the Department at the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

• Rebrov A.P. – MD, Professor, Head of the Department of Hospital Therapy at the V.I. Razumovsky Saratov State Medical University.

• Saidova M.A. – MD, Professor, Head of Department, Head of Clinical Division at the Myasnikov Institute of Clinical Cardiology.

• Sedov V.P. – MD, Professor at the Department of Radiology, Faculty of General Medicine, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health.

• Sinitsyn V.E. – MD, Professor, Head of the Department of Radiology and Theranostics at the Faculty of Fundamental Medicine of Lomonosov Moscow State University, Head of the Department of Radiology at the Medical Research and Educational Centre of Lomonosov Moscow State University, President of the Russian Society of Roentgenologists and Radiologists.

• Sitnikova M.Yu. – MD, Chief Researcher, Head of the Heart Failure Research Department, Professor at the Department of Therapy at the Almazov National Medical Research Centre of the Russian Ministry of Health.

• Skvortsov A.A. – MD, Leading Researcher at the Myasnikov Institute of Clinical Cardiology.

• Skibitsky V.V. – MD, Professor, Head of the Department of Hospital Therapy at the Kuban State Medical University of the Russian Ministry of Health.

• Stukalova O.V. – PhD, Senior Researcher at the Myasnikov Institute of Clinical Cardiology.

• Tarlovskaya E.I. – MD, Professor, Head of the Department of Internal Diseases at Nizhny Novgorod State Medical Academy.

• Tereshchenko S.N. – MD, Professor, First Deputy General Director, Deputy General Director for Scientific Work, General Director of the National Medical Research Center of Cardiology of the Russian Ministry of Health.

• Usov V.Yu. – MD, Professor, Head of the Department of X-ray and Tomographic Diagnostic Methods at the Tomsk National Research Medical Centre, Cardiology Research Institute.

• Famin I.V. – MD, Professor at the Department of Internal Diseases of Nizhny Novgorod State Medical Academy, Chief Specialist in Therapy at the Privolzhsky District Medical Center.

• Chesnikova A.I. – MD, Professor at the Department of Internal Diseases No. 1 at Rostov State Medical University.

• Shaposhnik I.I. – MD, Professor, Head of the Department of Propaedeutics of Internal Diseases at South Ural State Medical University, Chief Cardiologist of Chelyabinsk.

• Shostak N.A. – MD, Professor, Head of the Department at the Pirogov Russian National Research Medical University of the Russian Ministry of Health

• Shlyakhto E.V. – MD, Professor, Academician of the Russian Academy of Sciences, General Director of the Almazov National Medical Research Centre of the Russian Ministry of Health, President of the Russian Society of Cardiology.

The working group members confirmed no financial support/conflict of interest. In the event of a reported conflict of interest, the working group member(s) were excluded from discussions related to the area of conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Cardiologist

2. General practitioner / Internist

3. General practitioner (family physician)

4. District general practitioner

Due to the fact that the Russian Society of Cardiology (RSC) is a constituent of the European Society of Cardiology (ESC), and RSC members are also ESC members, all European guidelines are formulated with the participation of Russian experts who co-authored the guidelines. Thus, the existing ESC guidelines reflect the consensus of leading Russian and European cardiologists.

Therefore, the national guidelines were developed based on ESC recommendations, taking into account national specifics, examination and treatment features, and the availability of certain medical care. For this reason, during the development of the Russian clinical guidelines by the RSC, international recommendation classes of indications were used to assess the necessity of performing a recommendation statement and the levels of evidence for these classes (Tables 1/A2 and 2/A2).

In cases where European guidelines lacked classes and levels of evidence, but in the opinion of RSC experts these statements were extremely necessary for implementation or, conversely, strictly not recommended for use, RSC experts—based on the rules for formulating recommendation classes according to the European Society of Cardiology guidelines—assigned the classes and levels themselves. In such instances, the ESC designation is replaced with RSC classes and levels assigned by RSC experts.

In addition, a new system of levels of evidence (LE) and grades of recommendations (GR) scales for therapeutic, rehabilitative, preventive, and diagnostic interventions (Tables 3/A2, 4/A2, and 5/A2) introduced in 2018 by the Center for Healthcare Quality Assessment and Control of the Russian Ministry of Health was added. Thus, two scales were used simultaneously in the text of the clinical guidelines developed by RSC experts (Tables 1/A2, 2/A2, 3/A2, 4/A2, 5/A2).

Table 1/A2. Classes of recommendations according to the European Society of Cardiology (ESC) guidelines.

Table 2/A2. Levels of evidence according to the European Society of Cardiology (ESC) guidelines.

Table 4/A2. Scale for assessing levels of evidence (LoE) for diagnostic methods (diagnostic interventions)

Table 5/A2. Scale for assessing levels of evidence (LoE) for methods of prevention, treatment, medical rehabilitation, including those based on natural therapeutic factors (preventive, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

• Order of the Ministry of Health of the Russian Federation No. 918n dated November 15, 2012, "On Approval of the Procedure for Providing Medical Care to Patients with Cardiovascular Diseases."

• Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017 "On approval of criteria for assessing the quality of medical care"

• Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On Approval of the Procedure and Deadlines for the Development of Clinical Guidelines, Their Revision, the Standard Form of Clinical Guidelines, and Requirements for Their Structure, Composition, and Scientific Validity of the Information Included in Clinical Guidelines" (Registered on May 8, 2019, No. 54588)

Table PA3-1. Clinical and Morphological Classification of Myocarditis by E. B. Lieberman et al. (1991)

Note: LV – left ventricle, EF – ejection fraction, DCM – dilated cardiomyopathy, CMP – cardiomyopathy

Table PA3-2. Clinical variants of myocarditis onset (Mayo Clinic classification)

Note: LV – left ventricle, AV block – atrioventricular block

Table PA3-3. Clinical variants of myocarditis onset

Normal values and grading of severity of increased dimensions and volumes, and decreased left ventricular ejection fraction [219, 228]

Note: EDD – end-diastolic diameter, BSA – body surface area, ESD – end-systolic diameter, EDV – end-diastolic volume, ESV – end-systolic volume, EF – ejection fraction.

Appendix B. Physician Action Algorithms

ALGORITHM for selecting management tactics for a patient with acute myocarditis based on the baseline hemodynamic profile

Scenario (1) The patient has obvious hypervolemia, but organ perfusion is adequate; according to the classification of J. S. Forrester and L. W. Stevenson, this phenotype is characterized as "warm and wet". Administration of diuretics, vasodilators for cardiac diseases, and—if ineffective—blood ultrafiltration is indicated.

Scenario (2) The patient has obvious hypervolemia, but organ perfusion is inadequate; according to the classification of J. S. Forrester and L. W. Stevenson, this phenotype is characterized as "cold and wet". If the systolic blood pressure is less than 90 mmHg, the following are indicated: positive inotropic drugs – adrenergic and dopaminergic agents (C01CA), vasopressors, diuretics, and—if ineffective—mechanical circulatory support methods.

If the systolic blood pressure is greater than 90 mmHg, the following are indicated: vasodilators for cardiac diseases, diuretics, and—if diuretic therapy is ineffective—positive inotropic drugs – adrenergic and dopaminergic agents (C01CA).

Scenario (3) The patient has no hypervolemia and organ perfusion is inadequate; according to the classification of J. S. Forrester and L. W. Stevenson, this phenotype is characterized as "cold and dry". In this situation, positive inotropic drugs – adrenergic and dopaminergic agents (C01CA) are indicated.

Scenario (4) The patient has no hypervolemia and organ perfusion is adequate; according to the classification of J. S. Forrester and L. W. Stevenson, this phenotype is characterized as "warm and dry". In this situation, standard therapy is indicated.

Appendix C. Patient Information

Myocarditis is a collective term (a group of independent nosological entities or a manifestation of other diseases), representing myocardial damage of an inflammatory nature—infectious, toxic (including drug-induced), allergic, autoimmune, or of unclear etiology—with a wide spectrum of clinical symptoms: ranging from an asymptomatic course, mild dyspnea, and mild chest pain that resolves spontaneously, to heart failure, cardiogenic shock, life-threatening arrhythmias, and sudden cardiac death.

Advice for the patient and their family

Satisfactory well-being and the absence of symptoms of circulatory failure do not rule out the occurrence of relapses. Therefore, regular follow-up with a physician is necessary (for at least 1 year).

Regular prevention of infectious diseases is necessary.

— Vaccination against measles, rubella, mumps, influenza, and poliomyelitis

— Pneumococcal vaccination (using a vaccine for the prevention of pneumococcal infections)

Intensive physical exertion must be avoided during the acute period of myocarditis.

During the rehabilitation period, low- to moderate-intensity physical activity under the supervision of a specialist physician is indicated.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Tei Index (Myocardial Performance Index) [129,130]

• Type: index

The Tei index is an echocardiographic parameter for the relative quantitative assessment of left ventricular systolic and diastolic function.

The Tei index is calculated using the following formula:

Tei index = IVRT+IVCT/ET,

where:

• IVCT – left ventricular isovolumic contraction time;

• IVRT – left ventricular isovolumic relaxation time;

• ET – aortic ejection time.

Key (interpretation): Normal values of the Tei index vary; usually ≤ 0.39 is considered normal. Elevated values of the index (≥ 0.40) indicate impaired myocardial function, reflecting a decline in overall cardiac performance.

Notes: The Tei index allows for a comprehensive assessment of cardiac function by combining parameters of systolic and diastolic myocardial activity.

Appendix G2. Minnesota Living with Heart Failure Questionnaire

Original title: Minnesota Living with Heart Failure Questionnaire (MLHFQ) [221]

• Type: questionnaire

Key (interpretation): * 0 points – excellent quality of life, 105 points – worst possible quality of life

Explanations: This questionnaire is designed to assess how heart failure has limited your activities over the past month. The questions below reflect various ways in which heart failure affects the lives of patients suffering from it. If you are certain that you do not have this symptom, or that it did not significantly affect your life this month, circle «0» (No). If you do experience this symptom and it prevents you from living the way you would like, circle a number from 1 to 5 according to the increasing severity of the symptom.

Appendix G3. CHA2DS2-VASc Risk Assessment Scale for Thromboembolic Complications

Russian title: CHA2DS2-VASc. Score for assessing the risk of thromboembolic events in patients with atrial fibrillation/flutter

Original title (if applicable): CHA2DS2-VASc

Source (official developer website, validation publication):

Olesen, Jonas Bjerring, et al. Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study. Bmj 342 (2011): d124.

Type (underline):

— rating scale

Purpose: clinical tool for predicting the risk of ischemic stroke and systemic thromboembolism in atrial fibrillation and flutter

Content (template):

Key (interpretation):

Notes: none