Pericarditis: Clinical Guidelines

List of Abbreviations

BP — blood pressure

ASA — acetylsalicylic acid**

HIV — human immunodeficiency virus

GCs — glucocorticoids

DNA — deoxyribonucleic acid

ESC — European Society of Cardiology

ACEI — ACE inhibitor

IHD — ischemic heart disease

MI — myocardial infarction

IRP — idiopathic recurrent pericarditis

CT — computed tomography

CK — creatine kinase

CK-MB — creatine kinase-MB

PA — pulmonary artery

LV — left ventricle

MB — Mycobacterium tuberculosis

IVS — interventricular septum

MRI — magnetic resonance imaging

MSCT — multislice computed tomography

NSAIDs — non-steroidal anti-inflammatory and antirheumatic drugs

AHF — acute heart failure

SPECT — single-photon emission computed tomography

RV — right ventricle

RA — right atrium

PPT — postpericardiotomy

PPS — postpericardiotomy syndrome

PCR — polymerase chain reaction

PET/CT — positron emission tomography combined with computed tomography

CEA — carcinoembryonic antigen

ESR — erythrocyte sedimentation rate

PPS — post-cardiac injury syndromes

CRP — C-reactive protein

TBP — tuberculous pericarditis

TSH — thyroid-stimulating hormone

FC — functional class

COPD — chronic obstructive pulmonary disease

CHF — chronic heart failure

COX — cyclooxygenase

PCI — percutaneous coronary intervention

ECG — electrocardiogram

EchoCG — echocardiography

ADA — adenosine deaminase

AFP — alpha-fetoprotein

CYFRA — cytokeratin family tumor marker

ESC — European Society of Cardiology

IGRA — interferon-gamma release assay

IL — interleukin

NYHA — New York Heart Association

T4 — free thyroxine

** — drug included in the list of vital and essential drugs

# — medicinal product for medical use used in non-compliance with the instructions for use regarding indications, contraindications, routes of administration, or dosages

Terms and Definitions

Acute pericarditis is a newly occurring clinical syndrome of polyetiological nature, typically presenting with symptoms of inflammation and chest pain, and in some cases with a pericardial friction rub and/or inflammatory pericardial effusion.

Recurrent pericarditis is a condition in which a recurrent episode of acute pericarditis occurs after a 4–6 week symptom-free period following the resolution of the first episode.

Subacute pericarditis is pericarditis with a disease duration of more than 4–6 weeks, but less than 3 months, without achieving remission after an episode of acute pericarditis.

Chronic pericarditis is pericarditis referring to pericardial effusions that persist for 3 months or longer.

Constrictive pericarditis is a late consequence of any pathological process developing in the pericardium as a result of fibrous thickening and calcification of the parietal and, less commonly, visceral pericardium, which impedes normal diastolic filling of the cardiac chambers.

Cardiac tamponade is a life-threatening condition characterized by rapidly progressive or gradual compression of the heart due to the accumulation of fluid, blood, pus, thrombotic masses, or gas in the pericardial cavity resulting from inflammation, trauma, cardiac rupture, or aortic dissection.

Myopericarditis is pericarditis with known or clinically suspected myocardial involvement. According to the ESC Working Group decision, pericarditis accompanied by myocardial involvement should be designated as "myopericarditis", while predominantly myocarditis with pericardial involvement should be designated as "perimyocarditis".

Beck's triad is the combination of arterial hypotension, muffled heart sounds ("quiet heart"), and high venous pressure.

Effusive-constrictive pericarditis is a rare form of constrictive pericarditis characterized by cardiac compression in the presence of an effusion. The main sign is elevated right atrial pressure (not decreasing by more than 50% from baseline or to less than 10 mm Hg), which persists after removal of the pericardial effusion and reduction of intrapericardial pressure to normal levels.

Sali–Chudnowsky sign — unusual systolic depression or retraction of the lower sternum and intercostal spaces occurring during a deep breath, sometimes detectable in constrictive pericarditis.

Mediastinopericarditis is combined inflammation of the mediastinal fatty tissue and pericardium, typically a complication of pericarditis.

Cardiolysis is a surgical procedure to dissect adhesions between the pericardial layers and between the heart and surrounding tissues.

Pericardiectomy is a surgical procedure to excise the pericardial layers.

Pericardium (pericardial sac) is a closed slit-like cavity surrounding the heart and containing up to 15–50 ml of serous fluid.

Dressler's syndrome (post-myocardial infarction syndrome) is an autoimmune complication of myocardial infarction manifesting as a combination of pericarditis, pleuritis, and pneumonitis.

Post-cardiac injury syndromes (PCIS) is a term used to denote pericardial syndromes that occur after any damage to the heart muscle membranes. They include postpericardiotomy syndrome, post-traumatic pericarditis, and post-myocardial infarction syndrome.

Hydropericardium (pericardial effusion) is an excessive accumulation of transudate in the pericardial cavity.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Acute pericarditis is a newly occurring clinical syndrome of polyetiological nature, typically presenting with symptoms of inflammation and chest pain, and in some cases with a pericardial friction rub and/or inflammatory pericardial effusion.

Recurrent pericarditis — is a condition in which a recurrent episode of acute pericarditis occurs after a 4–6 week symptom-free period following the resolution of the first episode.

Subacute pericarditis is pericarditis with a disease duration of more than 4–6 weeks, but less than 3 months, without achieving remission after an episode of acute pericarditis.

Chronic pericarditis — is pericarditis referring to pericardial effusions that persist for 3 months or longer.

Constrictive pericarditis is a late consequence of any pathological process developing in the pericardium as a result of fibrous thickening and calcification of the parietal and, less commonly, visceral pericardium, which impedes normal diastolic filling of the cardiac chambers.

Cardiac tamponade is a life-threatening condition characterized by rapidly progressive or gradual compression of the heart due to the accumulation of fluid, blood, pus, thrombotic masses, or gas in the pericardial cavity resulting from inflammation, trauma, cardiac rupture, or aortic dissection.

Myopericarditis is pericarditis with known or clinically suspected myocardial involvement. According to the ESC Working Group decision, pericarditis accompanied by myocardial involvement should be designated as "myopericarditis", while predominantly myocarditis with pericardial involvement should be designated as "perimyocarditis".

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

Pericarditis, as an inflammatory process, can be either an independent nosological entity or a secondary manifestation of another disease.

Etiological factors of pericardial disease can be described as infectious, non-infectious (immune and non-immune — involvement of adjacent organs, metabolic, neoplastic, traumatic, iatrogenic, etc.) and idiopathic [1–4].

Etiology of pericardial diseases:

1. Idiopathic pericarditis.

2. Infectious causes:

• viral (common) (herpesviruses (Epstein-Barr virus, cytomegaloviruses, human herpesvirus type 6), influenza, rubella viruses, enteroviruses (Coxsackie viruses, ECHO viruses), adenoviruses, hepatitis B and C viruses, human immunodeficiency virus, parvovirus B19 (possible overlap with viral agents of myocarditis), etc.);

• bacterial or purulent (Mycobacterium tuberculosis, less commonly Mycobacterium avium; Coxiella burnetii, Borrelia burgdorferi; rarely S. pneumoniae, N. meningitidis, S. aureus, Haemophilus parainfluenzae, Chlamydophila pneumoniae, Mycoplasma pneumoniae, Legionella, Leptospira interrogans, Listeria, Providencia stuartii, Eikenella corrodens, etc.);

• fungal (rare) (Histoplasma spp. (in immunocompetent individuals), Candida spp., Aspergillus spp., Blastomyces spp., Cryptococcus neoformans, etc. (in immunocompromised states);

• parasitic (very rare) (Entamoeba histolytica, Echinococcus spp., Toxoplasma spp., etc.).

3. Non-infectious causes:

a. Autoimmune and autoinflammatory:

• systemic connective tissue diseases (systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjögren's syndrome, dermatomyositis/polymyositis);

• systemic vasculitides (giant cell arteritis, Takayasu arteritis, polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis, Behçet's disease);

• acute rheumatic fever;

• familial Mediterranean fever;

• adult-onset Still's disease;

• sarcoidosis;

• IgG4-related disease;

• inflammatory bowel disease;

• chronic graft-versus-host disease following allogeneic hematopoietic stem cell transplantation;

b. Traumatic and iatrogenic:

Early onset (rare):

• direct injury (penetrating injury, thoracic surgery, esophageal perforation);

• indirect injury (non-penetrating injuries, blunt chest trauma, radiation therapy);

Late onset:

• postpericardiotomy syndrome (coronary artery bypass grafting, heart valve replacement, etc.);

• postthoracotomy syndrome;

• post-traumatic, including post-interventional forms (pacemaker implantation, radiofrequency ablation of arrhythmogenic zones, transcatheter aortic valve implantation, percutaneous coronary intervention, endomyocardial biopsy);

c. Pericarditis due to heart and adjacent organ disorders:

• myocarditis;

• myocardial infarction (early [epistenocardiac] pericarditis and Dressler's syndrome);

• disorders caused by high venous pressure (chronic heart failure, pulmonary hypertension);

• thoracic aortic dissection;

• pulmonary infarction;

• pneumonia;

• pleural empyema;

• esophageal diseases;

• paraneoplastic syndromes;

d. Metabolic:

• end-stage chronic kidney disease;

• hypothyroidism;

• thyrotoxicosis;

• anorexia;

e. Pericardial neoplasms:

• primary:

  • malignant (rare) (mesotheliomas, fibro- and angiosarcomas);

  • benign (fibromas, lipomas);

• secondary (metastatic):

  • lung cancer;

  • breast cancer;

  • gastric cancer;

  • colon cancer;

  • lymphomas;

  • melanoma;

  • sarcomas, etc.;

f. Drug-induced (rare):

• Lupus-like syndrome (procainamide**, methyldopa**, isoniazid**, phenytoin**);

• conventional antineoplastic drugs (more commonly associated with secondary cardiomyopathy, including direct pericardiopathy) – doxorubicin**, daunorubicin**, bleomycin**, pyrimidine analogues, fluorouracil**, cyclophosphamide**, methotrexate**;

• targeted antineoplastic drugs — dasatinib**, imatinib**, tretinoin**, arsenic trioxide;

• tumor immunotherapy — Interleukin-2, interferon alfa-2b**;

• immune checkpoint inhibitors (ATC monoclonal antibodies) — ipilimumab**, nivolumab**, pembrolizumab**, atezolizumab**, durvalumab**, avelumab**;

• beta-lactam antibacterial drugs: penicillins (hypersensitivity pericarditis associated with eosinophilia);

• amiodarone**, thiazide diuretics;

• streptokinase, oral anticoagulants (ATC — antithrombotic agents);

• mesalazine**, bromocriptine**, propylthiouracil, clozapine, cyclosporine**, tumor necrosis factor alpha (TNF-alpha) inhibitors, adalimumab**, human recombinant granulocyte colony-stimulating factor [rHuG-CSF];

• certain vaccines;

g. Pericarditis in other situations or syndromes:

• amyloidosis and other causes of nephrotic syndrome;

• polycystic kidney disease;

• Stevens-Johnson syndrome;

• eosinophilic syndrome;

• chylopericardium;

• congenital partial and complete absence of the pericardium.

• pericardial cysts.

Established infectious causes account for only 14% of acute pericarditis cases [5]. In developed countries, idiopathic/viral pericarditis is the most common form (up to 85–90% of patients), typically preceded by gastrointestinal or flu-like symptoms [6–10] and observed somewhat more frequently during the cold season [11]. Meanwhile, tuberculosis—frequently in the setting of HIV infection—remains the leading cause of the disease in developing countries (64.9–70% in African nations) [12, 13].

With the widespread use of systemic antibacterial drugs and preventive vaccination in high-risk patients to prevent pneumococcal pneumonia, the incidence of bacterial pericarditis has significantly decreased to 1–2% [29]. Among these, S. aureus remains the most prevalent pathogen, causing primary pericardial abscess and/or purulent pericarditis in 22–31% of patients [14]. However, the etiological significance of anaerobic pathogens (Prevotella spp., Peptostreptococcus spp., Propionibacterium acnes, etc.) as well as Borrelia burgdorferi has simultaneously increased [6, 5].

Cytomegalovirus pericarditis is becoming increasingly prevalent, observed in immunocompromised individuals and HIV-infected patients.

Non-infectious causes of pericardial involvement account for approximately 15–20% of cases [15, 16]. Among them, post-cardiotomy pericarditis constitutes 8.9–20%, and its incidence in developed countries is progressively increasing due to the rise in invasive procedures (coronary artery bypass grafting, artificial pacemaker implantation (A16.10.014 pacemaker implantation), radiofrequency ablation of arrhythmogenic zones, transcatheter aortic valve replacement, and less commonly, percutaneous coronary interventions) [17–24]. In contrast, recent decades have been characterized by a decrease in the incidence of pericarditis in patients with prior ST-segment elevation myocardial infarction, driven by advances in the treatment of coronarogenic myocardial injury. Specifically, the incidence of early (epistenocardic) pericarditis decreased from 10–20% to 6%, while for Dressler syndrome, the reduction was from 3–4% to < 1% [25]. Other non-infectious causes include autoimmune diseases (2–24%), end-stage chronic kidney disease (5–13% prior to dialysis, 20% during dialysis), primary hypothyroidism (secondary to chronic autoimmune thyroiditis and postoperative) (3–37%), primary and secondary pericardial neoplasms (5–35%), and radiation therapy for breast, lung, or esophageal cancer, or mediastinal Hodgkin lymphoma at a cumulative dose greater than 30 Gy [16, 26–32]. Myopericarditis has recently been described as part of immune-related adverse events (1%) associated with the use of immune checkpoint inhibitor monoclonal antibodies: PD-1/PD-L1 inhibitors (programmed cell death protein 1 / programmed death-ligand 1) (ipilimumab**, nivolumab**, pembrolizumab**) in the immunotherapy of malignant neoplasms (metastatic melanoma, mesothelioma, non-small cell lung cancer, Hodgkin lymphoma, urothelial cancer) [33–40].

Viral invasion is the leading etiological cause of myopericarditis [41–43]. As with isolated myocardial and pericardial involvement, myopericarditis frequently develops following an acute respiratory viral infection, acute tonsillitis, pneumonia, gastroenteritis, or enterocolitis [44, 45]. In developing countries, other infectious agents, particularly tuberculosis, play a significant role in the development of myopericarditis [1].

It is important to note that the onset of acute pericarditis can be one of the manifestations of paraneoplastic syndrome [46, 2, 74, 3, 36]. Therefore, targeted oncological screening is advisable in overweight, smoking elderly patients who develop acute pericarditis, as they carry a higher risk of malignancy (4.8% of patients) [46, 47].

Idiopathic pericarditis, for which a specific etiology remains unidentified upon routine investigation, is observed in 55–80% of cases in developed countries, whereas on the African continent it accounts for only 15% [48, 5]. It is hypothesized to be based on direct or indirect viral injury to the pericardium [6, 10, 49]. Virological studies in the setting of acute pericarditis have low statistical power, and their results do not significantly influence patient management [50]. Consequently, a critical step in diagnosing idiopathic/suspected viral pericarditis and determining further patient management is the exclusion of non-viral causes of the disease [3].

Constrictive pericarditis develops in less than 1% of cases as a sequela of acute idiopathic pericarditis. The development of constrictive pericarditis is more characteristic of a specific etiology. The risk of constriction increases to 2–5% in autoimmune, autoinflammatory, and paraneoplastic pericarditis. The highest risk of constriction, reaching 20–30%, is characteristic of bacterial, particularly purulent and tuberculous pericarditis [51–54].

Purulent pericarditis is rare, occurring in less than 1% of cases [55]. It is frequently associated with pleural empyema or pneumonia and is caused by staphylococci, streptococci, pneumococci, or fungi in immunocompromised patients or following thoracic surgery [56, 57]. The spread of infection is also possible from the oropharynx, via hematogenous routes, along the retropharyngeal space, from heart valves, and from the subdiaphragmatic region [55, 58]. Meningococcal pericarditis may present as a primary meningococcal infection or as a secondary form resulting from disseminated meningococcemia [59].

1.3 Epidemiology of the Disease or Condition

The true prevalence of pericarditis in the population is unclear due to the lack of specific symptoms, which are often masked by the clinical picture of other diseases or fail to raise suspicion among either patients or physicians. Consequently, among all patients seeking inpatient medical care, the diagnosis is established in only 0.2% of cases [6], whereas signs of pericarditis (active or past) are found at autopsy in 1–6.1% [48]. The incidence of acute pericarditis is 27.7 cases per 100,000 population per year in urban areas of Northern Italy, with concurrent myocarditis observed in 15% of cases [60–64]. Meanwhile, according to the Danish National Patient Registry, over the past two decades there has been a 47% increase in the incidence of acute pericarditis (from 10.5 per 100,000 population in 1994 to 15.4 per 100,000 population in 2016) [15].

Purulent pericarditis is currently rare, accounting for 1 case per 18,000 hospitalized patients, with the diagnosis established only postmortem in half of the cases [65, 66].

A recurrent course of pericarditis within the first 18 months is observed in 25–30% of cases [60, 7, 67], and the probability of a subsequent relapse increases to up to 50% [60, 67].

Inpatient mortality from acute pericarditis against the background of adequate therapy is 1.1% and increases in elderly patients, as well as in the presence of severe comorbid conditions (pneumonia, sepsis) and risk factors (HIV infection, immunosuppression, uncontrolled diabetes mellitus, dialysis, alcoholism, cardiac surgery) [1]. At the same time, there is a downward trend in early overall mortality among elderly patients with acute pericarditis (from 7.6% in 1999 to 5.7% in 2012) [68]. Purulent pericarditis, characterized by a fulminant course with rapid development of cardiac tamponade and a mean hospital stay of about 3 days, is accompanied by a high mortality rate ranging from 42 to 77% [65, 69–71].

The incidence of tuberculous pericarditis (TBP) depends on the regional endemicity of tuberculosis. In developed countries, its prevalence does not even reach 4% [13], whereas in developing countries it accounts for 70%, representing the leading cause of acute pericarditis [13, 12, 72]. The HIV pandemic exacerbates the burden of TBP, particularly in Southern Africa [13, 73, 74]. The disease can develop at any age. It has been noted that men are affected more often than women [13]. Mortality in TBP remains extremely high, despite the use of glucocorticoids, Colchicum autumnale seed extract (source of the alkaloid colchicine), and antituberculosis drugs that penetrate poorly into the pericardium, reaching up to 40% [75].

1.4 Features of Coding the Disease or Condition

Classification of pericarditis and pericardial effusions according to ICD-10 (Russian-language editions of 1995 and 2019, with ICD-10 versions from 1989 and 2016, respectively. This section of ICD-10 has not changed)

I30 Acute pericarditis

Includes: acute pericardial effusion

Excludes: rheumatic pericarditis (acute) — I01.0

I30.0 Acute nonspecific idiopathic pericarditis

I30.1 Infectious pericarditis (including pneumococcal, purulent, staphylococcal, streptococcal, viral, pyopericardium)

If it is necessary to identify the infectious agent, a second additional code (B95-B98) is used. Note: in the Russian Federation, the second additional code is not applied [76-78].

I30.8 Other forms of acute pericarditis

I30.9 Acute pericarditis, unspecified

I31 Other diseases of pericardium

Excludes: certain current complications following acute myocardial infarction (I23.0 Hemopericardium as current complication following acute myocardial infarction, I23.8 Other current complications following acute myocardial infarction), postcardiotomy syndrome (I97.0), heart injury (S26.-).

I31.0 Chronic adhesive pericarditis (including adherent, adhesive mediastinopericarditis)

I31.1 Chronic constrictive pericarditis (including pericardial calcification)

I31.2 Hemopericardium, not elsewhere classified

I31.3 Pericardial effusion (noninflammatory) (including chylopericardium)

I31.8 Other specified diseases of pericardium (including epicardial plaques, focal pericardial adhesions)

I31.9 Diseases of pericardium, unspecified (including cardiac tamponade and chronic pericarditis without further specification)

I32* Pericarditis in diseases classified elsewhere

Note: according to ICD-10 rules, these are used only as second, additional codes to the primary codes (with the † dagger symbol). In the Russian Federation, second additional codes are not used (Letters of the Russian Ministry of Health No. 14-6/10/2-178 dated 19.01.2009 "On the procedure for issuing and filling out medical birth and death certificates", No. 14-9/10/2-4150 dated 26.04.2011 "On the specifics of coding certain diseases of ICD-10 Class IX", Methodological Recommendations of the Moscow Healthcare Department "Rules for formulating a pathoanatomical diagnosis, selection and ICD-10 coding of causes of death". Zairatyants O.V. et al. Nos. 45-56, 2019. www.mosgorzdrav.ru).

I32.0* Pericarditis in bacterial diseases classified elsewhere

I32.1* Pericarditis in other infectious and parasitic diseases classified elsewhere

I32.8* Pericarditis in other diseases classified elsewhere

I97.0 Postpericardiotomy (postoperative) pericarditis.

1.5 Classification of the disease or condition

Clinical classification of pericarditis

1. By course:

a. acute pericarditis (maximum up to 4–6 weeks):

b. subacute pericarditis (pericarditis lasting more than 4–6 weeks, but less than 3 months without remission);

c. chronic pericarditis (more than 3 months):

d. recurrent pericarditis (pericarditis occurring after resolution of the first episode of acute pericarditis and an asymptomatic period of at least 4–6 weeks):

2. By presence or absence of effusion:

a. dry (fibrinous),

b. exudative/exudative-constrictive:

o by character of effusion:

▪ transudate (hydropericardium),

▪ exudate:

▪ serous (transudate, e.g., in hypoalbuminemia of any etiology);

▪ serous-hemorrhagic (transudate mixed with blood — in tumors and their metastases involving the pericardium, chest radiation therapy, blunt heart and chest injuries);

▪ hemorrhagic — hemopericardium (blood in myocardial rupture during myocardial infarction or arrhythmogenic right ventricular dysplasia, dissection and rupture of ascending aortic arch aneurysms, heart injuries, etc.);

▪ purulent and putrid (pyopericardium);

▪ chylous — chylopericardium (in obstruction of the thoracic duct and impaired lymphatic drainage from the pericardium of any etiology);

o by degree of effusion (effusion volume or echocardiographic measurement at end-diastole):

▪ small effusion (50–100 ml or < 10 mm),

▪ moderate effusion (100–500 ml or 10–20 mm),

▪ large effusion (> 500 ml or > 20 mm).

3. By presence of hemodynamic disturbances:

a. cardiac tamponade,

b. pericardial constriction (constrictive (compressive) pericarditis or "corset heart" / " armour heart").

Morphological classification of pericardial diseases

1. Fluid accumulations in the pericardial cavity (noninflammatory pericardial effusion, hydropericardium);

2. Pericarditis (can be either an independent nosological entity or a secondary manifestation of another disease.);

3. Other pericardial diseases:

▪ Malformations (complete and partial absence, congenital cysts and diverticula);

▪ Epicardial plaques (focal epicardial sclerosis);

▪ Pericardial adhesions;

▪ Acquired pericardial cysts and diverticula;

4. Pericardial tumors

▪ Primary pericardial tumors;

▪ Metastases of malignant tumors of other sites or their invasion into the pericardium;

▪ Lesions in lymphomas and leukemias.

Pericarditis (inflammation of the pericardial layers)

By pathogenesis:

• primary (acute nonspecific idiopathic pericarditis, infectious and parasitic pericarditis, mostly viral);

• secondary (infectious, autoimmune, neoplastic, metabolic, traumatic, iatrogenic and other manifestations and complications of myocarditis, various chest diseases, systemic diseases, cardiac surgery, radiation therapy, etc.).

By character of inflammation and inflammatory exudate:

• serous, with a mixture of blood — serous-hemorrhagic (acute nonspecific idiopathic pericarditis, primary viral infectious, in tumors and their metastases involving the epi- and/or pericardium, blunt heart and chest injuries, chest radiation therapy, after cardiac surgery, etc.);

• fibrinous, "dry" ("hairy heart", “bread and butter pericarditis” — primary infectious, in uremia, focal fibrinous — in transmural myocardial infarction, Dressler post-infarction syndrome, etc.);

• fibrinous-suppurative (primary infectious — bacterial and/or mycotic, with infection of the effusion, other types of pericarditis, sepsis);

• fibrinous-hemorrhagic (primary infectious, in tumors and their metastases involving the epi- and/or pericardium, blunt heart and chest trauma, chest radiation therapy, after cardiac surgery, uremia, etc.);

• purulent and (rarely) putrid (pyopericardium, primary infectious — bacterial and/or mycotic, secondary — when inflammation spreads from mediastinal organs, infection of effusion, other types of pericarditis, sepsis);

• caseous (in tuberculosis, three stages — dry — fibrinous, wet — exudative, serous-fibrinous, and absorption-constrictive);

• fibrous — adhesive (adherent), obliterating, constrictive (stenosing), mediastinopericarditis (usually as an outcome of other types of pericarditis, rarely primary).

Other pericardial diseases

• developmental anomalies (complete and partial absence, congenital cysts and diverticula);

• epicardial plaques (focal epicardial sclerosis);

• pericardial adhesions (single adhesions);

• pericardial cysts and diverticula (acquired).

Pericardial tumors

• primary pericardial tumors (benign and malignant — mesothelioma, etc.);

• metastases of malignant tumors of other sites or their invasion into the pericardium (most often — lung, breast, stomach cancer);

• involvement in lymphomas and leukemias.

1.6 Clinical presentation of the disease or condition

1.6.1 Clinical presentation of pericarditis

Acute viral or idiopathic pericarditis typically presents at onset with the following manifestations: chest pain, pericardial friction rub, and specific concordant ST-segment changes and PQ or PR interval depression. The onset is acute in most cases, with chest pain being the first manifestation. Typical is acute, diffuse pain radiating to the shoulders, scapula, and back. The pain intensifies on inspiration, which requires differential diagnosis with pleuritis, and with coughing and swallowing (water swallow test). The pain eases in the prone position. Hyperthermia, myalgia, weakness, and rhythm disturbances are possible but not mandatory in the acute period. Dyspnea is not typical in the early debut of the disease. Its appearance and progression indicate an increasing volume of effusion. Acute pericarditis resolves within 2–6 weeks. Most patients with acute viral or idiopathic pericarditis have a favorable long-term prognosis [52].

Cardiac tamponade rarely develops in acute idiopathic pericarditis; its development is characteristic of malignant tumors, tuberculosis, or purulent pericarditis.

1.6.2 Clinical presentation of cardiac tamponade

The main complaints presented by patients with cardiac tamponade or its threat in acute pericarditis are episodes of severe weakness, dizziness, syncope, and worsening dyspnea due to pulmonary hypovolemia. The patient's typical posture is sitting leaning forward. The skin is pale, cold, with cyanosis. Puffiness of the face, predominantly of the left arm due to compression of the brachiocephalic vein, and the appearance and progression of edema are possible. On physical examination, distension of the neck veins is noted (less noticeable in patients with hypovolemia). Central venous pressure rises up to 200–300 mm H2O (except for cases of low-pressure tamponade in patients with hypovolemia), with persistence of the decrease in venous pressure during inspiration. Arterial hypotension progresses or may be absent, especially in patients with pre-existing arterial hypertension. The combination of arterial hypotension, muffled heart sounds, and distended jugular veins is called Beck's triad. Pulsus paradoxus appears, and tachycardia progresses. Dyspnea or tachypnea is observed in the absence of rales in the lungs. The liver enlarges, and ascites appears.

1.6.3 Clinical presentation of recurrent pericarditis

There are no clear differences in the clinical picture between acute and recurrent pericarditis. However, diagnosis requires an asymptomatic interval of 4 to 6 weeks and evidence of new pericardial inflammation [6]. As a rule, patients with prolonged fever are more prone to relapses than patients with normalization of temperature by days 5–7.

1.6.4 Clinical presentation of subacute and chronic pericarditis

In the clinical picture of subacute and chronic pericarditis, along with chest pain, pericardial friction rub, and pericardial effusion, dyspnea may be present.

1.6.5 Clinical presentation of myopericarditis

The most frequent complaints of patients with myopericarditis include the following:

- chest pain, localized retrosternally and/or in the left hemithorax, intensifying with deep breathing and in the supine position. Radiation of pain to the neck, left shoulder, and mandible is possible [79]. Chest pain is observed in more than 90% of patients [80];

- non-specific symptoms such as fever (> 50%), general weakness (> 50%), sweating, etc.

Sudden cardiac death may also be a fatal manifestation (solely or in combination with other symptoms) of myopericarditis [81].

1.6.6 Clinical presentation of bacterial pericarditis

The clinical picture of chronic cardiac compression most often mimics heart failure [13, 82]. The main manifestations are pericardial effusion (found in 79% of cases), effusive-constrictive pericarditis, and constrictive pericarditis, the frequency of which has decreased from 30–60% to 5–25% due to the active use of antituberculosis drugs [12].

1.6.7 Clinical presentation of constrictive pericarditis

Four periods can be distinguished in the course of constrictive pericarditis:

1. latent;

2. initial clinical manifestations;

3. pronounced clinical manifestations;

4. dystrophic (terminal).

The latent period corresponds to the development of adhesive pericarditis, when the pericardial cavity fills with delicate adhesions that do not affect heart function and overall hemodynamics. The classical "Beck's triad" (high venous pressure, ascites, "small quiet heart") is absent. It can last from several months to several years.

The initial period, characterized by progressive hemodynamic disturbances that manifest only during physical exertion. Diastolic ventricular dysfunction leads to elevated systemic venous pressure; in addition, adhesions between the parietal and visceral layers of the pericardium compress the superior and inferior venae cavae at their entry into the right atrium. Distension of the neck veins appears, intensifying on inspiration, along with facial puffiness.

Special forms of constrictive pericarditis

In addition to classical chronic constrictive pericarditis, rarer forms are distinguished: transient constrictive and effusive-constrictive.

Transient constrictive pericarditis develops after past acute or exudative inflammation of the pericardium with minimal effusion and resolves after anti-inflammatory therapy [6, 83]. It is characterized by clinical manifestations of the latent or initial period of constrictive pericarditis.

Effusive-constrictive pericarditis is a rare form of constrictive pericarditis characterized by cardiac compression in the presence of effusion that significantly affects hemodynamics [84]. It develops as a result of tumor involvement, chemotherapy, bacterial infection (especially tuberculosis in endemic countries), as well as after cardiac surgery [85]. The main sign is the persistence of elevated pressure in the right atrium (does not decrease by more than 50% from baseline or to a level less than 10 mm Hg) after removal of the pericardial effusion and reduction of pressure in the pericardial cavity to normal levels [84].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the disease or condition

The diagnosis of pericarditis is established on the basis of:

characteristic complaints and medical history.

Complaints may vary depending on the type of pericarditis (acute, recurrent, chronic, pericardial effusion, myopericarditis, cardiac tamponade, constrictive pericarditis). Complaints and anamnestic features in patients with pericarditis are described in detail in Chapter 2.2 "Complaints and History".

detection of signs of pericarditis on laboratory examination:

• Elevated levels of inflammatory markers CRP, ESR.

• Elevated levels of myocardial damage markers CK-MB and troponins I, T.

detection of signs of pericarditis on instrumental examination:

• Detection of signs of pericarditis according to echocardiography.

• Detection of signs of pericarditis according to CT.

• Detection of pericardial thickening according to MRI.

• Detection of signs of pericarditis on ECG (dynamically).

2.1 Complaints and Anamnesis

History and symptoms in pericarditis

The most characteristic are:

• Chest pain, pain is acute, intense, burning, which practically coincides with the characteristics of pain in acute myocardial infarction (noted in 85–90%);

• Dyspnea is present in almost all cases of acute pericarditis and is caused by the development of diastolic dysfunction;

• Fever lacks a strict pattern and may be absent in some cases. Febrile fever is mainly observed in patients with an autoinflammatory etiology of pericarditis. The classic variant of acute pericarditis is characterized by mild subfebrile temperature.

• Patients with localized small effusions are asymptomatic [87, 88]. In moderate effusions, patients complain of progressive dyspnea, initially upon exertion and later at rest, as well as dull, aching pain behind the sternum and/or in the precordial region, described as a feeling of "fullness" or "tightness" [89]. In significant effusions and hemodynamic impairment, complaints of dizziness and palpitations arise due to hypotension and reflex tachycardia. In gradually progressive massive effusions, symptoms of compression of adjacent organs may occur: nausea and anorexia (compression of the diaphragm), dysphagia (esophageal compression), hoarseness (compression of the recurrent laryngeal nerve), and hiccups (phrenic nerve compression).

2.2 Physical Examination

Physical examination in acute pericarditis

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Comments: in rare situations, a characteristic patient posture can be observed: the patient tends to sit leaning forward with the knees pressed as tightly as possible against the chest. This posture indicates the presence of a large effusion in the pericardial cavity.

A high rate of decline in systolic blood pressure or absolute systolic BP values below 100 mm Hg suggest the presence of a large pericardial effusion. On auscultation, heart sounds are muffled or distant. A pericardial friction rub is detected in one-third of patients on the first day of the disease. In subsequent days, the detection rate drops sharply, occurring only sporadically.

In significant effusions and a high risk of cardiac tamponade, signs of hemodynamic compromise known as Beck's triad appear: hypotension, jugular venous distension, and muffled heart sounds [93].

Physical examination in cardiac tamponade

Objective examination reveals typical clinical signs and symptoms: hypotension, tachycardia, jugular venous distension due to stretching and elevated pressure, pulsus paradoxus, and significantly diminished heart sounds across all auscultation points. Pulsus paradoxus is a pathognomonic sign of cardiac tamponade, manifested by a drop in systolic blood pressure of more than 10 mm Hg during inspiration under quiet breathing [94].

Physical examination in myopericarditis

In most cases, patients present with fever and tachycardia. Body temperature rarely exceeds 38°C [95]. Cardiac auscultation may reveal a pericardial friction rub heard over the area of absolute cardiac dullness. With the development of cardiac tamponade, signs of biventricular heart failure may be detected.

Physical examination in constrictive pericarditis

The period of pronounced clinical changes is characterized by persistent elevation of venous pressure (200–300 mm H2O). Due to marked compression of the superior vena cava, the patient acquires a characteristic appearance: a bloated, cyanotic head creating a monumental impression ("consular head"), and Stokes' collar develops. Notably, there is no orthopnea, despite progressive cyanosis and tachypnea in the recumbent position. Progressive dyspnea worsening month by month is continuous and never occurs in paroxysms, with no increase in intensity during physical exertion.

One of the most characteristic signs on objective examination is pronounced ascites and hepatomegaly, resulting from post-sinusoidal portal hypertension. A distinctive feature of constrictive pericarditis is that ascites and hepatomegaly precede lower extremity edema.

During a deep inspiration, an unusual systolic retraction or depression of the lower sternum and intercostal spaces may sometimes be detected (Broadbent's sign / Cheвnovsky sign), which is explained by the formation of extracardiac adhesions. On auscultation, the first and second heart sounds are muffled. Persistent tachycardia appears, and pulsus paradoxus may occur, though unlike in tamponade, it is observed in no more than 33% of cases [1, 3, 96]. Fibrous replacement of the atrial myocardium leads to atrial fibrillation.

2.3 Laboratory Diagnostics

Laboratory diagnostic tests in acute pericarditis

Determination of inflammatory marker levels is mandatory. Elevated inflammatory markers, primarily serum C-reactive protein (CRP), increased erythrocyte sedimentation rate (ESR) on the complete blood count, and leukocytosis are found in most patients. Elevation of these markers is considered a diagnostically significant sign confirming an inflammatory disease. Due to the polyetiological nature of acute pericarditis, specific biochemical markers do not exist. Monitoring the dynamics of inflammatory markers is essential to assess disease activity and treatment efficacy [97]. In patients with myocardial involvement concomitant with pericarditis, elevated levels of specific myocardial injury markers—serum creatine kinase MB isoenzyme (CK-MB) and cardiac troponins I and T—are noted [98, 99].

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Laboratory diagnostic tests in recurrent, subacute, and chronic pericarditis

In 8–50% of cases, patients with recurrent pericarditis show elevated aminotransferases [100, 101]. Elevated myocardial injury markers (troponin, CK-MB) are registered in one-third of patients with recurrent pericarditis [6]. In addition, blood tests frequently (up to 80% of cases) reveal neutrophilic leukocytosis, accelerated ESR, and elevated C-reactive protein levels. The latter is associated with a high risk of disease recurrence. Ferritin serves as a marker of the autoinflammatory nature of the disease and macrophage immune activation associated with elevated interleukin-18 levels. Therefore, ferritin levels should be measured during a disease relapse alongside C-reactive protein. Assessing the cytokine profile in routine clinical practice is impractical because the concentration of proinflammatory cytokines fluctuates widely throughout the day. If the recurrent process is not associated with systemic connective tissue diseases, the levels of rheumatoid factor, complement system, antinuclear antibodies, and other specific autoantibodies are not elevated.

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Laboratory diagnostic tests in pericardial effusion

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Laboratory diagnostic tests in myopericarditis

The diagnosis of "myopericarditis" is based on the presence of criteria for acute pericarditis accompanied by evidence of myocardial injury (elevated troponin I or T, CK-MB). The de novo appearance of focal or diffuse LV dysfunction in patients with elevated myocardial biomarkers and clinical signs of acute pericarditis indicates the predominance of myocarditis with pericardial involvement ("perimyocarditis") [1].

Laboratory diagnostic methods used in patients with myopericarditis include the following:

- serum C-reactive protein assay;

- markers of myocardial injury: blood troponin I and T assay, blood creatine kinase isoenzyme (CK-MB) assay/activity measurement.

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Laboratory diagnostic tests in bacterial pericarditis

Purulent pericarditis is characterized by high fever. It may accompany sepsis [55]. If purulent pericarditis is suspected, diagnostic pericardiocentesis should be performed as soon as possible. Pericardial fluid is characterized by a low pericardial-to-serum glucose ratio (average 0.3) and an elevated leukocyte count in the pericardial fluid with a high proportion of neutrophils (average cell count 2.8/µL, 92% neutrophils), which distinguishes the purulent form from tuberculous (glucose ratio 0.7, cell count 1.7/µL, 50% neutrophils) and neoplastic forms (glucose ratio 0.8, cell count 3.3/µL, 55% neutrophils) [106]. Microbiological (culture) examination of pericardial fluid for aerobic and facultatively anaerobic microorganisms is mandatory.

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• It is recommended that all patients undergo microbiological (culture) examination of pericardial fluid for aerobic and facultatively anaerobic microorganisms to rule out purulent pericarditis [55].

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2.4 Instrumental Diagnostics

Echocardiography

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Comments: three-dimensional echocardiography provides greater opportunities for a comprehensive analysis of the entire pericardium in any anatomical plane, and therefore its performance increases the likelihood of detecting a localized effusion and ensures a more accurate quantitative assessment of its fluid volume.

Normally, the pericardial thickness is < 3 mm. Overall, transesophageal echocardiography is considered more sensitive and therefore more accurate than transthoracic echocardiography in assessing pericardial thickness.

Echocardiography may reveal early signs of constrictive pericarditis, such as paradoxical diastolic motion of the interventricular septum (IVS) (Appendix A3, Fig. A3-1) [83].

In constrictive pericarditis, there is a significant dependence of the blood flow profile across the mitral and tricuspid valves on the phases of respiration:

- according to pulsed-wave Doppler data, at the beginning of inspiration, the maximum velocity of the transmitral E-wave decreases by ≥ 25%;

- at the beginning of expiration, the maximum velocity of the transtricuspid E-wave decreases by ≥ 40% (Appendix A3, Fig. A3-1) [116].

Tissue Doppler imaging can also be useful in the diagnosis of constrictive pericarditis, demonstrating the so-called "annulus reversus" phenomenon, which consists in the fact that the normal or increased early diastolic velocity of the medial part of the mitral annulus (medial e') turns out to be higher than the early diastolic velocity of the lateral part of the fibrous annulus (lateral e') (Appendix A3, Fig. A3-2) [117].

The combination of bidirectional displacement of the IVS depending on respiratory phases with an increase in the early diastolic velocity of the medial part of the mitral annulus (medial e') ≥ 9 cm/s has the highest diagnostic sensitivity (87%) and specificity (91%) [118].

Additional parameters, including strain, can be used in echocardiographic examination to detect pericardial constriction. In constrictive pericarditis, global longitudinal strain is usually preserved, whereas circumferential strain, rotation, and early diastolic untwisting are reduced [119]. This type of strain abnormality, "strain reversus," is the counterpart of "annulus reversus" detected by tissue Doppler imaging. This abnormality has been shown to be reversible following pericardiectomy [119].

Constrictive pericarditis

Transthoracic echocardiography is a reliable method for diagnosing constrictive pericarditis: the detection of a thickening of ≥ 3 mm has a 95% sensitivity and an 86% specificity (Appendix A3, Fig. A3-3) [3].

A more valuable finding is areas of adhesion, which on two-dimensional echocardiography manifest as inward motion of the pericardium following the myocardium during systole without changing the echo-negative space between them. The detection of widespread areas of adhesion anterior to the pulmonary artery and posterior to the lateral wall of the left ventricle (or posterior to the left ventricular wall on M-mode imaging) indicates generalized thickening of the pericardial layers.

Paradoxical motion of the interventricular septum during early diastole is characteristic of patients with constrictive pericarditis. During inspiration, the motion is directed toward the left ventricle; during expiration, it moves in the opposite direction [3]. On M-mode imaging, this manifests as an early diastolic notch in the motion pattern of the interventricular septum, resembling the myocardial contraction-relaxation abnormalities observed in left bundle branch block or right ventricular pacing (Appendix A3, Fig. A3-4). When this sign is determined by two-dimensional echocardiography, the sensitivity is 62% and the specificity is 93% [3]. The use of tissue Doppler imaging can significantly increase the sensitivity of the method to 82.5% [122].

Doppler echocardiography allows the detection of the annulus paradox. This consists in the fact that with relative preservation of the myocardial ability to stretch in the longitudinal direction, left ventricular longitudinal axis strain and longitudinal early diastolic velocity are either normal or, as constrictive pericarditis progresses, increased. In contrast, in restrictive cardiomyopathy or myocardial disease, these parameters decrease. Meanwhile, the averaged peak tissue velocity of early diastolic displacement of the septal part of the mitral annulus is higher than that of the lateral part (Appendix A3, Fig. A3-5) [117, 123, 124–128]. Despite high sensitivity and specificity (95% and 96%, respectively), the limitation of this sign in diagnosis is manifested in cases of heterogeneous pericardial involvement or mitral annular calcification.

A dynamic change in atrioventricular blood flow depending on the respiratory phase is characteristic (Appendix A3, Fig. A3-6), which distinguishes constrictive pericarditis from restrictive cardiomyopathy. During inspiration, peak blood velocity decreases, and the isovolumetric relaxation time of the ventricles increases. During expiration, atrioventricular blood flow returns to normal values. As a rule, the increase in peak velocity is ≥ 25% during inspiration compared to expiration [129]. This sign has 85% sensitivity and 90% specificity [118].

However, up to 20% of patients with constrictive pericarditis may not have characteristic blood flow changes, which is associated with the presence of mixed constrictive-restrictive diseases and/or a significant increase in left atrial pressure [130].

Other signs of constrictive pericarditis include a decrease in mitral valve opening during atrial systole and premature opening of the pulmonary valve [131].

Systemic congestion is manifested by the absence of collapse of the venae cavae and hepatic veins. A distinctive feature is reverse blood flow detected by Doppler echocardiography, which increases more during expiration than during inspiration (Appendix A3, Fig. A3-7) [132]. Unlike constrictive pericarditis, restrictive cardiomyopathy is characterized by the inverse ratio.

Blood flow variations depending on the respiratory phase are also detected in the pulmonary veins, similar to the variations in blood flow through the atrioventricular orifices, but with more pronounced velocity indicators [133]. In restrictive cardiomyopathy, a decrease in blood flow velocity is observed in all phases of the respiratory cycle without pronounced variations. In addition, constrictive pericarditis is often accompanied by ascites and hydrothorax, which are also detected by echocardiography.

Table 1. Sensitivity and specificity of echocardiographic signs of constrictive pericarditis

Pericardial effusion

A large amount of pericardial effusion (echonegative space in diastole greater than 20 mm), cardiac tamponade, along with elevated temperature > 38 °C, subacute course, and lack of response to nonsteroidal anti-inflammatory drugs for 7 days are poor prognostic factors [136, 137, 93]. If at least one poor prognostic factor is present, hospitalization and etiological workup are required [1] (Appendix A3-14).

Normally, the pericardial cavity contains 10–50 ml of fluid, which is a plasma ultrafiltrate that serves as a lubricant between the pericardial layers [1]. The inflammatory process of the pericardium leads to the formation of exudate in the pericardial cavity; in severe chronic heart failure and/or severe pulmonary hypertension, transudate accumulates between the pericardial layers due to reduced reabsorption with increased systemic venous pressure [87].

Cardiac tamponade

The presence of pericardial effusion in cardiac tamponade can be easily identified by echocardiography. As a rule, the heart has normal dimensions. At the same time, small dimensions of the atria and ventricles are determined due to their inadequate filling with blood in diastole, but their good systolic function (compensatory wall hyperkinesia) is noted.

If the effusion is not very large, the development of tamponade is determined by the rate of fluid accumulation rather than its volume. If fluid accumulates rapidly, cardiac tamponade may develop with a small pericardial effusion with separation of its layers by only 10 mm. Conversely, cardiac tamponade may not develop even with a large pericardial effusion if it accumulates slowly. As a rule, the amount of pericardial effusion is easily assessed in diastole by measuring the size of the effusion between its layers in centimeters (perpendicular to the ventricular walls), usually in the parasternal view:

1) minimal pericardial effusion is usually visible only in systole and without hemodynamic consequences;

2) separation of the pericardial layers < 1 cm corresponds to approximately 300 ml of effusion;

3) separation of the pericardial layers by 1–2 cm corresponds to about 500 ml of effusion;

4) separation of the pericardial layers by > 2 cm usually corresponds to more than 700 ml of effusion.

5) The "swinging heart" sign occurs with a large pericardial effusion when conditions are created for excessive oscillatory movements of the heart. This condition is often accompanied by tamponade and electrical alternans on the ECG.

When performing transthoracic echocardiography, features of the pericardial effusion such as the presence and localization of fibrinous strands or clots can be detected. Pericardial effusion associated with end-stage renal disease can also be effectively analyzed by echocardiography [141].

With an increase in pericardial effusion, echocardiographic visualization confirms the formation of tamponade, which is manifested by:

1) stable dilatation of the inferior vena cava, which does not collapse significantly at peak inspiration;

2) reduced volume of direct transmitral blood flow in the LV detected by Doppler examination;

3) compression of the RV during diastole, or its collapse in severe cases;

4) collapse of the right atrium (RA) in systole [142].

Patients with cardiac tamponade may reveal significant changes in heart chamber sizes during respiration. Thus, on inspiration, there is an enlargement of the RV with a concomitant decrease in LV size. Conversely, during expiration, the RV decreases in size with a simultaneous increase in LV size.

However, it should be noted that under certain conditions, some echocardiographic features of cardiac tamponade formation, such as right ventricular compression, severe pulmonary hypertension, and RV hypertrophy, may be absent (Appendix A3, Fig. A3-8) [142].

Usually, in cardiac tamponade, significant changes in transmitral and transtricuspid flows are observed in different phases of respiration. During the first heart beat after inspiration, the maximum velocity of the transmitral E wave decreases by more than 30 %, while during the first heart beat after expiration, the maximum velocity of the transtricuspid E wave decreases by more than 60 % [142, 143].

Ventricular interdependence

Usually, the pericardium allows normal, unrestricted blood filling of the left and right ventricles, but in cardiac tamponade, the RV cannot expand freely into diastole during blood filling, so the IVS shifts to the left, and subsequently the LV becomes underfilled. This IVS shift can be provoked by respiratory maneuvers. The described ventricular interdependence can be observed in both cardiac tamponade and constrictive pericarditis.

In patients with cardiac tamponade, changes in intrathoracic pressure are well transmitted to the pulmonary veins and capillaries, but due to the expansion of the pericardial cavity, they are poorly transmitted to the LV. As a consequence, the pressure difference between the pulmonary capillaries and the LV during inspiration is markedly reduced compared to expiration, which leads to a decrease in LV filling and, consequently, to a decrease in its output in the form of a reduction in stroke volume [144].

As a result, during inspiration, the following Doppler characteristics are observed: in the left heart, the effective gradient of LV filling decreases due to a reduction in pulmonary capillary pressure, while the diastolic pressure of the PA and LV remains relatively preserved due to reduced transmission of intrathoracic pressure to the heart. Thus, LV filling will decrease.

Echocardiography can be useful for identifying rare pericardial pathologies, such as congenital absence of the pericardium, which is often detected as an incidental finding during cardiac imaging. Patients may be asymptomatic or present with a wide range of atypical symptoms, such as chest pain and palpitations [145].

Transthoracic echocardiography should also be the first-line imaging modality in patients with suspected congenital absence of the pericardium.

Imaging features on transthoracic echocardiography suggesting congenital absence of the pericardium include:

1) presence of unusual imaging acoustic windows;

2) appearance of right ventricular dilatation;

3) excessive cardiac motion.

Diagnostic imaging of pericardial diseases

Radiological diagnostic methods include radiography, computed tomography (CT), and magnetic resonance imaging (MRI). Radionuclide diagnostic methods (SPECT and cardiac PET/CT) are practically not used for diagnosing pericardial diseases.

In general, it should be noted that as a result of the introduction of echocardiography, CT, and MRI into cardiology practice, chest radiography plays an auxiliary role in the evaluation of patients with pericarditis. If acute or chronic pericarditis is suspected on chest radiography, the patient is referred for echocardiography, and in some cases, for cardiac CT or MRI.

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Radiography

Plain radiography makes it possible to suspect exudative pericarditis based on a rapid increase in the heart shadow on the radiograph (if serial prior images are available or in the absence of a history of diseases that can lead to cardiomegaly). In exudative pericarditis, the heart assumes the appearance of a horizontally oriented oval resting on the diaphragm (the "water-bottle" sign). This configuration differs from cardiomegaly caused by the enlargement of all heart chambers, where the shadow of the enlarged heart has a shape closer to trapezoidal. In chronic pericarditis with calcification of the pericardial layers and in constrictive pericarditis, areas of marked calcification of the pericardial layers can be seen on the radiograph. However, the sensitivity of radiography in detecting pericardial layer calcification is inferior to that of CT. Radiography can be used for a rapid semi-quantitative assessment of changes in pericardial fluid volume during conservative or interventional treatment of pericarditis. This method is helpful in cases where pericarditis is combined with pulmonary diseases (pneumonia, tuberculosis) or mediastinal diseases.

In acute fibrinous pericarditis, targeted chest radiography is usually performed to rule out pathology of the mediastinum and lungs, which are anatomically close to the pericardial sac. In other cases, the study has low diagnostic value due to the absence of any characteristic changes in the heart shadow [3, 152].

At the same time, when other forms of pericarditis are suspected, radiography can serve as an additional diagnostic tool [1, 3, 96]. Achieving a moderate sensitivity of 70%, it has a low specificity of 41%, which makes it impossible to use this method in isolation from the clinical picture [1, 3, 149].

In constrictive pericarditis, a small, "immobile" heart does not change its position with body movement or respiratory excursion. The compressed heart loses its waist and border differentiation, and contour irregularities appear due to numerous adhesions in the pericardial cavity. Small ventricles are detected with simultaneous enlargement of the atria. The absence of pulmonary congestion is characteristic.

The development of a "corset" heart occurs in 25% of cases of constrictive pericarditis. Calcified areas are best visualized on lateral and right anterior oblique projections (Appendix A3, Fig. A3-9) [1, 3].

Computed tomography

Pericardial layers, epicardial fat, fluid, pericardial masses, and pericardial calcification are very well visualized on CT. Even on chest CT without intravenous contrast enhancement of the heart chambers and vessels, the pericardial changes described above are clearly visible. CT makes it possible to very accurately estimate the volume of intraperitoneal fluid (based on the summation of its volumes across slices), measure the thickness of the pericardial layers in all its sections, and measure (including quantitatively) the degree of calcification. However, today, when referring a patient with pericarditis for CT, it is recommended to perform cardiac CT with electrocardiographic (ECG) synchronization and intravenous contrast enhancement of the heart chambers and vessels in the arterial phase (A06.10.009.001). In this case, high-quality images of the heart, pericardium, and mediastinum are obtained. Multiplanar and volumetric three-dimensional reconstructions can be created. Cardiac CT for pericardial diseases can be performed on all modern CT scanners of any class (starting from 16-detector row systems and higher) equipped with an ECG gating option.

If cardiac CT with ECG synchronization cannot be performed, chest CT with intravenous bolus contrast enhancement (in the arterial or venous phase) or unenhanced CT can be performed. When indications for their use are present (see below), these techniques will also provide additional diagnostic information.

The main advantages of CT are:

- high anatomical detail of all heart and mediastinal structures, pericardial layers, and pericardial cavity without artifacts and the ultrasound "window" problem;

- the ability to perform three-dimensional assessment of pericardial fluid volumes and accurate measurement of pericardial layer thickness in all segments;

- semi-quantitative assessment of the degree of calcification (based on measuring the density of pericardial layer calcification in Hounsfield units or based on measuring the calcium score of regions in Agatston units—analogous to the analysis of coronary artery calcification on CT);

- the ability to perform morphological and quantitative assessment of the heart chambers, myocardium, mediastinal vessels, and coronary arteries;

- CT allows for the assessment of pericardial effusion density (diagnosis of effusion with high-protein, hemorrhagic, or chylous contents);

- detailed visualization of lung fields, pleura, and mediastinum (the diagnostic value of CT for these organs is higher than that of radiography). This feature is important if pericardial diseases are a manifestation of systemic or multiorgan diseases.

Contraindications to contrast-enhanced cardiac CT in pericarditis are general (allergy to contrast agents, severe renal impairment, undesirability of ionizing radiation in pregnant women, children, and young adults). It should be noted that even in these cases, CT is possible if certain measures and precautions described in the relevant guidelines are followed, or CT can be replaced by MRI.

Indications for cardiac CT:

- the need to clarify echocardiographic data (artifacts, poor ultrasound "window");

- suspected neoplastic involvement of the pericardium or pericardial involvement associated with lung or mediastinal diseases;

- chronic pericarditis, especially in cases of partial or complete pericardial calcification or constrictive pericarditis;

- planning of pericardiocentesis or surgical treatment (if echocardiographic data need to be clarified);

- dynamic follow-up of patients with pericarditis (if necessary).

Due to its high resolution, which allows the detection of pericardial layer thickening from 2 mm (which is approximately 2 times greater than the thickness of a normal pericardium), CT is used to diagnose constrictive pericarditis with or without calcification [1].

Features of the CT picture that allow distinguishing pericardial layer thickening from pericardial effusion include: the presence of areas of decreased density, typical thickening of the anterior pericardial wall, no change in position when the patient is supine, and contrast enhancement. However, with a small amount of fluid, CT is not always able to detect this difference, unlike MRI.

The high spatial resolution of CT plays an important role in the differential diagnosis of constrictive pericarditis and restrictive cardiomyopathy. The detected thickening of the parietal pericardial layer, averaging 4 to 20 mm, helps differentiate these conditions [153]. However, in 28% (18% at autopsy) of patients with constrictive pericarditis, pericardial thickening is not detected [154].

Pericardial calcification, to varying degrees, is visualized in 50% of patients. At the same time, unlike echocardiography, CT allows the visualization of calcium deposits on any surface of the heart, especially in areas with high epicardial fat content (atrioventricular grooves and the base of the heart) (Appendix A3, Fig. A3-10) [154, 155].

Indirect signs of constrictive pericarditis include: reduction and circular deformation of the right and left ventricles. Impairment of right ventricular diastolic function is manifested by dilatation of the inferior vena cava and hepatic veins, hepatosplenomegaly, ascites, and pleural effusion.

Magnetic resonance imaging

As with CT, MRI allows for direct analysis of pericardial fluid volume based on three-dimensional volume reconstruction.

MRI is performed using "black-blood" sequences and cine-MRI. To detect inflammation of the pericardial layers and pericardial tumors, contrast-enhanced MRI is used—administering paramagnetic contrast agents (gadolinium) in the early phase and late phase (late gadolinium enhancement — LGE).

It should be noted that MRI does not allow for the detection and evaluation of pericardial calcification as reliably as CT.

Contraindications to contrast-enhanced cardiac MRI in pericarditis:

- presence of a pacemaker or implantable cardioverter-defibrillator*** incompatible with MRI, or other metal-containing devices for which MRI is contraindicated;

- allergy to gadolinium-based agents (ATC Paramagnetic contrast media) (extremely rare);

- presence of severe renal failure.

Indications for cardiac MRI:

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Constrictive pericarditis is characterized by pericardial thickening, which is more pronounced along the right ventricle and the anterior atrioventricular groove (Appendix A3, Fig. A3-11) [156].

At the same time, the criteria for leaflet thickening on MRI are considered to be [157]:

• 2 mm or less — no pathology;

• 2–5 mm in the presence of clinical symptoms — constrictive pericarditis;

• 5–6 mm — constrictive pericarditis.

The thickened pericardium has low signal intensity not only on T1- and T2-weighted spin-echo MRI, but also on cine images; in the terminal stage of constrictive pericarditis, the administration of paramagnetic contrast agents (gadolinium-based) does not lead to increased image detail (Appendix A3, Fig. A3-12) [158].

Indirect signs of constrictive pericarditis include: atrial enlargement, dilatation of the venae cavae and hepatic veins, ascites, and pleural effusion.

In cases of constrictive pericarditis, significant thickening of the pericardium is revealed, with adhesions containing foci of caseous degeneration and transformation into scar tissue found between its layers. Calcification of the pericardial sac may also be detected.

Electrocardiography

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Comments: electrocardiogram recording — an obligatory diagnostic procedure in a patient with acute pericarditis (Appendix A3, Fig. A3-13). Characteristic ECG changes are observed in 60% of cases of acute pericarditis [8, 9].

The presence of a progressive decrease in QRS complex amplitudes indicates an increase in exudate volume, although this sign is not absolute [62, 98, 99].

Constrictive pericarditis on an ECG may manifest with a triad of symptoms: a tall P wave, low-voltage QRS complex, and negative T wave [3, 162].

Analysis of effusion and biopsy specimens

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Comments. Analysis of pericardial effusion allows for the diagnosis of viral, bacterial, tuberculous, fungal, and malignant pericarditis. Clinical manifestations should be taken into account when choosing methods.

Hemorrhagic pericardial effusion is generally associated with malignant tumors and is also encountered after cardiac surgery, in post-traumatic, autoimmune, and viral pericarditis. Hemorrhagic staining of the effusion may occur following prior pericardiocentesis [108].

Biochemical analysis of the fluid makes it possible to distinguish transudate from exudate, but does not indicate the etiology of the disease.

If malignant effusion is suspected, a cytological examination and tumor marker analysis should be performed.

If tuberculosis is suspected, the pericardial fluid is examined for acid-fast mycobacteria by direct microscopy, by PCR to detect MTB DNA, and by cultures on liquid and solid media for Mycobacterium tuberculosis.

PCR to detect viruses makes it possible to diagnose viral pericarditis.

It is necessary to perform cultures of the pericardial fluid, preferably repeated ones, to identify aerobic and anaerobic pathogens. A promptly performed cytological examination may also reveal the pathogen.

Pathological anatomical examination of biopsy (surgical) material of the pericardium using immunohistochemical methods makes it possible to establish the diagnosis of neoplastic and tuberculous pericarditis. Immunohistochemical examination allows for the differentiation of autoimmune pericarditis, malignant mesotheliomas, and lung adenocarcinomas [212].

2.5 Other Procedures

Other diagnostic examinations within the framework of diagnosing pericarditis are not provided for; expanding diagnostic examinations may be possible by decision of the physician depending on the clinical situation and the patient's condition.

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

3.1 Conservative Treatment

3.1.1 Treatment of acute pericarditis

Non-drug treatment. For patients not engaged in professional sports, a drastic restriction of physical activity is indicated. Either strict bed rest (in the first days of the illness) or semi-bed rest is always preferable (the volume of exertion corresponds to the concept of a "sedentary lifestyle"). The duration of the sparing regimen is regulated by the duration of the period of pain, fever, and normalization of CRP levels, i.e., in typical cases it is a few days [163].

For professional athletes, the sparing regimen is prolonged for a minimum period of up to 3 months. Resumption of training is possible only after the persistent disappearance of clinical symptoms and normalization of inflammatory markers (CRP, ESR), ECG, and echocardiographic data [163, 164]. The use of a prolonged sparing regimen in treatment regimens is justified only for professional athletes.

Drug treatment. #Acetylsalicylic acid** (ASA), #Ibuprofen**, and #Colchicum autumnale seed extract (source of the alkaloid colchicine) are the mainstay drugs for the treatment of acute nonspecific pericarditis. The choice of drug should be based on the gathered medical history, in particular on the analysis of the drug's efficacy in previous periods, the presence of adverse reactions and contraindications to the drug, and the presence of comorbid conditions. #ASA** should be preferred over other NSAIDs if it is already being used by the patient as an antithrombotic agent. The personal experience of the physician should not dominate over the principle of rational individualized drug selection when choosing a medication [1, 165].

The drug of first choice may be #ASA** in high doses — from 750 to 1000 mg every 8 hours. The duration of administration is 2–3 g of #ASA** until normalization of temperature (usually 1–2 weeks). Subsequently, if any syndromes persist (presence of effusion, weakness, malaise, feeling of shortness of breath), administration of #Acetylsalicylic acid** should be continued, but at a dose of 500 mg every 8 hours for 1 week, and then switched to #ASA** at a dose of 250 mg twice daily for another 2 weeks [1].

In case of intolerance to #ASA**, the drug of choice is #Ibuprofen** at a dose of 600 mg every 8 hours [1]. The duration of treatment is until the complete disappearance of any manifestations of pericarditis, usually 1–2 weeks for uncomplicated cases. The choice of #Ibuprofen** as a first-line drug is due to the minimal number of side effects. Clinical experience shows that NSAID therapy stabilizes 90–95% of all pericarditis cases. Gastroprotection starting from the first hours of treatment for acute pericarditis is mandatory.

Taking into account the high probability of recurrence of acute pericarditis, to improve the response to drug therapy and reduce the risk of recurrence, #Colchicum autumnale seed extract (source of the alkaloid colchicine) in low doses should be added to #ASA** or #Ibuprofen** therapy according to a special regimen taking into account the patient's weight (Appendix A3, Table A3-11) [1, 6]. #Colchicum autumnale seed extract (source of the alkaloid colchicine) can be used as monotherapy in case of NSAID intolerance. The duration of therapy is until the complete disappearance of clinical symptoms [8, 9, 166–169]. It is not strictly necessary to taper #Colchicum autumnale seed extract, but such a tapering regimen allows for an additional reduction in the risk of recurrence [62, 166].

Glucocorticoids should be considered only as a second-line therapy for acute pericarditis in patients with contraindications to #ASA** or NSAIDs, or upon failure of #ASA** or NSAIDs, since glucocorticoid therapy carries a risk of chronic disease progression. To reduce the risk of chronization, improve treatment response, and prevent recurrence, glucocorticoids must be prescribed in combination with #Autumn crocus seed extract. Glucocorticoids should be used in low doses: #Prednisolone** 0.2–0.5 mg/kg per day or equivalent doses of other glucocorticoids. High doses of glucocorticoids (#Prednisolone** 1.0 mg/kg per day or equivalent doses of other glucocorticoids) are not recommended [62, 145]. The starting dose should be maintained until symptoms resolve or CRP normalizes, followed by a gradual taper [62, 145, 165].

#ASA**, #Ibuprofen**, and #Autumn crocus seed extract (source of the alkaloid colchicine) are the mainstay drugs for the treatment of acute nonspecific pericarditis [1, 165].

Given the high probability of recurrence in acute pericarditis, to improve response to pharmacotherapy and reduce the risk of relapse, #Autumn crocus seed extract in low doses should be added to #ASA** or #Ibuprofen** therapy according to a special weight-based regimen (the dosing schedule is specified in Appendix A3, Table A3-11). #Autumn crocus seed extract can be used as monotherapy in case of NSAID intolerance. The duration of therapy is until complete disappearance of clinical symptoms [8, 9, 166–168].

Glucocorticoids should be considered only as a second-line therapy for acute pericarditis in patients with contraindications to #ASA** or NSAIDs, or upon failure of #ASA** or NSAIDs [145].

ESC IA (LE 5, GR C)

ESC IB (LoE 4, GoR C)

3.1.2 Treatment of recurrent pericarditis

First-line therapy for patients with recurrent pericarditis includes NSAIDs: #Ibuprofen**, #Indometacin, #ASA** [173]. #Acetylsalicylic acid** is rarely used in routine clinical practice due to the high risk of adverse events. When prescribing other drugs, maximum therapeutic daily doses should be adhered to, which are 1600–3200 mg/day for #Ibuprofen** with a dose reduction of 200–400 mg every 1–2 weeks, and 75–150 mg/day for #Indometacin. To date, there are no studies confirming the feasibility of using novel NSAIDs (selective COX-2 inhibitors) in patients with recurrent pericarditis (the dosing schedule is specified in Appendix A3, Table A3-12).

Another first-line therapy option for patients with recurrent pericarditis is #Autumn crocus seed extract, which is used either as monotherapy or in combination with NSAIDs. Combining NSAIDs with low-dose #Autumn crocus seed extract (up to 1 mg per day) is generally safe and provides a synergistic anti-inflammatory effect. One of the targets of #Autumn crocus seed extract is the NLRP3 inflammasome, the activation of which underlies classic autoinflammatory diseases [174]. Additionally, #Autumn crocus seed extract inhibits the activation (pore formation) of P2X2 and P2X7 receptors on the neutrophil surface, which also reduces inflammasome activation [175]. The efficacy of #Autumn crocus seed extract has been demonstrated in three randomized clinical trials (Table 2) [6].

Table 2. Randomized placebo-controlled clinical trials of the efficacy of #Autumn crocus seed extract in patients with recurrent pericarditis

Note: #ASA** — #Acetylsalicylic acid**, NSAIDs — non-steroidal anti-inflammatory and antirheumatic drugs.

Glucocorticoids (GCs) belong to second-line therapy. The dose of the drug, selected depending on the clinical picture and symptom severity, should not exceed 0.5 mg/kg of the patient's weight. The need for their prescription is driven by the failure of first-line therapy. The action of GCs is realized by blocking transcription factors, which in turn leads to a decrease in the synthesis of pro-inflammatory cytokines. The advantages of GCs are their high efficacy, rapid relief of pericarditis symptoms, and the absence of undesirable drug interactions. At the same time, the administration of this class of drugs often leads to steroid dependence and adverse side effects [176]. In cases of steroid resistance and steroid dependence, it is recommended to consider steroid-sparing therapy in combination with #Azathioprine**, IV immunoglobulins, or interleukin inhibitors (interleukin-1 beta blockers). In recurrent pericarditis, a slow tapering of GCs is required in accordance with the existing algorithm.

#Azathioprine**, as a purine base antimetabolite, has a favorable safety profile. The most common adverse events include a moderate increase in aminotransferase activity, leukopenia, and dyspepsia. In patients with thiopurine S-methyltransferase enzyme deficiency, prescribing #Azathioprine** at standard doses (1.5–2.5 mg/kg/day) can cause myelosuppression (dosing schedule in Appendix A3, Table A3-14). Recommendations for the use of #Azathioprine** as part of combination immunosuppressive therapy in conjunction with GCs are based on two small pilot studies involving patients with idiopathic recurrent pericarditis and post-pericardiotomy syndrome. The greater efficacy of #Azathioprine** in patients with post-pericardiotomy syndrome indicates that this class of drugs is advisable to use when the genesis of pericarditis is autoimmune [177].

For the majority of recurrent pericarditis cases, the etiology remains unknown (> 80%), providing grounds to speak of idiopathic recurrent pericarditis (IRP) [309]. Innate immunity plays an important role in the pathogenesis of IRP. The cyclical nature of clinical manifestations, their uniformity, and the pronounced systemic nature of the inflammatory process indicate the autoinflammatory nature of the disease. From a pathophysiological standpoint, the use of medicinal products aimed at the direct blockade of IL-1 is recognized as the most effective method for treating recurrent pericarditis with an inflammatory phenotype [295, 296, 310, 311, 312]. However, to date, among all interleukin-1 (IL-1) inhibitors, only the domestic drug goflikicept is registered in the Russian Federation and globally for the treatment of idiopathic recurrent pericarditis. The efficacy of goflikicept was confirmed in the COURSE clinical study (COURSE - a double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of the interleukin-1 (IL-1) inhibitor goflikicept for the treatment of patients with idiopathic recurrent pericarditis) [312]. In the randomized withdrawal phase, there were no disease relapses against the background of goflikicept monotherapy, whereas in the AIRTRIP study, 18% of relapses were recorded in the #Anakinra** group [297, 299, 312]. The safety profile of goflikicept therapy generally did not differ from the results of studies on other interleukin-1 (IL-1) inhibitors, but adverse events at the injection site were observed in 4.5% of cases on goflikicept therapy and in 95.2% of patients receiving #Anakinra**. The results of the COURSE study showed that in patients with an autoinflammatory phenotype receiving long-term combination therapy of NSAIDs with #Colchicine, after the development of a second relapse, earlier administration of interleukin-1 (IL-1) inhibitors may be considered due to greater efficacy and safety compared to glucocorticoids [310, 311, 312]. Administration of goflikicept implies a loading regimen: administration at a dose of 160 mg subcutaneously once on Day 0, followed by administrations at a dose of 80 mg on Day 7 and Day 14. The maintenance regimen implies administration of 80 mg subcutaneously once every 2 weeks. The duration of therapy is determined individually. If a combination of NSAIDs with #Colchicine was prescribed as baseline anti-inflammatory therapy, then upon prescribing goflikicept, the discontinuation of baseline therapy was carried out simultaneously on day 14. If the patient was receiving glucocorticoid therapy, then upon prescribing goflikicept, slow tapering of glucocorticoids begins from day 14 in accordance with the recommendations [312]. Prescribing goflikicept therapy implies an additional examination (checklist in Appendix A3-15 A, B) and coordination with a regional or federal level expert center. Interleukin-1 (IL-1) inhibitors increase the risk of bacterial infections. Therefore, they should be temporarily discontinued upon the development of a severe bacterial infection. Do not resume therapy until the infection has completely resolved and the patient is clinically stable. In mild and localized bacterial infections, discontinue interleukin-1 (IL-1) inhibitors if there is fever or systemic manifestations, and resume after 48–72 hours of antibiotic therapy upon clinical improvement. In asymptomatic or localized infection, continuation of therapy under medical supervision is possible.

ESC IA (LE 5, GR C)

ESC IIaC (LE 5, GR C)

ESC IA (LE 3, GR B)

ESC IIaC (LE 5, GR C)

RSC IIaB (LE C, GR 5)

RSC IIaB (LE 2, GR A)

ESC IIIB (LE 4, GR C)

ESC IIbC (LEL 4, GRC)

ESC IIaC (LEL 5, GRC)

ESC IIaC (LEL 5, GRC)

ESC IIaC (LE 5, GR C)

3.1.3 Treatment of incessant and chronic pericarditis

The algorithms for pharmacotherapy do not fundamentally differ from the management of patients with recurrent pericarditis. In the treatment of patients with persistent or chronic exudative pericarditis, alternative treatment methods are more frequently required. In cases of ineffective pharmacotherapy in patients with chronic or "persistent" pericarditis, surgical treatment methods may be discussed.

3.1.4 Treatment of pericardial effusion and tamponade

Treatment of pericardial effusion should be maximally directed at its underlying cause [93, 140, 181]. In approximately 50% of cases, the cause of pericardial effusion is known. If the pericardial effusion is small or moderate and associated with pericarditis (inflammation), treatment with #ASA**, NSAIDs, and/or #Colchicum autumnale seed extract is carried out in accordance with the principles of acute pericarditis management. If the effusion is not associated with inflammation, the administration of #ASA**, NSAIDs, or #Colchicum autumnale seed extract is ineffective, its volume is increasing, and the risk of cardiac tamponade is rising, then drainage of the effusion (pericardiocentesis) must be considered. Pericardiocentesis with prolonged drainage up to 30 ml/24 h should be considered to prevent further accumulation of effusion in case of its recurrence.

ESC IIaC (LoE C, GoR 5)

ESC IIIC (LoE B, LoR 3)

ESC IIIC (LEL 5 GRC)

3.1.5 Treatment of myopericarditis

Recommendations on rest and restriction of physical activity are necessary for all patients with myopericarditis for 6 months. Management of patients with myopericarditis does not fundamentally differ from the management of patients with pericarditis. Hospitalization of patients is necessary for diagnostic purposes and differential diagnosis.

First-line drugs are nonsteroidal anti-inflammatory and antirheumatic drugs (NSAIDs):

- #Acetylsalicylic acid** 1500–3000 mg/day;

- #Ibuprofen** 1200–2400 mg/day [1].

Small prospective studies have shown that long-term NSAID therapy (4 weeks) is safe in patients with myopericarditis [182].

Second-line drugs are glucocorticoids, used in case of intolerance or ineffectiveness of NSAIDs.

Frequent echocardiographic monitoring is mandatory; if the ejection fraction decreases, therapy with ACE inhibitors and beta-blockers should be initiated. Previous levels of physical activity are allowed only upon complete recovery of the ejection fraction, inflammatory markers, and ECG [183, 184, 80].

ESC IIaC (GRC, LEL 4)

3.1.6 Treatment of bacterial pericarditis

The main goals in the management of patients with tuberculous pericarditis are: reducing the activity of the tuberculous process, relieving cardiac tamponade and symptoms of heart failure, as well as preventing complications such as pericardial remodeling and the development of constrictive pericarditis [13]. Standard 4-drug antituberculosis regimens have not shown superiority in comparative studies [75, 103]. Poor drug penetration into the pericardial fluid causes low treatment efficacy, high mortality, and entails the use of high drug doses. The use of rifampicin**, isoniazid**, pyrazinamide**, or ethambutol** for at least 2 months, followed by isoniazid** and rifampicin** up to 6 months of therapy, can be effective in treating extrapulmonary tuberculosis. A serious complication of tuberculous pericarditis, which usually develops within 6 months of disease onset in 17–40% of patients, is its transformation into constrictive pericarditis, often with pericardial thickening [13, 185]. The addition of #Colchicum autumnale seed extract and high-dose #Prednisolone** for 6 weeks, as well as timely pericardiocentesis, reduces the risk from 30 to 15% [103, 185, 186]. However, #Prednisolone** therapy should not be prescribed to HIV-infected patients due to existing data on the increase of oncological diseases in them against the background of this therapy [103].

Purulent pericarditis requires prompt active management, as it is fatal without treatment; however, with adequate therapy, it has a good prognosis in 85% of cases [187]. Intravenous antimicrobial therapy should be initiated empirically before culture results are obtained. Purulent effusions are usually loculated and tend to accumulate rapidly, therefore timely drainage is important. Intrapericardial thrombolysis can be performed to prevent loculation, but surgical treatment is often the only correct approach. Subxiphoid pericardiotomy and irrigation of the pericardial cavity are performed [187].

ESC IC (LoE C, GoR 5)

ESC IC (LoE C, GoR 5)

3.1.7 Treatment of constrictive pericarditis

Although the treatment of constrictive pericarditis is predominantly surgical, conservative therapy can be useful in three aspects:

• etiological therapy (as in the case of tuberculous pericarditis) helps slow down the further progression of constriction [1, 3, 188, 4];

• anti-inflammatory treatment helps prevent the development of constriction, observed in 10–20% of cases and occurring within a few months after the resolution of pericarditis [1, 3, 4, 189, 93];

• as symptomatic therapy in advanced cases.

3.2 Surgical Treatment

3.2.1 Interventional and surgical treatment methods for pericardial diseases

In most cases, pericardial involvement is secondary, and the diagnosis of the underlying cause is often difficult. The main indications for interventional and surgical interventions in pericardial diseases are the presence of significant pericardial effusion, cardiac tamponade, and constrictive pericarditis. Intervention is also required in bacterial pericarditis, and for diagnostic purposes in large and moderate effusions of unknown etiology [108, 190].

For the purpose of cardiac decompression, drainage, and sanitation of the pericardial cavity, treatment methods such as pericardiocentesis, open subxiphoid pericardial drainage with creation of a pericardial window, thoracoscopic creation of a pericardial window (or pericardial fenestration), and pericardiectomy are currently used [6, 191-193].

To increase the diagnostic value of the intervention, subxiphoid pericardial drainage can be supplemented by pericardioscopy and targeted tissue sampling for molecular, histological, and immunohistological research methods to identify the etiology and pathogenesis of the disease [108]. This approach also provides the possibility of intrapericardial therapy by administering drugs into the pericardial cavity [194].

RSC IC (LEL 4 GRC)

RSC IC (LEL 4 GRC)

RSC IC (LEL 4 GRC)

ESC I C (LoE 5, GoR C)

3.2.2 Pericardiocentesis and pericardial drainage

The main goal of intervention for a large pericardial effusion and cardiac tamponade is adequate drainage. Pericardiocentesis is the simplest and most rapidly performed intervention for draining the pericardium. In cardiac tamponade, pericardiocentesis is a lifesaving intervention [108, 6].

Pericardiocentesis is optimally performed in a resuscitation or intensive care unit or in a specially equipped catheterization laboratory with anesthetic monitoring.

Blind intervention should not be performed. To prevent injury to the heart and other internal organs, pericardiocentesis must be performed under echocardiographic or fluoroscopic guidance.

Pericardiocentesis under echocardiographic guidance is performed with continuous monitoring of blood pressure and ECG. The procedure is performed in a semi-recumbent/semi-sitting position with the head of the bed elevated by 45° (Fowler's position). After disinfecting the skin (D08A Antiseptics and disinfectants) in the xiphoid process region under local anesthesia with a 1–2% lidocaine** solution, a minimal skin incision is made. Pericardial puncture is performed at Larrey's point (the point between the xiphoid process and the left costal margin). Alternatively, the optimal site for echocardiography-guided pericardial drainage may be the point where the maximum amount of effusion abuts the chest wall and there is no risk of injury to the liver, lung, internal thoracic artery (3–5 cm lateral to the parasternal line), and the intercostal vascular bundle along the lower edge of the rib. Puncture is performed using either an 18-G thin-walled needle or a Tuohy needle directed toward the left shoulder at a 30° angle with constant negative pressure in the syringe. After puncturing the pericardium and obtaining fluid, a 0.035” and 0.038” guidewire is advanced into the pericardial cavity. A pigtail catheter is introduced over the guidewire into the pericardial cavity and secured to the skin. The use of specialized pericardial drainage kits is optimal.

RCS IC (LE 4 GR C)

Fluoroscopy-guided pericardiocentesis is performed in a hybrid operating room or catheterization laboratory. Performing pericardiocentesis in the right or left anterior oblique projections is optimal. The pericardial halo (radiolucency) effect can serve as a landmark. After fluid is obtained, a small amount of contrast agent is injected into the pericardial cavity to ensure that the needle is inside the pericardial cavity. Thereafter, a guidewire and drainage catheter are advanced into the pericardial cavity.

Pericardiocentesis must be performed by an experienced physician, as it can be accompanied by complications in 4–10% of cases. The most frequent and serious complication of pericardiocentesis is myocardial injury and perforation. Life-threatening arrhythmias, internal thoracic artery injury, pneumothorax and hemothorax, abdominal organ injury, vasovagal reactions, and infectious complications are also possible [191].

Performing pericardiocentesis without percutaneous drainage of the pericardial cavity is impractical.

The indication for catheter removal is a fluid output of 50 ml or less per day.

Pericardiocentesis is associated with an increased risk in cases of loculated effusion along the lateral or posterior surface of the heart, or if the echo-free space on ultrasound is less than 10 mm. In these cases, open surgical drainage may be safer.

However, pericardiocentesis and percutaneous drainage are associated with a high recurrence rate [191, 195].

RCS IC (LE 4 GR C)

3.2.3 Surgical interventions in the treatment of pericardial diseases

Given the high percentage of recurrences after pericardiocentesis and percutaneous drainage, the creation of a pericardial window—resection of a portion of the pericardium to ensure prolonged drainage of fluid from the pericardial cavity—is indicated for the majority of patients [195]. There are two most frequently used techniques.

Surgical subxiphoid drainage is performed under general anesthesia or local anesthesia. The intervention allows for resection of a pericardial segment for histological examination, analysis of the effusion, pericardioscopy, and drainage of the pericardial cavity. Subxiphoid drainage is an effective method for treating patients with pericardial effusion, but the diagnostic value of the surgery is limited and contested by many [196–197].

In our country, an original method of open pericardial drainage according to Mintz–Bisenkov has also been proposed and successfully applied. This is an extrapleural approach to the pericardium, allowing for the exposure of a large surface area of the diaphragmatic pericardium and adequate drainage, especially in bacterial pericarditis. This method of open drainage can be useful in loculated effusions following open-heart surgery [198].

Another method of creating a pericardial window is the transpleural approach. Resection of a pericardial segment can be performed via minithoracotomy or thoracoscopically [192, 196, 199, 200]. Minimally invasive transpleural intervention also allows inspection of the pleural cavities and acquisition of additional tissue samples for examination (pleura, lungs, mediastinal lymph nodes, tumors). This helps improve the diagnostic value of the surgery [201].

RCS IC (LE 4 GR C)

Both interventions conclude with the placement of a drain in the pericardial cavity. The indication for catheter removal is a fluid output of 50 ml or less per day.

There is no consensus in the literature regarding which method of pericardial window creation is superior. Most researchers believe that subxiphoid drainage is a less invasive intervention with a fluid reaccumulation recurrence rate of 3.9–9.4% [191, 195]. Following transpleural pericardial window creation, recurrences are less frequent, but the procedure is more traumatic. Single-lung ventilation is required to perform the surgery, and the intervention is associated with a higher number of complications compared to subxiphoid drainage [196].

In malignant effusions, surgeries are palliative.

In constrictive and adhesive pericarditis, cardiolysis and pericardiectomy are indicated [202, 203]. Indications for surgery are determined by clinical data and the results of instrumental diagnostic methods. It is important to note that surgical intervention should not be delayed for long when the first signs of decompensation appear during conservative therapy, as subsequent secondary organ changes will be irreversible.

Cardiolysis is a surgical procedure to divide adhesions between the pericardial layers and between the heart and surrounding tissues. Currently, there are three types of cardiolysis:

• Delorme's procedure — consists of releasing the heart muscle from adhesions to the pericardium;

• Riolan's procedure — consists of dividing adhesions between the outer surface of the pericardium and the mediastinum with interposition of fascia lata;

• Brauer's procedure — consists of resecting the segments of the ribs overlying the heart and is indicated only when systole is impaired due to adhesions between the pericardial sac and the anterior chest wall.

None of the existing cardiolysis techniques can be considered radical and curative; furthermore, the likelihood of cardiac injury and the formation of new adhesions is high.

Pericardiectomy [1] is the only method to correct persistent cardiac constriction. To completely excise the pericardium, including areas behind the phrenic nerve, around the venae cavae and pulmonary veins, two approaches are used [204, 205]: anterolateral thoracotomy (in the right intercostal space) and median sternotomy (providing easier access to the aorta and right atrium for extracorporeal circulation).

The technical difficulty will lie in the presence of dense adhesions and pronounced calcification, which may also extend to the myocardium. In this case, to avoid excessive trauma and severe hemorrhage, areas of dense adhesion are left in place as islands, which will lead to an improvement in the patient's condition.

As a result of pericardiectomy, intracardiac hemodynamics are restored in 60% of patients [3, 204, 205]. The early diastolic filling time may remain prolonged, and minimal variations in atrioventricular blood flow depending on the respiratory phase persist in 9–25% of patients, while the ejection fraction will increase due to improved left ventricular filling.

Surgical mortality can reach 10–20%, which is due to preoperatively undetected myocardial atrophy or fibrosis leading to acute heart failure and cardiac rupture [1, 3, 204, 205]. Postoperative survival is reduced in patients with a history of prior cardiac surgery [3].

Predictors of an unfavorable prognosis, including after radical pericardiectomy, are: history of radiation therapy, comorbidities (especially COPD and decreased renal function, CAD, and a history of cardiac surgery), increased systolic pulmonary artery pressure, decreased LV systolic function (especially CHF functional class IV according to NYHA), and advanced/senile age [3, 203, 206].

In constrictive pericarditis, surgical treatment is indicated for NYHA functional class III or IV patients with progressive dyspnea and symptoms of right ventricular diastolic dysfunction such as jugular venous distension, leg and foot edema, hepatomegaly, ascites, as well as palpitations, oliguria, and low cardiac output [6].

To date, the question of how much of the pericardium needs to be removed has not been definitively resolved. There is even a lack of uniform terminology for the interventions. Most authors believe that complete (total) pericardiectomy is the method of choice to eliminate constriction in these patients [207]. Complete pericardiectomy involves the removal of the entire anterior pericardium (from phrenic nerve to phrenic nerve), the diaphragmatic part of the pericardium, and, where possible, the part of the pericardium posterior to the left phrenic nerve. The phrenic nerves must be preserved intact. The pericardium around the vena cava ostia must also be removed. Median sternotomy is the optimal surgical approach.

If complete pericardiectomy is technically impossible, partial pericardiectomy is performed. In some cases, partial pericardiectomy can be performed via a right- or left-sided thoracotomy [207].

Hospital mortality after pericardiectomy for constrictive pericarditis is 2.5–4.9% [207–209]. In rare cases, reoperation is required due to recurrent constrictive pericarditis (0.8–2.4%) [208, 209].

Pericardiectomy may be considered in patients with chronic recurrent effusive pericarditis unresponsive to medical therapy and creation of a pericardial window [6].

RSC IIaC (LEL 4 LOC C)

Pericardioscopy and biopsy are usually part of surgical procedures such as creation of a pericardial window or pericardiectomy [108].

Pericardioscopy provides visualization of the pericardial cavity, the epicardial surface of the heart, and the parietal pericardium. Macroscopically, tumor masses growing into the pericardial cavity, tumor protrusions from the outside, and hemorrhagic and hypervascular areas in malignant effusions can be identified. In viral, autoimmune, and radiation pericarditis, changes in the pericardial cavity usually cannot be detected [210, 211].

Pericardioscopy can be performed using either a flexible or rigid endoscope. Flexible pericardioscopy is safer than rigid pericardioscopy [210].

The procedure performed via a subxiphoid approach is more informative than the transpleural approach because it allows visualization of a larger part of the pericardial surface [211].

Visualization of pathological changes allows for targeted tissue biopsy. It is necessary to take at least 7–10 tissue pieces for examination [108].

RCS IIaC (LEL 4, GRD C)

Intrapericardial drug administration may be performed in patients with pericardial effusion following drainage.

RCS IIaC (LEL 4, GRD C)

RCS IIaC (LEL 4, GRD C)

High efficacy (86.7–96%) with a good tolerability profile and low toxicity has been noted. Intrapericardial IL-2 immunotherapy may be considered as one of the effective options in the complex treatment of patients with neoplastic pericarditis. Treatment should be carried out in cooperation with an oncologist [194].

RSC IIaC (LEL 3 LOC B)

RSC IIaC (LEL 5 LOC C)

RSC IIaC (LEL 4 LOC C)

For epicardial substrate ablation of ventricular tachycardias in 1996, E. Sosa described the "dry" pericardial puncture technique under fluoroscopic guidance. The procedure is performed under total intravenous anesthesia. Puncture is performed using a Tuohy needle in the left or right anterior oblique projections. A guidewire is passed through the needle, followed by an introducer. An ablation catheter is introduced into the pericardium through the introducer. Depending on the targeted ablation zone, the puncture can be performed via an anterior or posterior approach [213].

• As an alternative to percutaneous pericardial puncture for epicardial ablation of ventricular arrhythmias, it is recommended to perform an open subxiphoid approach [108].

RSC IIbC (LEL 5 LOC C)

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Physical rehabilitation methods have not been developed for patients with pericarditis.

Acute pericarditis is an absolute contraindication for exercise training. Resumption of sports is possible no earlier than 6 months later, provided that LV cavity volume has normalized and there are no threatening arrhythmias on Holter monitoring.

ESC IC (LoE C, GoR 5)

5. Prevention and Dispensary Observation

A patient who has recovered from acute pericarditis must remain under the supervision of an outpatient physician. It is recommended to repeat the echocardiogram within the first 12 weeks (even without pain recurrence, effusion formation is possible), and measure serum C-reactive protein levels during the same timeframe. A high CRP level should be considered a potential harbinger of acute pericarditis recurrence; moreover, it is an important sign requiring the search for a potentially previously unidentified underlying disease. For the first 3–6 months, heavy physical exertion (gym workouts, heavy lifting, etc.) is not recommended. There are no restrictions on normal physical activity.

Small pericardial effusions associated with pericarditis or idiopathic ones are associated with a favorable prognosis and a low complication rate [214]. Effusion volume correlates with prognosis. Moderate and large pericardial effusions characterized by a recurrent course are more frequently associated with a bacterial or neoplastic etiology and an unfavorable prognosis. Idiopathic chronic effusions are complicated by cardiac tamponade in every third patient. Subacute significant effusions can also lead to cardiac tamponade. Furthermore, prognosis varies significantly depending on the etiology. Bacterial, tuberculous, cancer-related, and connective tissue disease-related effusions have a worse prognosis than those in idiopathic pericarditis [6].

Small effusions (< 10 mm) are usually asymptomatic and do not require further monitoring [87]. A moderate effusion (10–20 ml) requires follow-up echocardiography every 6 months after resolution, and a large effusion requires follow-up every 3 months. Echocardiographic monitoring should preferably be performed using the same ultrasound machine and by the same investigator.

The prognosis of patients with myopericarditis is favorable; according to several prospective studies, the risk of heart failure and death in this category of patients is not increased [1, 80, 215, 216]. Cases of sudden cardiac death have been reported after strenuous physical exertion in military personnel and athletes who have had myopericarditis within the preceding 3–6 months.

ESC IC (LoE C, GoR 5)

ESC IC (LoE C, GoR 5)

RSC IIaC (LoE C, GoR 5)

6. Organization of Medical Care

6.1 Indications for elective hospitalization:

• diagnostic uncertainty and the need for special investigative methods (using diagnostic procedures that cannot be performed or are impractical in an outpatient setting) to clarify the cause of increased pericardial effusion;

• difficulties in selecting medical therapy (recurrent pericarditis);

6.2 Indications for emergency hospitalization:

• hospitalization of all patients presenting with cardiac tamponade;

• hospitalization of all patients at high risk for a negative prognosis in acute pericarditis;

• hospitalization of all patients with bacterial pericarditis;

• hospitalization of all patients with clinical manifestations of acute myopericarditis.

6.3 Indications for patient discharge from the hospital:

• Normalization of inflammatory markers: CRP, ESR.

• Normalization of myocardial injury markers.

• Return of the ST segment to the isoelectric line, development of T-wave inversion.

• Absence of chest pain in the patient.

• Regression of dyspnea.

• Normalization of the echocardiographic picture (regression of pericardial effusion).

• Absence of fever.

6.4 Other organizational technologies

When analyzing the performance of a medical organization regarding patients with pericarditis, it is advisable to evaluate the following indicators:

• percentage of patients with recurrent pericarditis within one month and within one year.

ESC IB (LOE 4 GoR C

ESC IB (LOE 4 GoR C)

ESC IC (LOE 4 GoR C)

7. Additional Information

7.1 Post-cardiac injury syndromes

Definition. The term "post-cardiac injury syndromes" (PCIS) is used to describe pericardial syndromes that occur following any type of injury to the heart muscle membranes. These include post-myocardial infarction pericarditis, post-pericardiotomy syndrome (PPS), and post-traumatic pericarditis [18].

Anamnestic features. The pathogenesis of such conditions is most likely associated with autoimmune processes resulting from myocardial necrosis, surgical interventions (cardiac surgery), or chest trauma [17]. Typically, several weeks elapse between the cardiac event and the development of pericarditis, which to some extent confirms the autoimmune nature of these conditions. However, for certain types of pericarditis (early post-infarction, traumatic), this period may be as short as 2–3 days. Processes such as pericardial hemorrhage, pleurotomy, and pericardiotomy during surgery are significant factors that facilitate the entry of autoantigens into the systemic circulation and trigger autoimmune reactions.

Clinical presentation. Diagnostic criteria for PCIS have currently been developed [217] and are formulated as follows:

- unexplained fever;

- patient complaints of typical pericardial and/or pleural chest pain, i.e., pain occurring at the peak of inspiration or with changes in body position;

- auscultation of pericardial or pleural friction rubs;

- detection of fluid in the pericardial and/or pleural cavity;

- elevated C-reactive protein levels.

It is important to emphasize some differences between the criteria for these types of pericarditis and the generally accepted ones. This is due to the frequent involvement of both the pericardium and pleura in PCIS. In some cases, pulmonary infiltrates may even develop [217]. Following heart and lung surgery, signs of fluid in the pericardial and/or pleural cavities sometimes appear due to mechanical trauma. However, to diagnose PPS, there must also be evidence of an inflammatory response, most commonly identified by an elevated CRP level.

Laboratory and instrumental diagnostics. General clinical methods such as physical examination and electrocardiography (ECG) are used to diagnose PCIS. Targeted chest radiography can reveal cardiomegaly, pleural effusion, and pulmonary infiltrates [18]. In diagnostically challenging cases, multislice computed tomography (MSCT) and cardiac MRI are used. Echocardiography plays a significant role in the diagnosis of PCIS, allowing differentiation between cardiomegaly associated with pericardial effusion and myocardial damage. In myocardial infarction, both processes may sometimes coexist. As previously noted, evidence of the inflammatory nature of the detected changes is of substantial importance.

Features of various types of PCIS

7.1.1 Post-myocardial infarction pericarditis

Three types of pericardial changes are distinguished in acute myocardial infarction: 1. Fluid accumulation (effusion) in the pericardial sac. It may appear in the first few days of acute myocardial infarction and is associated with the development of acute heart failure (AHF). As signs of AHF subside, the effusion decreases or disappears. However, if the effusion size exceeds 10 mm, impending myocardial rupture should be suspected [218]. 2. Early infarction-associated pericarditis (early post-infarction pericarditis). It occurs on days 2–4 after the onset of acute myocardial infarction and remains a sign of a large myocardial infarction, most commonly of the anterior wall [219]. Currently, this type of pericarditis is rare, which is attributed to early reperfusion via percutaneous coronary intervention (PCI) and/or thrombolysis [219]. A pericardial friction rub is usually auscultated, accompanied by pain typical of pericarditis. In this category of patients, ST-segment elevation persists for a long time or recurs while positive T waves are maintained. Sometimes T waves become positive again after their negative phase has already begun. Such ECG dynamics may prompt suspicion of new myocardial infarction foci. However, the clinical picture of developed pericarditis with stable MI biomarker levels helps rule out recurrent myocardial infarction. Pericarditis is usually fibrinous, but may be accompanied by effusion. 3. Late post-infarction pericarditis (Dressler's syndrome), which develops 2–3 weeks after the onset of myocardial infarction. Its incidence currently does not exceed 1%, which is also attributed to early reperfusion. The development of this type of pericarditis proceeds as an autoimmune reaction and is sometimes accompanied by blood eosinophilia and pleuritis (Dressler's syndrome).

7.1.2 Post-pericardiotomy (postoperative) pericarditis

Pericardial effusions following cardiac surgery occur in 25–30% of cases. They appear in the first days after cardiac surgery and are asymptomatic in 22% of patients for approximately 2 weeks [221]. In such cases, the prognosis is favorable. The use of NSAIDs in this category of patients is redundant and may only lead to an increased incidence of adverse events associated with the pharmacological profile of this drug group [222]. However, in 10% of cases, prominent effusions develop, which can lead to cardiac tamponade [223]. Although this complication can be observed within 1 month after surgery, it most commonly occurs on the first day postoperatively and is generally associated with hemorrhage into the pericardial cavity. The occurrence of cardiac tamponade due to postoperative hemopericardium requires emergency repeat surgical intervention. It should be noted that any cardiac surgical procedure, even minimally invasive (PCI, pacemaker implantation, radiofrequency ablation of arrhythmogenic zones, etc.), can be complicated by the development of hemopericardium and cardiac tamponade due to vascular or cardiac chamber perforation.

According to an analysis of cardiac pacing complications for 2011–2016 conducted by K.A. Kosonogov et al., which included 2,901 cases of antiarrhythmic device implantation, hemopericardium occurred in 0.2% of cases [224].

According to a systematic review by D. van Osch et al., independent predictors of post-pericardiotomy syndrome (PPTS) development were young age, postoperative packed red blood cell transfusion, and low preoperative hemoglobin and platelet levels [225]. Conversely, high body mass index values were associated with a reduced risk of PPTS development [226].

According to K. Gabaldo et al., the highest risk of PPTS development was observed in patients who underwent aortic and/or aortic valve surgery (26%), and was significantly lower after coronary artery bypass grafting (7.9%) and mitral valve surgery (8.3%) [227].

Although the risk of cardiac tamponade in patients with PPTS is significantly higher (20.9% vs. 2.5%), 1-year survival in this patient category did not significantly differ from that in patients without PPTS (4.2% vs. 5.5%) [228]. On the other hand, according to the Finnish National Register, the development of PPTS after cardiac surgery was associated with a 1.78-fold increase in the risk of death by the end of the first year of follow-up (95% CI 1.12–2.81; p = 0.014) [226].

A 2018 systematic review demonstrated that there is currently insufficient data regarding the potential efficacy of glucocorticoids in the prevention of PPTS [229].

In a systematic review by S. M. Yuan, it was shown that NSAIDs (59.2%), glucocorticoids (30.8%), and #Colchicum autumnale seed extract (9.8%) are most frequently used in clinical practice for the treatment of PPTS [230]. Among NSAIDs, #Acetylsalicylic acid** (47.5%) and #Ibuprofen** (31.4%) are most commonly used, while #Prednisolone** (56.3%) and #Hydrocortisone** (42.6%) are the most frequently used glucocorticoids (Appendix A3).

A 2019 meta-analysis established that perioperative administration of #Colchicum autumnale seed extract was associated with a significant reduction in the risk of developing PPTS [231].

7.1.3 Traumatic pericardial effusion

In approximately 20–30% of cases following severe chest trauma, especially of its left hemithorax, signs of pericarditis appear. In such cases, performing an electrocardiogram (ECG), targeted chest X-ray, and echocardiography helps clarify the diagnosis, assess the size of the effusion, and evaluate its hemodynamic significance. In the absence of hemodynamic disturbances, treatment of this condition includes antiinflammatory therapy. In life-threatening situations, emergency thoracotomy is performed, which has advantages over preliminary pericardiocentesis [232, 233].

Management of patients with post-pericardiotomy syndrome (PPTS)

Treatment of this category of patients is based on the use of antiinflammatory therapy, which reduces the clinical manifestations of the syndrome and decreases the risk of recurrence. In the absence of systemic inflammation signs, #Colchicum autumnale seed extract and NSAIDs are not recommended, as this therapy does not provide a significant effect while increasing the number of adverse drug reactions [222, 234]. If signs of an inflammatory response are present, these drugs are indicated for therapeutic purposes. #ASA** is recommended as the first-choice drug for post-myocardial infarction pericarditis and in patients receiving antiplatelet therapy [1].

7.2 Idiopathic recurrent pericarditis

Thanks to recent studies, compelling evidence has been obtained supporting the hypothesis of the autoinflammatory nature of idiopathic recurrent pericarditis (IRP), the main clinical manifestations of which are considered to be chest pain combined with fever and acute-phase markers, along with electrocardiographic and echocardiographic phenomena characteristic of all variants of pericarditis. The autoinflammatory nature of IRP is indicated by high acute-phase activity during relapse, an undulating disease course, the presence of systemic manifestations, and a positive response to interleukin (IL-1) inhibitor therapy, which brings this pathology closer to classical autoinflammatory diseases (familial Mediterranean fever, periodic fever syndrome), for which cases of recurrent pericarditis have also been described. Therefore, in patients with IRP refractory to standard antiinflammatory therapy, genetic testing for pathogenic variants in the MEFV, TRAPS, and TNFRSF1A genes is recommended [235, 236, 237]. Data on the incidence and prevalence of recurrent pericarditis are sparse. The estimated calculated number of patients with IRP can range from 5.4 to 11.2 cases per 100,000 population [86, 313]. In half of the patients with the first relapse of the disease, repeated relapses are observed. Moreover, the probability of a repeated relapse generally increases with each subsequent episode, and the time between relapses steadily decreases, negatively affecting patients' quality of life. Due to the lack of specific symptoms for the diagnosis and treatment of patients with IRP, a multidisciplinary approach involving cardiologists, rheumatologists, radiologists, endovascular surgeons, clinical laboratory diagnosticians, cardiovascular surgeons, thoracic surgeons, and general surgeons is required. It is often necessary to perform a differential diagnosis between IRP and adult-onset Still's disease, which belongs to non-classical autoinflammatory diseases. Currently, several diagnostic criteria options for this disease have been proposed [239, 240] (Table 3). Cardiac involvement, ranging from subclinical to overt forms, occurs in more than 50% of cases in this disease [241].

Table 3. Classification criteria for adult-onset Still's disease

Despite a benign course with rare life-threatening conditions such as cardiac tamponade and constrictive pericarditis, IRP is associated with frequent episodes of temporary disability. According to a number of studies, healthcare costs for patients with ≥ 2 relapses were 74% higher than for patients with 1 episode (total healthcare costs are driven higher mainly by hospitalizations) [295]. To establish a preliminary diagnosis of recurrent pericarditis, the patient's history must include a documented episode of acute pericarditis combined with a symptom-free period of at least 4–6 weeks after the first episode of acute pericarditis, and chest pain as a mandatory symptom (pain intensity > 3 points on the Numerical Rating Scale – NRS) (Appendix G). The diagnostic criteria for IRP and the scope of examination required to make the diagnosis are presented in the checklist in Appendix 3. IRP as a nosological entity is included in the list of rare diseases in the Russian Federation with the ICD-10 code I09.2.

7.3 Hydropericardium in endocrine diseases

Hydropericardium can develop in endocrine diseases, in particular, in thyroid pathology. The most common cause of hydropericardium among endocrine diseases is hypothyroidism.

The severity of hydropericardium depends on the degree of thyroid failure and the duration of the disease. Cases of hydropericardium in elderly and senile patients with subclinical hypothyroidism have been described [244]. Cardiac tamponade in hypothyroidism is rare due to the slow accumulation of fluid in the pericardial cavity [245, 246].

Clinical manifestations include symptoms of both pericardial effusion and hypothyroidism: dyspnea, chest pain, fatigue, edema, and bradycardia. In addition, frequently encountered symptoms of hypothyroidism include drowsiness, dry skin, hair loss, slowed speech, constipation, memory impairment, feeling cold, hoarseness, and depressed mood. Diastolic arterial hypertension frequently develops. Typical external manifestations include general and periorbital edema, a pale-yellowish puffy face, and sluggish facial expressions [245]. Underestimating the symptoms of hypothyroidism in patients with hydropericardium makes it difficult to establish the cause and leads to a delayed start of effective treatment.

Laboratory and instrumental examination reveals pronounced dyslipidemia characteristic of hypothyroidism, low QRS voltage, and QT interval prolongation on the ECG. To diagnose pericardial effusion and assess its volume, echocardiography is recommended; CT and MRI provide more complete information.

When pericardial effusion of unknown origin is detected, thyroid function should be evaluated first, even when signs and symptoms of hypothyroidism are absent [243, 247]. Timely diagnosis of hypothyroidism as a cause of hydropericardium is essential. Diagnosis of hypothyroidism is recommended to begin with testing blood thyroid-stimulating hormone (TSH) levels. If the TSH level is elevated, blood free thyroxine (T4) levels and thyroid peroxidase antibody levels in the blood should be determined [248]. In overt hypothyroidism, an elevated TSH level and a low blood free thyroxine (T4) level are detected; in subclinical hypothyroidism, an elevated TSH level is detected.

It should be borne in mind that in patients with hypothyroidism (both subclinical and overt), the risk of CAD and HF is significantly increased, which complicates diagnosis and the choice of management tactics for patients [249, 250].

Currently, there are insufficient data on the management specifics of patients with hydropericardium caused by thyroid disorders. Initiating treatment at an early stage of the disease and preventing complications (the development of cardiac tamponade) depends on the early diagnosis of hypothyroidism [27, 243].

First of all, all patients with hypothyroidism and hydropericardium are indicated for replacement therapy to achieve and maintain normal blood levels of TSH and thyroid hormones. The drug of choice for the replacement therapy of hypothyroidism is levothyroxine sodium** due to its efficacy, long-term experience of use, high bioavailability, and favorable adverse event profile. Patients with comorbid cardiac pathology are recommended to start therapy with low doses (25 mcg daily), followed by an increase under the control of TSH levels [243, 251].

Recommendations for the treatment of hydropericardium in patients with hypothyroidism are based on clinical observation data; randomized clinical trials in this direction have not been conducted. There are data on the efficacy of #ASA** and NSAIDs, #Colchicum autumnale seed extract, and glucocorticoids [27, 252]. However, it must be taken into account that thyroid dysfunction can affect not only the cardiovascular system, but also drug metabolism, pharmacokinetics, and pharmacodynamics, and increase the risk of drug interactions.

It is known that some NSAIDs can affect thyroid hormone levels, making it difficult to assess the efficacy of replacement therapy. At the same time, according to clinical observations, such an effect has not been revealed with the use of #indometacin and #ibuprofen** [252].

When using #Colchicum autumnale seed extract, it must be taken into account that the presence of hypothyroidism requires a more cautious approach to dose selection. Colchicum autumnale seed extract is excreted via the P-glycoprotein system, the expression of which may decrease when thyroid functional activity is reduced. In patients with hypothyroidism, the excretion of #Colchicum autumnale seed extract may decrease and its plasma concentration may increase, which can lead to adverse effects (nausea, diarrhea, myopathy, liver dysfunction). It should be noted that hypothyroidism itself can cause myopathy in 25–60% of cases, increasing the likelihood of an adverse effect in patients receiving #Colchicum autumnale seed extract [252]. Therefore, in patients with hypothyroidism, #Colchicum autumnale seed extract should be prescribed in lower doses, and careful monitoring of clinical symptoms of myopathy and creatine phosphokinase (CPK) levels is required. It is recommended to consider treatment with #Colchicum autumnale seed extract until the TSH level reaches the normal range [27, 253].

Glucocorticoids can be used in patients with hypothyroidism-induced hydropericardium in case of intolerance or contraindications to therapy with #ASA**, NSAIDs, and #Colchicum autumnale seed extract, as well as in patients with recurrent pericarditis [252]. At the same time, monitoring of vitamin D levels is necessary, since both hypothyroidism and glucocorticoids increase the risk of osteoporosis.

In hyperthyroidism, pericardial effusion is rarely detected. Cases of hydropericardium have been described in patients with severe thyrotoxicosis, symptoms of congestive heart failure, and atrial fibrillation [252]. In patients with Graves' disease receiving anticoagulants (antithrombotic agents) due to atrial fibrillation, cases of hemopericardium have been observed [254]. Cardiac tamponade is extremely rare.

As in hypothyroidism, patients with hyperthyroidism and hydropericardium primarily need treatment aimed at achieving stable euthyroidism. In addition to antithyroid drugs, #ASA**, NSAIDs, #Colchicum autumnale seed extract, and/or glucocorticoids can be used [27, 242, 244]. It should be taken into account that hyperthyroidism increases the expression of P-glycoprotein, which may necessitate an increase in the dose of drugs, in particular #Colchicum autumnale seed extract [255].

7.4 Pericardial involvement in oncological diseases

Malignant tumors are the most common cause of exudative pericarditis with a hemodynamically significant amount of pericardial fluid. Early diagnosis and treatment of malignant pericarditis can significantly improve the patient's prognosis [256]. On the other hand, untreated malignant pericardial effusion is a potentially fatal complication of cancer [257], especially in patients with lung cancer [258].

The prevalence of oncological diseases in exudative pericarditis ranges from 12 to 23% [46]. In cancer patients, pericardial effusion develops in 5–15% of patients and is more often a manifestation of late-stage disease [259]. The pericardium can be affected by direct tumor extension or metastasis via the lymphatic system or blood. Pericardial effusion can also develop as a result of chemotherapy, radiation therapy, or opportunistic infections [260, 261]. Pericardial tumors include primary and secondary cancers, as well as benign neoplasms. Primary pericardial tumors are rare and account for about 10% of all primary cardiac tumors [262], with their prevalence in the general population ranging from 0.001 to 0.007% [30]. Secondary tumors or direct invasion of the pericardium are approximately 1000 times more common [28, 263].

Malignant pericardial mesothelioma accounts for 2–3% of all pericardial tumors, and its prevalence in the general population is < 0.002%. Risk factors include asbestos exposure, genetic susceptibility, infection, and radiation exposure. This tumor is more common in men than in women and typically manifests in middle and late age groups. The disease carries a poor prognosis with a median survival of 6 months [263–265].

Other pericardial malignancies include lymphomas and sarcomas. Sarcomas are rare, and subtypes include angiosarcoma, fibrosarcoma, liposarcoma, rhabdomyosarcoma, synovial sarcoma, and undifferentiated sarcoma. The prognosis for this tumor is poor: less than 1 year for all patients [28].

Primary cardiac lymphoma accounts for 1% to 2% of all cardiac neoplasms and an even smaller percentage of all extranodal lymphomas. Approximately 1 in 5 primary cardiac lymphomas affects immunocompromised patients. Primary cardiac lymphomas predominantly involve the right heart chambers and the pericardium [266, 267]. Although initially asymptomatic, their rapid growth leads to symptoms caused either by direct tumor extension or tumor embolization. Primary cardiac lymphomas respond well to chemotherapy, the regimens of which are primarily determined by the lymphoma subtype [267].

Pericardial involvement by secondary malignant tumors is most commonly observed in lung cancer (29%), breast cancer (up to 10%), malignant melanoma, lymphomas, and acute myeloblastic leukemia; involvement is much less frequent in gastrointestinal cancer, urogenital cancer, acute lymphoblastic leukemia, chronic myeloblastic leukemia, and multiple myeloma [258].

Pericardial cysts (mesothelial cysts) and lipomas are the most common benign pericardial masses and are often asymptomatic. Symptoms, when present, are related to compression and may in such cases necessitate surgical resection. Other rare and generally benign pericardial tumors include lipoblastomas, paragangliomas, germ cell tumors, hemangiomas, and fibromas [267].

Pericarditis can be a marker of occult cancer. According to the Danish Registry, more than 10% of 13,759 individuals diagnosed with pericarditis were subsequently diagnosed with cancer [28]. This nationwide cohort study observed a higher-than-expected incidence of lung cancer, non-Hodgkin lymphoma, and myeloid leukemia during the first 3 months following a pericarditis diagnosis. Although the excess risk declined for several cancer types after the first 3 months, it nevertheless persisted for lung cancer, non-Hodgkin lymphoma, and bladder cancer for several years following the diagnosis of pericarditis [46].

Cancer Therapy-Related Pericardial Disease

Chemotherapy-induced pericardial involvement typically manifests as pericarditis, with or without associated myocarditis [268]. The development of pericarditis as a complication of chemotherapy can occur with the following agents [268]:

• Anthracyclines and related compounds: doxorubicin**;

Nitrogen mustard analogues: cyclophosphamide**;

● Other antineoplastic antibiotics: mitomycin**;

● Alkyl sulfonates: busulfan**;

• Antimetabolites: clofarabine, cytarabine**, fluorouracil** [269];

• Protein kinase inhibitors (Low-molecular-weight tyrosine kinase inhibitors: dasatinib**, imatinib**) [270];

• Monoclonal antibodies: nivolumab** [271, 272];

• Alkylating agents (Taxanes: docetaxel**);

• Other agents: tretinoin**, interferon alfa-2b**.

Tretinoin** induces a syndrome characterized by fever, hypotension, acute renal failure, and pericardial effusion. High doses of busulfan** can cause pericardial and endomyocardial fibrosis 4 to 9 years after treatment [273]. Myopericarditis may also occur as a side effect of chemotherapy, as reported with doxorubicin**, cyclophosphamide**, and tretinoin** [28].

Effusive or constrictive pericarditis may also occur in 6% to 30% of patients following radiation therapy [274]. Acute pericarditis can develop within days or months after radiation therapy and is more frequently constrictive pericarditis. Chronic radiation pericarditis is often effusive-constrictive [261, 267].

Diagnosis of Pericardial Involvement in Oncological Diseases

The diagnosis of pericardial involvement in cancer patients is established using imaging modalities, pericardial fluid cytology, and biopsy.

Transthoracic echocardiography is the primary method of choice for the initial evaluation of patients with suspected pericardial disease. In most cases, it not only diagnoses the condition but also guides pericardiocentesis [268].

Three-dimensional echocardiography is the preferred method for monitoring left ventricular function and detecting pericarditis in cancer patients. Its advantages include higher accuracy in determining left ventricular ejection fraction, better reproducibility, and lower temporal variability compared with two-dimensional echocardiography in cancer patients receiving chemotherapy.

On echocardiography, endocardial border dropout is frequently observed in patients undergoing chemotherapy (particularly in breast cancer patients following mastectomy and chest irradiation). In such cases, contrast echocardiography is the method of choice. According to current guidelines, contrast agents should be used when 2 adjacent left ventricular segments are poorly visualized on unenhanced apical views. However, contrast-enhanced three-dimensional echocardiography is not recommended for long-term follow-up of cancer patients [268].

In certain cases, other imaging modalities such as CT or cardiac MRI can be a useful adjunct to echocardiographic evaluation. They should be considered particularly when assessing primary cardiac tumors, with or without pericarditis, or when the diagnosis of constrictive pericarditis remains uncertain after a thorough echocardiographic evaluation. Cardiac MRI is especially useful for detecting late gadolinium enhancement (V08CA Paramagnetic contrast media) to identify patients with transient constriction who will benefit from aggressive anti-inflammatory regimens rather than pericardiectomy [268].

The definitive diagnosis is based on confirming malignant pericardial infiltration through pericardial fluid cytology or biopsy data.

• All cancer patients with a pericardial effusion are recommended to undergo cytological analysis of the effusion to confirm the malignant etiology of the disease [275].

ESC IB (Level of Evidence 5, Grade of Recommendation C)

• All cancer patients with pericardial and/or epicardial involvement are recommended to undergo pericardial and/or epicardial biopsy to confirm malignant pericardial disease [275, 276].

ESC IIa B (LoE 5 GoR C)

Comment. Malignant cells are identified via pericardial fluid analysis in only approximately 40% of cases [276]. When malignant cells cannot be identified by cytological analysis, alternative mechanisms must be suspected. Pericardial effusion may be related to mediastinal lymphatic obstruction via tumor infiltration or radiation-induced fibrosis. Other potential causes include opportunistic infections (cytomegalovirus, tuberculosis, Candida pericarditis, and Aspergillus), systemic therapies such as alkylating agents, localized inflammation, chest radiation-induced pericarditis, or fluid retention caused by certain chemotherapeutic agents [276].

• All cancer patients with a pericardial effusion are recommended to consider testing for tumor markers (CA 19-9, CA 72-4) to differentiate between benign and malignant effusions [256, 275].

ESC IIa B (LoE 5 GoR C)

Comment. The diagnostic value of tumor markers is insufficient, as none of them (carcinoembryonic antigen, CYFRA 21-1, neuron-specific enolase, CA 19-9, CA 72-4, SCC, GATA-3, vascular endothelial growth factor) has demonstrated adequate sensitivity and specificity in distinguishing benign from malignant effusions [28]. Epidermal growth factor receptor mutation has diagnostic and prognostic significance in patients with malignant effusion associated with pulmonary adenocarcinoma [28].

The management of pericarditis in cancer patients is generally conducted according to standard guidelines. However, it should be considered that many cancer patients may be predisposed to bleeding due to hemostatic disorders secondary to their underlying disease or treatment. Consequently, routine therapies such as nonsteroidal anti-inflammatory drugs may be difficult to administer. As a result, other drugs, such as Colchicum autumnale seed extract and glucocorticoids, are frequently used more broadly and at an earlier stage, although this may not alter outcomes [28].

General principles for the management of pericarditis in cancer patients include [277]:

• All cancer patients are recommended to receive appropriate systemic antitumor therapy in confirmed cases of neoplastic etiology of pericarditis [278].

ESC IB (Level of Evidence 4, Grade of Recommendation C)

• Pericardiocentesis is recommended for patients with cardiac tamponade to relieve symptoms and establish the diagnosis of malignant effusion [279].

ESC IB (Level of Evidence 4, Grade of Recommendation C)

Comment. For patients with recurrent pericardial effusion, repeat pericardiocentesis is indicated in patients with limited life expectancy.

• An extended pericardial drainage is recommended in patients with suspected or confirmed malignant effusion to prevent recurrence and enable intrapericardial treatment [28, 279].

ESC IB (Level of Evidence 4, Grade of Recommendation C)

Comment. Extended pericardial drainage reduces the recurrence rate to approximately 10–20% [277]. In patients with a longer expected life expectancy, surgical drainage provides the lowest recurrence rate. The surgical approach to the procedure depends on the effusion site and clinical status. Subxiphoid and thoracoscopic approaches yield similar results [273].

• Intrapericardial administration of cytostatic/sclerosing agents (antineoplastic drugs) is recommended to be considered in patients with malignant effusion to prevent recurrence [257, 28, 280–282].

ESC IIa B (LoE 4, GoR C)

Comment. The use of sclerosing agents also slightly reduces the recurrence rate, but is accompanied by severe pain syndrome and may lead to constrictive pericarditis, which limits the usefulness of the procedure. Various sclerosing agents are used for intrapericardial instillation, such as #doxycycline**, #cisplatin**, #thiotepa, #mitomycin**, #bleomycin**, #mitoxantrone** [257, 280, 282, 292-294] (Appendix A3, Table A3-16).

• Intrapericardial administration of #cisplatin** is recommended to be considered in patients with myocardial involvement in lung cancer; intrapericardial administration of #thiotepa is recommended to be considered in patients with pericardial metastases in breast cancer [257, 282, 293].

ESC IIa B (LoE 5 GoR C)

ESC IIa B (LoE 5 GoR C)

Comment. However, cardiac radiation therapy itself can cause myocarditis and pericarditis.

• In patients in whom pericardiocentesis cannot be performed, surgical pericardiotomy is recommended [273].

ESC IIa B (LoE 5 GoR C)

Comment. However, this method is associated with a higher complication rate and does not improve outcomes compared to pericardiocentesis [273], but it can be performed if the anatomy is unsuitable for pericardiocentesis (large distance between the xiphoid process and the pericardial cavity, enlarged liver blocking access to the pericardium, solid tumor adhering to the pericardium) or the estimated fluid volume is limited according to echocardiography [276].

ESC IIb B (LoE 5 GoR C)

Comment. Percutaneous balloon pericardiotomy creates a direct pleuropericardial communication and allows fluid drainage into the pleural space: for large malignant pericardial effusions and recurrent tamponade, it is effective (90–97%) and safe. This technique can be considered in advanced cases of severe malignant pericardial effusion. The features of this procedure make it especially useful for this group of patients to avoid more aggressive, poorly tolerated approaches, given their very poor oncological prognosis [284].

ESC IIb B (LoE 4 GoR C)

Pleuropericardiotomy allows drainage of malignant pericardial fluid into the pleural space. This is associated with a higher complication rate and offers no advantages over pericardiocentesis or pericardiotomy [33].

Pericardiectomy is rarely indicated, mainly for pericardial constriction or complications of previous procedures. Surgical removal of the pericardium is technically difficult, and long-term results are mixed. Outcomes are worse if the pericardial disease was caused by radiation therapy [28, 276, 204].

In practice, the treatment of pericarditis in oncological diseases is generally palliative and aimed at symptom relief rather than curing the underlying oncological process. However, situations may arise where the treatment of pericarditis in cancer can have a positive impact on the patient's prognosis [256, 277].

Prognosis of patients with pericardial involvement in oncological pathology

Current data indicate that the presence of pericardial effusion is associated with high mortality in cancer patients. The presence of symptomatic pericardial effusion indicates more advanced carcinomatous disease (especially in the case of solid tumors) with direct invasion into the heart or severe mediastinal infiltration. Pericardial effusion can be diagnosed in the absence of any previously detected metastases in one-third of patients, and it may be a stronger prognostic factor for outcomes than metastasis [276, 287].

The type of cancer and the nature of the pericardial effusion are the main factors influencing long-term survival in surgically treated patients. Survival time in the hematological malignancies group is significantly longer than in the lung cancer and other cancer groups, and life expectancy in the breast cancer group is significantly longer compared to the lung cancer group.

Criteria for Evaluating the Quality of Medical Care

Criteria for evaluating the quality of primary health care provided to adults with pericarditis (ICD-10 codes: I30, I30.1, I30.8, I30.9, I31, I31.1, I31.2, I31.3, I31.8, I31.9, I32, I32.0, I32.1, I32.8)

Criteria for evaluating the quality of specialized medical care provided to adults with pericarditis (ICD-10 codes: I30, I30.1, I30.8, I30.9, I31, I31.1, I31.2, I31.3, I31.8, I31.9, I32, I32.0, I32.1, I32.8)

References

Appendix A1. Working Group Composition

Working Group Presidium

1. Arutyunov G.P. — MD, Professor, Corresponding Member of the Russian Academy of Sciences, Chief Therapist of the Moscow Healthcare Department, Honored Doctor of the Russian Federation, Head of the Department, Pirogov Russian National Research Medical University.

2. Zhirov I.V. — MD, Professor, Leading Researcher, National Medical Research Center for Cardiology named after Academician E.I. Chazov of the Russian Ministry of Health.

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

Working Group Members

4. Ayvazyan Sergey Artemovich — Candidate of Medical Sciences, Cardiac Surgeon, Privolzhsky District Medical Center, Clinical Hospital No. 1, Federal Medical-Biological Agency of Russia, Nizhny Novgorod.

5. Arutyunov A.G. — MD, Professor, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

6. Vasyuk Yuriy Aleksandrovich — MD, Professor, Head of the Department of Hospital Therapy No. 1, Faculty of General Medicine, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Moscow.

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

8. Grigor'eva Natal'ya Yur'evna — MD, Head of the Department of Faculty and Polyclinic Therapy, Privolzhsky Research Medical University of the Ministry of Health of the Russian Federation, Nizhny Novgorod.

9. Dragunov D.O. — Candidate of Medical Sciences, Associate Professor, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

10. Zayrat'yants O.V. — Professor, MD, Head of the Department, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health, Moscow.

11. Irtyuga O.B. — Candidate of Medical Sciences, Associate Professor, Almazov National Medical Research Centre of the Russian Ministry of Health.

12. Koziolova, N.A. — MD, PhD, Professor, Head of the Department of Propaedeutics of Internal Diseases No. 2, Academician E.A. Vagner Perm State Medical University of the Russian Ministry of Health.

13. Koroleva, Lyubov Yuryevna — MD, PhD, Professor at the Department of Hospital Therapy, Privolzhsky Research Medical University of the Russian Ministry of Health, Nizhny Novgorod.

14. Malchikova, Svetlana Vladimirovna — MD, PhD, Professor, Professor at the Department of Hospital Therapy, Head of the Therapeutic Department of the KSMU Clinic, Kirov State Medical University of the Russian Ministry of Health, Kirov.

15. Moiseeva, O.M. — MD, PhD, Head of the Research Department of Non-Coronary Heart Diseases, Almazov National Medical Research Centre.

16. Myachikova, Valentina Yuryevna — PhD, Almazov National Medical Research Centre of the Russian Ministry of Health.

17. Nosov, Vladimir Pavlovich — MD, PhD, Professor at the Department of Hospital Therapy, Privolzhsky Research Medical University of the Russian Ministry of Health, Nizhny Novgorod.

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

19. Petrova, M.M. — MD, PhD, Professor, Head of the Department of Outpatient Therapy, Family Medicine and Healthy Lifestyle with a Postgraduate Education Course, Professor V.F. Voйно-Yasenetsky Krasnoyarsk State Medical University of the Russian Ministry of Health, Krasnoyarsk.

20. Rebrov, A.P. — MD, PhD, Professor, Head of the Department of Hospital Therapy at V.I. Razumovsky Saratov State Medical University, Honored Doctor of the Russian Federation.

21. Sinitsyn, V.E. — MD, PhD, Professor, Head of the Department of Radiation Diagnostics and Therapy at the Faculty of Fundamental Medicine of Lomonosov Moscow State University, Head of the Department of Radiation Diagnostics at the Medical Research and Educational Centre of Lomonosov Moscow State University, President of the Russian Society of Roentgenologists and Radiologists, Moscow.

22. Sokolova, A.V. — PhD, Associate Professor, Pirogov Russian National Research Medical University of the Russian Ministry of Health.

23. Tarlovskaya, E.I. — MD, PhD, Professor, Head of the Department of Internal Diseases, Nizhny Novgorod State Medical Academy.

24. Tereshchenko, S.N. — MD, PhD, Professor, Head of the Department of Myocardial Diseases and Heart Failure, National Medical Research Center for Cardiology of the Russian Ministry of Health.

25. Fomin, Igor Vladimirovich — MD, PhD, Professor, Director of the Institute of Therapy, Head of the Department of Hospital Therapy, Privolzhsky Research Medical University of the Russian Ministry of Health, Nizhny Novgorod.

26. Chesnikova, A.I. — MD, PhD, Professor at the Department of Internal Diseases No. 1, Rostov State Medical University.

27. Shaposhnik, I.I. — MD, PhD, Professor, Head of the Department of Propaedeutics of Internal Diseases, South Ural State Medical University, Chief Cardiologist of Chelyabinsk.

The Working Group members confirmed the absence of financial support / conflict of interest. In case of reporting a conflict of interest, the working group member(s) was/were excluded from the discussion of sections related to the conflict of interest area.

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

5. Functional Diagnostics Physician

Methods used for collecting/selecting evidence: electronic database search.

Description of methods used to assess the quality and strength of evidence: the evidence base for the guidelines includes publications indexed in the PubMed and Scopus databases. The literature search depth was 30 years.

Methods used to assess the quality and strength of evidence

• expert consensus;

• evaluation of the quality of recommendations in accordance with the grading scheme (Tables 3/A2 and 4/A2);

• evaluation of the strength of evidence in accordance with the grading scheme (Table 5/A2).

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 reliable evidence (LRE) and levels of clinical usefulness (LCU) scales for therapeutic, rehabilitative, preventive, and diagnostic interventions has been added (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. Thus, the text of the clinical guidelines developed by the Russian Society of Cardiology experts simultaneously utilizes two scales (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 3/A2. Scale for assessing levels of reliable evidence (LRE) for diagnostic methods (diagnostic interventions)

Table 4/A2. Scale for assessing levels of reliable evidence (LRE) for methods of prevention, treatment, and rehabilitation (preventive, therapeutic, and rehabilitative interventions)

Table 5/A2. Scale for assessing the levels of evidence (LE) for prevention, diagnostic, treatment and rehabilitation methods (preventive, diagnostic, therapeutic, rehabilitation interventions)

Procedure for updating clinical guidelines

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

Appendix A3. Reference Materials

1. 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."

2. 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".

3. Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019, "On approval of the procedure and timeframe for the development of clinical guidelines, their revision, the standard template for clinical guidelines, and requirements for their structure, composition, and the scientific validity of the information included in the clinical guidelines" (registered on May 8, 2019, No. 54588).

Table A3-1. Differential diagnosis of pain syndrome in acute pericarditis and acute myocardial infarction

Table A3-2. ECG changes in patients with acute pericarditis and acute myocardial infarction

Table A3-3. Echocardiographic differential diagnosis of constrictive pericarditis and restrictive cardiomyopathy [3, 315]

Table A3-4. Differential diagnosis of myopericarditis and acute myocardial infarction

In clinical practice, differential diagnosis between myopericarditis and acute myocardial infarction is most frequently required [291]. A prerequisite for making a correct diagnosis is a thorough collection of complaints and medical history to identify features characteristic of myopericarditis (e.g., history of recent infection, fever). Echocardiography also helps detect changes characteristic of myopericarditis, such as alterations in the pericardial layers and hyperechoic foci in the myocardium [45]. Coronary angiography and cardiac MRI are also often necessary for differential diagnosis with myocardial infarction.

Table A3-5. Electrocardiographic changes in myocardial infarction and myopericarditis

Table A3-6. Diagnosis of constrictive pericarditis [1, 3]

Table A3-7. Instrumental differential diagnosis of constrictive pericarditis and restrictive cardiomyopathy [3]

Table A3-8. Differential diagnosis of various etiological variants of pericardial effusion [1]

Table A3-9. Signs of pleural effusion according to instrumental imaging methods

Table A3-10. Key parameters to determine when analyzing pericardial effusion

Echocardiography in pericarditis

Figure A3-8. Echocardiographic evaluation of pericardial effusion in pulmonary hypertension. A sign of pulmonary hypertension is a significant increase in right ventricular systolic pressure (A). Transthoracic echocardiography in the parasternal long-axis view (B) and parasternal short-axis view (C) visualizes a significant pericardial effusion. However, in the presence of right ventricular hypertrophy and pulmonary hypertension, echocardiographic features of tamponade, such as significant chamber compression (B and C), are absent. The inferior vena cava is also not dilated and collapses by more than 50% during forced inspiration, suggesting normal right atrial pressure (D).

Imaging modalities in pericardial disease

Figure A3-10. Pericardial calcification along the entire perimeter of the heart.

ECG in pericarditis

Figure A3-13. ECG of a patient with acute pericarditis

Table A3-11. Dosages and tapering regimens for drugs used to treat acute pericarditis [1, 6, 177]

Table A3-12. Dosages and tapering regimens for drugs used to treat recurrent pericarditis [1, 6, 173]

Table A3-13. Glucocorticoid taper rates in recurrent pericarditis

Table A3-14. Alternative therapy for recurrent and chronic pericarditis [4, 177-180]

Table A3-15. Treatment of constrictive pericarditis (adapted from Imazio et al. [93])

Table A3-16. Dosing regimen for intrapericardial catheter administration

Appendix B. Physician Action Algorithms

Stages of acute pericarditis diagnosis

Stage one. If acute pericarditis is suspected, the following are performed: physical examination, auscultation (pericardial friction rub, uniform weakening of the first and second heart sounds), peripheral blood pressure (BP) measurement (decrease in systolic BP during inspiration), palpation of the apex beat (disappearance in cardiac tamponade)

- electrocardiogram (ECG) recording;

- targeted chest X-ray;

- Echocardiography (fluid volume calculation);

- complete (clinical) blood count and general biochemical blood test (white blood cell count, erythrocyte sedimentation rate (ESR), serum C-reactive protein (CRP), blood fibrinogen, blood creatinine, etc.).

When taking the medical history, it is essential to clarify whether procainamide**, isoniazid**, or antineoplastic agents were used. During patient monitoring, the rate of resolution of clinical symptoms is analyzed. Acute pericarditis (viral etiology, idiopathic) is typically characterized by resolution of the process within the coming week. History taking and examination reveal any underlying disease (follow-up with an endocrinologist or oncologist).

At the first stage of the diagnostic work-up, virological testing is not advisable.

As part of the first stage of diagnostic evaluation, if lymphadenopathy is detected, a lymph node biopsy is advisable; if a lung infiltrate is detected, bronchoscopy, chest computed tomography, and PCR (testing for Mycobacterium tuberculosis) are indicated.

In 90% of cases, the scope of first-stage interventions is sufficient to establish a diagnosis and choose a treatment strategy.

Second stage of diagnostic evaluation. Performed only if there are indications for pericardiocentesis, has strict indications, and should not be performed routinely. This procedure is necessary to confirm a tuberculous, purulent, or neoplastic origin of the effusion.

Indications for pericardial puncture

Thus, in all situations where the fluid volume is small (separation of pericardial layers less than 10 mm), the pericardial puncture procedure is not the procedure of first choice, and if the attending physician or medical board insists on it, it should be performed in a specialized institution. During pericardiocentesis, fluid is collected for subsequent analysis. The optimal volume of fluid examination from the pericardial cavity includes the determination of: hematocrit level (in all cases of hemorrhagic fluid), specific gravity of the fluid (greater than 1.015), protein level (greater than 3 g/dL), fluid-to-plasma ratio (greater than 0.5), LDH (greater than 200 IU/L), and glucose level—which allows diagnosing the exudate, but does not clarify the diagnosis; cytological analysis (looking for atypical cells); culture for aerobic and anaerobic flora, parallel culture of pericardial fluid and three blood samples for aerobic and anaerobic bacteria in case of suspected purulent pericarditis; molecular biological testing of pericardial fluid for Mycobacterium tuberculosis complex, and PCR to identify cardiotropic viruses. Determination of tumor marker levels: testing for carcinoembryonic antigen (CEA) in blood; testing for serum alpha-fetoprotein (AFP), hydrocarbon antigens; testing for CA 125 adenocarcinoma antigen in blood; testing for CA 72-4 adenocarcinoma antigen in blood; testing for CA 15-3 tumor-associated marker in blood; testing for CA 19-9 adenocarcinoma antigen in blood; testing for tumor necrosis factor in serum (CD 30); CD 25 — if oncopericarditis is suspected.

Contraindications for pericardiocentesis: the fluid volume is small or progressively decreases during anti-inflammatory therapy, the diagnosis can be established by any other method without pericardiocentesis, uncontrolled coagulopathy, ongoing anticoagulant therapy (ATC — antithrombotic agents), platelet count less than 50 × 10⁹/L, presence of aortic dissection (thoracic aorta).

With significant fluid volumes, it is not recommended to evacuate more than 1 liter of fluid at once, as this can lead to acute dilation of the right ventricle.

In a number of cases, when there is a high rate of exudate accumulation in the pericardial cavity after the first puncture, it is advisable to place a catheter. Fluid should be evacuated through the catheter every 4–6 hours. The catheter must be left in place until the volume of evacuated fluid decreases to 25 mL/day.

Third stage of the diagnostic workup in acute pericarditis (pericardial biopsy).

Pericardial biopsy is performed only during pericardioscopy, meaning the patient must be in a specialized surgical hospital. Pericardioscopy and pericardial biopsy should be considered exclusive procedures and should only be considered in isolated cases at the third stage of diagnostics.

Predictors of a negative prognosis. The initial examination of a patient with acute pericarditis must end with a prognostic assessment of the disease course—determining high, moderate, and low risk of a negative prognosis.

Major predictors of high risk for a negative prognosis include the following symptoms: fever > 38° C, subacute onset of the disease, pronounced pericardial effusion, cardiac tamponade, lack of a clinically significant response to therapy with #acetylsalicylic acid** or NSAIDs within 1 week of therapy [62, 171, 172, 11]. Minor predictors of high risk for a negative prognosis include: developed myopericarditis, receiving immunosuppressive therapy, chest trauma, taking oral anticoagulants (antithrombotic agents). At least one predictor of a negative prognosis is sufficient to verify high risk.

Moderate risk for a negative prognosis in the course of acute pericarditis includes clinical cases where there are no predictors of a negative prognosis, but NSAID therapy for one week did not lead to significant clinical improvement.

Low risk for a negative prognosis in the course of acute pericarditis includes clinical cases where there are no predictors of a negative prognosis, and NSAID therapy for one week led to significant clinical improvement.

Any clinical manifestation that makes it possible to suspect a specific etiology of acute pericarditis other than viral, or the presence in the patient of at least one predictor of a high risk of negative prognosis, requires mandatory hospitalization [172, 174, 288, 169]. Patients with moderate and low risk of a negative disease prognosis, without signs of complications, may receive treatment — empirical anti-inflammatory therapy on an outpatient basis. Status monitoring should be performed at least once a week [172].

Figure A3-14. Management algorithm for a patient with pericardial effusion

Step 1-A.

Step 2-B.

Step-by-step diagnostic protocol for suspected tuberculous pericarditis

Appendix C. Patient Information

Acute pericarditis is a clinical syndrome of polyetiological nature, typically presenting with symptoms of inflammation and chest pain, and in some cases with a pericardial friction rub and/or inflammatory pericardial effusion. Acute pericarditis is most frequently a complication of a prior infection, various internal organ diseases, and their treatment methods [289, 290].

It is essential to remember that such a formidable complication of pericarditis as cardiac tamponade may develop. This condition is associated with compression of the heart resulting from the accumulation of blood or other fluid in the pericardial sac. Cardiac tamponade occurs when the pressure in the pericardial space exceeds the pressure in one or more cardiac chambers, which in turn leads to restricted filling followed by increased intracardiac diastolic pressure and impaired cardiac output. The development of tamponade can be acute, subacute, or localized. Blood or other fluid accumulates between the parietal and visceral layers of the pericardium, which impedes the expansion and adequate blood filling of the ventricles in diastole, thereby leading to a decrease in their pumping function.

During the acute phase of pericarditis, intense physical exertion should be avoided.

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

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

Numeric rating scale for pain (NRS,  Numeric rating scale for pain) (https://www.carepatron.com/templates/numeric-pain-rating-scale).

Type: rating scale.

Purpose: assessment of pain severity.

The NRS consists of a sequential series of numbers from 0 to 10. Patients are asked to rate pain intensity using numbers: 0 – no pain, 5 – moderate pain, and 10 – the worst pain imaginable.