Anti-heart Antibodies Research Articles

Systematic Aetiological Assessment of Myocarditis: A Prospective Cohort Study.

Myocarditis is commonly diagnosed in the intensive care cardiology unit (ICCU). No current recommendation nor guideline aids exist for aetiological assessments. From September 2021 to October 2023, 84 patients with acute myocarditis underwent thorough and systematic serum and blood cell panel evaluations to determine the most common causes of myocarditis. Of the 84 patients (median age 34 years, range 22-41 years, 79% male), 16 presented with complicated myocarditis. The systematic aetiological assessment revealed that 36% of patients were positive for lupus anticoagulant, 12% for antinuclear antibodies, 8% for anti-heart antibodies, and 12% for anti-striated muscle antibodies. Viral serology did not yield any significant results. After the aetiological assessment, one patient was diagnosed with an autoimmune inflammatory disorder (Still's disease). T-cell subset analyses indicated that myocarditis severity tended to increase with the T-cell lymphopenia status. A comprehensive, systematic aetiological assessment was of limited value in terms of predicting the clinical or therapeutic outcomes in myocarditis patients presenting to the ICCU.

P369 AUTOIMMUNE LYMPHOCYTIC MYOCARDITIS: ONE SIZE DOES NOT FIT ALL

Abstract Fulminant myocarditis (MF) is an acute onset, rapidly progressive and potentially fatal inflammatory cardiomyopathy which could manifests with cardiogenic shock and incessant arrhythmias. There is often a need for aminic or mechanical support to the circulation in the acute phase, waiting to obtain a histological diagnosis as quickly as possible to establish a specific therapy. Mortality in the acute phases is high, with a worse prognosis than in other forms of presentation of myocarditis, even in the long term. We report the case of a 45–year–old Asian woman suffering from autoimmune hypothyroidism, who had been reporting atypical chest pain for about 3 days, associated with fever, asthenia, and vomiting. On admission, the patient was in cardiogenic shock; an echocardiogram revealed biventricular dysfunction. Pulmonary embolism and acute coronary syndrome were excluded. Blood tests showed a significant troponin rise, neutrophilic leukocytosis, and hypertransaminasemia. Anti heart antibodies (AHA) were negative. Amine support with dobutamine and norepinephrine was then started. The first EKG showed an advanced atrioventricular block with a ventricular escape with the need for emergency temporary PM placement. Right heart catheterization showed pressures in the pulmonary circulation at the upper limits with average resistance and reduced cardiac index. An endomyocardial biopsy (EMB) was performed, subsequently complicated by cardiac tamponade due to lead displacement, treated with urgent pericardiocentesis. At the end of the procedure, the appearance of incoming episodes of complete BAV was highlighted, for which ICD implantation was performed. The biopsy showed virus–negative diffuse acute lymphocytic myocarditis. Cortisone therapy was therefore started, with immediate benefit, until the aminic support was suspended. A follow–up echocardiogram showed a complete recovery of normal biventricular function. In MF, early diagnosis, and the possibility of establishing specific therapy are crucial to reduce mortality. EMB is the only method that allows you to make an etiological diagnosis and exclude a possible infectious genesis. The patient‘s prognosis, in fact, in addition to supportive therapy, depends on the possibility of establishing a targeted treatment as soon as possible, which in virus–negative autoimmune forms consists of an immunosuppressive therapy modulated on the patient‘s histological type and clinic.

Chronic biopsy proven post-COVID myoendocarditis with SARS-Cov-2 persistence and high level of antiheart antibodies.

PurposeTo study the clinical signs and mechanisms (viral and autoimmune) of myoendocarditis in the long‐term period after COronaVIrus Disease 2019 (COVID‐19).MethodsFourteen patients (nine male, 50.1 ± 10.2 y.o.) with biopsy proven post‐COVID myocarditis were observed. The diagnosis of COVID‐19 was confirmed by IgG seroconversion. The average time of admission after COVID‐19 was 5.5 [2; 10] months. An endomyocardial biopsy (EMB) of the right ventricle was obtained. The biopsy analysis included polymerase chain reaction diagnosis of viral infection, morphological, immunohistochemical (IHC) examination with antibodies to CD3, CD45, CD68, CD20, SARS‐Cov‐2 spike, and nucleocapsid antigens. Coronary atherosclerosis was ruled out in all patients over 40 years.ResultsThe new cardiac symptoms (congestive heart failure 3–4 New York Heart Association class with severe right ventricular involvement, various rhythm, and conduction disturbances) appeared 1–5 months following COVID‐19. Magnetic resonance imaging showed disseminated or focal subepicardial and intramyocardial late gadolinium enhancement, hyperemia, edema, and increased myocardial native T1 relaxation time. Antiheart antibodies levels were increased 3–4 times in 92.9% of patients. The mean left ventricular (LV) ejection fraction (EF) was 28% (24.5; 37.8). Active lymphocytic myocarditis was diagnosed in 12 patients, eosinophilic myocarditis in two patients. SARS‐Cov‐2 RNA was detected in 12 cases (85.7%), in association with parvovirus B19 DNA—in one. Three patients had also endocarditis (infective and nonbacterial, with parietal thrombosis). As a result of steroid and chronic heart failure therapy, the EF increased to 47% (37.5; 52.5).ConclusionsCOVID‐19 can lead to long‐term severe post‐COVID myoendocarditis, that is characterized by prolonged persistence of coronavirus in cardiomyocytes, endothelium, and macrophages (up to 18 months) in combination with high immune activity. Corticosteroids and anticoagulants should be considered as a treatment option of post‐COVID myoendocarditis.

Long-term Results of Drug and Interventional Treatment in Patients with Morphologically Verified Idiopathic Arrhythmias

Aim. To study the late results of medical and interventional treatment in patients with morphologically verified nature of idiopathic arrhythmias.Methods. The prospective study included 20 patients (mean age 43.1±11.3 years, 10 female) with atrial fibrillation (AF), supraventricular and ventricular extrasystole, supraventricular and ventricular tachycardia, conduction disturbance without structural heart changes. In addition to the standard examination, the level of anti-heart antibodies was initially determined; endomyocardial biopsy (EMB) of the right ventricle with PCR study for the viral genome; DNA diagnostics (n=4), coronary angioraphy (n=6), skin biopsy (n=1) were performed. The median follow-up was 134 [128; 138] months.Results. By EMB in the initial examination were diagnosed: active (n=8)/borderline (n=3) infectious immune myocarditis; parvovirus-positive endomyocarditis (n=1); undifferentiated vasculitis (n=2); myocardial vasculitis (n=1); Fabry disease (n=1); arrhythmogenic right ventricular dysplasia (n=1); unspecified cardiomyopathy (n=2). Anti-heart antibodies were the most important in myocarditis diagnosis and monitoring. All patients with myocarditis/vasculitis (n=15) received its basic therapy: acyclovir (n=10); immunoglobulin G 10-12.5 g (n=2); hydroxychloroquine 200 mg/day (n=15); glucocorticoids (n=14); azathioprine 150 mg/day (n=2). The late results were evaluated in all patients with myocarditis. Initially, in 62.5% of patients a resistance of AF to all antiarrhythmic drugs was noted. After treatment the average frequency of AF paroxysms decreased (from 8 [5; 8] to 3 [1,25; 7,75] points). By the end of the follow-up, six patients underwent radiofrequency ablation (RFA) for AF, the full effect was achieved once. All patients without RFA have AF partially or completely resistant to drugs. Two patients (without RFA) died from ischemic stroke/ pulmonary embolism.Conclusion. Using EMB the causes of idiopathic arrhythmias (mainly AF) were diagnosed: immune inflammatory diseases in 75% and genetic in 25% of patients. As a result of complex treatment, the general burden of arrhythmias has decreased. But the presence of myocarditis and primary cardiomyopathy, without reducing the cardiac contractility and dilatation, does not allow achieving a stable antiarrhythmic effect. Lethality for 11 years was 10%. The causes of death were thromboembolic complications.

The correlation of anti-heart antibodies levels with clinical manifestations and outcomes in patients with COVID-19

PurposeTo evaluate the blood level of anti-heart antibodies (AHA) and its correlation with clinical outcomes in patients with severe and moderate COVID-19.MethodsThe study included 34 patients (11 females and 23 males, mean age 58.3±17.6 years, from 20 to 87 years) who underwent treatment for moderate and severe COVID-19 at the Sechenov University hospital in April-June 2020. The diagnosis was confirmed by 50% using nasopharyngeal smears. In other cases, the diagnosis of COVID-19 was based on the following criteria: contact with a serologically confirmed COVID-19 patient, persistent fever of at least 38 degrees Celsius, typical CT findings of viral pneumonia, typical changes in blood tests in the absence of evidence for other diseases. Besides standard medical examination the AHA blood levels by immunoassay were observed, including antinuclear antibodies (ANA), antiendothelial cell antibodies (AECA), anti-cardiomyocyte antibodies (AbC), anti-smooth muscle antibodies (ASMA) and cardiac conducting tissue antibodies (CCTA). Median hospital length of stay was 14 [13; 18] days.ResultsAHA levels were increased in 25 (73.5%) patients. The patients were divided into the five groups: 1.Patients with previous chronic myocarditis who had already been receiving immunosuppressive therapy at the admission (n=4). Moderate titer increase was noted only in one patient. 2.Patients with severe COVID-19 and high inflammatory activity, in whom the degree of AHA increase matched the general disease activity. 3. Patients with severe COVID-19 and high inflammatory activity without AHA increase. 4. Patients with moderate COVID-19, in whom high AHA titers may reflect chronic latent myocarditis not associated with SARS-Cov2. 5. Patients with moderate COVID-19 and nearly normal / normal AHA titers. Significant correlation (p<0.05) of AHA levels with cardiovascular manifestations (r=0.459) was found. AbC levels correlated significantly with pneumonia severity (r=0.472), respiratory failure (r=0.387), need for invasive ventilation (r=0.469), chest pain (r=0.374), low QRS voltage (r=0.415) and high levels of CRP (r=0.360) and LDH (r=0.360). ASMA levels were found to correlate significantly with atrial fibrillation (r=0.414, p<0.05). ANA and AbC levels correlated significantly with pericardial effusion (r=0.721 and r=0.745 respectively, p<0.05). The lethality rate was 8.8%. AbC and ASMA levels correlated significantly with lethality (r=0.363, and r=0.426 respectively, p<0.05) and were prognostically important.ConclusionElevated titres of AHA were found in 73.5% of patients. AHA correlated with lethality, in most cases reflecting the overall activity and severity of the disease and may be considered within the systemic immune and inflammatory response in COVID-19. At the same time, the correlation with signs of myocardial injury and pericardial effusion, confirms the direct role of AHA in the inflammatory heart disease (myopericarditis).FUNDunding AcknowledgementType of funding sources: None.

Post-COVID myocarditis diagnosed by endomyocardial biopsy and/or magnetic resonance imaging 2–9 months after acute COVID-19

Abstract Purpose To study clinical features of myocarditis and its possible mechanisms (including persistence of SARS-Cov-2 in the myocardium) in the long-term period after acute COVID-19. Methods Fifteen patients (8 male and 7 female, mean age 47.8±13.4, 24–65 years) diagnosed with postcovid myocarditis were included in the study. The diagnosis of COVID-19 was confirmed by positive PCR results in 40%, and seroconversion in all patients. The average time of admission after COVID-19 was 4 [3; 7] months, from 2 to 9 months. The diagnosis of myocarditis was confirmed by cardiac MRI in 10 patients and by right ventricular endomyocardial biopsy (EMB) in 6 patients. The PCR for cardiotropic viruses and PCR with immunohistochemical study for SARS-Cov2 detection were used. All patients had study for anti-heart antibodies (AHA), EchoCG, and Holter ECG. Coronary atherosclerosis was excluded in all patients over 40 years (7 coronary angiography, 4 cardiac CT). Results A clear association of the cardiac symptoms with a previous new coronavirus infection was noted in all patients. The symptoms started 1–5 months following COVID-19. MRI showed subepicardial and intramyocardial LGE, signs of hyperemia, increased T1 relaxation time, edema. AHA levels were increased 3–4-fold in 73%. Two variants of postcovid myocarditis were observed. 1. Arrhythmic variant (n=6) – newly developed frequent supraventricular or ventricular extrasystole, recurrent atrial fibrillation in the absence of systolic dysfunction. 2. Decompensated variant with biventricular heart failure (n=9): the mean LV EF was 34.1±7.8% (23 to 46%), LV EDD 5.8±0.7 cm, EDV 153.8±46.1 ml, pulmonary artery systolic pressure 40.7±11.2 mmHg. In one case, myocarditis was accompanied by IgG4- and ANCA-negative aortitis. SARS-Cov-2 RNA was detected in 4 of 5 myocardial biopsies (in one case the material in the study). The longest period of virus persistence after COVID-19 was 9 months. By using spike and nucleocapsid antibodies, coronavirus was detected in cardiomycytes and macrophages. Data of patients with morphologically proved myocarditis are presented in Table 1. Lymphocytic myocarditis was diagnosed and confirmed immunohistochemically (n=5); giant cell myocarditis with atrial standstill was detected in one more case (Fig. 1). Three patients had also signs of endocarditis, in two cases with parietal thrombosis. Conclusions COVID-19 can lead to the subacute and chronic myocarditis of varying severity. Post-COVID myocarditis manifests itself in two main clinical forms - isolated arrhythmias and systolic dysfunction with heart failure. Post-COVID myocarditis is characterized by prolonged persistence of coronavirus (up to 9 months in this study, in most patients with decompensated variant) in combination with high immune activity (high titers of AHA), which should be considered as the main mechanisms of its long-term course. Treatment approaches for such myocarditis require investigation. Funding Acknowledgement Type of funding sources: None. Table 1. Patients with EMB proved myocarditisFigure 1. The EMB in postcovide myocarditis

Post-COVID morphologically proved endocarditis: infective and nonbacterial forms

PurposeTo study clinical features of endocarditis and its possible mechanisms (infective and nonbacterial) in the long-term period after acute COVID-19.MethodsThree patients (two male and one female, age 64, 39 and 46 years) diagnosed with postcovid endocarditis were included in the study. One patient had severe bilateral coronavirus pneumonia; the other two had only fever and weakness. The diagnosis of COVID-19 was confirmed by seroconversion. The time of admission after COVID-19 was from 4 to 7 months. All patients had study for anti-heart antibodies (AHA), EchoCG, Holter ECG, and endomyocardial biopsy (EMB) with PCR for SARS-Cov2 and cardiotropic viruses. The indication for EMB was suspected myocarditis. Blood cultures and procalcitonin levels were tested in one patient due to a prolonged febrile fever.ResultsTwo variants of postcovid endocarditis have been diagnosed. The first variant was detected in two patients by EMB only. This patients had severe lymphocytic and giant cell myocarditis. In addition, EMB showed signs of lymphocytic endocarditis with infiltrates, marked thickening and fibrosis of the endocardium (Fig. 1). Some biopsy specimen were represented by fresh thrombotic masses, infiltrated with neutrophilic leukocytes. No intraventricular thrombus was detected on EchoCG and MRI. The second variant of postcovid endocarditis developed in a patient with bicuspid aortic valve and met the criteria of infectious endocarditis 2015: mobile vegetations on the valve with aortic regurgitation II, splenomegaly, irregular fever up to 39°C for six months, marked increase of CRP, procalcitonin and ferritin, hypochromic anemia, LV EF 25%. Blood culture was negative. After intravenous therapy with antibiotics and immunoglobulin, EMB confirmed the active lymphocytic myocarditis and only slight fibrosis of right ventricular endocardium. The bacteriological study of endocardium was negative. SARS-Cov-2 RNA was detected by PCR in myocardial biopsy specimens of two patients; the biopsy of one patient is in the study now. All patients had significantly elevated antibody titers to various cardiac antigens, but the level of antibodies to endothelial antigens remained completely normal. It is possible to suggest an active deposition of immune complexes in the endothelium. Two surviving patients receive steroid therapy (in case of IE with antibiotics).ConclusionsSARS-Cov-2 infection induces the prolonged non-bacterial thromboendocarditis or infective endocarditis. In both cases, autoimmune mechanisms play a significant role, as evidenced by the simultaneous lymphocytic/giant cell myocarditis and high titers of AHA. Long-term persistence of coronavirus in the myocardium can also be considered as an etiological factor of endocarditis. In favor of this hypothesis is the parietal thrombosis in the absence of bacterial infection. Corticosteroids and anticoagulants should be considered for the treatment of postcovid endocarditis.Funding AcknowledgementType of funding sources: None. Figure 1. The EMB in in postcovid endocarditis

Comparative efficacy and safety of mycophenolate mofetil and azathioprine in combination with corticosteroids in the treatment of lymphocytic myocarditis

Abstract Purpose To compare of the efficacy and safety of mycophenolate mofetil (MM) and azathioprine in combination with corticosteroids in the treatment of lymphocytic myocarditis. Methods The study included 45 patients with lymphocytic myocarditis, 34 male, the average age 48.1±11.2 years. The diagnosis of myocarditis is verified by endomyocardial biopsy. In ten patients of both groups, the parvovirus B19 DNA was detected in the myocardium. All patients had heart failure 3 [3; 3] NYHA class. High immune activity was indicated by the presence of anti-heart antibodies in all patients. Group 1 included twenty-six patients who received MM 2 g per day. Twenty of them were naive; six patients received MM instead of azathioprine, which was canceled due to cytopenia and/or insufficient effect. Group 2 included nineteen patients who received azathioprine at an average dose of 100 [75; 150] mg per day. Patients of both groups also received methylprednisolone in an average starting dose 24 [24; 32] mg per day and standard therapy for heart failure. Initial group distribution was random. Patients in both groups did not differ significantly in baseline parameters. The mean follow-up period was 23 [8; 57] months (12 and 34 months in the groups). The study is approved by the university ethics committee. Results The level of anti-heart antibodies significantly decreased in both groups. In both groups there was a significant improvement in the structural and functional parameters of the heart: NYHA class decreased from 3 [2.75; 3] to 2 [1; 2] (group 1, p&amp;lt;0.001) and from 3 [3; 3] to 2 [1; 2] (group 2, p&amp;lt;0.001), LV EF increased initially from 30.6±7.8 to 40.1±7.5% (group 1, p&amp;lt;0.001) and from 27.9±8.1 to 37.1±7.6% (group 2, p&amp;lt;0.01), by the end of follow-up to 45.9±9.0% (group 1, p&amp;lt;0.001) and to 42.4±13.7% (group 2, p&amp;lt;0.01). LV EDD significantly decreased from 6.4±0.6 to 6.1±0.8 cm (p&amp;lt;0.01), left atria size from 4.9±0.7 to 4.3±0.6 cm (p&amp;lt;0.05) and pulmonary arteria systolic pressure from 37.8±12.3 to 29.3±7.6 (p&amp;lt;0.05) only in the group 1. No direct side effects of MM were noted. Cytopenia due to treatment of azathioprine developed in 3 patients and required its replacement. There were no significant differences between groups 1 and 2 in overall mortality (7.7 vs 15.8%) and the transplant + death rate (7.7 vs 21.1%). The better survival in the MM group may be due to a shorter follow-up period. Conclusion In patients with lymphocytic myocarditis, a combination of moderate doses of corticosteroids with MM is at least no less effective and safe than steroids with azathioprine. With a shorter follow-up period, the tendency to lower mortality and a more pronounced improvement in structural parameters with better tolerance was noted in the MM group. MM should be considered as an alternative option in the treatment of isolated lymphocytic myocarditis. Funding Acknowledgement Type of funding sources: None.

Previous and First Detected Cardiovascular Diseases in Patients with New Coronavirus Pneumonia: Possible Mechanisms and Place in a Unified Prognostic Model

Purpose: The aim of this study is to evaluate the frequency of cardiac involvement in patients with coronavirus disease 2019 (COVID-19), possible immune mechanisms of myocardial injury, and the place of cardiovascular pathology among other prognostic factors. Methods: The study included 86 patients (48 male, 60.2 ± 16.6 years) with COVID-19. In addition to common investigation, examination of troponin T (n = 18) and anti-heart antibodies (AHA, n = 34) were used. The average hospital period was 14 [12; 18] days. Results: The incidence of cardiovascular disease and symptoms was 45.3%. Arrhythmias, heart failure, low-QRS voltage, repolarization disorders, and pericardial effusion were the typical for coronavirus cardiac injury. The level of AHA was increased in 73.5%. Significant (p < 0.05) correlations of AHA level with inflammatory activity, pneumonia, respiratory failure, cardiac symptoms, and death were found. D-dimer >0.5 μg/mL had a sensitivity of 79.2% and specificity of 60% in the prediction of cardiovascular manifestations. Cardiac failure was one of the causes of death in 3/8 patients (37.5%). Lethality in the presence of cardiovascular pathology was 17.9 versus 2.2% without it, p < 0.05. The most powerful prognostic model includes age, diabetes, oxygen therapy volume, maximum leukocyte level, C-reactive protein, and D-dimer (correlation coefficient 0.871, p < 0.001). The model with only age, diabetes, and cardiovascular disease included also had predictive power (correlation coefficient 0.568, p < 0.001). Conclusions: The cardiovascular pathology is frequent in patients with COVID-19 and strong correlates with the D-dimer. It indicates the high significance of prothrombotic and ischemic mechanisms. High AHA levels may reflect an inflammatory heart injury. The cardiovascular pathology is associated with higher lethality.

Anti-heart antibodies levels and their correlation with clinical symptoms and outcomes in patients with confirmed or suspected diagnosis COVID-19.

The aim of this study is to evaluate the blood level of anti-heart antibodies (AHA) and its correlation with clinical outcomes in patients with severe and moderate coronavirus disease 2019 (COVID-19). The study included 34 patients (23 males; mean age 60.2 ± 16.6 years) with COVID-19 pneumonia. Besides standard medical examination, the AHA blood levels were observed, including antinuclear antibodies, antiendothelial cell antibodies, anti-cardiomyocyte antibodies (AbC), anti-smooth muscle antibodies (ASMA), and cardiac conducting tissue antibodies. Median hospital length of stay was 14 [13; 18] days. AHA levels were increased in 25 (73.5%) patients. Significant correlation (p < 0.05) of AHA levels with cardiovascular manifestations (r = 0.459) was found. AbC levels correlated with pneumonia severity (r = 0.472), respiratory failure (r = 0.387), need for invasive ventilation (r = 0.469), chest pain (r = 0.374), low QRS voltage (r = 0.415), and levels of C-reactive protein (r = 0.360) and lactate dehydrogenase (r = 0.360). ASMA levels were found to correlate with atrial fibrillation (r = 0.414, p < 0.05). Antinuclear antibodies and AbC levels correlated with pericardial effusion (r = 0.721 and r = 0.745, respectively, p < 0.05). The lethality rate was 8.8%. AbC and ASMA levels correlated significantly with lethality (r = 0.363 and r = 0.426, respectively, p < 0.05) and were prognostically important. AHA can be considered as part of the systemic immune and inflammatory response in COVID-19. Its possible role in the inflammatory heart disease requires further investigation.

Transcriptomic Coupling of PKP2 With Inflammatory and Immune Pathways Endogenous to Adult Cardiac Myocytes.

Plakophilin-2 (PKP2) is classically defined as a component of the desmosome. Besides its role in cell–cell adhesion, PKP2 can modulate transcription through intracellular signals initiated at the site of cell–cell contact. Mutations in PKP2 associate with arrhythmogenic right ventricular cardiomyopathy (ARVC). Recent data demonstrate that inflammation plays a key role in disease progression; other results show an abundance of anti-heart antibodies in patients with confirmed diagnosis of ARVC. Here, we test the hypothesis that, in adult cardiac myocytes, PKP2 transcript abundance is endogenously linked to the abundance of transcripts participating in the inflammatory/immune response. Cardiac-specific, tamoxifen (TAM)-activated PKP2-knockout mice (PKP2cKO) were crossed with a RiboTag line to allow characterization of the ribosome-resident transcriptome of cardiomyocytes after PKP2 knockdown. Data were combined with informatics analysis of human cardiac transcriptome using GTEx. Separately, the presence of non-myocyte cells at the time of analysis was assessed by imaging methods. We identified a large number of transcripts upregulated consequent to PKP2 deficiency in myocytes, inversely correlated with PKP2 abundance in human transcriptomes, and part of functional pathways associated with inflammatory/immune responses. Our data support the concept that PKP2 is transcriptionally linked, in cardiac myocytes, to genes coding for host-response molecules even in the absence of exogenous triggers. Targeted anti-inflammatory therapy may be effective in ARVC.

Pericarditis in contemporary therapeutic clinic: nosological spectrum, approaches to diagnosis and treatment

To analyze the register of pericarditis in a therapeutic clinic, to evaluate their nosological spectrum, to optimize approaches to diagnosis and treatment. For the period 20072018, the register includes 76 patients with the diagnosis of pericarditis (average age 53.115.7 years, 2085 years, 46 female). Patients with hydropericardium were not included in the register. Diagnostic puncture of pericardium was carried out in 5 patients, pleural puncture in 11 patients. Morphological diagnostics included endomyocardial/ intraoperative biopsy of myocardium (n=4/2), thoracoscopic/intraoperative biopsy of pericardium (n=1/6), pleural puncture (n=5), transbronchial (n=1), thoracoscopic biopsy of intrathoracic lymph nodes (n=2), lung (n=1), supraclavicular lymph node biopsy (n=1), salivary gland (n=1), subcutaneous fat and rectum biopsy per amyloid (n=6/1). The genome of cardiotropic viruses, level of anti-heart antibodies, C-reactive protein, antinuclear factor, rheumatoid factor (antibodies to cyclic citrullinized peptide), antibodies to neutrophil cytoplasm were determined, extractable nuclear antigens (ENA), protein immunoelectrophoresis, diaskin test, computed tomography of lungs and heart, cardiac magnetic resonance imaging, oncologic search. The following forms of pericarditis were verified: tuberculosis (14%, including in combination with hypertrophic cardiomyopathy HCM), acute / chronic viral (8%) and infectious immune (38%), including perimyocarditis in 77%, pericarditis associated with mediastinum lymphoma/sarcoma (4%), sarcoidosis (3%), diffuse diseases of connective tissue and vasculitis (systemic lupus erythematosus, rheumatoid arthritis, diseases of Horton, Takayasu, Shegren, Wegener, 12%), leukoclastic vasculitis, Loefflers endomyocarditis, AL-amyloidosis, thrombotic microangiopathy (1% each), HCM (8%), coronary heart disease (constriction after repeated punctures and suppuration; postinfection and immune, 4%), after radiofrequency catheter ablation and valve prosthetics (2%). Tuberculosis was the main causes of constrictive pericarditis (36%). Treatment included steroids (n=39), also in combination with cytostatics (n=12), anti-tuberculosis drugs (n=9), acyclovir/ganclovir (n=14), hydroxychloroquine (n=23), colchicine (n=13), non-steroidal anti-inflammatory drugs (n=21), L-tyroxine (n=5), chemotherapy (n=1). In 36 patients different types of therapy were combined. Treatment results observed in 55 patients. Excellent and stable results were achieved in 82% of them. Pericardiectomy/pericardial resection was successfully performed in 8 patients. Lethality was 13.2% (10 patients) with an average follow-up 9 [2; 29.5] months (up to 10 years). Causes of death were chronic heart failure, surgery for HCM, pulmonary embolism, tumor. During a special examination, the nature of pericarditis was established in 97% of patients. Morphological and cytological diagnostics methods play the leading role. Tuberculosis pericarditis, infectious-immune and pericarditis in systemic diseases prevailed. Infectious immune pericarditis is characterized by small and medium exudate without restriction and accompanying myocarditis. Steroids remain the first line of therapy in most cases. Hydroxychloroquine as well as colchicine can be successfully used in moderate / low activity of immune pericarditis and as a long-term maintenance therapy after steroid stop.

Instrumental and laboratory parameters of myocardial function in adult patients with autoimmune polyglandular syndrome type 2, 3

Аutoimmune polyglandular syndrome (APS) it is characterized by damage to two or more endocrine glands, which eventually results in the hormonal failure. Some clinical studies describe the development of myocardial lesion in the setting of combined autoimmune endocrine pathology. In Russia the myocardial condition in adult patients with APS types 2 and 3 was examined for the first time. To evaluate the structure and functional state of the myocardium according to magnetic resonance imaging (MRI), to analyze changes in the spectrum of specific antiheart autoantibodies and markers of heart lesion in patients with APS types 2 and 3. 50 patients with APS types 2, 3 were studied. 45 of them were performed with delayed contrast heart MRI. All 50 patients were tested for IgG antibodies to heart muscle antigens by indirect enzymatic immunoassay (EIA), for troponin I and natriuretic peptide by chemiluminescence immunoassay (CLIA), for creatine phosphokinase (CPK) by NAC (N - acetyl-L-cysteine), and for C-reactive protein (CRP) by immunoturbidimetry. According to the results of heart MRI (n=45), 91% showed signs of functional changes in the left ventricular (LV) myocardium without any signs of myocarditis. 38 of 45 examined patients had deviation of 2 or more indicants of the LV functional state, MEF 68.9±6.6%, IUMm - 86 [75; 99] g, IUSV - 60.9 [50; 66] ml, IUEDVi - 52 [44; 59] ml/m2 , IUESVi - 17 [15.3; 18] ml/m2 , IUESV - 26 [23; 31] ml, IUEDV - 85 [70; 92] ml. 1 patient (2%) had positive result according to the determination of antibodies (AB) to heart muscle antigens (AG). Troponin 1 indicants did not exceed the reference values. The level of CPK exceeded the reference values in 3 patients (6%), an increase of CRP, NT-proBNP was observed in 7 patients (14%), and a combined increase was observed in 1 case. We obtained MRI data indicating functional changes in the myocardium in patients with APS types 2 and 3. The autoimmune cause of these changes according to the results of determining of antiheart antibodies was not confirmed in most of the examined patients, the indicants of «damage» to the myocardium (troponin 1 and NT-proBNP) did not deviate from the reference range.

An update on the pathophysiology of acute and recurrent pericarditis.

Pericarditis is an inflammatory disease of the pericardium. Progress has been done in recent years in the understanding of its pathophysiology. In particular, preclinical and clinical studies have contributed to increasing our knowledge on the role of interleukin (IL)-1 and NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome. Information for this study has been retrieved in original articles, reviews, systematic reviews, and meta-analyses identified through PubMed using the following search terms (or combination of terms): "pericarditis," "acute pericarditis," "recurrent pericarditis," "idiopathic recurrent acute pericarditis," "autoimmunity," "autoinflammation," "outcomes." Only articles published in English were included. Additional papers identified from the reference list of the retrieved articles were also considered. Based on current evidence, pericarditis should be considered as an inflammatory reaction to various stimuli, including chemical/physical, infectious, or ischemic ones, with a viral infection being a common etiology. Interaction of pathogens or irritants with toll-like receptor (TLRs) and stimulation of IL-1 receptor by IL-1α and IL-1β leads to an increased transcription of proinflammatory genes, including those needed for NLRP3 inflammasome assembly. This pathway is confirmed indirectly by the beneficial effect of colchicine (an indirect NLRP3 inflammasome inhibitor) and IL-1 blockers in patients with recurrent pericarditis. More recently, a direct evidence of the NLRP3 inflammasome within the inflamed pericardium has been provided as well. It may, however, occur that self-antigens on the surface of mesothelial cells or microbial peptides may stimulate autoreactive T cells along with B cells producing antiheart antibodies, although less evidence is available on this. Some uncertainties still remain about the role of neutrophils, neutrophil extracellular traps (NETs), and pericardial interstitial cells in recurrent and constrictive pericarditis. Unraveling these aspects might have a direct impact on the development of novel targeted therapies, especially considering the increasing number of drugs targeting NETs.

Predictors of death, heart transplantation and relapse in clinically suspected and biopsy-proven myocarditis in the pre-immunosuppression era

Abstract Background Myocarditis is an infectious or autoimmune inflammatory disease of the myocardium; diagnosis relies on the exclusion of an acute coronary syndrome, and is confirmed by endomyocardial biopsy (EMB). Prognosis is highly variable, outcome predictors are not well defined. Purpose To identify clinical, imaging and immunological predictors of death, heart transplantation (HTx) and relapse in patients with myocarditis in the pre-immunosuppression era. Methods From 1993 to 2012 we consecutively enrolled 466 patients (68% male, mean age 37±17 years), 216 with clinically suspected and 250 with EMB-proven myocarditis. All patients underwent coronary angiogram and transthoracic echocardiogram, 44% of patients underwent cardiac magnetic resonance (CMR). Circulating auto-antibodies were measured in patients' sera by indirect immunofluorescence. All patients were prospectively followed-up at the local Cardio-immunology outpatient clinic. Results After a median follow-up of 50 months (IQR 25–75), 366 patients (79%) were alive, while 42 (9%) were dead or underwent HTx; 58 were lost to follow-up. Ten-year survival free from death or HTx was overall 83%, but was lower in patients with EMB-proven myocarditis (76% vs 94% in patients with clinically suspected myocarditis, p&amp;lt;0.001). On univariate analysis, predictors of death and HTx were female gender (p=0.003), previous myocarditis (p=0.03), heart failure on presentation and advanced NYHA class (p&amp;lt;0.001, respectively), histological diagnosis of giant-cell myocarditis (p=0.002), positivity for anti-heart antibodies (AHA, p=0.04), anti-cardiac endothelial cell (AECA, p=0.002) and anti-nucleus antibodies (ANA, p=0.003). On multivariate analysis, female gender (HR 2.69, p=0.02), lower left ventricular ejection fraction on echocardiogram (p&amp;lt;0.001), positivity for high-titre organ-specific AHA (HR 4.1, p=0.02) and for ANA (HR 5.1, p&amp;lt;0.001) were independent predictors of death and HTx. Seventy-seven patients had relapsing myocarditis; on univariate analysis, young age (p&amp;lt;0.001), previous myocarditis (p&amp;lt;0.001), symptoms preceding diagnosis (p=0.004), positivity for anti-intercalated disk autoantibody (AIDA, p=0.02), and presence of diffuse late gadolinium enhancement (LGE) on CMR (p&amp;lt;0.001) were predictors of relapse. On multivariate analysis young age (p=0.02) and previous myocarditis (HR 8.4, p&amp;lt;0.001) were independent predictors of relapse. Predictors of death, HTx and relapse, respectively, did not differ when considering separately patients with EMB-proven myocarditis and those with clinically suspected myocarditis. Conclusions In the pre-immunosuppressive era, young age and a previous episode of myocarditis were independent predictors of relapse, female gender, left ventricular dysfunction at presentation and high-titre organ-specific AHA and ANA were independent predictors of death and HTx, suggesting that autoimmune features in myocarditis predict worse prognosis. Funding Acknowledgement Type of funding source: None

Immunosuppressive Therapy and Risk Stratification of Patients With Myocarditis Presenting With Ventricular Arrhythmias

This study sought to investigate the effects of immunosuppression on arrhythmic myocarditis. The effects of immunosuppressive therapy (IST) on ventricular arrhythmia (VA) have not been reported in patients with immune-mediated biopsy-proven myocarditis. Furthermore, myocarditis arrhythmic risk is still unpredictable. We enrolled 255 patients with biopsy-proven virus-negative myocarditis and VA (major: ventricular fibrillation, ventricular tachycardia; minor: nonsustained ventricular tachycardia, Lown grade≥2 premature ventral complexes) at presentation. Serum cardiac autoantibodies (antiheart antibodies, anti-intercalated disk autoantibodies [AIDA]) were detected by a standardized indirect immunofluorescence technique. Whenever accepted and noncontraindicated, IST was started. Control individuals (IST-) were chosen after 1:1 matching to IST+ patients by age, sex, ethnicity, left ventricular ejection fraction, VA type, and treatment. A total of 58 matched patient couples (age 42 ± 13 years; 67% male) were analyzed in the main study cohort. IST duration was 12 ± 1months. By the 24-month prospective follow-up, major VA occurred in 6 IST+ versus 10 IST- patients (p=0.42), with no episodes following IST termination. As compared to IST- patients, IST+ patients showed a significant reduction in minor VA burden, as well as improvement in clinical, laboratory, and imaging findings (all p<0.05). Major VA onset and positive AIDA status were independently associated with major VA at follow-up (hazard ratio [HR]: 14.2; 95% confidence interval [CI]: 2.9 to 68.7 and HR: 8.0; 95%CI: 2.6 to 25.2, respectively; both p<0.001). Furthermore, in the whole study population (N=255), IST was independently associated with protection from major VA (HR: 0.3; 95%CI: 0.2 to 0.7; p=0.01) at 38 ± 21months of follow-up. In patients with immune-mediated virus-negative myocarditis presenting with VA, IST is associated with positive effects on minor VA and nonarrhythmic endpoints. Short-term effects are limited on major VA, which were independently associated with major VA onset and positive AIDA.

P5564The myocarditis as a regular phenomenon in primary noncompact myocardium: clinical and morphological diagnostics, significance and treatment

Abstract Purpose To estimate the frequency of myocarditis in adult patients with noncompact myocardium (NCM) of the left ventricle (LV), its influence on the disease, the outcome and results of treatment. Methods We included 103 adult patients with NCM (61 males, 45.6±14.9 years). The average EDD LV was 6.0±0.8 cm, LV EF 38.8±14.5%. To diagnose NCM were performed Echo-CG, CT (n=81) and MRI (n=39). We performed NGS sequencing, followed by Sanger sequencing of detected variants (revealed in 9% of patients in the genes MYH7, MyBPC3, LAMP2, DES, DSP, TTN). The examination also included anti-heart antibodies and viruses (PCR) study and morphological study in 19 patients (endomyocardial biopsy in 14, intraoperative biopsy in 1, explanted heart study in 1 and autopsy in 3). The mean follow-up was 12 [2; 32] months. Results The myocarditis was diagnosed in 55 (53.4%) patients with NCM: in 19 patients by morphological study (active in 10 and borderline in 9 patients) and in 36 patients on the basis of a complex examination (the relationship with a respiratory infection, a 3–4-fold increase in the anti-heart antibodies, the viral genome in the blood, pericardial effusion, subepicardial LGE). The myocarditis was virus-positive in 17 patients (36.1%). The parvovirus B19, human herpes virus type 6, cytomegalovirus, herpes simplex virus and Epstein-Barr virus were detected in the myocardium in 8 patients (42.1%), and in 14 patients (25.5%) in the blood. Pathogenic genetic variants were revealed in four patients with morphologically verified myocarditis. The rate of myocarditis depended on the clinical form of NCM: 44.4% in arrhythmic form, 12.5% in chronic ischemic form, 57.5% in dilated pattern and 50.0% in association of NCM with other cardiomyopathies. In 10% of all patients, acute myocarditis was the first manifestation of the disease. In 5% the myocardial necrosis was the main manifestation of the myocarditis. The association of NCM with myocarditis led to more severe myocardial dysfunction (NYHA class 2 [1; 3] v 1.75 [0; 2], p&lt;0.01, EF 33.8±13.5 v 44.7±13.6%, p&lt;0.001), higher rate of the nonsustained ventricular tachycardia (67.3% v 29.3%, p&lt;0.01), appropriate shocks of defibrillators (38.9% v 0, p&lt;0.05), death (16.4 and 4.2%, OR 5.75, 95% CI 1.21–27.43, p&lt;0.05), and heart transplantation (7.3% v 2.1%, p&gt;0.05). Only in patients with myocarditis, there was a significant increase in EF (in acute myocarditis from 25.4±7.9 to 38.6±9.5%, p&lt;0.01), decrease sizes of the LV and systolic pulmonary artery pressure as a result of basic therapy. Morphological verification of myocarditis Conclusion Myocarditis is a regular phenomenon that develops in half of patients with primary NCM. The nature of myocarditis in NCM may be different (primary infectious and immune, secondary in response to genetic/ischemic damage to cardiomyocytes). However, it leads to a significant deterioration of structural and functional parameters, an increase in life-threatening arrhythmias, unfavorable outcomes and requires basic therapy.

P339The factors associated with death, transplantation and appropriate defibrillators shocks in patients with dilated cardiomyopathy depending on its etiology

Abstract Purpose To study the predictors of death, transplantation and appropriate shocks (AS) of defibrillators in patients with dilated cardiomyopathy (DCM) depending on its etiology. Methods In 300 patients with DCM syndrome (206 males, 47.6±12.7 years, the average left ventricle (LV) end-diastolic diameter 6.4 [5.9; 7.1] cm, LV ejection fraction (EF) 32 [25; 40] %) were performed viral genome (real-time PCR) and anti-heart antibodies investigation, ECG, Holter, Echo-CG, cardiac CT, MRI, coronary angiography, and also morphological study of myocardium in 103 (34%) patients. Defibrillators were implanted in 80 (26.7%) patients: 47 ICD, 33 CRTD. The follow-up was 15 [6; 42] months. Results The following causes of DCM syndrome have been identified: the isolated myocarditis (n=164, 54.7%), the primary/genetic DCM (n=58, 19.3%), the genetic DCM with myocarditis (n=71, 23.7%), peripartum (n=1, 0.3%) and chemotherapy-induced cardiomyopathy (n=5, 1.7%), arteriovenous malformation (n=1, 0.3%). Genetic forms of DCM were represented by noncompact myocardium (n=64), ARVC (n=12), TTR-amyloidosis (n=1), myopathy (n=6). The pathogenic mutations in the genes LMNA (n=1), DES (n=2), DSP (n=2), EMD (n=2), PKP2 (n=1), MUH7+MyBPC3 (n=2), MyBPC3 (n=4) were detected. The AS rate was 23.8%. The only predictor of AS was identified the genetic/primary nature of DCM, that is diagnosed in 100% of patients with AS in comparison with 57% in patients without AS, p&lt;0.001 (AUC 0.716, RR 1.76, 95% CI 1.43–2.17). The patients with AS had higher LVEF (35.7±10.3 vs 28.3±9.7%, p&lt;0.01), smaller LV end-diastolic diameter (6.2±0.6 vs 6.8±0.9 cm, p&lt;0.01), low QRS voltage (39 vs 13%, p=0.077), absence of LV hypertrophy on ECG (79 vs 52%, p&lt;0.05), underuse of beta-blockers (74 vs 92%), sustained VT (32 vs 4%, p&lt;0.05), but not isolated unsustained VT (54 vs 70%, p&gt;0.05). The mortality in patients with DCM was 19.7%, rate of transplantation 4.3%, death + transplantation 23.0%, SCD 2.7%. There were no differences depending on devises implantation due to adequate selection to procedure. The following factors were associated with mortality: high NYHA class and severe heart dysfunction, absence of improvement after start of therapy, acute debut of symptoms, viral genome in the myocardium, absence of anti-heart antibodies, absence of immunosuppressive therapy, beta-blockers and ACE inhibitors and MRA. The predictors of transplantation were genetic/primary DCM, younger age (38.3±10.3 vs 48.0±12.7, p&lt;0.05), low QRS voltage, more frequent PVBs and unsustained VT, severe restrictive dysfunction, absence of immunosuppressive therapy, beta-blockers, and sustained reduction of EF. Conclusions The etiology of DCM syndrome plays a key role in the prognosis and should be considered when selecting patients for ICD and heart transplantation. The genetic nature of DCM is the more important predictor of shocks than EF. The total mortality is clearly associated with resistant myocardial dysfunction.

P5559Biopsy-proven myocarditis: clinical and diagnostic correlates of late gadolinium enhancement

Abstract Background Cardiovascular magnetic resonance (CMR) is an accurate diagnostic tool providing detailed myocardial tissue characterization. Correlates of late gadolinium enhancement (LGE) with clinical and diagnostic features are poorly defined in endomyocardial biopsy (EMB)-proven myocarditis. Purpose We sought to identify clinical, laboratory and imaging correlates of LGE in patients with EMB-proven myocarditis. Methods We analyzed our prospective cohort of patients with EMB-proven myocarditis (n=366) to identify patients who underwent CMR (n=154, aged 39±13, 108 males). Presence of LGE was qualitatively assessed. CMR and EMB were performed in all cases at the time of hospitalization. Clinical, laboratory, and imaging features at diagnosis were analyzed to identify correlates of LGE presence. Results Demographic characteristics (age, gender), cardiovascular risk factors (hypertension, diabetes) and cardiovascular therapy did not differ between patients with and without LGE. Patients with history of myocarditis tended to have a higher prevalence of LGE (25 vs 4 patients, p=0.07). There was a trend towards a higher prevalence of LGE in patients presenting with heart failure or acute coronary syndrome (p=0.07) as opposed to those presenting with arrhythmias. Patients with LGE were more symptomatic in the 6 months preceding diagnosis (palpitations, p=0.03, chest pain p=0.02). Clinical left and right ventricular systolic dysfunction at presentation were more common in patients with LGE (p=0.02, p=0.02 respectively). LGE presence failed to distinguish patients according to EMB findings (active vs. borderline myocarditis) (p=0.66) or to the histological type of myocarditis. Troponin I levels were higher in patients with LGE (p=0.03). There was no difference in bi-ventricular volumes and function, as assessed both by echocardiography and heart catheterization. There was no correlation between anti-heart antibodies and LGE presence, nor were patients with LGE more likely to receive immunosuppressive therapy; however, response to immunosuppression tended to be more common in patients without LGE (13/13 vs 29/38 patients, p=0.09). The rate of heart transplant, death and myocarditis relapse did not differ between patients with and without LGE. Conclusions Presence of LGE on CMR was associated with longer symptom duration before diagnosis, presentation with heart failure and higher troponin release, but failed to correlate with specific EMB features or myocarditis aetiopathogenetic markers. Acknowledgement/Funding None

Diagnostic Value of Different Noninvasive Criteria of Latent Myocarditis in Comparison with Myocardial Biopsy

Purpose: The aim of this study was to quantify the value of various clinical, laboratory, and instrumental signs in the diagnosis of myocarditis in comparison with morphological studies of the myocardium. Methods: In 100 patients (65 men, 44.7 ± 12.5 years old) with “idiopathic” arrhythmias (n = 20) and dilated cardiomyopathy (DCM; n = 80), we performed the following: 71 endomyocardial biopsies (EMB), 13 intraoperative biopsies, 5 studies of explanted hearts, and 11 autopsies with virus investigation (real-time PCR) of the blood and myocardium. Antiheart antibodies (AHA) were also measured as well as cardiac CT (n = 45), MRI (n = 25), and coronary angiography (n = 47). The comparison group included 50 patients (25 men, 53.7 ± 11.7 years old) with noninflammatory heart diseases who underwent open heart surgery. Results: Active/borderline myocarditis was diagnosed in 76.0% of the study group and in 21.6% of patients in the comparison group (p < 0.001). The myocardial viral genome was observed more frequently in patients in the comparison group than in the study group (65.0 and 40.2%; p < 0.01). We evaluated the diagnostic value of noninvasive markers of myocarditis. The panel of AHA had the greatest importance in the identification of myocarditis: sensitivity was 81.5%, and the positive and negative predictive values were 75.0 and 60.5%. This defined the diagnostic value of noninvasive markers of myocarditis and established a diagnostic algorithm providing an individual assessment of the likelihood of myocarditis development. Conclusion: AHA have the greatest significance in the diagnosis of latent myocarditis in patients with “idiopathic” arrhythmias and DCM. The use of a complex of noninvasive criteria allows the probability of myocarditis to be estimated and the indications for EMB to be determined.