115 Prognostic significance of iron deficiency status in chronic inflammatory cardiomyopathy

Aims Iron deficiency (ID) and associated anaemia (IDA) represent major comorbidities in chronic diseases. However, their prevalence and prognostic significance have never been investigated in chronic inflammatory cardiomyopathy (CIC). Methods and results This is a single-centre, prospective study, on consecutive adult patients with CIC (symptom onset > 3 months, endomyocardial biopsy-proven chronic myocarditis) undergoing iron status assessment (enrollment: January 2014–January 2019). ID was defined as either serum ferritin < 100 µg/l or transferrin saturation < 20%. IDA was defined as haemoglobin < 12 g/dl in women, < 13 g/dl in men. The primary endpoint was the occurrence of heart failure events (HFE) and/or arrhythmic events (AE). The study cohort is composed by 219 CIC patients (mean age 46 ± 15 y, 71% males, mean LVEF 50 ± 14%). Diagnosis was furtherly supported by cardiac magnetic resonance in 194 cases (89%). Baseline characteristics of patients with IDA (n = 48), ID (n = 70), and non-ID controls (n = 101) were largely comparable. We found that median in-hospital stay length was 13 days (IQR: 6–20) in IDA patients vs. 8 (IQR: 5–11) in the remaining groups (P = 0.002), and was inversely correlated with haemoglobin values on admission. By 3.9 ± 1.8 year prospective follow-up, events occurred in 86 patients (39%). For the composite endpoint, the only factors associated with events were ID status (HR: 6.3, 95% CI: 2.1–19.5, P = 0.001) and male gender (HR: 5.4, 95% CI: 1.2–24.9, P = 0.030). In detail, HFE occurred in 48 patients (40/118 IDA or ID vs. 8/101 controls, P < 0.001), and AE in 51 (34/118 IDA or ID vs. 17/101 controls, P = 0.039). All cardiac deaths (n = 7) occurred in ID or IDA patients (P = 0.016; n = 1 and 6, respectively). Conclusions ID and IDA are common among CIC patients, and may bare a negative prognostic value. Our findings suggest a careful evaluation of haemoglobin levels and iron status, and call for further investigation on both pathophysiological and prognostic implications of ID and IDA among CIC patients.

Viral Myocarditis—From Pathophysiology to Treatment

The diagnosis of acute and chronic myocarditis remains a challenge for clinicians. Characterization of this disease has been hampered by its diverse etiologies and heterogeneous clinical presentations. Most cases of myocarditis are caused by infectious agents. Despite successful research in the last few years, the pathophysiology of viral myocarditis and its sequelae leading to severe heart failure with a poor prognosis is not fully understood and represents a significant public health issue globally. Most likely, at a certain point, besides viral persistence, several etiological types merge into a common pathogenic autoimmune process leading to chronic inflammation and tissue remodeling, ultimately resulting in the clinical phenotype of dilated cardiomyopathy. Understanding the underlying molecular mechanisms is necessary to assess the prognosis of patients and is fundamental to appropriate specific and personalized therapeutic strategies. To reach this clinical prerequisite, there is the need for advanced diagnostic tools, including an endomyocardial biopsy and guidelines to optimize the management of this disease. The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) has currently led to the worst pandemic in a century and has awakened a special sensitivity throughout the world to viral infections. This work aims to summarize the pathophysiology of viral myocarditis, advanced diagnostic methods and the current state of treatment options.

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

Purpose To evaluate the blood level of anti-heart antibodies (AHA) and its correlation with clinical outcomes in patients with severe and moderate COVID-19. Methods The 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. Results AHA 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. Conclusion Elevated 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 Acknowledgement Type of funding sources: None.

Clinical and morphological characteristics of COVID-19-associated myocarditis

Background COVID-19 is accompanied by the development of a wide range of cardiovascular lesions. The goal: to study the clinical and morphological features of SARS-CoV-2-associated myocarditis (SCM), determining the presence of viral RNA and proteins in myocardial tissue. Methods The study was based on 32 autopsies with a confirmed diagnosis of myocarditis. The average age of the patients was 72.7±15.5 years. Men predominated in the group (53%). The immunohistochemical determination of the surface markers of CD45, CD3, CD20, CD 68 inflammatory infiltrates and SARS-CoV-2 nucleocapsid and spike protein has been done. Detection of coronavirus RNA was performed. Results The clinical manifestations SCM included heart failure and variety of rhythm disturbances. Increased level of anticardiac antibodies was detected. Lymphomacrophage infiltrates (more than 7 CD3+ T-lymphocytes, more than 14 CD45+ lymphocytes and more than 7 CD68+ macrophages per 1 mm2) were found in 100% of cases. RNA of the virus was detected in myocardial tissue. Virus proteins were identified in macrophages of the inflammatory infiltrate and cardiomyocytes. Conclusion The results suggest persistence of the virus in the myocardium and the development of chronic myocarditis. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Russian Foundation for Fundamental Research

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

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. FUNDunding Acknowledgement Type of funding sources: None. Table 1. Patients with EMB proved myocarditis Figure 1. The EMB in postcovide myocarditis

Diagnosis and treatment of myocarditis

The recommendations are dedicated to contemporary aspects of epidemiology, etiology, pathogenesis, diagnosis, etiology-based, pathogenetic and symptomatic treatment of myocarditis. Various pathogenetic mechanisms that cause the development and progression of inflammatory heart disease and cause dilatation and systolic dysfunction, lead to heart failure and the development of other complications of myocarditis are described in detail. These recommendations present the modern classification of myocarditis, approved in Ukraine, and modern algorithms for diagnosis and clinical management of patients, in particular the algorithm that justifies the appointment of glucocorticoids for patients with myocarditis. The characteristics of different variants of myocarditis are also presented with clarifications concerning diagnosis and treatment. Much attention is paid to various approaches to the etiotropic and pathogenetic treatment of myocarditis and their possible prospects. It is obvious that in order to standardize approaches to the diagnosis and management of acute and chronic myocarditis, it is necessary to conduct large-scale multicenter studies and create special registries. In addition, in the current context of the COVID-19 pandemic, the pathological effects of SARS-Cov-2 as a trigger of myocarditis need further study, in particular in terms of impact on the prognosis and approaches to pathogenetic therapy in such patients. Unification of terminology and approaches to diagnosis and clinical monitoring of patients with myocarditis can improve management tactics and increase the survival rate of such patients. To identify high-risk patients (with arrhythmias, high probability of recurrence or transformation of myocarditis into dilated cardiomyopathy) and candidates for heart transplantation, the most promising is the creation of special databases of such patients

Myeloid-Derived Suppressor Cells Restrain Natural Killer Cell Activity in Acute Coxsackievirus B3-Induced Myocarditis

Murine models of coxsackievirus B3 (CVB3)-induced myocarditis well represent the different outcomes of this inflammatory heart disease. Previously, we found that CVB3-infected A.BY/SnJ mice, susceptible for severe acute and chronic myocarditis, have lower natural killer (NK) cell levels than C57BL/6 mice, with mild acute myocarditis. There is evidence that myeloid-derived suppressor cells (MDSC) may inhibit NK cells, influencing the course of myocarditis. To investigate the MDSC/NK interrelationship in acute myocarditis, we used CVB3-infected A.BY/SnJ mice. Compared to non-infected mice, we found increased cell numbers of MDSC in the spleen and heart of CVB3-infected A.BY/SnJ mice. In parallel, S100A8 and S100A9 were increased in the heart, spleen, and especially in splenic MDSC cells compared to non-infected mice. In vitro experiments provided evidence that MDSC disrupt cytotoxic NK cell function upon co-culturing with MDSC. MDSC-specific depletion by an anti-Ly6G antibody led to a significant reduction in the virus load and injury in hearts of infected animals. The decreased cardiac damage in MDSC-depleted mice was associated with fewer Mac3+ macrophages and CD3+ T lymphocytes and a reduced cardiac expression of S100A8, S100A9, IL-1β, IL-6, and TNF-α. In conclusion, impairment of functional NK cells by MDSC promotes the development of chronic CVB3 myocarditis in A.BY/SnJ mice.