Lymphocytic Myocarditis Research Articles

Viral presence-guided immunomodulation in lymphocytic myocarditis: an update.

Latest statements from European and American societies recommend to rule out viral presence in endomyocardial biopsy (EMB) via polymerase chain reaction (PCR) analysis before starting immunosuppression or immunomodulation in acute lymphocytic myocarditis presenting with life‐threatening scenarios. However, recommendations in myocarditis are mostly based on heterogeneous studies enrolling patients with inflammatory cardiomyopathies and established heart failure rather than acute myocarditis. Thus, definitive evidence of a survival benefit from immunomodulation guided by viral presence is currently lacking. Finally, distinguishing innocent bystanders from causative agents among EMB‐detected viruses remain challenging and a major goal to achieve in the near future. Therefore, considerable divergence remains between official recommendations and clinical practice, including the possibility of starting immunosuppressive therapy empirically, without knowing viral PCR results. This review systematically discusses the unsolved issues of immunomodulation guided by viral presence in acute lymphocytic myocarditis, namely (i) virus epidemiology and prognosis, (ii) variability of viral presence rates, (iii) the role of potential viral bystander findings, and (iv) the main results of immunosuppression controlled trials in lymphocytic myocarditis. Furthermore, a practical approach for the critical use of viral presence analysis in guiding immunomodulation is provided, highlighting its importance before starting immunosuppression or immunomodulation. Future, multicentre studies are needed to address specific scenarios such as fulminant lymphocytic myocarditis and a virus‐tailored management as for parvovirus B19.

Clinical efficacy of atrial fibrillation ablation depending on histological changes in the myocardium

There is a group of patients with so-called idiopathic atrial fibrillation (AF) without the causes of arrhythmia established by a standard examination. Aim. To study the effect of histological changes in the myocardium in patients with idiopathic AF on the effectiveness of ablation. Material and methods. The study included 101 patients with idiopathic AF All patients underwent ablation, during which a myocardial biopsy was performed. Depending on the results of intervention, 3 groups were formed: 1 — no AF within 12 months, 2 — recurrent arrhythmia within first 3 months of follow-up, 3 — recurrent arrhythmia after first 3 months of follow-up. To assess inflammatory changes and the severity of fibrosis, histological and immunohistochemical tests of myocardial biopsies were performed. Results . Histological criteria for lymphocytic myocarditis in group 1 observed in 47,5% of patients, in groups 2 and 3 in 27,3% and 25%, respectively. Infiltration of less than 7 cells per 1 mm 2 by CD3+ lymphocytes prevailed in group 3. The activity of inflammation in the studied groups did not significantly differ. The minimum severity of fibrosis was significantly less frequently recorded in group 1 than in group 2 and 3. Nonexpression of viral antigens in the first group was significantly less common than in the second and third groups. Moreover, the combination of expression of enterovirus VP1 and human herpesvirus 6 antigens was significantly more often recorded in the first group. Positive correlation was found between the expression of viral antigens and markers of endo- and myocardial fibrosis. Conclusion. The primary risk factor for recurrent arrhythmia was the initial stage of fibrosis, while inflammatory changes and viral infection were not risk factors. The presence of viral antigens in the myocardium had an indirect effect on the clinical outcome.

Transradial left ventricular endomyocardial biopsy feasibility, safety and clinical usefulness: Initial experience of a tertiary university center

Introduction and objectivesOver the last decade, several studies have suggested that left ventricular endomyocardial biopsy is safer and has a higher diagnostic yield than transvenous right ventricular biopsy. In addition, recent publications indicate that the transradial approach is a feasible and safe alternative to the transfemoral approach for sampling the left ventricle. We report our initial experience with transradial endomyocardial biopsy with regards to feasibility, safety and usefulness. MethodsSingle-center registry of consecutive patients undergoing intended transradial left endomyocardial biopsy. Clinical and technical data were collected prospectively, with a particular focus on success rate and complications. ResultsTwenty-seven patients were screened for left ventricle biopsy. Twenty (25) were selected for an intended transradial approach (mean age 51±18 years old, 22 male). Success rate was 100% with no crossover to femoral approach. There were no major complications. Two patients experienced mild radial spasm. One of them also had a run of non-sustained ventricular tachycardia.Indication for biopsy was either myocarditis or cardiomyopathy of unknown etiology. The final diagnosis was acute lymphocytic myocarditis in five patients, chronic myocarditis in one patient, amyloid light-chain amyloidosis in four patients and transthyretin amyloidosis in six patients. Myocarditis was ruled out in eight patients and amyloidosis in one patient. ConclusionsTransradial left ventricle endomyocardial biopsy is a very safe and feasible method of sampling the myocardium for histopathological analysis, with a good diagnostic yield and clinically meaningful results in properly selected patients.

Histopathology and ultrastructural findings of fatal COVID-19 infections in Washington State: a case series

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of an ongoing pandemic, with increasing deaths worldwide. To date, documentation of the histopathological features in fatal cases of the disease caused by SARS-CoV-2 (COVID-19) has been scarce due to sparse autopsy performance and incomplete organ sampling. We aimed to provide a clinicopathological report of severe COVID-19 cases by documenting histopathological changes and evidence of SARS-CoV-2 tissue tropism.MethodsIn this case series, patients with a positive antemortem or post-mortem SARS-CoV-2 result were considered eligible for enrolment. Post-mortem examinations were done on 14 people who died with COVID-19 at the King County Medical Examiner's Office (Seattle, WA, USA) and Snohomish County Medical Examiner's Office (Everett, WA, USA) in negative-pressure isolation suites during February and March, 2020. Clinical and laboratory data were reviewed. Tissue examination was done by light microscopy, immunohistochemistry, electron microscopy, and quantitative RT-PCR.FindingsThe median age of our cohort was 73·5 years (range 42–84; IQR 67·5–77·25). All patients had clinically significant comorbidities, the most common being hypertension, chronic kidney disease, obstructive sleep apnoea, and metabolic disease including diabetes and obesity. The major pulmonary finding was diffuse alveolar damage in the acute or organising phases, with five patients showing focal pulmonary microthrombi. Coronavirus-like particles were detected in the respiratory system, kidney, and gastrointestinal tract. Lymphocytic myocarditis was observed in one patient with viral RNA detected in the tissue.InterpretationThe primary pathology observed in our cohort was diffuse alveolar damage, with virus located in the pneumocytes and tracheal epithelium. Microthrombi, where observed, were scarce and endotheliitis was not identified. Although other non-pulmonary organs showed susceptibility to infection, their contribution to the pathogenesis of SARS-CoV-2 infection requires further examination.FundingNone.

Immunosuppressive therapy of biopsy proved immune-mediated lymphocytic myocarditis in the virus-negative and virus-positive patients.

Purposeto study the effect of immunosupressive therapy (IST) in the virus-negative and virus-positive patients with immune-mediated myocarditis. Methodsin 60 patients (45 male, 46.7 ± 11.8 years, mean LV EDD, 6.7 ± 0.7 cm, EF 26.2 ± 9.1%) active/borderline myocarditis was verified by endomyocardial biopsy (n = 38), intraoperative biopsy (n = 10), examination of explanted heart (n = 3) and autopsy (n = 9). Indications for IST determined based on histological, immune activity. The follow-up was 19.0 [7.25; 40.25] months. ResultsThe viral genome in the myocardium was detected in 32 patients (V+ group), incl. parvovirus B19 in 23. The anti-heart antibody level was equally high in the V+ and V- patients. Antiviral therapy was administered in 24 patients. IST (in 22 V+ and 24 V- patients) include steroids (n = 40), hydroxychloroquine (n = 20), azathioprine (n = 21). The significant decrease of LV EDD (6.7 ± 0.7 to 6.4 ± 0.8), PAP (48.9 ± 15.5 to 39.4 ± 11.5 mm Hg, р<0,01), increase of EF (26.5 ± 0.9 to 36.0 ± 10.8), and lower lethality (23.9% and 64.3%; RR 0.37, 95% CI 0.19–0.71), p<0.01, were found only in IST group. Significant improvement due to IST were achieved not only in V-, but also in V+ patients. ConclusionsIST in patients with immune-mediated lymphocytic myocarditis is effective and is associated with lower lethality both in virus-negative and virus-positive patients.

Miocarditis in Patients with COVID-19 Confirmed by Immunohistochemical

Aim Despite the regular heart damage in patients with coronavirus pneumonia caused by SARS-Cov-2, a possibility of developing lymphocytic myocarditis as a part of COVID-19 remains unsubstantiated. The aim of this study was to demonstrate a possibility of lymphocytic myocarditis and to study its morphological features in patients with the novel coronavirus infection (COVID-19) with a severe course.Material and methods Postmortem data were studied for 5 elderly patients (74.8±4.4 years; 3 men and 2 women) with the novel coronavirus infection and bilateral, severe polysegmental pneumonia (stage 3-4 by computed tomography). COVID-19 was diagnosed based on the typical clinical presentation and positive polymerase chain reaction test in nasopharyngeal swabs. All patients were treated in different hospitals repurposed for the treatment of patients with COVID-19. A standard histological study was performed with hematoxylin and eosin, toluidine blue, and van Gieson staining. Serial paraffin slices were studied immunohistochemically with antibodies to CD3, СD68, CD20, perforin, and toll-like receptors (TLR) 4 and 9.Results In none of the cases, myocarditis was suspected clinically, added to the diagnosis or indicated as a possible cause of death. IHD and acute myocardial infarction were mentioned as error diagnoses not confirmed by the postmortem examination. The morphological examination of the heart identified signs of lymphocytic myocarditis consistent with Dallas criteria for this diagnosis. Myocardial infiltrate was characterized in detail, and a combined inflammatory damage of endocardium and pericardium was described. The immunohistochemical study with cell infiltrate typing confirmed the presence of CD3-positive Т lymphocytes and the increased expression of TLR-4. A picture of coronaritis, including that with microvascular thrombosis, was found in all cases.Conclusion A possibility for development of lymphocytic viral myocarditis in COVID-19 was confirmed morphologically and immunohistochemically. Specific features of myocarditis in COVID-19 include the presence of coronaritis and a possible combination of myocarditis with lymphocytic endo- and pericarditis.

Fulminant myocarditis triggered by OC43 subtype coronavirus: a disease deserving evidence-based care bundles

Fulminant myocarditis triggered by OC43 subtype coronavirus: a disease deserving evidence-based care bundles

Serum alarmin S100A8/S100A9 levels and its potential role as biomarker in myocarditis.

AimsThe alarmin S100A8/S100A9 (S100A8/A9) is released by activated monocytes/macrophages and neutrophils in the setting lymphocytic myocarditis (MC). We recently demonstrated its therapeutic potential in experimental acute MC. Now, we investigated the diagnostic relevance of S100A8/A9 serum levels in patients with suspected acute and chronic MC and in patients with heart failure without cardiac inflammation.Methods and ResultsSerum S100A8/A9 levels were analysed in patients with a recent onset of MC [≤ 30 days, n = 32; ejection fraction (EF): 45.4 ± 12.9%], dilated cardiomyopathy patients with inflammation (n = 112; EF: 29.0 ± 11.4%), or without inflammation (n = 58; EF: 26.6 ± 9.3%), and controls (n = 25; EF: 68.5 ± 4.6%), by using specific ELISAs. Blood samples were collected at Time Point 1 (T1), where also endomyocardial biopsies (EMBs) were withdrawn. Patients with a recent onset of MC showed a 4.6‐fold increase in serum S100A8/A9 levels vs. controls (MC: 1948 ± 1670 ng/mL vs. controls: 426 ± 307 ng/mL; P < 0.0001). Serum S100A8/A9 correlated with the disease activity, represented by EMB‐derived counts of inflammatory cells (CD3: r = 0.486, P = 0.0047, lymphocyte function‐associated antigen‐1: r = 0.558, P = 0.0009, macrophage‐1 antigen: r = 0.434, P = 0.013), the EMB mRNA levels of S100A8, S100A9 (r = 0.541, P = 0.002), and left ventricular ejection fraction (LVEF: r = 0.498, P = 0.0043). EMB immunofluorescence co‐stainings display macrophages/monocytes and neutrophils as the main source of S100A8 and S100A9 in recent onset MC. The diagnostic value of serum alarmin levels (cut‐off 583 ng/mL) was characterized by a specificity of 92%, a sensitivity of 90.6%, positive predictive value of 93.5%, negative predictive value of 88.5%, and an accuracy of 0.949 (95% confidence interval [0.89–1]). In a subgroup of MC patients, S100A8/A9 serum levels and EMBs at T1 (n = 12) and a follow‐up visit (T2, n = 12, mean follow‐up 8.5 months) were available. A fall of serum S100A8/A9 (T1: 2208 ± 1843 ng/mL vs. T2: 888.8 ± 513.7 ng/mL; P = 0.00052) was associated with a reduced cardiac inflammation (CD3 T1: 70.02 ± 107.4 cells per square millimetre vs. T2: 59.18 ± 182.5 cells per square millimetre; P = 0.0342, lymphocyte function‐associated antigen‐1 T1: 133.5 ± 187.1 cells per square millimetre vs. T2: 74.12 ± 190.5 cells per square millimetre; P = 0.0186, and macrophage‐1 antigen T1: 132.6 ± 129.5 cells per square millimetre vs. T2: 54.41 ± 65.16 cells per square millimetre; P = 0.0015). Serum S100A8/A9 levels were only slightly increased in patients within the chronic phase of MC and in heart failure patients without inflammation vs. controls.ConclusionsSerum S100A8/A9 might serve as an additional tool in the diagnostic workup of suspected acute MC patients.

Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly across the USA, causing extensive morbidity and mortality, particularly in the African American community. Autopsy can considerably contribute to our understanding of many disease processes and could provide crucial information to guide management of patients with coronavirus disease 2019 (COVID-19). We report on the relevant cardiopulmonary findings in, to our knowledge, the first autopsy series of ten African American decedents, with the cause of death attributed to COVID-19.MethodsAutopsies were performed on ten African American decedents aged 44–78 years with cause of death attributed to COVID-19, reflective of the dominant demographic of deaths following COVID-19 diagnosis in New Orleans. Autopsies were done with consent of the decedents' next of kin. Pulmonary and cardiac features were examined, with relevant immunostains to characterise the inflammatory response, and RNA labelling and electron microscopy on representative sections.FindingsImportant findings include the presence of thrombosis and microangiopathy in the small vessels and capillaries of the lungs, with associated haemorrhage, that significantly contributed to death. Features of diffuse alveolar damage, including hyaline membranes, were present, even in patients who had not been ventilated. Cardiac findings included individual cell necrosis without lymphocytic myocarditis. There was no evidence of secondary pulmonary infection by microorganisms.InterpretationWe identify key pathological states, including thrombotic and microangiopathic pathology in the lungs, that contributed to death in patients with severe COVID-19 and decompensation in this demographic. Management of these patients should include treatment to target these pathological mechanisms.FundingNone.

The emerging spectrum of cardiopulmonary pathology of the coronavirus disease 2019 (COVID-19): Report of 3 autopsies from Houston, Texas, and review of autopsy findings from other United States cities

This paper collates the pathological findings from initial published autopsy reports on 23 patients with coronavirus disease 2019 (COVID-19) from 5 centers in the United States of America, including 3 cases from Houston, Texas. Findings confirm that COVID-19 is a systemic disease with major involvement of the lungs and heart. Acute COVID-19 pneumonia has features of a distinctive acute interstitial pneumonia with a diffuse alveolar damage component, coupled with microvascular involvement with intra- and extravascular fibrin deposition and intravascular trapping of neutrophils, and, frequently, with formation of microthombi in arterioles. Major pulmonary thromboemboli with pulmonary infarcts and/or hemorrhage occurred in 5 of the 23 patients. Two of the Houston cases had interstitial pneumonia with diffuse alveolar damage pattern. One of the Houston cases had multiple bilateral segmental pulmonary thromboemboli with infarcts and hemorrhages coupled with, in nonhemorrhagic areas, a distinctive interstitial lymphocytic pneumonitis with intra-alveolar fibrin deposits and no hyaline membranes, possibly representing a transition form to acute fibrinous and organizing pneumonia. Multifocal acute injury of cardiac myocytes was frequently observed. Lymphocytic myocarditis was reported in 1 case. In addition to major pulmonary pathology, the 3 Houston cases had evidence of lymphocytic pericarditis, multifocal acute injury of cardiomyocytes without inflammatory cellular infiltrates, depletion of splenic white pulp, focal hepatocellular degeneration and rare glomerular capillary thrombosis. Each had evidence of chronic cardiac disease: hypertensive left ventricular hypertrophy (420 g heart), dilated cardiomyopathy (1070 g heart), and hypertrophic cardiomyopathy (670 g heart). All 3 subjects were obese (BMIs of 33.8, 51.65, and 35.2 Kg/m2). Overall, the autopsy findings support the concept that the pathogenesis of severe COVID-19 disease involves direct viral-induced injury of multiple organs, including heart and lungs, coupled with the consequences of a procoagulant state with coagulopathy.

Prevalence and new histopathological aspects of Haemoproteus spp. in pigeons from Iran

Haemoproteus spp. is pathogenic protozoan that effecting blood circulatory system of birds. The present study was undertaken to evaluate the presence of Haemoproteus spp. in pigeons from Iran and associatedhistopathological changes. A total of 108 blood samples were taken from pigeons to investigate Haemoproteus spp. presence by blood smear and semi-nested PCR targeting the cytochrome b gene methods. Also, to evaluate histopathological changes 12 infected pigeons to Haemoproteus were sacrificed and studied. 34.2% of pigeons infected with Haemoproteus showed macro and microgametocytes in their erythrocytes while based on the molecular method 63.8% were infected. Focal lymphocytic aggregates, pigmentation and cell swelling were the main histopathological lesions in infected livers. Multifocal non- suppurative interstitial nephritis, pigmentation and splenic lymphoid hyperplasia were also seen in the infected pigeons. Mild lymphocytic myocarditis in the heart of one pigeon was the other finding. No histopathological changes were seen in brain, intestine, and pancreas. Schizonts with variable shapes and sizes were detected in infected livers, lungs, kidneys, and spleens but megaloschizonts were not found. This study also reports the molecular prevalence of Haemoproteus spp. in Iran

Histopathologic Characterization of Myocarditis Associated With Immune Checkpoint Inhibitor Therapy.

Cardiac complications of immune checkpoint inhibitor therapy are rare, but reports of myocarditis are increasing. The findings have been described in case reports as lymphocytic myocarditis, but its histopathology is underreported. To review the histology of myocardial biopsy-proven cases of immune checkpoint-associated myocarditis and provide immunohistochemical characterization of the inflammatory infiltrate. We have encountered 6 patients with biopsy-proven myocarditis in conjunction with therapy using anti-programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) agents with and without cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitors and characterized the histopathology and immune cell profile. The myocarditis was multifocal/diffuse and characterized by a predominant CD163-positive histiocytic infiltrate, with an associated CD8+ and PD-1+ T-lymphocytic infiltrate, some of which were granzyme B positive. Cardiac myocytes showed immunoreactivity for PD-L1 in areas of injury, confirmed using 2 different anti-PD-L1 clones. Four of 6 patients recovered from their cardiac injury. One patient had residual tachycardia-bradycardia syndrome and 1 patient expired. The diffuse lymphohistiocytic myocarditis associated with this therapy is relatively distinctive, and this diagnosis is strongly suggested based on the histopathologic findings in the correct clinical setting.

Immunotherapy-Associated Myocarditis.

The influence of checkpoint inhibitors on the balance between activation and inhibition of T-lymphocytes is strong. The development of checkpoint inhibitors has led to treatments for many malignancies but has also facilitated auto-immune disease. These immunotherapeutic agents could exacerbate already present autoimmune disease or could cause new complications in patients with no prior history of autoimmunity. Monoclonal antibodies targeting immune check points, namely anti-CTLA4 or anti-PD-1/PD-L1, are generally well tolerated; however, treatment with these drugs is associated with a variety of adverse events, such as cardiotoxicity, among others. The main mechanism of cardiac damage is lymphocytic myocarditis, which can consequently cause many symptoms of cardiovascular disease - from asymptomatic elevation of cardiac markers, heart failure, and arrhythmias to cardiogenic shock. Other adverse events include pericardium damage or Tako-tsubo cardiomyopathy. The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.

Anatomopathological changes in canine distemper seropositive dogs and virus detection in sinoatrial nodes

Canine distemper is a viral disease that affects several systems on dogs, among them, the cardiovascular system. The aim of this study was to identify canine distemper virus (CDV) in the sinoatrial node (SAN) of dogs serologically positive for distemper by Polymerase Chain Reaction preceded by reverse transcription (RT-PCR), and to analyze gross and microscopic changes of distemper in the heart and other tissues. SAN and tissue fragments were collected from 17 serologically positive dead animals, necropsied from October 2015 to December 2016. In the heart, right heart dilatation was observed in 13 dogs (76.47%) and left concentric hypertrophy in two dogs (11.76%). Microscopically, lymphocytic myocarditis was observed in four (23.53%) dogs and 41.18% presented viral inclusion corpuscles of CDV in the bladder epithelium. Only one (5.88%) dog presented a 319 bp target fragment for distemper virus using primers CDV 1 and CDV 2 at the sinoatrial node. In conclusion, CDV can be located in the sinoatrial node of naturally infected dogs, as demonstrated in this study by the RT-PCR technique, reinforcing the hypothesis that CDV is capable of causing inflammatory lesions in the sinoatrial node of this species. Macroscopic and microscopic cardiac changes are frequently observed in dogs with distemper, mainly cardiac dilatation and myocarditis. Viral inclusions of CDV in bladder epithelial cells are an important microscopic finding for the diagnosis of distemper.

A standardized postmortem protocol to assess the real burden of sudden infant death syndrome

Sudden unexpected infant death (SUID) is a major cause of death in infants < 1 year of age. Sudden infant death syndrome (SIDS) is a SUID still unexplained after post-mortem examination. In 2014, a protocol of post-mortem investigation was introduced to assess both the prevalence and the etiopathogenesis of SUID. Our aim was to compare SUID data before and after the application of a standardized autopsy protocol of investigation. In the time interval 2004–2018, SUID cases occurring in the Veneto Region, North-East Italy, were referred to our Core Lab. Since 2014, a complete autopsy was performed, including gross and histological study with toxicologic and molecular analysis carried out at the referral center. A total of 36 SUIDs (22 M, mean age 95.5 ± 80 days), 17 before (group A) and 19 after (group B) 2014, were collected. In group A, only 1 (6%) resulted as explained SUID, due to lymphocytic myocarditis and 16 (94%) were SIDS. In group B, 8 were SIDS (42%) and 11 (58%) explained SUID cases (p < 0.01), consisting of interstitial pneumonia and bronchiolitis in 9 and lymphocytic myocarditis in 2 cases. Molecular analysis was positive for viruses in 8 of them (73%). In conclusion, since the application of a standardized protocol of post-mortem investigation, inflammatory, mostly infective, cardio-pulmonary diseases have been identified as the most common cause of SUID, with SIDS falling from 94 to 42% of SUID. Efforts must be made to implement a uniform autopsy protocol to provide reliable epidemiological data on SIDS.

Ulcerative nodules on the entire body

Ulcerative nodules on the entire body

Detection of Pseudomonas aeruginosa in Dead Chicken Embryo with Reference to Pathological Changes and Virulence Genes

This work was designed to investigate incidence of P. aeruginosa in dead in shell chicken embryos and molecular detection of virulence genes and study their pathogenicity effect on embryonated chicken eggs and chicks. Out of 100 pooled samples were collected from liver, heart and yolk sac of dead in shell chicken embryos, a total of 24 (24%) P. aeruginosa isolates were isolated.On carrying PCR test for 24 P. aeruginosa isolates there were high distribution of (opr L) and ( lasI ) genes with 100% while distribution of other virulence genes was as follows: toxA (83.3%), lasR (75%), Rhl1 (70.8%). Pathogenicity of P. aeruginosa on embryonated chicken eggs was studied either by inoculation of P. aeruginosa strain via yolk sac route in a dose of 0.1 ml suspension 14x10⁷. Which gave 100% embryonic mortalities after 3 days or by dipping group of 17 days –old embryonated chicken eggs in a dose of 6.1X 109 /ml which gave 90% embryonic mortality. Experimentaly infected chicks showed 70% mortality. Histopathological changes in dead embryos from infected embryonated eggs and sacrificed, dead infected chicks revealed lymphocytic hepatitis with presence of gram negative bacteria. Lymphocytic nephritis with hemosiderosis found in renal parenchyma. Heart showed lymphocytic myocarditis. Lung showed alveolar emphysema, interstitial pneumonia and perivascular fibrosis. P. aeruginosa was re-isolated from internal organs of sacrificed hatched chicks and from liver and yolk sac of dead embryos.

Work-up of an inflammatory cardiomyopathy

Abstract A 72-year-old woman was admitted for acute heart failure. The echocardiography revealed moderate depression of the left ventricular ejection fraction. Coronary disease was excluded by coronarography. Cardiac magnetic resonance showed predominantly left ventricular septal hypertrophy and severe depression of the left ventricular systolic function. There was also a bright, multifocal and patchy late gadolinium enhancement with subendocardial, mesocardial and subepicardial involvement, suggestive of sarcoidosis. Biochemical study, thoracic computed tomography and positron emission tomography were inconclusive for extra-cardiac sarcoidosis. Therefore, an endomyocardial biopsy was performed. The procedure was complicated by the development of complete atrioventricular block, requiring implantation of a cardiac resynchronization pacing device. A few days after device implantation, the patient developed fever. The echocardiography revealed extensive vegetations, and thus the diagnosis of a device-associated infective endocarditis was made. Even though antibiotic therapy was promptly started, the patient ended up dying. Biopsy results revealed lymphocytic myocarditis. This case is paradigmatic because it shows how the etiologic diagnosis of dilated cardiomyopathy can be challenging. Non-invasive diagnostic exams may not provide a definite diagnosis, requiring an endomyocardial biopsy. However, the benefits versus risks of such procedure must always be carefully weighted.

Heart non-specific effector CD4+ T cells protect from postinflammatory fibrosis and cardiac dysfunction in experimental autoimmune myocarditis

Heart-specific CD4+ T cells have been implicated in development and progression of myocarditis in mice and in humans. Here, using mouse models of experimental autoimmune myocarditis (EAM) we investigated the role of heart non-specific CD4+ T cells in the progression of the disease. Heart non-specific CD4+ T cells were obtained from DO11.10 mice expressing transgenic T cell receptor recognizing chicken ovalbumin. We found that heart infiltrating CD4+ T cells expressed exclusively effector (Teff) phenotype in the EAM model and in hearts of patients with lymphocytic myocarditis. Adoptive transfer experiments showed that while heart-specific Teff infiltrated the heart shortly after injection, heart non-specific Teff effectively accumulated during myocarditis and became the major heart-infiltrating CD4+ T cell subset at later stage. Restimulation of co-cultured heart-specific and heart non-specific CD4+ T cells with alpha-myosin heavy chain antigen showed mainly Th1/Th17 response for heart-specific Teff and up-regulation of a distinct set of extracellular signalling molecules in heart non-specific Teff. Adoptive transfer of heart non-specific Teff in mice with myocarditis did not affect inflammation severity at the peak of disease, but protected the heart from adverse post-inflammatory fibrotic remodelling and cardiac dysfunction at later stages of disease. Furthermore, mouse and human Teff stimulated in vitro with common gamma cytokines suppressed expression of profibrotic genes, reduced amount of α-smooth muscle actin filaments and decreased contraction of cardiac fibroblasts. In this study, we provided a proof-of-concept that heart non-specific Teff cells could effectively contribute to myocarditis and protect the heart from the dilated cardiomyopathy outcome.

Clinicopathological manifestations of myocarditis in a heart failure population.

Myocarditis continues to present challenges in diagnosis and management. The goal of this study is to determine the occurrence and manifestations of myocarditis in a heart failure (HF) population. The analyzed patients had acute or persistent HF and were referred over a 6-year period to a quaternary HF center for advanced HF therapies including mechanical circulatory support, left ventricular assist device (LVAD) implantation, and/or heart transplantation. The histopathological diagnosis of myocarditis was made based on the presence of an inflammatory infiltrate of the myocardium, typically with associated cardiomyocyte (CMC) damage, combined as indicated with immunohistochemical and molecular biology characterization. The pathological findings were correlated with a panel of clinical parameters and clinical course of the patients. Myocarditis was identified in 36 patients, with initial diagnoses made in 10 (40%) of 25 by endomyocardial biopsy (EMB), 1 by atrial biopsy (maze procedure), 7 (2.1%) of 331at LVAD implantation, and 18 (7.8%) of 229 in the explanted heart. There were 20 cases of lymphocytic myocarditis, 4 cases of giant cell myocarditis, 3 cases of eosinophilic myocarditis, and 9 cases of lymphohistocytic with granulomas myocarditis - cardiac sarcoidosis. EMB was performed in 25 patients and was positive in 10 (40%) of cases. Myocarditis was found in 23 explanted hearts including 18 cases de novo and 5 cases with a previously positive specimen. Of the 23 explanted hearts, 21 were nonischemic cardiomyopathy and 2 were ischemic cardiomyopathy. Our findings show that, in patients presenting to a quaternary medical center, myocarditis can be manifest as acute HF as well as a complicating factor in chronic HF.