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International Journal of Molecular... May 2024The Epstein-Barr virus (EBV) is frequently found in endomyocardial biopsies (EMBs) from patients with heart failure, but the detection of EBV-specific DNA has not been...
The Epstein-Barr virus (EBV) is frequently found in endomyocardial biopsies (EMBs) from patients with heart failure, but the detection of EBV-specific DNA has not been associated with progressive hemodynamic deterioration. In this paper, we investigate the use of targeted next-generation sequencing (NGS) to detect EBV transcripts and their correlation with myocardial inflammation in EBV-positive patients with heart failure with reduced ejection fraction (HFrEF). Forty-four HFrEF patients with positive EBV DNA detection and varying degrees of myocardial inflammation were selected. EBV-specific transcripts from EMBs were enriched using a custom hybridization capture-based workflow and, subsequently, sequenced by NGS. The short-read sequencing revealed the presence of EBV-specific transcripts in 17 patients, of which 11 had only latent EBV genes and 6 presented with lytic transcription. The immunohistochemical staining for CD3 T lymphocytes showed a significant increase in the degree of myocardial inflammation in the presence of EBV lytic transcripts, suggesting a possible influence on the clinical course. These results imply the important role of EBV lytic transcripts in the pathogenesis of inflammatory heart disease and emphasize the applicability of targeted NGS in EMB diagnostics as a basis for specific treatment.
Topics: Humans; Herpesvirus 4, Human; Heart Failure; Male; Female; Epstein-Barr Virus Infections; Middle Aged; Myocarditis; Aged; High-Throughput Nucleotide Sequencing; Myocardium; DNA, Viral; Adult; Biopsy
PubMed: 38892033
DOI: 10.3390/ijms25115845 -
International Journal of Molecular... May 2024Myocarditis is characterized by an influx of inflammatory cells, predominantly of myeloid lineage. The progression of myocarditis to a dilated cardiomyopathy is markedly...
Myocarditis is characterized by an influx of inflammatory cells, predominantly of myeloid lineage. The progression of myocarditis to a dilated cardiomyopathy is markedly influenced by TGF-β signalling. Here, we investigate the role of TGF-β signalling in inflammatory cardiac macrophages in the development of myocarditis and post-inflammatory fibrosis. Experimental autoimmune myocarditis (EAM) was induced in the × × transgenic mice showing impaired TGF-β signalling in the myeloid lineage and the × control mice. In EAM, immunization led to acute myocarditis on day 21, followed by cardiac fibrosis on day 40. Both strains showed a similar severity of myocarditis and the extent of cardiac fibrosis. On day 21 of EAM, an increase in cardiac inflammatory macrophages was observed in both strains. These cells were sorted and analysed for differential gene expression using whole-genome transcriptomics. The analysis revealed activation and regulation of the inflammatory response, particularly the production of both pro-inflammatory and anti-inflammatory cytokines and cytokine receptors as TGF-β-dependent processes. The analysis of selected cytokines produced by bone marrow-derived macrophages confirmed their suppressed secretion. In conclusion, our findings highlight the regulatory role of TGF-β signalling in cytokine production within inflammatory cardiac macrophages during myocarditis.
Topics: Animals; Myocarditis; Transforming Growth Factor beta; Mice; Macrophages; Signal Transduction; Autoimmune Diseases; Cytokines; Mice, Transgenic; Disease Models, Animal; Myocardium; Fibrosis; Male
PubMed: 38891767
DOI: 10.3390/ijms25115579 -
Animals : An Open Access Journal From... Jun 2024An 8-month-old intact male domestic shorthair cat was referred to the Emergency Service of the Veterinary Teaching Hospital (VTH) of the Department of Veterinary Science...
An 8-month-old intact male domestic shorthair cat was referred to the Emergency Service of the Veterinary Teaching Hospital (VTH) of the Department of Veterinary Science of the University of Parma (Italy) from the Parma municipal multi-cat shelter, during the winter season (January 2023), for lethargy, anorexia, hypothermia, and hypoglycemia. At the VTH, upon cardiologic examination, an increase in heart rate, under normal blood pressure conditions, was detected. Signalment, clinical history, basal metabolic panel (BMP), ultrasound investigations, and cytological findings were all consistent with a diagnosis of feline infectious peritonitis (FIP). FIP was confirmed in the effusive abdominal fluid by a molecular genetic test (real-time PCR for feline coronavirus RNA). The molecular genetic investigation also detected an FCoV gene single-nucleotide mutation: biotype M1058L. At necropsy, an effusive collection was recorded in the abdomen, thoracic cavity, and pericardium sac. White parenchymal nodules, of about 1 mm diameter, were found on the surface and deep in the lungs, liver, kidneys, and heart. Histopathology revealed the typical FIP pyogranulomatous vasculitis and IHC confirmed the presence of the FIP virus (FIPV) antigen. The most relevant histopathological finding was the myocarditis/myocardial necrosis associated with the presence of the gene-mutated FCoV (M1058L biotype). This is the first case of myocarditis in a cat positive for the FCoV/FIP M1058L biotype. Further studies are necessary to support the mutated FCoV M1058L biotype, as an uncommon, but possible, causative pathogen of myocarditis in FCoV/FIP-positive cats. Studies including several FCoV/FIP M1058L-positive cases could allow us to make a correlation with heart gross pathology, histopathology, and immunolocalization of the FCoV/FIP M1058L biotype in the myocardium. The investigation will potentially allow us to determine the effective tropism of the FCoV/FIP M1058L biotype for myocardiocytes or whether myocardiocyte lesions are evident in the presence of concomitant causes related to the patient, its poor condition, or external environmental distress such as cold season, and whether the aforementioned concomitant events are correlated.
PubMed: 38891720
DOI: 10.3390/ani14111673 -
MedRxiv : the Preprint Server For... Jun 2024Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process...
BACKGROUND
Immune-checkpoint inhibitors (ICI) are associated with life-threatening myocarditis but milder presentations are increasingly recognized. The same autoimmune process that causes ICI-myocarditis can manifest concurrent generalized myositis, myasthenia-like syndrome, and respiratory muscle failure. Prognostic factors for this "cardiomyotoxicity" are lacking.
METHODS
A multicenter registry collected data retrospectively from 17 countries between 2014-2023. A multivariable cox regression model (hazard-ratio(HR), [confidence-interval]) was used to determine risk factors for the primary composite outcome: severe arrhythmia, heart failure, respiratory muscle failure, and/or cardiomyotoxicity-related death. Covariates included demographics, comorbidities, cardio-muscular symptoms, diagnostics, and treatments. Time-dependent covariates were used and missing data were imputed. A point-based prognostic risk score was derived and externally validated.
RESULTS
In 748 patients (67% male, age 23-94), 30-days incidence of the primary composite outcome, cardiomyotoxic death, and overall death were 33%, 13%, and 17% respectively. By multivariable analysis, the primary composite outcome was associated with active thymoma (HR=3.60[1.93-6.72]), presence of cardio-muscular symptoms (HR=2.60 [1.58-4.28]), low QRS-voltage on presenting electrocardiogram (HR for ≤0.5mV versus >1mV=2.08[1.31-3.30]), left ventricular ejection fraction (LVEF) <50% (HR=1.78[1.22-2.60]), and incremental troponin elevation (HR=1.86 [1.44-2.39], 2.99[1.91-4.65], 4.80[2.54-9.08], for 20, 200 and 2000-fold above upper reference limit, respectively). A prognostic risk score developed using these parameters showed good performance; 30-days primary outcome incidence increased gradually from 3.9%(risk-score=0) to 81.3%(risk-score≥4). This risk-score was externally validated in two independent French and US cohorts. This risk score was used prospectively in the external French cohort to identify low risk patients who were managed with no immunosuppression resulting in no cardio-myotoxic events.
CONCLUSIONS
ICI-myocarditis can manifest with high morbidity and mortality. Myocarditis severity is associated with magnitude of troponin, thymoma, low-QRS voltage, depressed LVEF, and cardio-muscular symptoms. A risk-score incorporating these features performed well.
TRIAL REGISTRATION NUMBER
NCT04294771 and NCT05454527.
PubMed: 38883792
DOI: 10.1101/2024.06.02.24308336 -
Cureus May 2024Immune checkpoint inhibitors (ICIs) are a class of immunotherapy agents that are often used in cancer treatment. A rare but life-threatening complication that...
Immune checkpoint inhibitors (ICIs) are a class of immunotherapy agents that are often used in cancer treatment. A rare but life-threatening complication that can be seen is ICI-induced myocarditis. We discuss a case of pembrolizumab-induced myocarditis and the nuances involved in timely diagnosis and treatment. A 64-year-old female with a past medical history significant for metastatic right-sided colorectal adenocarcinoma undergoing immunotherapy with pembrolizumab presented with worsening shortness of breath and was found to be hypoxic. Initial laboratory analysis was remarkable for troponin of 0.35 ng/mL, which later peaked at 6.01 ng/mL. The electrocardiogram showed non-specific ST segment changes in the anteroseptal leads, and a subsequent echocardiogram revealed severely reduced left ventricular systolic function with an ejection fraction of 25%. Coronary angiography showed non-obstructive coronary arteries. As the patient was on pembrolizumab immunotherapy for cancer, there was high suspicion of ICI-induced myocarditis, and the patient was started empirically on steroids. Subsequently, cardiac magnetic resonance imaging was done, which confirmed the diagnosis of myocarditis. Pembrolizumab therapy was discontinued, and she was started on guideline-directed medical therapy for heart failure. While ICIs have transformed cancer therapy, healthcare providers must be vigilant for immune-related adverse events such as myocarditis. Early recognition, prompt management, and close monitoring are crucial for optimizing patient outcomes.
PubMed: 38883125
DOI: 10.7759/cureus.60459 -
Cureus May 2024Adult-onset Still's disease (AOSD) is a rare multisystem inflammatory disorder. A 71-year-old lady who was on treatment for AOSD presented with clinical evidence of...
Adult-onset Still's disease (AOSD) is a rare multisystem inflammatory disorder. A 71-year-old lady who was on treatment for AOSD presented with clinical evidence of heart failure and was subsequently found to have impaired renal and hepatic function. Following extensive workup including a liver biopsy, the cause of liver dysfunction was determined to be congestive hepatopathy, while renal dysfunction was presumed to stem from the low output state. The etiology of myocardial dysfunction, driving liver and kidney injury, was considered to be myocarditis from AOSD or global myocardial dysfunction from a systemic inflammatory state. Management involved pulse-dose glucocorticoids followed by taper and anakinra for AOSD, alongside goal-directed medical therapy for cardiac failure. At follow-up after a month, hepatic and renal function had fully recovered, whereas cardiac function remained compromised, evidenced by persistently depressed ejection fraction and global hypokinesia on a repeat echocardiogram. This report delineates a systematic approach to multiorgan dysfunction in a patient with a rare condition such as AOSD and reviews the reported causes of hepatic and cardiac involvement in AOSD.
PubMed: 38883113
DOI: 10.7759/cureus.60400 -
American Heart Journal Plus :... Jul 2024The diagnosis of myocarditis remains challenging due to its diverse clinical manifestations. We recently demonstrated the ability of magnetocardiography (MCG) to screen...
BACKGROUND
The diagnosis of myocarditis remains challenging due to its diverse clinical manifestations. We recently demonstrated the ability of magnetocardiography (MCG) to screen for myocarditis and applied it successfully to detect myocarditis in this case study of a female-to-male (FtM) patient who had undergone sexual reassignment surgery. This case highlights two significant points: first, sex differences in myocarditis may be promoted by higher levels of testosterone, and second, the ability of MCG to diagnose myocarditis.
CASE PRESENTATION
We report on a 38-year-old FtM patient who was hospitalized for chest pain following testosterone therapy. The patient received testosterone every 2 weeks for 6 months following his FtM surgery. Two days after the last administration of testosterone, he developed chest pain. Electrocardiography identified non-significant ST elevations in V3-6, II and aVF and echocardiography revealed reduced left ventricular ejection fraction and apical hypokinesia. High-sensitivity troponin-T (539 ng/L to 676 ng/L) and creatine kinase elevation (592 U/L) were elevated. Coronary CT angiography ruled out coronary artery disease. Cardiac magnetic resonance imaging confirmed suspected myocarditis.Additionally, we used MCG to detect abnormalities in the electromagnetic field. A pathologic vector (0.179) supported the diagnosis of myocarditis in this patient. During therapy with ibuprofen the vector improved to 0.067 after 3 weeks accompanied by symptom improvement.
CONCLUSION
Testosterone treatment may have promoted myocarditis in a FtM individual. Additional MCG assessment was consistent with a diagnosis of myocarditis and highlights the promising potential of this method to facilitate diagnostic screening for cardiomyopathy in the future.
PubMed: 38882591
DOI: 10.1016/j.ahjo.2024.100412 -
Zhonghua Xin Xue Guan Bing Za Zhi Jun 2024
[A guideline that changes the diagnosis and treatment practices of fulminant myocarditis: review of the "Chinese guideline on the diagnosis and treatment of fulminant myocarditis in adults"].
Topics: Myocarditis; Humans; Adult; China; Practice Guidelines as Topic
PubMed: 38880740
DOI: 10.3760/cma.j.cn112148-20240307-00129 -
Journal of the American Heart... Jun 2024Cardiac troponin is extensively used as a biomarker in modern medicine due to its diagnostic capability for myocardial injury, as well as its predictive and prognostic... (Review)
Review
Cardiac troponin is extensively used as a biomarker in modern medicine due to its diagnostic capability for myocardial injury, as well as its predictive and prognostic value for cardiac diseases. However, heterophile antibodies, antitroponin antibodies, and macrotroponin complexes can be observed both in seemingly healthy individuals and patients with cardiac diseases, potentially leading to false positive or disproportionate elevation of cTn (cardiac troponin) assay results and introducing discrepancies in clinical interpretations with impact on medical management. In this review article, we describe the possible mechanisms of cTn release and the sources of variations in the assessment of circulating cTn levels. We also explore the pathophysiological mechanisms underlying antitroponin antibody development and discuss the influence exerted by macrotroponin complexes on the results of immunoassays. Additionally, we explore approaches to detect these complexes by presenting various clinical scenarios encountered in routine clinical practice. Finally, unsolved questions about the development, prevalence, and clinical significance of cardiac autoantibodies are discussed.
Topics: Humans; Biomarkers; Autoantibodies; Heart Diseases; Predictive Value of Tests; Troponin I; Prognosis
PubMed: 38879450
DOI: 10.1161/JAHA.123.035128 -
International Journal of Rheumatic... Jun 2024
Topics: Humans; Myocarditis; Antibodies, Monoclonal, Humanized; Acute Disease; Immunosuppressive Agents; Treatment Outcome; Female; Drug Hypersensitivity; Lupus Erythematosus, Systemic; Infusions, Intravenous; Adult; Middle Aged; Male
PubMed: 38874106
DOI: 10.1111/1756-185X.15232