Kinta Hatakeyama

We report the case of a 71-year-old woman with giant cell myocarditis presenting as acute heart failure and cardiogenic shock (LVEF 15%). She required mechanical ventilation, IMPELLA CP (Abiomed, Danvers, MA), veno-arterial extracorporeal (VA-ECMO), and continuous renal replacement therapy. Endomyocardial biopsy confirmed giant cell myocarditis, and treatment with corticosteroids, mycophenolate mofetil, and tacrolimus was initiated. Following multi-modal support and immunosuppressive therapy, left ventricular function recovered to 54%, allowing withdrawal of mechanical circulatory support and hemodialysis. However, the patient ultimately died on the 111th day due to the long treatment of cytomegalovirus infection and septic shock from catheter-related blood stream infection. Optimal immunosuppressive regimens remain undefined, so this case highlights successful recovery of cardiac function with intensive multi-modal management.

Background and Aims: Pathological examination is commonly used to diagnose immune checkpoint inhibitor (ICI)-related myocarditis. However, well-organized clinicopathological evidence remains limited. In this study, we aimed to investigate the pathological and clinical characteristics of myocarditis to enhance understanding. Methods: This multicentre retrospective observational study included 38 patients diagnosed with or suspected of having ICI-related myocarditis. Patients were stratified using the pathological grading system proposed by Palaskas et al. Lymphocyte infiltration was assessed using both global and hot-spot (hotspot) methods. Immunohistochemistry was performed for lymphocytes, macrophages, and inflammatory markers, including human leucocyte antigen–DR isotype (HLA-DR), programmed death-ligand 1 (PD-L1), granzyme B, and tenascin C. Results: An increased infiltration of CD3, CD4, CD8-positive T cells, and CD68 and CD163-positive macrophages was observed with higher pathological grades. HLA-DR and tenascin C (clone 4F10) were sensitive markers of inflammation, whereas PD-L1 and tenascin C (clone 4C8) were more specific for high-grade inflammation. Global assessment more accurately predicted myocarditis-related mortality than hotspot assessment, although both methods similarly predicted fulminant myocarditis and major adverse cardiac events. Two patients presented with suspected ICI-mediated non-inflammatory left ventricular dysfunction (NILVD), with minimal myocardial inflammation. Conclusions: Pathological grading using both global and hotspot assessment is valuable for the diagnosis and risk stratification of ICI-related myocarditis. As low-grade inflammation is not uncommon, supplementary markers such as HLA-DR, granzyme B, tenascin C, and PD-L1 may aid diagnosis. Furthermore, ICI-mediated NILVD may encompass cases of low-grade myocarditis.

Aims: Truncating variations in the titin gene (TTNtv) are the most common genetic cause of dilated cardiomyopathy (DCM) and have been implicated in various arrhythmic and heart failure phenotypes. Nonetheless, predicting the pathogenicity of a distinct subtype of TTNtv, canonical splice-site variations (TTNcsv), remains challenging. Furthermore, the precise transcriptional and phenotypic consequences associated with TTNcsv remain unclear. We evaluated the transcriptional profiles of TTN in vitro, focusing on TTNcsv found in patients with cardiac dysfunction, and compared them with their phenotypic manifestations. Methods and results: Genome-wide linkage analysis, whole-exome sequencing, and whole-genome sequencing were performed on a five-generation family with cardiac conduction disturbance (CCD). In addition, whole-genome sequencing was performed on 402 Japanese biobank patients with cardiomyopathy (CM) or unidentified cardiac dysfunction. Transcriptional profiles of TTNcsv were evaluated by RNA-Seq of induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and endomyocardial biopsy specimens, and by minigene assays. A rare segregating TTNcsv (c.49049-2A>C) was identified in the five-generation family with CCD. RNA-Seq and minigene assays revealed complex aberrant TTN splicing transcripts: predominantly non-truncating transcripts caused by an 18 bp in-frame deletion (83–90%) and minor truncating transcripts (10–17%). Two additional TTNcsv were identified in biobank participants by whole-genome sequencing. A minigene assay of TTNcsv c.67348+1G>A, identified in a CCD patient with mild cardiac dysfunction, revealed predominantly non-truncating transcripts (95%), caused by retention of a 90 bp in-frame intron, along with 5% truncating TTN transcripts, caused by a 50 bp frameshift deletion, mirroring the TTNcsv observed in the familial CCD. In contrast, the DCM-associated TTNcsv c.67637-2A>G generated 87% truncating TTN transcripts, attributed to frameshift intron retention and cryptic splicing. Conclusion: The clinical data from this family suggest a close association between TTNcsv and CCD, which may involve an increase in non-truncating transcripts. Further studies are required to determine their precise relationship and the underlying mechanisms.

Background: Myocarditis is a life-threatening disease with significant hemodynamic risks during the acute phase. Although histopathological examination of myocardial biopsy specimens remains the gold standard for diagnosis, there is no established method for objectively quantifying cardiomyocyte damage. We aimed to develop an AI model to evaluate clinical myocarditis severity using comprehensive pathology data. Methods: We retrospectively analyzed 314 patients (1076 samples) who underwent myocardial biopsy from 2002 to 2021 at the National Cerebrovascular Center. Among these patients, 158 were diagnosed with myocarditis based on the Dallas criteria. A Multiple Instance Learning (MIL) model served as a pre-trained classifier to detect myocarditis across whole-slide images. We then constructed two clinical severity-prediction models: (1) a logistic regression model (Model 1) using the density of inflammatory cells per unit area, and (2) a Transformer-based model (Model 2), which processed the top-ranked patches identified by the MIL model to predict clinical severe outcomes. Results: Model 1 achieved an AUROC of 0.809, indicating a robust association between inflammatory cell density and severe myocarditis. In contrast, Model 2, the Transformer-based approach, yielded an AUROC of 0.993 and demonstrated higher accuracy and precision for severity prediction. Attention score visualizations showed that Model 2 captured both inflammatory cell infiltration and additional morphological features. These findings suggest that combining MIL with Transformer architectures enables more comprehensive identification of key histological markers associated with clinical severe disease. Conclusions: Our results highlight that a Transformer-based AI model analyzing whole-slide pathology images can accurately assess clinical myocarditis severity. Moreover, simply quantifying the extent of inflammatory cell infiltration also correlates strongly with clinical outcomes. These methods offer a promising avenue for improving diagnostic precision, guiding treatment decisions, and ultimately enhancing patient management. Future prospective studies are warranted to validate these models in broader clinical settings and facilitate their integration into routine pathological workflows. What is new?: – This is the first study to apply an AI model for the diagnosis and severity assessment of myocarditis. – New evidence shows that inflammatory cell infiltration is related to the severity of myocarditis. – Using information from the entire tissue, not just inflammatory cells, allows for a more accurate assessment of myocarditis severity. What are the clinical implications?: – The use of the AI model allows for an unprecedented histological evaluation of myocarditis severity, which can enhance early diagnosis and intervention strategies. – Rapid and precise assessments of myocarditis severity by the AI model can support clinicians in making timely and appropriate treatment decisions, potentially improving patient outcomes. – The incorporation of this AI model into clinical practice may streamline diagnostic workflows and optimize the allocation of medical resources, enhancing overall patient care.

Background: The thrombogenic potential of cells within atherosclerotic plaques is critical in the formation of a coronary thrombus. We hypothesized that a combination of inflammatory and hypoxic stimuli enhances tissue factor (TF) expression and glycolysis in cells in atherosclerotic plaques and contributes to coronary thrombus formation. Aims: To identify TF- and hexokinase (HK)-II-expressing cells in coronary atherosclerotic plaques and thrombi and determine the effects of combined inflammatory and hypoxic stimuli and glycolysis on TF expression in peripheral blood mononuclear cell-derived macrophages. Methods: We immunohistochemically assessed TF and HK-II expression in stable (n = 20) and unstable (n = 24) human coronary plaques and aspirated acute coronary thrombi (n = 15). The macrophages were stimulated with tumor necrosis factor-α, interferon-γ, or interleukin-10 under normoxic (21% O₂) or hypoxic (1% O₂) conditions, and TF expression was assessed. Results: TF and HK-II expression were increased in unstable plaques compared with stable plaques. The number of CD68- and HK-II-immunopositive cells positively correlated with the number of TF-immunopositive cells. TF- and HK-II-expressing macrophages, which expressed M1- or M2-like markers, were involved in platelet-fibrin thrombus formation in ruptured plaques. The combination of inflammatory and hypoxic conditions additively augmented TF expression and procoagulant activity in the cultured macrophages. Inhibition of glycolysis with 2-deoxyglucose reduced the augmented TF expression and procoagulant activity. Conclusion: Combined inflammatory and hypoxic conditions in atherosclerotic plaques may markedly enhance procoagulant activity in macrophages and contribute to coronary thrombus formation following plaque disruption. Macrophage TF expression may be associated with glycolysis.

Background: Immunotherapy with immune checkpoint inhibitors (ICIs) enhances the host immune reaction against tumour cells by inhibiting intrinsic down-regulators of the T cell-mediated immune response. Although the advent of ICIs has dramatically changed oncology, ICIs may also trigger an overactivation of T cells against non-cancerous tissues, leading to off-target immune-related adverse events (irAEs). Case summary: A 64-year-old man with a history of seven courses of atezolizumab, an ICI, for small-cell lung cancer and coronavirus disease 2019 (COVID-19) was admitted to the hospital complaining of acute chest pain. Transthoracic echocardiography showed preserved ejection fraction (EF), but electrocardiography indicated precordial ST-elevations and marked increases in biomarkers for myocardial injury were observed. Emergent cardiac catheterization showed no significant coronary stenosis. On the fifth hospital day, EF decreased to 25% and pericardial effusion occurred. Endomyocardial biopsy was immediately performed, and prednisolone (60 mg/day) was administered. Troponin I level rapidly reduced, ST changed, and EF improved. Histological examinations demonstrated CD8-predominant T lymphocytic infiltration with myocardial cell injury, consistent with irAE-myocarditis. Discussion: In irAEs, myocarditis is the most common and severe cardiac manifestation with a high mortality. Even at 20 weeks after the initial ICI treatment, irAE-myocarditis occurs and the clinical presentation may mimic ST-elevation myocardial infarction. The histopathological findings suggested the high possibility of irAE-myocarditis rather than COVID-19-induced myocarditis, but COVID-19 has possibly played a role in the development of late-onset irAE-myocarditis. This educational case implies the importance of immediate recognition of irAE even after stable ICI treatment.

Background: Coronavirus disease 2019 (COVID-19) is predominantly known to cause respiratory injury; however, the present case series highlights four instances in which the infection resulted in significant cardiac complications. Among such cases, some represent severe cardiogenic shock, which necessitates the immediate introduction of mechanical circulatory support (MCS) for salvage. Case summary: This case series involved patients with COVID-19-associated myocardial injury leading to fulminant cardiogenic shock. These patients required immediate implementation of peripheral MCS, followed by an instant upgrade to a central MCS system due to anatomical limitations and severe biventricular dysfunction. Central MCS provided effective ventricular unloading, resulting in a significant and prompt improvement in ventricular function. The treatment timeline showed rapid deterioration followed by remarkable recovery within 2 weeks of MCS initiation, demonstrating the effectiveness of aggressive and tailored MCS strategies in managing severe COVID-19-related cardiac complications. Discussion: This study provides significant insights into the cardiovascular implications of COVID-19, particularly in the context of severe myocardial injury that leads to cardiogenic shock. The report underscores the importance of early recognition and intervention in such cases, focusing on the use of MCS as a life-saving modality. The findings also revealed unique pathological features of COVID-19-associated myocardial injury, including macrophage-predominant infiltration and microthrombosis, which are distinct from the features of conventional myocarditis. These findings highlight the need for further research on the pathophysiology of COVID-19-related cardiac injuries and the development of targeted therapeutic strategies.

This case report details the pathological findings of a vessel wall identified as the bleeding point for intracranial hemorrhage associated with Moyamoya disease. A 29-year-old woman experienced intracranial hemorrhage unrelated to hyperperfusion following superficial temporal artery-middle cerebral artery bypass surgery. A pseudoaneurysm on the lenticulostriate artery (LSA) was identified as the causative vessel and subsequently excised. Examination of the excised pseudoaneurysm revealed a fragment of the LSA, with a disrupted internal elastic lamina and media degeneration. These pathological findings in a perforating artery, akin to the circle of Willis, provide insights into the underlying mechanisms of hemorrhage in Moyamoya disease.