Pub Date : 2024-05-21DOI: 10.1016/j.carpath.2024.107654
Sarah Saxton , Amy R. Kontorovich , Dawei Wang , Bo Zhou , Sung Yon Um , Ying Lin , Lisa Rojas , Erin Tyll , Gregory Dickinson , Michelle Stram , Cynthia K. Harris , Bruce D. Gelb , Barbara A. Sampson , Jason K. Graham , Yingying Tang
Background
Few reports describe the yield of postmortem genetic testing from medical examiners’ offices or correlate genetic test results with autopsy-confirmed phenotypes from a large cohort.
Objectives
To report results from cardiomyopathy- and cardiac arrhythmia-associated genetic testing in conjunction with autopsy findings of cases investigated at the United States’ largest medical examiner office.
Methods
Postmortem cases tested from 2015 to 2022 with a cardiomyopathy- and cardiac arrhythmia-associated gene panel were reviewed. American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines were used to classify variant pathogenicity. Correlations of pathogenic/likely pathogenic variants (P/LPVs) with cardiac pathology were evaluated.
Results
The cohort included 1107 decedents of diverse ages and ethnicities. P/LPVs were detected in 87 (7.9%) cases, with 73 and 14 variants in cardiomyopathy and cardiac arrhythmia genes, respectively. Variants of uncertain significance were detected in 437 (39.5%) cases. The diagnostic yield (percentage of P/LPV) in decedents with cardiomyopathy (26.1%) was significantly higher than those without (P<.0001). The diagnostic yield was significantly lower in infants (0.7%) than older age groups (ranging from 1 to 74 years old, 5.7%-25.9%), which had no statistical difference between their yields. The diagnostic yields by cardiac autopsy findings were 54.0% for hypertrophic cardiomyopathy, 47.1% for arrhythmogenic cardiomyopathy, 20.0% for myocardial fibrosis, 19.0% for dilated cardiomyopathy, and 11.3% for myocarditis. Most P/LPVs were in MYBPC3, TTN, PKP2, SCN5A, MYH7, and FLNC. Ten P/LPVs were novel.
Conclusions
Our results support the importance of performing postmortem genetic testing on decedents of all ages with cardiomyopathy, cardiac lesions insufficient to diagnosis a specific cardiomyopathy (e.g., myocardial fibrosis), and myocarditis. Combined postmortem cardiac examination and genetic analysis are advantageous in accurately determining the underlying cause of death and informing effective clinical care of family members.
{"title":"Cardiac genetic test yields and genotype-phenotype correlations from large cohort investigated by medical examiner's office","authors":"Sarah Saxton , Amy R. Kontorovich , Dawei Wang , Bo Zhou , Sung Yon Um , Ying Lin , Lisa Rojas , Erin Tyll , Gregory Dickinson , Michelle Stram , Cynthia K. Harris , Bruce D. Gelb , Barbara A. Sampson , Jason K. Graham , Yingying Tang","doi":"10.1016/j.carpath.2024.107654","DOIUrl":"10.1016/j.carpath.2024.107654","url":null,"abstract":"<div><h3>Background</h3><p>Few reports describe the yield of postmortem genetic testing from medical examiners’ offices or correlate genetic test results with autopsy-confirmed phenotypes from a large cohort.</p></div><div><h3>Objectives</h3><p>To report results from cardiomyopathy- and cardiac arrhythmia-associated genetic testing in conjunction with autopsy findings of cases investigated at the United States’ largest medical examiner office.</p></div><div><h3>Methods</h3><p>Postmortem cases tested from 2015 to 2022 with a cardiomyopathy- and cardiac arrhythmia-associated gene panel were reviewed. American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines were used to classify variant pathogenicity. Correlations of pathogenic/likely pathogenic variants (P/LPVs) with cardiac pathology were evaluated.</p></div><div><h3>Results</h3><p>The cohort included 1107 decedents of diverse ages and ethnicities. P/LPVs were detected in 87 (7.9%) cases, with 73 and 14 variants in cardiomyopathy and cardiac arrhythmia genes, respectively. Variants of uncertain significance were detected in 437 (39.5%) cases. The diagnostic yield (percentage of P/LPV) in decedents with cardiomyopathy (26.1%) was significantly higher than those without (<em>P</em><.0001). The diagnostic yield was significantly lower in infants (0.7%) than older age groups (ranging from 1 to 74 years old, 5.7%-25.9%), which had no statistical difference between their yields. The diagnostic yields by cardiac autopsy findings were 54.0% for hypertrophic cardiomyopathy, 47.1% for arrhythmogenic cardiomyopathy, 20.0% for myocardial fibrosis, 19.0% for dilated cardiomyopathy, and 11.3% for myocarditis. Most P/LPVs were in <em>MYBPC3, TTN, PKP2, SCN5A, MYH7</em>, and <em>FLNC</em>. Ten P/LPVs were novel.</p></div><div><h3>Conclusions</h3><p>Our results support the importance of performing postmortem genetic testing on decedents of all ages with cardiomyopathy, cardiac lesions insufficient to diagnosis a specific cardiomyopathy (e.g., myocardial fibrosis), and myocarditis. Combined postmortem cardiac examination and genetic analysis are advantageous in accurately determining the underlying cause of death and informing effective clinical care of family members.</p></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-14DOI: 10.1016/j.carpath.2024.107652
Kasper Favere , Manon Van Hecke , Sander Eens , Matthias Bosman , Kim Stobbelaar , An Hotterbeekx , Samir Kumar-Singh , Peter L． Delputte , Erik Fransen , Johan De Sutter , Pieter-Jan Guns , Tania Roskams , Hein Heidbuchel
Background and aims
Viral infections are the leading cause of myocarditis. Besides acute cardiac complications, late-stage sequelae such as myocardial fibrosis may develop, importantly impacting the prognosis. Coxsackievirus B3 (CVB)-induced myocarditis in mice is the most commonly used translational model to study viral myocarditis and has provided the majority of our current understanding of the disease pathophysiology. Nevertheless, the late stages of disease, encompassing fibrogenesis and arrhythmogenesis, have been underappreciated in viral myocarditis research to date. The present study investigated the natural history of CVB-induced myocarditis in C57BL/6J mice, expanding the focus beyond the acute phase of disease. In addition, we studied the impact of sex and inoculation dose on the disease course.
Methods and results
C57BL/6J mice (12 weeks old; n=154) received a single intraperitoneal injection with CVB to induce viral myocarditis, or vehicle (PBS) as control. Male mice (n=92) were injected with 5 × 105 (regular dose) (RD) or 5 × 106 (high dose) (HD) plaque-forming units of CVB, whereas female mice received the RD only. Animals were sacrificed 1, 2, 4, 8, and 11 weeks after CVB or PBS injection. Virally inoculated mice developed viral disease with a temporary decline in general condition and weight loss, which was less pronounced in female animals (P<.001). In male CVB mice, premature mortality occurred between days 8 and 23 after inoculation (RD: 21%, HD: 20%), whereas all female animals survived. Over the course of disease, cardiac inflammation progressively subsided, with faster resolution in female mice. There were no substantial group differences in the composition of the inflammatory cell infiltrates: predominance of cytotoxic T cells at day 7 and 14, and a switch from arginase1-reactive macrophages to iNOS-reactive macrophages from day 7 to 14 were the main findings. There was concomitant development and maturation of different patterns of myocardial fibrosis, with enhanced fibrogenesis in male mice. Virus was almost completely cleared from the heart by day 14. Serum biomarkers of cardiac damage and cardiac expression of remodeling genes were temporarily elevated during the acute phase of disease. Cardiac CTGF gene upregulation was less prolonged in female CVB animals. In vivo electrophysiology studies at weeks 8 and 11 demonstrated that under baseline conditions (i.e. in the absence of proarrhythmogenic drugs), ventricular arrhythmias could only be induced in CVB animals. The cumulative arrhythmia burden throughout the entire stimulation protocol was not significantly different between CVB and control groups.
Conclusion
CVB inoculation in C57BL/6J mice represents a model of acute self-limiting viral myocarditis, with progression to different patterns of myocardial fibrosis. Sex, but not inoculation dose, seems t
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Pub Date : 2024-05-11DOI: 10.1016/j.carpath.2024.107653
José Edson Caetano-da-Silva , Elda Gonçalves-Santos , Elisa L.B.C. Domingues , Ivo S. Caldas , Graziela D.A. Lima , Lívia F. Diniz , Reggiani V. Gonçalves , Rômulo D. Novaes
By uncoupling oxidative phosphorylation, 2,4-dinitrophenol (DNP) attenuates reactive oxygen species (ROS) biosynthesis, which are known to aggravate infectious myocarditis in Chagas disease. Thus, the impact of DNP-based chemotherapy on Trypanosoma cruzi-induced acute myocarditis was investigated. C56BL/6 mice uninfected and infected untreated and treated daily with 100 mg/kg benznidazole (Bz, reference drug), 5 and 10 mg/kg DNP by gavage for 11 days after confirmation of T. cruzi infection were investigated. Twenty-four hours after the last treatment, the animals were euthanized and the heart was collected for microstructural, immunological and biochemical analyses. T. cruzi inoculation induced systemic inflammation (e.g., cytokines and anti-T. cruzi IgG upregulation), cardiac infection (T. cruzi DNA), oxidative stress, inflammatory infiltrate and microstructural myocardial damage in untreated mice. DNP treatment aggravated heart infection and microstructural damage, which were markedly attenuated by Bz. DNP (10 mg/kg) was also effective in attenuating ROS (total ROS, H2O2, and O2−), nitric oxide (NO), lipid (malondialdehyde - MDA) and protein (protein carbonyl - PCn) oxidation, TNF, IFN-γ, IL-10, and MCP-1/CCL2, anti-T. cruzi IgG, cardiac troponin I levels, as well as inflammatory infiltrate and cardiac damage in T. cruzi-infected mice. Our findings indicate that DNP aggravated heart infection and microstructural cardiomyocytes damage in infected mice. These responses were related to the antioxidant and anti-inflammatory properties of DNP, which favors infection by weakening the pro-oxidant and pro-inflammatory protective mechanisms of the infected host. Conversely, Bz-induced cardioprotective effects combined effective anti-inflammatory and antiparasitic responses, which protect against heart infection, oxidative stress, and microstructural damage in Chagas disease.
2,4-二硝基苯酚（DNP）通过解偶联氧化磷酸化，可抑制活性氧（ROS）的生物合成，而众所周知，活性氧会加重南美锥虫病感染性心肌炎的病情。因此，我们研究了基于 DNP 的化疗对克鲁兹锥虫诱发的急性心肌炎的影响。研究人员对未感染和感染的 C56BL/6 小鼠进行了调查，这些小鼠在确认感染 T. cruzi 后，每天灌胃 100 毫克/千克苯并咪唑（Bz，参考药物）、5 毫克/千克和 10 毫克/千克 DNP，连续 11 天。最后一次治疗 24 小时后，动物被安乐死，收集心脏进行显微结构、免疫学和生化分析。在未经处理的小鼠中，接种 T. cruzi 会诱发全身炎症（如细胞因子和抗 T. cruzi IgG 上调）、心脏感染（T. cruzi DNA）、氧化应激、炎症浸润和心肌微结构损伤。DNP 处理会加重心脏感染和微结构损伤，而 Bz 则会明显减轻这些损伤。DNP（10 毫克/千克）还能有效减轻 ROS（总 ROS、H2O2 和 O2-）、一氧化氮（NO）、脂质（丙二醛 - MDA）和蛋白质（蛋白质羰基 - PCn）氧化、TNF、IFN-γ、IL-10 和 MCP-1/CCL2、抗 T. cruzi IgG、心肌肌钙蛋白 I 水平，以及 T. cruzi 感染小鼠的炎症浸润和心脏损伤。我们的研究结果表明，DNP 会加重感染小鼠的心脏感染和心肌细胞微结构损伤。这些反应与 DNP 的抗氧化和抗炎特性有关，DNP 会削弱感染宿主的促氧化和促炎症保护机制，从而有利于感染。相反，Bz诱导的心脏保护作用结合了有效的抗炎和抗寄生虫反应，可防止恰加斯病的心脏感染、氧化应激和微结构损伤。
{"title":"The mitochondrial uncoupler 2,4-dinitrophenol modulates inflammatory and oxidative responses in Trypanosoma cruzi-induced acute myocarditis in mice","authors":"José Edson Caetano-da-Silva , Elda Gonçalves-Santos , Elisa L.B.C. Domingues , Ivo S. Caldas , Graziela D.A. Lima , Lívia F. Diniz , Reggiani V. Gonçalves , Rômulo D. Novaes","doi":"10.1016/j.carpath.2024.107653","DOIUrl":"10.1016/j.carpath.2024.107653","url":null,"abstract":"<div><p>By uncoupling oxidative phosphorylation, 2,4-dinitrophenol (DNP) attenuates reactive oxygen species (ROS) biosynthesis, which are known to aggravate infectious myocarditis in Chagas disease. Thus, the impact of DNP-based chemotherapy on <em>Trypanosoma cruzi</em>-induced acute myocarditis was investigated. C56BL/6 mice uninfected and infected untreated and treated daily with 100 mg/kg benznidazole (Bz, reference drug), 5 and 10 mg/kg DNP by gavage for 11 days after confirmation of <em>T. cruzi</em> infection were investigated. Twenty-four hours after the last treatment, the animals were euthanized and the heart was collected for microstructural, immunological and biochemical analyses. <em>T. cruzi</em> inoculation induced systemic inflammation (e.g., cytokines and anti-<em>T. cruzi</em> IgG upregulation), cardiac infection (<em>T. cruzi</em> DNA), oxidative stress, inflammatory infiltrate and microstructural myocardial damage in untreated mice. DNP treatment aggravated heart infection and microstructural damage, which were markedly attenuated by Bz. DNP (10 mg/kg) was also effective in attenuating ROS (total ROS, H<sub>2</sub>O<sub>2</sub>, and O<sub>2</sub><sup>−</sup>), nitric oxide (NO), lipid (malondialdehyde - MDA) and protein (protein carbonyl - PCn) oxidation, TNF, IFN-γ, IL-10, and MCP-1/CCL2, anti-<em>T. cruzi</em> IgG, cardiac troponin I levels, as well as inflammatory infiltrate and cardiac damage in <em>T. cruzi-</em>infected mice. Our findings indicate that DNP aggravated heart infection and microstructural cardiomyocytes damage in infected mice. These responses were related to the antioxidant and anti-inflammatory properties of DNP, which favors infection by weakening the pro-oxidant and pro-inflammatory protective mechanisms of the infected host. Conversely, Bz-induced cardioprotective effects combined effective anti-inflammatory and antiparasitic responses, which protect against heart infection, oxidative stress, and microstructural damage in Chagas disease.</p></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140915908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-03DOI: 10.1016/j.carpath.2024.107649
Angela Pucci , Martina Rossetti , Chiara Lenzi , Maximilian L Buja
Aortic diseases require a multidisciplinary management for diagnosis, treatment and follow-up with better outcomes in referral centers using a team-based approach. The setting up of a multi-disciplinary aortic team for the discussion of complex cases has been already proposed; it is also supported by the ACC/AHA. Surgeons and radiologists, more or less other physicians such as cardiologists, geneticists, rheumatologists/internal medicine specialists and pathologists are involved into such a team. The role of the cardiovascular pathologist is to examine the aortic specimens, to diagnose and classify the aortic lesions. Herein, the role of the pathologist in the aortic team is discussed and the pathobiology of aortic diseases is reviewed for reference by pathologists. The aortic specimens are mainly obtained from emergency or elective surgical procedures on the thoracic aorta, less frequently from organ/tissue (including cardiac or heart valve) donors, post-mortem procedures or abdominal aortic surgery. In the last decade, together with the progress of medical sciences, the histological definitions and classifications of the aortic pathology are undergoing thorough revisions that are addressed to an etiopathogenetic approach because of possible clinico-pathological correlations, therapeutic and prognostic impact. Pathologists may also have an important role in research and teaching. Therefore, histological analyses of the aortic specimens require adequate sample processing and pathologist expertise because histology contributes to definite diagnosis, correct management of patients and even (in genetic diseases) families, but also to research in the challenging field of aortopathies.
{"title":"The cardiovascular pathologist in the aortic team","authors":"Angela Pucci , Martina Rossetti , Chiara Lenzi , Maximilian L Buja","doi":"10.1016/j.carpath.2024.107649","DOIUrl":"10.1016/j.carpath.2024.107649","url":null,"abstract":"<div><p>Aortic diseases require a multidisciplinary management for diagnosis, treatment and follow-up with better outcomes in referral centers using a team-based approach. The setting up of a multi-disciplinary aortic team for the discussion of complex cases has been already proposed; it is also supported by the ACC/AHA. Surgeons and radiologists, more or less other physicians such as cardiologists, geneticists, rheumatologists/internal medicine specialists and pathologists are involved into such a team. The role of the cardiovascular pathologist is to examine the aortic specimens, to diagnose and classify the aortic lesions. Herein, the role of the pathologist in the aortic team is discussed and the pathobiology of aortic diseases is reviewed for reference by pathologists. The aortic specimens are mainly obtained from emergency or elective surgical procedures on the thoracic aorta, less frequently from organ/tissue (including cardiac or heart valve) donors, <em>post-mortem</em> procedures or abdominal aortic surgery. In the last decade, together with the progress of medical sciences, the histological definitions and classifications of the aortic pathology are undergoing thorough revisions that are addressed to an etiopathogenetic approach because of possible clinico-pathological correlations, therapeutic and prognostic impact. Pathologists may also have an important role in research and teaching. Therefore, histological analyses of the aortic specimens require adequate sample processing and pathologist expertise because histology contributes to definite diagnosis, correct management of patients and even (in genetic diseases) families, but also to research in the challenging field of aortopathies.</p></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140859840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-27DOI: 10.1016/j.carpath.2024.107651
Wei Qu, Youping Chen, Zhenlu Zhang
Background
This study aimed to explore the clinical and pathological features of aortitis in China, which is a rare disease that is often overlooked preoperatively.
Methods
We reviewed the records of 2950 patients who underwent aortic surgery at Wuhan Asia General Hospital from 2016 to 2023. Clinical and pathological data were collected and compared across different groups.
Results
Out of 2950 patients, 15 had healed aortitis, 2 were healed Takayasu aortitis (TAK), and 13 were not further classified. Forty-two had active aortitis, including clinically isolated aortitis ([CIA], 42.9%), infectious aortitis ([IA], 26.2%), TAK (16.7%), and Behçet's syndrome ([BS], 14.3%), half of these cases were not recognized preoperatively. All patients who developed perivalvular leakage during follow-up had concurrent non-infectious valvulitis with mixed inflammatory pattern at the time of initial surgery. Seventeen out of 18 patients with CIA survived without complications, as did 8 out of 11 patients with IA, 6 out of 7 patients with TAK, and 2 out of 6 patients with BS.
Conclusions
Half of the aortitis cases were initially diagnosed by pathologists. Noninfectious valvulitis with mixed inflammatory pattern is a risk factor for perivalvular leakage. BS is associated with a higher rate of complications. Patients with CIA have a good prognosis in China, which is different from the West.
{"title":"Clinical and pathological spectrum of aortitis in a Chinese cohort","authors":"Wei Qu, Youping Chen, Zhenlu Zhang","doi":"10.1016/j.carpath.2024.107651","DOIUrl":"10.1016/j.carpath.2024.107651","url":null,"abstract":"<div><h3>Background</h3><p>This study aimed to explore the clinical and pathological features of aortitis in China, which is a rare disease that is often overlooked preoperatively.</p></div><div><h3>Methods</h3><p>We reviewed the records of 2950 patients who underwent aortic surgery at Wuhan Asia General Hospital from 2016 to 2023. Clinical and pathological data were collected and compared across different groups.</p></div><div><h3>Results</h3><p>Out of 2950 patients, 15 had healed aortitis, 2 were healed Takayasu aortitis (TAK), and 13 were not further classified. Forty-two had active aortitis, including clinically isolated aortitis ([CIA], 42.9%), infectious aortitis ([IA], 26.2%), TAK (16.7%), and Behçet's syndrome ([BS], 14.3%), half of these cases were not recognized preoperatively. All patients who developed perivalvular leakage during follow-up had concurrent non-infectious valvulitis with mixed inflammatory pattern at the time of initial surgery. Seventeen out of 18 patients with CIA survived without complications, as did 8 out of 11 patients with IA, 6 out of 7 patients with TAK, and 2 out of 6 patients with BS.</p></div><div><h3>Conclusions</h3><p>Half of the aortitis cases were initially diagnosed by pathologists. Noninfectious valvulitis with mixed inflammatory pattern is a risk factor for perivalvular leakage. BS is associated with a higher rate of complications. Patients with CIA have a good prognosis in China, which is different from the West.</p></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140850848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-26DOI: 10.1016/j.carpath.2024.107646
Matthew Glass , Zhicheng Ji , Richard Davis , Elizabeth N. Pavlisko , Louis DiBernardo , John Carney , Gregory Fishbein , Daniel Luthringer , Dylan Miller , Richard Mitchell , Brandon Larsen , Yasmeen Butt , Melanie Bois , Joseph Maleszewski , Marc Halushka , Michael Seidman , Chieh-Yu Lin , Maximilian Buja , James Stone , David Dov , Carolyn Glass
Background
Pathologic antibody mediated rejection (pAMR) remains a major driver of graft failure in cardiac transplant patients. The endomyocardial biopsy remains the primary diagnostic tool but presents with challenges, particularly in distinguishing the histologic component (pAMR-H) defined by 1) intravascular macrophage accumulation in capillaries and 2) activated endothelial cells that expand the cytoplasm to narrow or occlude the vascular lumen. Frequently, pAMR-H is difficult to distinguish from acute cellular rejection (ACR) and healing injury. With the advent of digital slide scanning and advances in machine deep learning, artificial intelligence technology is widely under investigation in the areas of oncologic pathology, but in its infancy in transplant pathology. For the first time, we determined if a machine learning algorithm could distinguish pAMR-H from normal myocardium, healing injury and ACR.
Materials and Methods
A total of 4,212 annotations (1,053 regions of normal, 1,053 pAMR-H, 1,053 healing injury and 1,053 ACR) were completed from 300 hematoxylin and eosin slides scanned using a Leica Aperio GT450 digital whole slide scanner at 40X magnification. All regions of pAMR-H were annotated from patients confirmed with a previous diagnosis of pAMR2 (>50% positive C4d immunofluorescence and/or >10% CD68 positive intravascular macrophages). Annotations were imported into a Python 3.7 development environment using the OpenSlide™ package and a convolutional neural network approach utilizing transfer learning was performed.
Results
The machine learning algorithm showed 98% overall validation accuracy and pAMR-H was correctly distinguished from specific categories with the following accuracies: normal myocardium (99.2%), healing injury (99.5%) and ACR (99.5%).
Conclusion
Our novel deep learning algorithm can reach acceptable, and possibly surpass, performance of current diagnostic standards of identifying pAMR-H. Such a tool may serve as an adjunct diagnostic aid for improving the pathologist's accuracy and reproducibility, especially in difficult cases with high inter-observer variability. This is one of the first studies that provides evidence that an artificial intelligence machine learning algorithm can be trained and validated to diagnose pAMR-H in cardiac transplant patients. Ongoing studies include multi-institutional verification testing to ensure generalizability.
{"title":"A machine learning algorithm improves the diagnostic accuracy of the histologic component of antibody mediated rejection (AMR-H) in cardiac transplant endomyocardial biopsies","authors":"Matthew Glass , Zhicheng Ji , Richard Davis , Elizabeth N. Pavlisko , Louis DiBernardo , John Carney , Gregory Fishbein , Daniel Luthringer , Dylan Miller , Richard Mitchell , Brandon Larsen , Yasmeen Butt , Melanie Bois , Joseph Maleszewski , Marc Halushka , Michael Seidman , Chieh-Yu Lin , Maximilian Buja , James Stone , David Dov , Carolyn Glass","doi":"10.1016/j.carpath.2024.107646","DOIUrl":"10.1016/j.carpath.2024.107646","url":null,"abstract":"<div><h3>Background</h3><p>Pathologic antibody mediated rejection (pAMR) remains a major driver of graft failure in cardiac transplant patients. The endomyocardial biopsy remains the primary diagnostic tool but presents with challenges, particularly in distinguishing the histologic component (pAMR-H) defined by 1) intravascular macrophage accumulation in capillaries and 2) activated endothelial cells that expand the cytoplasm to narrow or occlude the vascular lumen. Frequently, pAMR-H is difficult to distinguish from acute cellular rejection (ACR) and healing injury. With the advent of digital slide scanning and advances in machine deep learning, artificial intelligence technology is widely under investigation in the areas of oncologic pathology, but in its infancy in transplant pathology. For the first time, we determined if a machine learning algorithm could distinguish pAMR-H from normal myocardium, healing injury and ACR.</p></div><div><h3>Materials and Methods</h3><p>A total of 4,212 annotations (1,053 regions of normal, 1,053 pAMR-H, 1,053 healing injury and 1,053 ACR) were completed from 300 hematoxylin and eosin slides scanned using a Leica Aperio GT450 digital whole slide scanner at 40X magnification. All regions of pAMR-H were annotated from patients confirmed with a previous diagnosis of pAMR2 (>50% positive C4d immunofluorescence and/or >10% CD68 positive intravascular macrophages). Annotations were imported into a Python 3.7 development environment using the OpenSlide™ package and a convolutional neural network approach utilizing transfer learning was performed.</p></div><div><h3>Results</h3><p>The machine learning algorithm showed 98% overall validation accuracy and pAMR-H was correctly distinguished from specific categories with the following accuracies: normal myocardium (99.2%), healing injury (99.5%) and ACR (99.5%).</p></div><div><h3>Conclusion</h3><p>Our novel deep learning algorithm can reach acceptable, and possibly surpass, performance of current diagnostic standards of identifying pAMR-H. Such a tool may serve as an adjunct diagnostic aid for improving the pathologist's accuracy and reproducibility, especially in difficult cases with high inter-observer variability. This is one of the first studies that provides evidence that an artificial intelligence machine learning algorithm can be trained and validated to diagnose pAMR-H in cardiac transplant patients. Ongoing studies include multi-institutional verification testing to ensure generalizability.</p></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":null,"pages":null},"PeriodicalIF":2.3,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140849738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-25DOI: 10.1016/j.carpath.2024.107650
Silvia Farkašová Iannaccone , Ivana Kholová , Alžbeta Ginelliová , Lucia Fröhlichová , Daniel Farkaš
We report an unexpected death of a 22-year-old primigravida who was admitted to the hospital with sudden abdominal pain two days before a scheduled delivery. During an emergency caesarean section due to intrauterine asphyxia, intraabdominal bleeding was observed with no apparent source of bleeding. Newly formed blood clots in the subdiaphragmatic space and arterial bleeding near the splenic hilum required a surgery on the next day. Hemorrhagic shock led to multiple organ failure on the fourth day of admission. The autopsy revealed ruptured splenic artery at the pancreatic tail and near the splenic hilum. Microscopically, different stages of segmental arterial mediolysis were observed in partially thinned and aneurysmatic artery.
{"title":"Segmental arterial mediolysis leading to spontaneous rupture of splenic artery and fatal hemorrhage in pregnancy","authors":"Silvia Farkašová Iannaccone , Ivana Kholová , Alžbeta Ginelliová , Lucia Fröhlichová , Daniel Farkaš","doi":"10.1016/j.carpath.2024.107650","DOIUrl":"10.1016/j.carpath.2024.107650","url":null,"abstract":"<div><p>We report an unexpected death of a 22-year-old primigravida who was admitted to the hospital with sudden abdominal pain two days before a scheduled delivery. During an emergency caesarean section due to intrauterine asphyxia, intraabdominal bleeding was observed with no apparent source of bleeding. Newly formed blood clots in the subdiaphragmatic space and arterial bleeding near the splenic hilum required a surgery on the next day. Hemorrhagic shock led to multiple organ failure on the fourth day of admission. The autopsy revealed ruptured splenic artery at the pancreatic tail and near the splenic hilum. Microscopically, different stages of segmental arterial mediolysis were observed in partially thinned and aneurysmatic artery.</p></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1054880724000462/pdfft?md5=647ad1f2a549155580777893a934ea45&pid=1-s2.0-S1054880724000462-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140792746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder that can affect almost any organ. IgG4-RD has also been reported in coronary arteries as periarteritis. IgG4-related coronary periarteritis may cause coronary artery aneurysms, and IgG4-related coronary artery aneurysms (IGCAs) are life-threatening. We describe a case of a patient with IGCA that highlights the usefulness and limitations of various IGCA evaluation modalities and provides insight into disease pathophysiology.
Case summary
A 60-year-old man with IgG4-RD diagnosed 2 years before and with IGCA at the proximal right coronary artery (RCA) on coronary angiography (CAG) 9 months prior to admission to the hospital presented with acute coronary syndrome. Emergent CAG revealed the rapid progression of IGCA at the RCA, an obstruction of the diagonal branch, and stenosis of the left anterior descending artery (LAD) and the high lateral branch (HL). The patient underwent percutaneous coronary intervention for the diagonal branch. The RCA aneurysm was resected and bypassed with a saphenous vein graft (SVG); coronary bypass grafting (left internal mammary artery to LAD and SVG to HL) was performed. Pathological findings showed inflammatory cell infiltration and disruption of the elastic plate.
Conclusion
IGCAs require careful follow-up with computed tomography scans for early detection of aneurysmal enlargement.
{"title":"Rapid progression of a coronary artery aneurysm caused by IgG4-related disease","authors":"Yohei Miura , Kohei Koyama , Takashi Kohno , Kyoko Soejima , Sho Torii , Gaku Nakazawa","doi":"10.1016/j.carpath.2024.107647","DOIUrl":"10.1016/j.carpath.2024.107647","url":null,"abstract":"<div><h3>Background</h3><p>IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder that can affect almost any organ. IgG4-RD has also been reported in coronary arteries as periarteritis. IgG4-related coronary periarteritis may cause coronary artery aneurysms, and IgG4-related coronary artery aneurysms (IGCAs) are life-threatening. We describe a case of a patient with IGCA that highlights the usefulness and limitations of various IGCA evaluation modalities and provides insight into disease pathophysiology.</p></div><div><h3>Case summary</h3><p>A 60-year-old man with IgG4-RD diagnosed 2 years before and with IGCA at the proximal right coronary artery (RCA) on coronary angiography (CAG) 9 months prior to admission to the hospital presented with acute coronary syndrome. Emergent CAG revealed the rapid progression of IGCA at the RCA, an obstruction of the diagonal branch, and stenosis of the left anterior descending artery (LAD) and the high lateral branch (HL). The patient underwent percutaneous coronary intervention for the diagonal branch. The RCA aneurysm was resected and bypassed with a saphenous vein graft (SVG); coronary bypass grafting (left internal mammary artery to LAD and SVG to HL) was performed. Pathological findings showed inflammatory cell infiltration and disruption of the elastic plate.</p></div><div><h3>Conclusion</h3><p>IGCAs require careful follow-up with computed tomography scans for early detection of aneurysmal enlargement.</p></div>","PeriodicalId":9451,"journal":{"name":"Cardiovascular Pathology","volume":null,"pages":null},"PeriodicalIF":3.7,"publicationDate":"2024-04-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140797649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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