Cardiovascular Pathologists Research Articles

Virtual pathology: Reaching higher standards for noninvasive CTA tissue characterization capability by using histology as a truth standard

AimsDespite advances in therapy, reduction in myocardial infarction or death remains elusive. Whereas computed tomography angiography (CTA) is increasingly appreciated, the analyses are often subjective or qualitative. Methods for specific tissue characterization using histopathologic correlates have recently been reported. We extend this here to demonstrate accurate discrimination between, and quantitation of, lipid-rich necrotic core (LRNC), intraplaque hemorrhage (IPH), and fibrotic tissues. MethodsNCT02143102 collected 576 tissue samples with paired CTA. Cardiovascular pathologists annotated LRNC, IPH, and dense calcification (CALC) regions as a reference standard. Blinded to histology, CTA was analyzed using ElucidVivo (Elucid Bioimaging Inc., Boston, MA USA). Structure and tissue characteristics of atherosclerotic plaque from CTA, accounting for both the imaging acquisition process and the biology, accounting for differences in density distributions that result from the different cellular and molecular level milieu of the relevant tissue types. ResultsLRNC was tested across a true range of 0–10 mm2, with a difference of 0.15 mm2 and a slope of 0.92. IPH was tested across a true range of 0–18 mm2, with a difference from histology of 1.68 mm2 and a slope of 0.95. CALC was tested across a range of 0–14 mm2, with a difference of −0.06 mm2 and a slope of 0.99. Matrix tissue (MATX) was tested across a range of 4–52 mm2, with a difference of 0.02 mm2 and a slope of 0.91. ConclusionLRNC, IPH, CALC, and MATX may be objectively quantified using histopathologic correlates automatically from CTA for use singly or in combination to optimize patient care. The availability of objectively validated quantitative markers that may be followed longitudinally may extend the clinical utility of CTA. Additionally, these measures contribute efficacy variables for developing novel drugs and clinical decision support tools for tailored therapeutics.

Relationship between histopathological features of non-infectious aortitis and the results of pre-operative 18F-FDG-PET/CT: a retrospective study of 16 patients.

To describe the characteristics of 18F-fluorodeoxyglucose positron-emission tomography/computed-tomography (18FDG-PET/CT) findings before surgery in patients with active, histologically confirmed aortitis, and to correlate the degree of arterial wall inflammation with PETVAS score. This was a multiple-centre retrospective study including cases with histologically proven active, non-infectious aortitis who had a 18FDG-PET/CT performed within one year before surgery for aneurysm repair. PETVAS score was determined by radiologists blinded to the pathology findings. Cardiovascular pathologists reviewed aortic tissue samples and graded the degree of inflammation in the vessel wall. Sixteen patients were included (8 giant cell arteritis, 4 clinically isolated aortitis, 2 Takayasu's arteritis, 1 relapsing polychondritis, and 1 rheumatoid arthritis). In 5/16 (31%) patients, 18FDG-PET/CT did not detect the presence of aortic inflammation; two of whom were being treated with glucocorticoids at the time of procedure. Ascending thoracic and abdominal aorta had the highest FDG uptake among the affected territories. Patients without active aortitis on 18FDG-PET/CT were significantly older (p=0.027), had a lower PETVAS score (p=0.007), and had a lower degree of adventitial inflammation (p=0.035). In contrast, there was no difference between 18FDG-PET/CT active and inactive aortitis patients as regards the timing between PET/CT and surgery, serum CRP level (during 18FDG-PET/CT) and, FDG uptake per study site. In histologically proved aortitis, 18FDG-PET/CT before surgery did not detect vascular inflammation in 31% patients, and PETVAS score correlated with the degree of adventitial histopathologic inflammation.

Abstract 349: Segmentation Of Atherosclerotic Plaque Features From Histopathology Images Using Novel Deep Learning Techniques

Objective: Atherosclerotic plaques have a complex composition, consisting of inflammation, fibrosis, cholesterol crystals, hemorrhage, and/or calcification. The segmentation and quantification of plaque features in histopathology images form the foundation for studies evaluating plaque instability and the mechanisms that underlie the atherosclerotic process. Manual segmentation of plaque features from histology images is a tedious, time-consuming, and subjective visual recognition task. Herein, we present a fully automatic approach using state-of-the-art deep learning techniques to identify three major features of the atherosclerotic plaque: calcification, lipid core, and fibrosis. Methods: Plaques (n=70) were collected from patients who underwent a carotid endarterectomy at McGill University-affiliated hospitals. Hematoxylin and Eosin-stained sections were obtained from the region with the largest plaque burden. The “ground truth annotations” for lipid core, calcification, and fibrosis were performed manually by three blinded cardiovascular pathologists, using Sedeen Viewer. A total of 23,000 patches with 512x512 pixel size were extracted from our image dataset, and divided into train, validate, and test sets. Using Transfer Learning, multi-class U-Net models for semantic segmentation were trained on the patches to extract fibrosis, lipid, and calcification plaque features. Evaluation of model performance was based on the mean value of the Intersection over Union (Mean-IOU) between the prediction results and the “ground truth annotations”. Results: Our models resulted in an overall performance of 77% for test images, and a per-class performance for the three plaque features: fibrosis = 0.77±0.2, lipid core = 0.80±0.3, calcification = 0.75±0.25. However, a qualitative evaluation by the pathologists confirmed that the prediction results in fact outperformed the “ground truth annotations”, and detected non-annotated regions. Conclusion: To our knowledge, this is a first attempt at developing a fully automatic approach for atherosclerotic plaque feature segmentation from histology images. Our models can accelerate atherosclerosis research, by improving the speed, quality, and reproducibility of plaque analysis.

Pathological features of COVID-19-associated myocardial injury: a multicentre cardiovascular pathology study.

AimsCoronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement including elevated serum troponin levels and acute heart failure with reduced ejection fraction. The cardiac pathological changes in these patients with COVID-19 have yet to be well described.Methods and resultsIn an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists. The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry. Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement. Lymphocytic myocarditis was present in 3 (14%) of the cases. In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant. Increased interstitial macrophage infiltration was present in 18 (86%) of the cases. A mild pericarditis was present in four cases. Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases. There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified.ConclusionsIn SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases. Other forms of myocardial injury are also present in these patients. The macrophage infiltration may reflect underlying diseases rather than COVID-19.

Pathobiology of cardiovascular diseases: an update.

This article introduces the Second Special Issue of Cardiovascular Pathology (CVP), the official journal of the Society for Cardiovascular Pathology (SCVP). This CVP Special Issue showcases a series of commemorative review articles in celebration of the 25th anniversary of CVP originally published in 2016 and now compiled into a virtual collection with online access for the cardiovascular pathology community. This overview also provides updates on the major categories of cardiovascular diseases from the perspective of cardiovascular pathologists, highlighting publications from CVP, as well as additional important review articles and clinicopathologic references.

Assessment of atherosclerotic luminal narrowing of coronary arteries based on morphometrically generated visual guides.

Determination of the degree of stenosis of atherosclerotic coronary arteries is an important part of postmortem examination of the heart, but, unfortunately, estimation of the degree of luminal narrowing can be imprecise and tends to be approximations. Visual guides can be useful to assess this, but earlier attempts to develop such guides did not employ digital technology. Using this approach, we have developed two computer-generated morphometric guides to estimate the degree of luminal narrowing of atherosclerotic coronary arteries. The first is based on symmetric or eccentric circular or crescentic narrowing of the vessel lumen and the second on either slit-like or irregularly shaped narrowing of the vessel lumens. Using the Aperio ScanScope XT at a magnification of 20× we created digital whole-slide images of 20 representative microscopic cross sections of the left anterior descending (LAD) coronary artery, stained with either hematoxylin and eosin (H&E) or Movat's pentachrome stain. These cross sections illustrated a variety of luminal profiles and degrees of stenosis. Three representative types of images were selected and a visual guide was constructed with Adobe Photoshop CS5. Using the "Scale" and "Measurement" tools, we created a series of representations of stenosis with luminal cross sections depicting 20%, 40%, 60%, 70%, 80%, and 90% occlusion of the LAD branch. Four pathologists independently reviewed and scored the degree of atherosclerotic luminal narrowing based on our visual guides. In addition, digital technology was employed to determine the degree of narrowing by measuring the cross-sectional area of the 20 microscopic sections of the vessels, first assuming no narrowing and then comparing this to the percent of narrowing determined by precise measurement. Two of the observers were very experienced general autopsy pathologists, one was a first-year pathology resident on his first rotation on the autopsy service, and the fourth observer was a highly experienced cardiovascular pathologist. Interobserver reliability was assessed by determination of the intraclass correlation coefficient. The degrees of agreement for two H&E- and Movat-stained sections of the LADs from each of 10 decedents were 0.874 and 0.899, respectively, indicating strong interobserver agreement. On the average, the mean visual scores were ~8% less than the morphometric assessment (52.7 vs. 60.2), respectively. The visual guides that we have generated for scoring atherosclerotic luminal narrowing of coronary arteries should be helpful for a broad group of pathologists, from beginning pathology residents to experienced cardiovascular pathologists.

Anatomopathological changes of the cardiac conduction system in sudden cardiac death, particularly in infants: advances over the last 25 years.

Sudden cardiac death (SCD) is defined as the unexpected death without an obvious noncardiac cause that occurs within 1 h of witnessed symptom onset (established SCD) or within 24 h of unwitnessed symptom onset (probable SCD). In the United States, its incidence is 69/100,000 per year. Dysfunctions of the cardiac conduction and autonomic nervous systems are known to contribute to SCD pathogenesis, even if most clinicians and cardiovascular pathologists lack experience with detailed examination of the cardiac conduction system and fail to recognize lesions that are crucial to explain the SCD itself. In this review, we sought to describe the advances over the last 25 years in the study of the anatomopathological changes of the conducting tissue, in SCD, in mature hearts and particularly in sudden infant death syndrome (SIDS) and sudden intrauterine unexpected death syndrome (SIUDS), through the articles published in our journal Cardiovascular Pathology (CVP). We carried out an extensive Medline search to retrieve and review all articles published in CVP in which the sudden unexpected death of one or more subjects believed healthy was reported, especially if associated with lesions of the conducting tissue in settings that revealed no other explained causes of death, particularly in infants and fetuses. The cardiac conduction findings of resorptive degeneration, His bundle dispersion, Mahaim fibers, cartilaginous meta-hyperplasia, persistent fetal dispersion, left-sided His bundle, septation of the bifurcation, atrioventricular node dispersion, sinus node hypoplasia, Zahn node, His bundle hypoplasia, atrioventricular node, and His bundle dualism were similarly detected in SIDS and SIUDS victims.

Heart valve health, disease, replacement, and repair: a 25-year cardiovascular pathology perspective.

The past several decades have witnessed major advances in the understanding of the structure, function, and biology of native valves and the pathobiology and clinical management of valvular heart disease. These improvements have enabled earlier and more precise diagnosis, assessment of the proper timing of surgical and interventional procedures, improved prosthetic and biologic valve replacements and repairs, recognition of postoperative complications and their management, and the introduction of minimally invasive approaches that have enabled definitive and durable treatment for patients who were previously considered inoperable. This review summarizes the current state of our understanding of the mechanisms of heart valve health and disease arrived at through innovative research on the cell and molecular biology of valves, clinical and pathological features of the most frequent intrinsic structural diseases that affect the valves, and the status and pathological considerations in the technological advances in valvular surgery and interventions. The contributions of many cardiovascular pathologists and other scientists, engineers, and clinicians are emphasized, and potentially fruitful areas for research are highlighted.

Establishing a Multidisciplinary Network for the Workup of Sudden Cardiac Death

Sudden cardiac death (SCD) often falls under the jurisdiction of the medical examiner (ME). A recent expert consensus statement recommends cardiac evaluation for all first degree blood relatives of an individual with SCD and supports the referral of these family members to a multidisciplinary inherited arrhythmia clinic; however, most MEs lack the appropriate clinical network for a specific referral and family members are often not followed up. In 2010, Minnesota MEs and cardiovascular pathologists began collaborating with a cardiology referral center specializing in familial cardiac conditions to form a regional Sudden Death Network (SDN). The cardiac pathologists and MEs have established protocols for appropriate specimen retention in accordance with the National Association of Medical Examiners position paper on postmortem deoxyribonucleic acid (DNA) collection and for referring families for clinical evaluation. The expertise of a genetic counselor has been essential to the evaluation of these families in coordinating appropriate genetic testing and assisting with the identification of at-risk family members in extended pedigrees. This SDN uses a multidisciplinary approach for referral of family members for screening and treatment of SCD risk and represents an important resource for MEs. Development of SDNs across the country would lead to a more uniform approach to SCD follow-up and a more efficient use of clinical resources. The ME's role is essential in consulting cardiac pathologists when needed, establishing the correct diagnosis, collecting and retaining appropriate specimens, and initiating the referral of at-risk family members to specialists.

In memoriam: Jack L. Titus, M.D., Ph.D., 1926–2011

Jack L. Titus, M.D., Ph.D., passed away in North Oaks, MN, after a long illness on June 15, 2011, at the age of 84 (Fig. 1). I will miss Jack as a friend and as a highly respected colleague and collaborator, who had a long and distinguished career. He was for me the ideal mentor at an extremely pivotal stage of my career, and we continued to be close, sharing many professional and other interests as my career continued to develop. He trained and collaborated with numerous other cardiovascular pathologists, many of whom themselves have made important contributions to the field. I and the many others he touched have lost an important leader in academic medicine and pathology, nationally and internationally, and a giant in the world of cardiovascular pathology. Born in South Bend, IN, Dec. 7, 1926, Dr. Titus entered the University of Notre Dame at the age of 16, then was called to serve as a sergeant in Germany during WWII. In 1948, he graduated cum laude from Notre Dame, receiving a Bachelor of Science in 1948. He matriculated at the Washington University School of Medicine in St. Louis receiving his M.D. degree in 1952. Following internship at the Wayne County Hospital in Detroit, MI, and subsequently general medical practice in Rensselaer, IN, from 1953 to 1957, he decided to pursue a career in anatomic and clinical pathology. He was accepted as a resident in the Mayo Foundation and Graduate School at the University of Minnesota, serving from 1957 to 1961, and he became board certified in Anatomic and Clinical Pathology. Dr. Titus earned a Ph.D., degree in pathology from the University of Minnesota, Mayo Graduate School of Medicine in 1962 (under the mentorship of Jesse E.

Quo Vadis? The Society for Cardiovascular Pathology over the next 25 years and beyond

Cardiovascular pathology is a subspecialty of anatomic pathology that requires both clinical education and expertise in contemporary physiopathology. The Society for Cardiovascular Pathology sponsored a special workshop within the frame of the USCAP Annual Meeting, held in Vancouver, March 6–12, 2004, to address the present and future role of cardiovascular pathology in research, clinical care, and education. Clearly, the recruitment and training of young pathologists are crucial to this aim. The forum tried to answer a series of questions. First, is there room for cardiovascular pathologists and clinicopathologic correlations in the era of extraordinary advances of in vivo human body imaging? What is the evolving role of the autopsy? How can the cardiovascular pathologist simultaneously be an autopsy prosector, a surgical pathologist, a molecular pathologist, and an experimental pathologist? Is there a specific domain content for training in cardiovascular pathology and does it meet the constellation of market needs and demands? What are the experiences in Europe, North America and elsewhere? What is the influence of cardiovascular pathology in departments of pathology? Is the subdiscipline still a Cinderella in the anatomic theatre or a Princess with a double helix coat of arms? The Society for Cardiovascular Pathology is strongly committed to optimizing the academic and professional profile of the future generation of cardiovascular pathologists. This article reports the outcome of the forum and directions that may lead to a vibrant future for well-trained cardiovascular pathologists.

AECVP and SCVP 2009 Recommendations for Training in Cardiovascular Pathology

Cardiovascular disease is of continuing importance as the result of a growing burden of risk factors in both developing and developed countries and the increasing number of elderly people worldwide. The recruitment and training of a new generation of Cardiovascular Pathologists is crucial to sustaining clinical excellence and to advancing our knowledge of cardiovascular disease. These pathologists will also have a key role in undergraduate and postgraduate training. In 2005 a task force of the Society for Cardiovascular Pathology published a document on the role of Cardiovascular Pathology as subspecialty of Anatomical Pathology (Pathological Anatomy). The 2005 report emphasized the need for a core curriculum and structured learning for residents and fellows in Cardiovascular Pathology. This new consensus statement on training is the result of collaboration between Cardiovascular Pathology Societies based in Europe and North America. It includes a detailed curriculum and describes three levels of expertise that can be developed.

Minimally invasive valve surgery: What the pathologist should know

Minimally invasive approaches in cardiac surgery have emerged as an alternative to standard techniques particularly in patients undergoing valvular surgery. Their established benefits for the patients are likely to cause their widespread use in the future. The purpose of this is to provide an overview of modern minimally invasive approaches in valvular surgery with an emphasis on aspects of the surgery relevant for cardiovascular pathologists.

Editorial: “Longitudinal changes in risk variables of insulin resistance syndrome from childhood to young adulthood in offspring of parents with type 2 diabetes: The Bogalusa Heart Study” by Srinivasan et al

The Bogalusa Heart Study is a biracial (black and white) community-based investigation of the origins of cardiovascular disease which focuses on children, adolescents, and young adults using a multidisciplinary approach. This Study is a medical research treasure in which the investigators are systematically elucidating the origins of our country's major cause of death. Cardiovascular pathologists, clinicians, and epidemiologists have the overall goals to determine, at the earliest possible age, improved cardiovascular risk analyses, treatment paradigms, and, in the end, the prevention of cardiovascular diseases.

The histologic estimation of coronary artery stenoses: Accuracy and the effect of lumen shape

The authors have recently investigated the histologic estimation of coronary artery stenoses (CAS) to determine its reproducibility and the effect of training on reproducibility. The present study extends this work, examining the accuracy, the sensitivity, and the specificity of the estimation of CAS. Further, the effect of one histologic variable (i.e., arterial lumen shape) on the evaluation of CAS is examined. As described previously, 20 randomly selected Movat-stained coronary artery cross-sections were reviewed three times, at 3-month intervals, by six clinical pathologists (CPs), six pathology residents (Res), seven anatomic pathologists (APs), and two cardiovascular pathologists (CVPs). Before the third iteration, training in CAS assessment was provided. In the present study, for comparison with observer estimates, image analysis was used to establish the actual percent CAS and determine observer accuracy. The results of this study showed, paradoxically, that greater experience did not correlate with greater accuracy: The CPs consistently had the highest accuracy scores and the CVPs consistently had the lowest. Training, however, improved the accuracy scores of all groups. Stenotic arterial cross-sections with residual lumens showing concentric or eccentric polymorphous shapes were consistently underestimated compared to image analysis, while lumens with a eccentric slitlike shape were consistently overestimated.

Histologic Estimation of Coronary Artery Stenoses: Reproducibility and the Effect of Training

Histologic estimation of coronary artery stenoses (CAS) provides the ‘gold-standard’ for clinicopathologic correlations and medicolegal investigations, yet little evidence supports histology as a reproducible diagnostic measure, and none addresses the effect of training on its use. To study these questions, 20 randomly selected Movat-stained coronary artery cross-sections were reviewed 3 times, at 3-month intervals, by six clinical pathologists (CPs), six pathology residents (Res), seven anatomic pathologists (APs), and two cardiovascular pathologists (CVPs). Before the third iteration, a guide to CAS assessment with illustrations was provided. Inter- and intraobserver reproducibility were determined using interclass correlation coefficients (ICC) (0.40–0.75 = fair–good; ≥0.76 = excellent agreement beyond chance). Surprisingly, all study groups had excellent interobserver reproducibility. Before training, at Time 1, the scores were CPs, 0.77; Res, 0.89; APs, 0.93; and CVPs, 0.93. After training, at Time 3, the results were CPs, 0.81; Res, 0.91; APs, 0.86; and CVPs, 0.88. Intraobserver reproducibility for CPs overall was good (ICC, 0.74), and excellent for Res, APs, and CVPs (0.89, 0.94, and 0.97, respectively). In conclusion, statistical analysis failed to demonstrate any significant effect of training or experience on observer reproducibility.

The Pathology of Congenital Heart Disease: A Personal Experience With More Than 6300 Congenitally Malformed Hearts

As leaders in a small cadre of cardiovascular clinicians and pathologists with a comprehensive understanding of and experience in the morphology of congenital heart disease, Dr Bharati (over 25 years) and the late Dr Lev (over 60 years) have made immense contributions. This impressive, informative, and richly illustrated two-volume work of more than 1500 pages summarizes their experience with the evaluation of over 6300 hearts. The book has two major sections. The first, only 64 pages long, has nine chapters describing general concepts of external and internal cardiac functional anatomy, embryology, terminology, and methods of examination. The second section has approximately 40 chapters of varying length and complexity, nearly all devoted to specific disease entities. The initial and largest disease-oriented chapter, on tetralogy of Fallot, has 66 pages and 154 illustrations, describing both simple and complex, acyanotic and cyanotic types, with individual consideration of the aorta, pulmonary tract, ventricular septal