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* Context.--Distinguishing true antemortem thrombus (AMT) from artifactual postmortem clot (PMC) can occasionally be challenging at autopsy. Lines of Zahn are cited as pathognomonic of AMT, but review of literature reveals heterogeneous definitions of the term. Neutrophil karyorrhexis and CD61 immunohistochemistry can also be used to define AMT, but there has been no systematic study determining the specificity of these features. Objective.--To identify features that distinguish AMT from PMC, and to clarify the definition of lines of Zahn. Design.--PMC from the heart was collected in 50 hospital autopsies. Fifty arterial and 50 venous surgical thrombectomy specimens were reviewed for comparison. The microscopic features with hematoxylin-eosin staining, phosphotungstic acid-hematoxylin (PTAH) staining, and CD61 immunohistochemistry were documented. Results.--Thin curvilinear strands of fibrin and clumps of fibrin were frequently observed in both AMT and PMC. Thick bands of nested platelets wrapped in fibrin were nearly exclusive to AMT. Neutrophil karyorrhexis was readily apparent on low power in AMT but was seen in 40 of 50 PMCs (80%) only sparsely on high-power examination. Bone marrow elements were identified in 38 of 50 PMCs (76%). CD61 staining showed a geographic pattern in AMT and a speckled pattern in PMC. PTAH staining confirmed features seen with hematoxylin-eosin. Conclusions.--Thin curvilinear strands of fibrin are found in both AMT and PMC and can be misinterpreted as lines of Zahn. We define lines of Zahn as thick bands formed by nested platelets wrapped in fibrin. Diffuse neutrophil karyorrhexis is common in AMT; in contrast, bone marrow elements are often seen in PMC. doi: 10.5858/arpa.2022-0147-OA), Distinguishing antemortem thrombus (AMT) from postmortem clot (PMC) is of critical importance for autopsy pathologists. True thrombi or thromboemboli can cause or contribute to death, while PMC has no clinical [...]

Post-translational modification and functional impairment of proteins through carbamylation is thought to promote vascular dysfunction during end-stage renal disease. Cyanate, a reactive species in equilibrium with urea, carbamylates protein lysine residues to form [epsilon]-carbamyllysine (homocitrulline), altering protein structure and function. We now report the discovery of an alternative and quantitatively dominant mechanism for cyanate formation and protein carbamylation at sites of inflammation and atherosclerotic plaque: myeloperoxidase-catalyzed oxidation of thiocyanate, an anion abundant in blood whose levels are elevated in smokers. We also show that myeloperoxidase-catalyzed lipoprotein carbamylation facilitates multiple pro-atherosclerotic activities, including conversion of low-density lipoprotein into a ligand for macrophage scavenger receptor A1 recognition, cholesterol accumulation and foam-cell formation. In two separate clinical studies (combined n = 1,000 subjects), plasma levels of protein-bound homocitrulline independently predicted increased risk of coronary artery disease, future myocardial infarction, stroke and death. We propose that protein carbamylation is a mechanism linking inflammation, smoking, uremia and coronary artery disease pathogenesis., Author(s): Zeneng Wang [1]; Stephen J Nicholls [1, 2]; E Rene Rodriguez [3]; Outi Kummu [4]; Sohvi Horkko [4]; John Barnard [5]; Wanda F Reynolds [6]; Eric J Topol [2, [...]

Sustained cardiac pressure overload induces hypertrophy and pathological remodeling, frequently leading to heart failure. Genetically engineered hyperstimulation of guanosine 3',5'-cyclic monophosphate (cGMP) synthesis counters this response. Here, we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase-5A (PDE5A) inhibitor (sildenafil) suppresses chamber and myocyte hypertrophy, and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction. Sildenafil also reverses pre-established hypertrophy induced by pressure load while restoring chamber function to normal. cGMP catabolism by PDE5A increases in pressure-loaded hearts, leading to activation of cGMP-dependent protein kinase with inhibition of PDE5A. PDE5A inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load (the calcineurin/NFAT, phosphoinositide-3 kinase (PI3K)/Akt, and ERK1/2 signaling pathways). But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo, suggesting upstream targeting of these pathways. PDE5A inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling., Author(s): Eiki Takimoto [1, 5]; Hunter C Champion [1, 5]; Manxiang Li [1, 5]; Diego Belardi [1]; Shuxun Ren [2]; E Rene Rodriguez [3]; Djahida Bedja [4]; Kathleen L Gabrielson [...]

Inflammation has been recognized increasingly as a critical pathologic component of a number of heart diseases. A mouse model of autoimmune myocarditis was developed to study the role of immune mediators in the development of cardiac dysfunction. We have found previously that IFN-[gamma] deficiency promotes inflammation in murine myocarditis, it has been unclear, however, how IFN-[gamma] deficiency in myocarditis affects cardiac function and what underlying immune mechanisms are responsible for these effects. In this work, we show that IFN-[gamma] knockout (KO) mice have more pronounced systolic and diastolic dysfunction and greater frequency of progression to dilated cardiomyopathy and heart failure compared with WT mice. Cardiac dysfunction in the KO mice is associated with the expansion of activated (CD[44.sup.high]) CD[3.sup.+] T cells due to reduced apoptosis of CD[4.sup.+], but not CD[8.sup.+], T cells. CD[4.sup.+] T cells in the KO mice show impaired up-regulation of CD25 upon activation, resulting in the expansion of CD[4.sup.+]CD[44.sup.+]CD[25.sup.-] T cells and their infiltration into the heart. CD[4.sup.+]CD[25.sup.-] T cells are less apoptosis-prone compared with the CD[25.sup.+] population, and their infiltration into the heart is associated with greater severity of myocarditis. We conclude that IFN-[gamma] deficiency in autoimmune myocarditis is associated with preferential expansion of CD[4.sup.+]CD[44.sup.+]CD[25.sup.-] T cells resulting in increased cardiac inflammation. An exaggerated inflammatory response in IFN-[gamma] KO mice causes cardiac dysfunction, leading to dilated cardiomyopathy and heart failure. activation-induced cell death | autoimmunity | pressure-volume relations

Mitral annular calcification (MAC) refers to calcium deposition in the fibrous skeleton of the mitral valve. It has many cardiovascular associations, including mitral valve dysfunction, elevated cardiovascular risk, arrhythmias, and endocarditis. Echocardiography conventionally is the first-line imaging modality for anatomic assessment, and evaluation of mitral valve function. Cardiac computed tomography (CT) has demonstrated importance as an imaging modality for the evaluation and planning of related procedures. It also holds promise in quantitative grading of MAC. Currently, there is no universally accepted definition or classification system of MAC severity. We review the multimodality imaging evaluation of MAC and associated valvular dysfunction and propose a novel classification system based on qualitative and quantitative measurements derived from echocardiography and cardiac CT. [ABSTRACT FROM AUTHOR]

Author(s): Lili A. Barouch [1, 2]; Robert W. Harrison [1, 2]; Michel W. Skaf [1, 2]; Gisele O. Rosas [1]; Thomas P. Cappola [1]; Zoulficar A. Kobeissi [1]; Ion A. [...]

* Context.--Endovascular infection is an uncommon but devastating manifestation of histoplasmosis, which is often diagnosed late in disease. Objectives.--To evaluate the clinical and pathologic characteristics of patients with endovascular infections caused by Histoplasma capsulatum. Design.--All cases of patients with documented endovascular histoplasmosis at a single tertiary care center in an endemic region during the period 1993-2010 were reviewed. Results.--Patients presented with a subacute febrile illness and a history of endovascular devices. All patients had positive Histoplasma serology. Routine bacterial culture results were negative for all patients. In addition to yeast forms typical of histoplasmosis, pathologic findings also revealed mycelial forms in 4 of 5 patients. Inflammation was scant. Urinary antigen detection was positive in 4 of 5 patients and Histoplasma blood culture results were positive for 3 of 5 patients. Four patients were treated with a combination of surgical and medical therapy, which consisted of amphotericin B followed by itraconazole; these 4 patients had complete resolution of symptoms and no documented relapse. One patient died before planned surgery. Conclusions.--Histoplasma capsulatum endovascular infections are clinically characterized by a subacute febrile illness with negative bacterial cultures in patients with prosthetic endografts or valves. Noninvasive diagnostics are often the initial clue to the diagnosis. Combined medical and surgical treatment is associated with survival. On histopathologic examination both mycelial and yeast forms are often observed, with absent to minimal tissue inflammatory reaction. (Arch Pathol Lab Med. 2012; 136:640-645; doi: 10.5858/arpa.2011-0050-OA), Histoplasma capsulatum var capsulatum, hereafter referred to as H capsulatum, is a thermally dimorphic fungus that is endemic in certain areas in the Americas, notably the Mississippi and Ohio River [...]

* Fistulas between the aorta and tracheobronchial tree are rare fatal complications that occur in patients treated with external and endobronchial radiation for carcinomas of the upper and lower respiratory tract. The etiopathogenesis can be multifactorial. We report the case of a patient with irradiated tracheal carcinoma who died of massive hemoptysis 25 months after completing therapy. Autopsy revealed a fistula between the trachea and arch of the aorta. Multiple colonies of cocci and bacilli were demonstrated within the media at the site of rupture and were absent in other areas of the aorta. The development of an aortotracheal fistula in this patient was most probably related to infection in an area of tracheal and vascular wall previously damaged by exposure to high doses of radiation., Fistulas between the aorta and the tracheobronchial tree often arise as a complication in the setting of aortic atherosclerotic aneurysms or previous thoracic vascular surgery. (1,2) While the pathology in [...]

Context.--The endomyocardial biopsy is the mainstay for monitoring acute allograft rejection in heart transplantation. Objective and accurate assessment of cellular and humoral types of rejection is important to optimize immunosuppressive therapy, avoid therapeutic complications, and improve patient outcome. The grading system for evaluation of heart transplant biopsies published in 1990 was revised in 2004 after more than a decade of implementation. Objective.--In this review, we focus on a practical approach to the evaluation of human heart transplant biopsies as diagnostic surgical pathologic specimens. We discuss the revised International Society of Heart and Lung Transplantation working formulation. Data Sources.--We reviewed pertinent literature, incorporating ideas and vast experience of participants in various work groups that led to the revision of the 1990 grading system. Conclusions.--The grading system for cellular rejection is presented with detailed light microscopic morphology and comparison of the 1990 and 2004 International Society of Heart and Lung Transplantation working formulations. We show how the pathologic recognition of cellular rejection and antibody-mediated rejection has evolved. We emphasize the interpretation of immunostains for complement components C4d and C3d in the diagnosis of antibody-mediated rejection. Evidence of regulation of complement activation in human heart transplant biopsies is presented in this context. We also discuss the pitfalls, caveats, and artifacts in the interpretation of allograft endomyocardial biopsies. Lastly, we discuss the pathology of human cardiac allograft vasculopathy in practical detail. (Arch Pathol Lab Med. 2007;131:1169-1191), Heart transplantation remains the most effective therapy for end-stage heart disease of coronary and noncoronary etiology, with continued improvement in survival during the years. The most common indications for cardiac [...]