Application of postmortem imaging modalities in cases of sudden death due to cardiovascular diseases-current achievements and limitations from a pathology perspective : Endorsed by the Association for European Cardiovascular Pathology and by the International Society of Forensic Radiology and Imaging.

Postmortem imaging (PMI) is increasingly used in postmortem practice and is considered a potential alternative to a conventional autopsy, particularly in case of sudden cardiac deaths (SCD). In 2017, the Association for European Cardiovascular Pathology (AECVP) published guidelines on how to perform an autopsy in such cases, which is still considered the gold standard, but the diagnostic value of PMI herein was not analyzed in detail. At present, significant progress has been made in the PMI diagnosis of acute ischemic heart disease, the most important cause of SCD, while the introduction of postmortem CT angiography (PMCTA) has improved the visualization of several parameters of coronary artery pathology that can support a diagnosis of SCD. Postmortem magnetic resonance (PMMR) allows the detection of acute myocardial injury-related edema. However, PMI has limitations when compared to clinical imaging, which severely impacts the postmortem diagnosis of myocardial injuries (ischemic versus non-ischemic), the age-dating of coronary occlusion (acute versus old), other potentially SCD-related cardiac lesions (e.g., the distinctive morphologies of cardiomyopathies), aortic diseases underlying dissection or rupture, or pulmonary embolism. In these instances, PMI cannot replace a histopathological examination for a final diagnosis. Emerging minimally invasive techniques at PMI such as image-guided biopsies of the myocardium or the aorta, provide promising results that warrant further investigations. The rapid developments in the field of postmortem imaging imply that the diagnosis of sudden death due to cardiovascular diseases will soon require detailed knowledge of both postmortem radiology and of pathology.

Coronial postmortem reports and indirect COVID-19 pandemic-related mortality.

AIMS: Widespread disruption of healthcare services and excess mortality not directly attributed to COVID-19 occurred between March and May 2020. We undertook the first UK multicentre study of coroners' autopsies before and during this period using postmortem reports. METHODS: We reviewed reports of non-forensic coroners' autopsies performed during the first COVID-19 lockdown (23 March to 8 May 2020), and the same period in 2018. Deaths were categorised as natural non-COVID-19, COVID-19-related, non-natural (suicide, drug and alcohol-related, traumatic, other). We provided opinion regarding whether delayed access to medical care or changes in behaviour due to lockdown were a potential factor in deaths. RESULTS: Seven centres covering nine coronial jurisdictions submitted a total of 1100 coroners' autopsies (498 in 2018, 602 in 2020). In only 54 autopsies was death attributed to COVID-19 (9%). We identified a significant increase in cases where delays in accessing medical care potentially contributed to death (10 in 2018, 44 in 2020). Lockdown was a contributing factor in a proportion of suicides (24%) and drug and alcohol-related deaths (12%). CONCLUSIONS: Postmortem reports have considerable utility in evaluating excess mortality due to healthcare and wider societal disruption during a pandemic. They provide information at an individual case level that is not available from assessment of death certification data. Detailed evaluation of coroners' autopsy reports, supported by appropriate regulatory oversight, is recommended to mitigate disruption and indirect causes of mortality in future pandemics. Maintaining access to healthcare, including substance misuse and mental health services, is an important consideration.

Excision of a rare cardiac tumor aided by endocardial electroanatomical mapping.

Glomus tumors are rare benign soft tissue lesions, most commonly found on the skin. They are an extremely rare cause of the cardiac tumor. We report a case of right atrial glomus tumor excised using a novel technique utilizing cardiac electroanatomical mapping techniques ordinarily used for arrhythmia surgery.

Digital pathology for intraoperative frozen section diagnosis of thoracic specimens: an evaluation of a system using remote sampling and whole slide imaging diagnosis.

BACKGROUND: Digital pathology is now used for primary diagnostic work as well as teaching, research and consultation. In our multisite institution service reorganisation led to histopathology being located in a separate hospital from some surgical specialities. We implemented remotely supervised specimen sampling and frozen section diagnosis using digital pathology. In this study we assessed the concordance of glass and digital slide diagnosis using this system. METHODS: We reviewed cases from the first 2 years of digital frozen section reporting at our institution. Cases with potential digital to glass slide discordance were reviewed by three experienced thoracic histopathologists. The reasons for discordance were determined and common themes identified. We also reviewed critical incidents relating to digital pathology during the study period. RESULTS: The study population comprised 211 cases. Frozen section to final diagnosis concordance between digital and glass slide diagnosis was found in 196 (92.6%) cases. The 15 potentially discordant cases were reviewed. Intraobserver concordance between glass and digital slide review ranged from 9/15 to 12/15 cases across the three pathologists. Glass slide review diagnosis showed better concordance with ground truth in two cases; digital slide review was more accurate in two cases. One relevant critical incident was identified during the study period. DISCUSSION: This is the largest study to examine digital pathology for thoracic frozen section diagnosis and shows that this is a safe and feasible alternative to glass slide diagnosis. Discordance between digital and glass slide diagnoses were unrelated to the processes of whole slide imaging and digital microscopy.

Myeloid Tribbles 1 induces early atherosclerosis via enhanced foam cell expansion.

Macrophages drive atherosclerotic plaque progression and rupture; hence, attenuating their atherosclerosis-inducing properties holds promise for reducing coronary heart disease (CHD). Recent studies in mouse models have demonstrated that Tribbles 1 (Trib1) regulates macrophage phenotype and shows that Trib1 deficiency increases plasma cholesterol and triglyceride levels, suggesting that reduced TRIB1 expression mediates the strong genetic association between the TRIB1 locus and increased CHD risk in man. However, we report here that myeloid-specific Trib1 (mTrib1) deficiency reduces early atheroma formation and that mTrib1 transgene expression increases atherogenesis. Mechanistically, mTrib1 increased macrophage lipid accumulation and the expression of a critical receptor (OLR1), promoting oxidized low-density lipoprotein uptake and the formation of lipid-laden foam cells. As TRIB1 and OLR1 RNA levels were also strongly correlated in human macrophages, we suggest that a conserved, TRIB1-mediated mechanism drives foam cell formation in atherosclerotic plaque and that inhibiting mTRIB1 could be used therapeutically to reduce CHD.

Histamine H4 receptor mediates chemotaxis of human lung mast cells.

The diverse effects of histamine are mediated by discrete histamine receptors. The principal repository of histamine in the body is the mast cell. However, the effects of histamine on mast cells, especially those of human origin, have not been fully elucidated. In this study, the expression of histamine receptors in human lung mast cells was evaluated. Moreover, the effects of histamine receptor engagement on both mediator release and chemotaxis were investigated. Mast cells were isolated and purified from human lung tissue. Histamine receptor expression was determined by RT-PCR and q-PCR. Both methods for the detection of histamine receptors were in accordance and human lung mast cells expressed mRNA for histamine H4 and histamine H1 receptors, variably expressed histamine H2 receptor but did not express histamine H3 receptor. The effects of selective histamine receptor agonists on the release of both pre-formed (histamine) and newly-synthesised (cysteinyl-leukotriene, prostaglandin D2) mediators were investigated. None of the agonists tested had any direct effects on mediator release. None of the agonists modulated release stimulated by anti-IgE. Further studies showed that histamine induced migration of mast cells. Chemotaxis appeared to be mediated by the histamine H4 receptor since JNJ28610244 (H4 agonist) was chemotactic for mast cells whereas 2-(2-pyridyl) ethylamine (H1 agonist) was not. Furthermore, the selective histamine H4 receptor antagonist, JNJ7777120, effectively reversed the chemotaxis of mast cells induced by JNJ28610244. Overall, these experiments identify the histamine H4 receptor as chemotactic for human lung mast cells. This mechanism might influence mast cell accumulation in the lung.

Spindle cell sarcoma of the mitral valve: a rare indication for mitral valve replacement.

Primary cardiac tumours are a rare finding and even rarer cause of valvular heart disease. We report a case of cardiac spindle cell sarcoma mimicking mitral valve stenosis and the subsequent operative management.

Prostaglandin D2 generation from human lung mast cells is catalysed exclusively by cyclooxygenase-1.

Mast cells are an exceptionally rich source of prostaglandin D2 (PGD2). PGD2 is pro-inflammatory and can cause bronchoconstriction. The enzyme cyclooxygenase (COX) is central to the generation of prostanoids such as PGD2. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX. COX exists as two isoforms, COX-1 and COX-2. The principal aim of this study was to establish whether COX-1 and/or COX-2 mediates PGD2 generation from human lung mast cells. Mast cells were isolated from human lung tissue and purified by flotation over Percoll and immunomagnetic bead separations. The cells were activated with anti-IgE or Stem Cell Factor (SCF). The generation of PGD2 was determined by ELISA. The effects of NSAIDs (aspirin, ibuprofen, diclofenac, naproxen, indomethacin), COX-1 selective (FR122047), and COX-2 selective (celecoxib) inhibitors on PGD2 generation were determined. The expression of COX-1 and COX-2 in mast cells was determined by Western blotting. All the NSAIDs tested abrogated stimulated PGD2 generation from mast cells except aspirin which was only weakly effective. FR122047 was an effective inhibitor of PGD2 generation (EC50 ~25nM) from mast cells whereas celecoxib was ineffective. Immunoblotting indicated that COX-1 was strongly expressed in all mast cell preparations while COX-2 expression was weak. No induction of COX-2 was observed following activation of mast cells. These findings indicate that COX-1 is the principal isoform involved in generating PGD2 from human lung mast cells. These studies provide insight into the potential behaviour of NSAIDs in the context of respiratory diseases.

Multi-elemental analysis of human lung samples using inductively coupled plasma mass spectrometry.

The aim of this study was to establish concentrations of a wide range of elements in human lung samples to allow better identification of potential exposures in subsequent cases. This study reports concentrations of 48 elements (Al, As, Au, B, Ba, Be, Bi, Br, Cd, Ce, Co, Cr, Cs, Cu, Fe, Ga, Gd, Ge, Hf, Hg, In, Li, Mn, Mo, Nb, Ni, Os, Pb, Pd, Pt, Rb, Re, Ru, Sb, Se, Sm, Sn, Sr, Ta, Te, Ti, Tl, Tm, V, W, Y, Zn and Zr) in fresh lung tissue samples from 54 hospital patients, of which 93% exhibited various forms of neoplasia. The lung samples were taken from unaffected, background tissue. The samples were stored as fresh tissue in alcohol, dried and microwave digested before analysis by inductively coupled mass spectrometry (ICP-MS). It was possible to establish 95th percentiles for all elements except for rhenium and for 40 elements mixed effects modelling was undertaken. Overall, the levels reported are commensurate with ranges for those elements that had been reported previously. The data were examined for gender, smoking and occupational exposures to metals. The results show that males have higher lung concentrations of Ni, Cr, Gd, Au and Be than females, but significantly lower lung concentrations of Co, Sn, W and In. Cadmium lung concentrations were significantly higher in smokers. Platinum lung concentrations were higher in those who had undergone chemotherapy and gadolinium concentrations were predictably high in those who had undergone imaging scans. More essential elements such as Cu, Br, Fe and also Ge varied the least within lung samples from individuals whilst Be, Hf and Pt had the greatest variances. Between individuals V and Li lung concentrations varied the most, whilst Cu varied least. Analysis of the data for those who reported as having previously worked with metals showed 24 of the 48 elements determined were higher than those from those who had not reported working with metals.

Evaluation of the anti-inflammatory effects of ß-adrenoceptor agonists on human lung macrophages.

The principal mechanism by which bronchodilator ß-adrenoceptor agonists act is to relax airways smooth muscle although they may also be anti-inflammatory. However, the extent of anti-inflammatory activity and the cell types affected by these agonists are uncertain. The purpose of this study was to evaluate whether ß-adrenoceptor agonists prevent pro-inflammatory cytokine generation from activated human lung macrophages. Macrophages were isolated and purified from human lung. The cells were pre-treated with both short-acting (isoprenaline, salbutamol, terbutaline) and long-acting (formoterol, salmeterol, indacaterol) ß-agonists before activation with lipopolysaccharide (LPS) to induce cytokine (TNFα, IL-6, IL-8 and IL-10) generation. The experiments showed that short-acting ß-agonists were poor inhibitors of cytokine generation. Of the long-acting ß-agonists studied, formoterol was also a weak inhibitor of cytokine generation whereas only indacaterol and salmeterol showed moderate inhibitory activity. Further experiments using the ß2-adrenoceptor antagonist ICI-118,551 suggested that the effects of indacaterol were likely to be mediated by ß2-adrenoceptors whereas those of salmeterol were not. These findings were corroborated by functional desensitization studies in which the inhibitory effects of indacaterol appeared to be receptor-mediated whereas those of salmeterol were not. Taken together, the data indicate that the anti-inflammatory effects of ß-adrenoceptor agonists on human lung macrophages are modest.

Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association For European Cardiovascular Pathology: II. Noninflammatory degenerative diseases - nomenclature and diagnostic criteria.

Surgical aortic specimens are usually examined in Pathology Departments as a result of treatment of aneurysms or dissections. A number of diseases, genetic syndromes (Marfan syndrome, Loeys-Dietz syndrome, etc.), and vasculopathic aging processes involved in vascular injury can cause both distinct and nonspecific histopathologic changes with degeneration of the media as a common denominator. Terminology for these changes has varied over time leading to confusion and inconsistencies. This consensus document has established a revised, unified nomenclature for the variety of noninflammatory degenerative aortic histopathologies seen in such specimens. Older terms such as cystic medial necrosis and medionecrosis are replaced by more technically accurate terms such as mucoid extracellular matrix accumulation (MEMA), elastic fiber fragmentation and/or loss, and smooth muscle cell nuclei loss. A straightforward system of grading is presented to gauge the extent of medial degeneration and synoptic reporting tables are provided. Herein we present a standardized nomenclature that is accessible to general pathologists and useful for future publications describing these entities.

Pulmonary artery denervation reduces pulmonary artery pressure and induces histological changes in an acute porcine model of pulmonary hypertension.

BACKGROUND: Pulmonary arterial hypertension is a devastating disease with high morbidity and mortality and limited treatment options. Recent studies have shown that pulmonary artery denervation improves pulmonary hemodynamics in an experimental model and in an early clinical trial. We aimed to evaluate the nerve distribution around the pulmonary artery, to determine the effect of radiofrequency pulmonary artery denervation on acute pulmonary hypertension induced by vasoconstriction, and to demonstrate denervation of the pulmonary artery at a histological level. METHODS AND RESULTS: Histological evaluation identified a circumferential distribution of nerves around the proximal pulmonary arteries. Nerves were smaller in diameter, greater in number, and located in closer proximity to the luminal aspect of the pulmonary arterial wall beyond the pulmonary artery bifurcation. To determine the effect of pulmonary arterial denervation acute pulmonary hypertension was induced in 8 pigs by intravenous infusion of thromboxane A2 analogue. Animals were assigned to either pulmonary artery denervation, using a prototype radiofrequency catheter and generator, or a sham procedure. Pulmonary artery denervation resulted in reduced mean pulmonary artery pressure and pulmonary vascular resistance and increased cardiac output. Ablation lesions on the luminal surface of the pulmonary artery were accompanied by histological and biochemical alteration in adventitial nerves and correlated with improved hemodynamic parameters. CONCLUSIONS: Pulmonary artery denervation offers the possibility of a new treatment option for patients with pulmonary arterial hypertension. Further work is required to determine the long-term efficacy and safety.

Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases.

Inflammatory diseases of the aorta include routine atherosclerosis, aortitis, periaortitis, and atherosclerosis with excessive inflammatory responses, such as inflammatory atherosclerotic aneurysms. The nomenclature and histologic features of these disorders are reviewed and discussed. In addition, diagnostic criteria are provided to distinguish between these disorders in surgical pathology specimens. An initial classification scheme is provided for aortitis and periaortitis based on the pattern of the inflammatory infiltrate: granulomatous/giant cell pattern, lymphoplasmacytic pattern, mixed inflammatory pattern, and the suppurative pattern. These inflammatory patterns are discussed in relation to specific systemic diseases including giant cell arteritis, Takayasu arteritis, granulomatosis with polyangiitis (Wegener's), rheumatoid arthritis, sarcoidosis, ankylosing spondylitis, Cogan syndrome, Behçet's disease, relapsing polychondritis, syphilitic aortitis, and bacterial and fungal infections.

Oral presentation of malignant mesothelioma.

We report a case of metastatic mesothelioma presenting as an oral metastasis in a 46-year-old patient. The patient presented with 2 polypoid lesions that appeared to be benign on the dorsum of the tongue. Excisional biopsy showed the presence of metastatic carcinoma that on further investigation proved to be mesothelioma. The initial presentation of mesothelioma as an oral metastasis is not previously reported. This article highlights the importance of biopsy and histopathological diagnosis in presumed benign lesions and the role of the general dental practitioner in screening for oral neoplasms.

Influence of beta2-adrenoceptor gene polymorphisms on beta2-adrenoceptor expression in human lung.

BACKGROUND: The aim of the present study was to establish whether polymorphisms, especially those within the promoter region, of the beta(2)-adrenoceptor gene (ADRB2) influence beta(2)-adrenoceptor expression in human lung. METHODS: The density of beta-adrenoceptors in human lung tissue (n=88) was determined by saturation binding using the radioligand, iodinated cyanopindolol. Discrimination of beta(1)- and beta(2)-adrenoceptors was determined using the highly selective beta(1)-adrenoceptor antagonist, CGP20712A. Genotype was determined at 5 positions of ADRB2 previously reported as polymorphic. Potential influences of single nucleotide polymorphisms (SNPs) within the promoter region (-367, -47) and coding block (46, 79, 491) of ADRB2 on beta(2)-adrenoceptor expression were investigated. RESULTS: The density of beta(2)-adrenoceptors was variable among the 88 lung preparations studied ranging from 17 to 177fmol/mg protein (mean+/-S.E.M., 72+/-4fmol/mg protein). There was no influence of genotype on beta(2)-adrenoceptor expression for any of the polymorphisms studied except at position 491. The polymorphism at position 491C>T, leading to a change from thr to ile at amino acid 164, is uncommon. Preparations genotyped as heterozygous (126+/-15fmol/mg protein; n=5) expressed significantly (P=0.0005) higher levels of beta(2)-adrenoceptor than those that were homozygous (69+/-4fmol/mg protein; n=83). CONCLUSION: With the exception of position 491, these data indicate that polymorphisms of ADRB2 do not influence beta(2)-adrenoceptor expression in human lung.

Flat adenomas in a colonic bladder augmentation patch: cystoscopic removal using an endoscopic mucosal resection technique.

Bladder augmentation using colonic patches is being increasingly performed and a substantial risk of neoplasia in such patches has been reported. We present the case of a 62-year-old man who developed a large flat adenoma in the colonic mucosa of an augmented bladder. The adenoma was indigo-carmine dye sprayed and completely resected via a cystoscope using an endoscopic mucosal resection technique. We discuss how methods used at colonoscopy to detect and remove early neoplastic lesions may readily be employed during colonic patch surveillance at cystoscopy.

Administration of the stress protein gp96 prolongs rat cardiac allograft survival, modifies rejection-associated inflammatory events, and induces a state of peripheral T-cell hyporesponsiveness.

High-dose gp96 has been shown to inhibit experimental autoimmune disease by a mechanism that appears to involve immunoregulatory CD4+ T cells. This study tested the hypothesis that high-dose gp96 administration modifies allograft rejection and associated inflammatory events. Wistar cardiac allografts were transplanted into Lewis recipient rats and graft function was monitored daily by palpation. Intradermal administration of gp96 purified from Wistar rat livers (100 microg) at the time of transplantation and 3 days later significantly prolonged allograft survival (14 vs 8 days in phosphate-buffered saline [PBS]-treated recipients; P = 0.009). Rejected allografts from gp96-treated animals were significantly less enlarged than allografts from their PBS-treated counterparts (2.8 vs 4.3 g; P < 0.004). Gp96 was also effective when administered on days 1 and 8 (13 vs 7 days), but not if it was derived from recipient (Lewis) liver tissue or administered on days 0, 3, and 6. In parallel studies, CD3+ T cells from gp96-treated untransplanted animals secreted less interleukin (IL)-4, IL-10, and interferon (IFN)-gamma after in vitro polyclonal stimulation than CD3+ T cells from PBS-treated animals. Gp96 administration might therefore influence the induction of immunity to coencountered antigenic challenges and inflammatory events by inducing what appears to be a state of peripheral T-cell hyporesponsiveness.

Human tribbles-1 controls proliferation and chemotaxis of smooth muscle cells via MAPK signaling pathways.

Migration and proliferation of smooth muscle cells are key to a number of physiological and pathological processes, including wound healing and the narrowing of the vessel wall. Previous work has shown links between inflammatory stimuli and vascular smooth muscle cell proliferation and migration through mitogen-activated protein kinase (MAPK) activation, although the molecular mechanisms of this process are poorly understood. Here we report that tribbles-1, a recently described modulator of MAPK activation, controls vascular smooth muscle cell proliferation and chemotaxis via the Jun kinase pathway. Our findings demonstrate that this regulation takes place via direct interactions between tribbles-1 and MKK4/SEK1, a Jun activator kinase. The activity of this kinase is dependent on tribbles-1 levels, whereas the activation and the expression of MKK4/SEK1 are not. In addition, tribbles-1 expression is elevated in human atherosclerotic arteries when compared with non-atherosclerotic controls, suggesting that this protein may play a role in disease in vivo. In summary, the data presented here suggest an important regulatory role for trb-1 in vascular smooth muscle cell biology.