The osteoarthritis bone score (OABS): a new histological scoring system for the characterisation of bone marrow lesions in osteoarthritis.

OBJECTIVES: Bone marrow lesions (BMLs) are associated with pain in osteoarthritis (OA), but histological scores for OA focus on cartilage pathology. We developed a new scoring system, the Osteoarthritis Bone Score (OABS), to characterise OA-related BMLs. METHODS: BML/non-BML tissues identified by Magnetic Resonance Imaging (MRI) in 10 knee OA subjects were harvested at total knee replacement (TKR). Osteochondral tissue from a further 140 TKR and 23 post-mortem (PM) cases was assessed. Histological features distinguishing MRI-defined BML/non-BML tissues on qualitative analysis were classified as present (0) or absent (1), summated for the OABS, validated by Rasch analysis and sensitivity to distinguish between sample groups. Immunohistochemistry for PGP9.5 assessed innervation. RESULTS: Subchondral characteristics associated with BML tissues were cysts, fibrosis, hypervascularity, cartilage islands, trabecular thickening, loss of tidemark integrity and inflammatory cell infiltration. PGP9.5 immunoreactive perivascular nerves were associated with BMLs. OABS performed well as a measurement tool, displayed good reliability (Cronbach alpha = 0.68), had a 2-factor structure (trabecular/non-trabecular), with moderate correlation between the two factors (r = 0.56, 95% CI 0.46, 0.65). OABS scores were higher in TKR than PM cases with chondropathy, median difference 1.5 (95% CI -2, 0). OABS and Mankin scores similarly distinguished TKR from non-OA controls, but only OABS was higher in BML than non-BML tissues, median difference -4 (95% CI -5 to -2). CONCLUSIONS: OABS identifies and validly quantifies histopathological changes associated with OA BMLs. Histopathology underlying BMLs may represent 2 inter-related pathological processes affecting trabecular/non-trabecular structures. Increased vascularity/perivascular innervation in BMLs might contribute to pain.

Characterisation of hypertensive heart disease: pathological insights from a sudden cardiac death cohort to inform clinical practice.

Hypertensive heart disease refers to changes in the myocardium that result from hypertension. The relationship between hypertensive heart disease and sudden cardiac death is well established, but there are few pathological studies. We examined the clinical and pathological features of hypertensive heart disease in sudden cardiac death victims from a national cardiovascular pathology registry. We investigated 5239 cases of sudden cardiac death between 1994 and 2018. Hearts were examined by two expert cardiac pathologists. Diagnostic criteria included history of hypertension, increased heart weight and left ventricular wall thickness in the absence of other causes. Collagen was quantified using picrosirius red staining and imaging software. Of 75 sudden cardiac death cases due to hypertensive heart disease (age at death: 54 ± 16 years; 56% males), 56 (75%) reported no prior cardiac symptoms. Thirty-four (45%) recorded a BMI ≥ 30. Only two (2.7%) had hypertensive heart disease diagnosed antemortem. Four (5%) were diagnosed clinically with hypertrophic cardiomyopathy, but lacked myocyte disarray at autopsy. All hearts showed concentric left ventricular hypertrophy and myocyte hypertrophy. Fibrosis was identified microscopically in 59 cases (81%). The posterior left ventricular wall showed the greatest increase in the percentage of collagen in hypertensive diseased hearts compared to controls (25.2% vs 17.9%, p = 0.034). Most sudden deaths due to hypertensive heart disease occur without prior cardiac symptoms; thus, clinical risk stratification is challenging. Hypertensive heart disease can be misdiagnosed in life as hypertrophic cardiomyopathy which has major implications for relatives. Pathologists require a history of hypertension and histology for a definitive diagnosis of hypertensive heart disease.

Review: The past, present and future challenges in epilepsy-related and sudden deaths and biobanking.

Awareness and research on epilepsy-related deaths (ERD), in particular Sudden Unexpected Death in Epilepsy (SUDEP), have exponentially increased over the last two decades. Most publications have focused on guidelines that inform clinicians dealing with these deaths, educating patients, potential risk factors and mechanisms. There is a relative paucity of information available for pathologists who conduct these autopsies regarding appropriate post mortem practice and investigations. As we move from recognizing SUDEP as the most common form of ERD toward in-depth investigations into its causes and prevention, health professionals involved with these autopsies and post mortem procedure must remain fully informed. Systematizing a more comprehensive and consistent practice of examining these cases will facilitate (i) more precise determination of cause of death, (ii) identification of SUDEP for improved epidemiological surveillance (the first step for an intervention study), and (iii) biobanking and cell-based research. This article reviews how pathologists and healthcare professionals have approached ERD, current practices, logistical problems and areas to improve and harmonize. The main neuropathology, cardiac and genetic findings in SUDEP are outlined, providing a framework for best practices, integration of clinical, pathological and molecular genetic investigations in SUDEP, and ultimately prevention.

Autopsy after transcatheter aortic valve implantation.

Autopsy after transcatheter aortic valve implantation (TAVI) is a new field of interest in cardiovascular pathology. To identify the cause of death, it is important to be familiar with specific findings related to the time interval between the procedure and death. We aimed to provide an overview of the autopsy findings in patients with TAVI in their medical history divided by the timing of death with specific interest in the added value of autopsy over a solely clinically determined cause of death. In 8 European centres, 72 cases with autopsy reports were available. Autopsies were divided according to the time interval of death and reports were analysed. In 32 patients who died ≤72 h postprocedure, mortality resulted from cardiogenic or haemorrhagic shock in 62.5 and 34.4%, respectively. In 31 patients with mortality >72 h to ≤30 days, cardiogenic shock was the cause of death in 51.6% followed by sepsis (22.6%) and respiratory failure (9.7%). Of the nine patients with death >30 days, 88.9% died of sepsis, caused by infective endocarditis in half of them. At total of 12 patients revealed cerebrovascular complications. Autopsy revealed unexpected findings in 61.1% and resulted in a partly or completely different cause of death as was clinically determined. Autopsy on patients who underwent TAVI reveals specific patterns of cardiovascular pathology that clearly relate to the time interval between TAVI and death and significantly adds to the clinical diagnosis. Our data support the role of autopsy including investigation of the cerebrum in the quickly evolving era of cardiac device technology.

Sudden cardiac arrest in sports - need for uniform registration: A Position Paper from the Sport Cardiology Section of the European Association for Cardiovascular Prevention and Rehabilitation.

There are large variations in the incidence, registration methods and reported causes of sudden cardiac arrest/sudden cardiac death (SCA/SCD) in competitive and recreational athletes. A crucial question is to which degree these variations are genuine or partly due to methodological incongruities. This paper discusses the uncertainties about available data and provides comprehensive suggestions for standard definitions and a guide for uniform registration parameters of SCA/SCD. The parameters include a definition of what constitutes an 'athlete', incidence calculations, enrolment of cases, the importance of gender, ethnicity and age of the athlete, as well as the type and level of sporting activity. A precise instruction for autopsy practice in the case of a SCD of athletes is given, including the role of molecular samples and evaluation of possible doping. Rational decisions about cardiac preparticipation screening and cardiac safety at sport facilities requires increased data quality concerning incidence, aetiology and management of SCA/SCD in sports. Uniform standard registration of SCA/SCD in athletes and leisure sportsmen would be a first step towards this goal.

Non-infectious aortitis of the ascending aorta: a histological and clinical correlation of 71 cases including overlap with medial degeneration and atheroma--a challenge for the pathologist.

AIMS: Aortitis is a rare but important cause of thoracic aortic disease. We describe its histopathological patterns and associations with other aortic pathologies and systemic inflammatory disease. METHODS: Database searches of thoracic specimens over 17 years from two centres yielded 71 cases of non-infectious aortitis. Histological verification of tunica media inflammation was required for inclusion. Clinical information and histopathological features were recorded. RESULTS: Three histological patterns emerged--necrotising aortitis with giant cells (53), diffuse band-like aortitis (16) and 'other' (2). 50/53 cases of necrotising aortitis with giant cells were isolated/idiopathic, while 9/16 cases of diffuse aortitis had a systemic inflammatory disease. Medial degeneration (MD) was prominent in 23/71 cases--all in the necrotising aortitis with giant cells category. CONCLUSIONS: Non-infectious aortitis is predominantly idiopathic/isolated in nature, occurring in elderly females. Two patterns emerge--(1) necrotising aortitis with giant cells, which is more likely to be idiopathic and linked to MD, suggesting a possible aetiological relationship; and (2) diffuse aortitis, which is linked to an increased risk of systemic inflammatory disease. Knowledge, therefore, of histopathological patterns may guide patient management and follow-up.

Fatal arrhythmogenic right ventricular cardiomyopathy in 2 related subadult chimpanzees (Pan troglodytes).

Cardiovascular disease is increasingly recognized as an important cause of morbidity and mortality in captive chimpanzees (Pan troglodytes). This report records 2 cases of sudden cardiac death in closely related subadult captive chimpanzees with marked replacement fibrosis and adipocyte infiltration of the myocardium, which resemble specific atypical forms of the familial human disease arrhythmogenic right ventricular cardiomyopathy. Changes were consistent with left-dominant and biventricular subtypes, which are both phenotypic variants found within human families with familial arrhythmogenic right ventricular cardiomyopathy. Previously reported fibrosing cardiomyopathies in chimpanzees were characterized by nonspecific interstitial fibrosis, in contrast to the replacement fibrofatty infiltration with predilection for the outer myocardium seen in these 2 cases. To the authors' knowledge, this case report is the first to describe cardiomyopathy resembling arrhythmogenic right ventricular cardiomyopathy in nonhuman primates and the first to describe left-dominant arrhythmogenic cardiomyopathy-type lesions in an animal.

Anomalous coronary origin: the challenge in preventing exercise-related sudden cardiac death.

The sudden cardiac death (SCD) of a young athlete is a catastrophic event, particularly in the absence of prodromal warning symptoms. Anomalous coronary origin (ACO) is a well-described cause of cardiac symptoms and SCD, but the diagnosis is usually missed by conventional non-invasive investigations designed to identify myocardial ischaemia. SCD is preventable by correction of the anomaly. A tragic case of a promising young athlete who had underlying ACO and who presented with prodromal symptoms with multiple "negative" investigations is described to highlight the typical clinical features and outline the difficulties encountered in accurate premortem diagnosis.

Primary cardiac lymphoma: B- and T-cell cases at a specialist UK centre.

BACKGROUND: Primary cardiac lymphoma is a very rare malignancy, which is typically of a non-Hodgkin's type, and involves only the heart and pericardium with no or minimal evidence of extracardiac involvement. In the past, they were frequently diagnosed at autopsy but modern imaging technology now permits early diagnosis and treatment which allows for improved prognosis. PATIENTS AND METHODS: This report describes the wide spectrum of clinical presentation, difficulty with correct clinical diagnosis, complications of treatment and pathologic findings of one of the largest series of primary cardiac lymphomas at a specialist UK centre. Our series comprised five males and one female with an age range of 10-81 years. RESULTS: Most cases involved at least two chambers with the ventricles being the most common site. Clinical presentation included arrhythmias, valve incompetence, cardiac failure, pericardial effusion, embolic stroke and sudden death. Our study, in contrast to other series, included both B- and T-cell lymphomas. CONCLUSIONS: All six cases illustrate the wide spectrum of clinical presentation of lymphomas presenting primarily in the heart and emphasise that histology of all mass lesions is essential. Other series are small like ours highlighting the rarity of these tumours in the heart with the emphasis on imaging, early diagnosis and treatment.

Aetiology of sudden cardiac death in athletes in the United Kingdom: a pathological study.

OBJECTIVE: To characterise the demographics and aetiology of sudden cardiac death (SCD) in athletes referred to a tertiary cardiac pathology centre in the UK. DESIGN: Retrospective non-case controlled analysis. SETTING: Cardiac pathology centre at the National Heart and Lung Institute and Royal Brompton Hospital. SUBJECTS: Between 1996 and 2008, the hearts of 118 athletes were referred for pathological assessment to ascertain the precise aetiology of SCD. RESULTS: The majority of athletes (n = 113; 96%) were male and most (107; 91%) were amateurs participating predominantly in football, rugby and running. The mean (SD) age of death was 28 (12) years (range 7-59); 75% athletes were aged < or =35 years. Most deaths (81%) occurred during or immediately after exercise. Antecedent symptoms of cardiac disease were reported in 21 (18%) subjects, and 20 (17%) had a family history of premature cardiovascular disease and/or SCD. 25 (21%) athletes had relevant past medical history which included a known history of cardiac disease. Cardiomyopathy was the commonest cause of death and accounted for 62% of all the SCDs. A significantly high proportion of athletes (23%) exhibited a morphologically normal heart. Atherosclerotic coronary disease accounted for only 3% of cases and was confined to athletes aged >35 years. CONCLUSIONS: SCD in sport is largely due to clinically silent cardiomyopathies or primary electrical disorders (morphologically normal heart). Antecedent symptoms and family history are absent in over 80% of cases, and therefore clinical screening with health questionnaires will fail to identify most athletes with potentially sinister cardiac disorders.

Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-Weber-Rendu syndrome): suggested approach for obstetric services.

OBJECTIVES: Hereditary haemorrhagic telangiectasia (HHT) affects 1 in 5-8000 individuals. Pregnancy outcomes are rarely reported. The major reason is that most women do not have their HHT diagnosed prior to pregnancy. Using a large well-characterised series, we studied all pregnancies known to have occurred in HHT-affected women, whether or not their diagnosis was known at the time of pregnancy. Our aim was to estimate rates and types of major complications of HHT in pregnancy, to guide management decisions. DESIGN: Cohort study, with prospective, retrospective and familial components. SETTING/POPULATION: Tertiary referral centre population. METHODS: All 262 pregnancies in the 111 women with HHT and pulmonary arteriovenous malformations (PAVMs) reviewed between 1999 and 2005 were studied. Eighty-two women (74%) did not have a diagnosis of HHT/PAVM at the time of pregnancy. 222 pregnancies in their 86 HHT-affected relatives were also studied. MAIN OUTCOME MEASURES: PAVM bleed, stroke and maternal death. RESULTS: Thirteen women experienced life-threatening events during pregnancy: 1.0% (95% CI 0.1-1.9) of pregnancies resulted in a major PAVM bleed; 1.2% (0.3-2.2%) in stroke (not all were HHT related); and 1.0% (0.13-1.9%) in maternal death. All deaths occurred in women previously considered well. In women experiencing a life-threatening event, prior awareness of HHT or PAVM diagnosis was associated with improved survival (P = 0.041, Fisher's exact test). CONCLUSIONS: Most HHT pregnancies proceed normally. Rare major complications, and improved survival outcome following prior recognition, means that pregnancy in a woman with HHT should be considered high risk. Recommendations for pregnancy management are provided.

Spectrum of pathological changes in both ventricles of patients dying suddenly with arrhythmogenic right ventricular dysplasia. Relation of changes to age.

AIMS: To quantify the variation in fibrosis, fat and muscle within the walls of both ventricles and within the different regions of the heart from six patients dying suddenly of arrhythmogenic right ventricular dysplasia (ARVD) aged 20-60 years. METHODS: Seven heart regions were examined both macroscopically and histologically using the Picro-Sirius red stain. Quantification of fibrosis, fat and muscle was performed in each region and transmural layer using grid counting. RESULTS: There were macroscopic changes in all examined hearts. A higher percentage of fat with less fibrosis and muscle was observed within the right ventricle of the older patients. The left ventricle had more pathology in the older age group. Statistical differences in pathology in the heart were found. Fat predominated in the epicardial layer in the right and left ventricles of all patients, while the interventricular septum was the least affected. CONCLUSIONS: In ARVD, the pathology varies with age in both ventricles, fibrosis being the earliest hallmark of disease, with fatty infiltration evolving later. It should be labelled arrhythmogenic ventricular dysplasia because of biventricular involvement. Histopathologists should therefore sample from whole slices of the heart, so that all the changes can be observed.

Sudden adult death syndrome and other non-ischaemic causes of sudden cardiac death.

OBJECTIVE: To evaluate non-atherosclerotic cardiac deaths in the UK population aged over 15 years including elderly patients and to highlight the concept of the structurally normal heart in sudden death. METHODS: Pathological data were collected prospectively for sudden adult deaths referred by UK coroners. RESULTS: 453 cases of sudden death from 1994 to 2003 (278 men (61.4%) and 175 women (38.6%), age range 15-81 years) were reviewed. Males predominated in both age groups (< or = 35 years, > 35 years). More than half of the hearts (n = 269, 59.3%) were structurally normal. In the other 40.7%, cardiac abnormalities were noted, which included: (1) cardiomyopathies (23%) such as idiopathic fibrosis, left ventricular hypertrophy, hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic right ventricular dysplasia; (2) inflammatory disorders (8.6%) including lymphocytic myocarditis and cardiac sarcoidosis; (3) non-atheromatous abnormalities of coronary arteries (4.6%); (4) valve diseases; and (5) miscellaneous and rare causes. CONCLUSION: The concept of the structurally normal heart in sudden death and the need for histological examination to detect underlying disease is highlighted. Relatives need to be referred for cardiological and genetic screening in cases of normal hearts found at necropsy.

CD56: a useful tool for the diagnosis of small cell lung carcinomas on biopsies with extensive crush artefact.

BACKGROUND/AIMS: The diagnosis of small cell lung carcinoma (SCLC) on bronchial biopsy is often problematical as a result of intense crush artefact. Several antibodies are now available to help in the diagnosis of SCLC and their value was assessed in this clinical situation. METHODS/RESULTS: Twenty cases of SCLC and 10 control cases (one non-Hodgkin lymphoma, three non-small cell carcinomas, one follicular reactive hyperplasia, and five chronic non-specific inflammations) with extensive crush artefact were stained using antibodies to CD56, MNF116, thyroid transcription factor 1 (TTF-1), and CD45. All SCLCs showed strong positive staining for CD56 in 75-100% of recognisable tumour cells, even in areas where there was extensive crush artefact. Eighteen of 20 cases were positive for TTF-1 and 16 of 20 were positive for MNF116 in the tumour cells, but both of these antibodies showed little or no staining in areas of crush artefact. Control cases comprising lymphoid cells were positive for CD45 in areas of crush artefact, but all cases of SCLC were negative. CONCLUSION: CD56, along with markers for cytokeratins-TTF-1, and CD45-are useful in the diagnosis of SCLC in biopsies with extensive crush artefact and can help confirm the diagnosis in cases where features are equivocal.

Fat in the right ventricle of the normal heart.

AIMS: Fibrofatty replacement of the right ventricle wall, often with associated inflammation, is the hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), a rare but established cause of sudden cardiac death in young adults. Fatty infiltration of the right ventricle alone without fibrosis may also occur but its relation to sudden death is not well established. In this study we assessed the amount of epicardial and intramyocardial fat in the right ventricle of 'normal' hearts from subjects who had died of non-cardiac causes. METHODS AND RESULTS: Hearts (n = 148) were examined from 81 males and 67 females, with an age range of 6 months to 68 years, who had died of non-cardiac causes. The extent and distribution of right ventricular epicardial and intramyocardial fat was assessed macro- and microscopically, respectively. The majority of hearts (85%) contained at least some intramyocardial fat with significantly more fat replacement noted in the right ventricles of older subjects and in females than in males. There was no significant fibrosis or inflammation in any of the 148 cases. CONCLUSION: Variable amounts of intramyocardial fat may be seen in the right ventricle of subjects dying of non-cardiac related causes. Care should be taken not to confuse this relatively common simple fatty infiltration with ARVC.