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Papers by mary sheppard

Circulation-arrhythmia and Electrophysiology, Jun 1, 2013

Background-The sudden death of young individuals is commonly attributed to inherited cardiac diso... more Background-The sudden death of young individuals is commonly attributed to inherited cardiac disorders, and familial evaluation is advocated. The identification of pathognomonic histopathologic findings, or the absence of cardiac pathology (sudden arrhythmic death syndrome [SADS]) at postmortem, directs familial evaluation targeting structural disorders or primary arrhythmogenic syndromes, respectively. In a proportion of autopsies, structural abnormalities of uncertain significance are reported. We explored the hypothesis that such sudden cardiac deaths represent SADS. Methods and Results-Families (n=340) of index cases of sudden cardiac deaths who underwent postmortem evaluation were evaluated in specialist cardiogenetics clinics. Families in whom the deceased exhibited structural abnormalities of uncertain significance (n=41), such as ventricular hypertrophy, myocardial fibrosis, and minor coronary artery disease, were included in the study. Results were compared with 163 families with normal postmortem (SADS). Relatives underwent comprehensive cardiac evaluation. Twenty-one families (51%) with autopsy findings of uncertain significance received a diagnosis based on the identification of an inherited cardiac condition phenotype in ≥1 relatives: 14 Brugada syndrome; 4 long-QT syndrome; 1 catecholaminergic polymorphic ventricular tachycardia; and 2 cardiomyopathy. A similar proportion of families (47.2%) received a diagnosis in the SADS cohort (P=0.727). An arrhythmogenic syndrome was the predominant diagnosis in both cohorts (46% versus 45%; P=0.863). Conclusions-Familial evaluation after sudden cardiac deaths with autopsy findings of uncertain significance identified a similar proportion of primary arrhythmogenic syndromes to a contemporary series of SADS. Our study highlights the need for accurate interpretation of autopsy findings to avoid erroneous diagnoses, with potentially devastating implications.

Virchows Archiv

Cardiomyopathies (CMP) comprise a heterogenous group of diseases affecting primarily the myocardi... more Cardiomyopathies (CMP) comprise a heterogenous group of diseases affecting primarily the myocardium, either genetic and/or acquired in origin. While many classification systems have been proposed in the clinical setting, there is no internationally agreed pathological consensus concerning the diagnostic approach to inherited CMP at autopsy. A document on autopsy diagnosis of CMP is needed because the complexity of the pathologic backgrounds requires proper insight and expertise. In cases presenting with cardiac hypertrophy and/or dilatation/scarring with normal coronary arteries, a suspicion of inherited CMP must be considered, and a histological examination is essential. Establishing the actual cause of the disease may require a number of tissue-based and/or fluid-based investigations, be it histological, ultrastructural, or molecular. A history of illicit drug use must be looked for. Sudden death is frequently the first manifestation of disease in case of CMP, especially in the yo...

Virchows Archiv, 2021

Since cardiac hypertrophy may be considered a cause of death at autopsy, its assessment requires ... more Since cardiac hypertrophy may be considered a cause of death at autopsy, its assessment requires a uniform approach. Common terminology and methodology to measure the heart weight, size, and thickness as well as a systematic use of cut off values for normality by age, gender, and body weight and height are needed. For these reasons, recommendations have been written on behalf of the Association for European Cardiovascular Pathology. The diagnostic work up implies the search for pressure and volume overload conditions, compensatory hypertrophy, storage and infiltrative disorders, and cardiomyopathies. Although some gross morphologic features can point to a specific diagnosis, systematic histologic analysis, followed by possible immunostaining and transmission electron microscopy, is essential for a final diagnosis. If the autopsy is carried out in a general or forensic pathology service without expertise in cardiovascular pathology, the entire heart (or pictures) together with mapped...

Progress in Pediatric Cardiology, 2021

This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Journal of the American College of Cardiology, 2021

BACKGROUND Electrophysiological, imaging, and pathological studies have reported the presence of ... more BACKGROUND Electrophysiological, imaging, and pathological studies have reported the presence of subtle structural abnormalities in hearts from patients with Brugada syndrome (BrS). However, data concerning disease involvement outside of the right ventricular outflow tract are limited. OBJECTIVES This study sought to characterize the presence and distribution of ventricular myocardial fibrosis in a cohort of decedents experiencing sudden cardiac death caused by BrS. METHODS The authors evaluated 28 whole hearts from consecutive sudden cardiac death cases attributed to BrS and 29 hearts from a comparator group comprised of noncardiac deaths (control subjects). Cardiac tissue from 6 regions across the right and left ventricle were stained with Picrosirius red for collagen and tissue composition was determined using image analysis software. Postmortem genetic testing was performed in cases with DNA retained for analysis. RESULTS Of 28 BrS decedents (75% men; median age of death 25 years), death occurred in sleep or at rest in 24 of 28 (86%). The highest proportion of collagen was observed in the epicardial right ventricular outflow tract of the BrS group (23.7%; 95% CI: 20.8%-26.9%). Ventricular myocardium from BrS decedents demonstrated a higher proportion of collagen compared with control subjects (ratio 1.45; 95% CI: 1.22-1.71; P < 0.001), with no significant interactions with respect to sampling location or tissue layer. There was insufficient evidence to support differences in collagen proportion in SCN5A-positive cases (n ¼ 5) when compared with control subjects (ratio 1.23; 95% CI: 0.75-1.43; P ¼ 0.27). CONCLUSIONS Brugada syndrome is associated with increased collagen content throughout right and left ventricular myocardium, irrespective of sampling location or myocardial layer.

Virchows Archiv, 2019

Ischemic heart disease is one of the leading causes of morbidity and death worldwide. Consequentl... more Ischemic heart disease is one of the leading causes of morbidity and death worldwide. Consequently, myocardial infarctions are often encountered in clinical and forensic autopsies, and diagnosis can be challenging, especially in the absence of an acute coronary occlusion. Precise histopathological identification and timing of myocardial infarction in humans often remains uncertain while it can be of crucial importance, especially in a forensic setting when third person involvement or medical responsibilities are in question. A proper post-mortem diagnosis requires not only up-to-date knowledge of the ischemic coronary and myocardial pathology, but also a correct interpretation of such findings in relation to the clinical scenario of the deceased. For these reasons, it is important for pathologists to be familiar with the different clinically defined types of myocardial infarction and to discriminate myocardial infarction from other forms of myocardial injury. This article reviews pr...

Journal of the American College of Cardiology, 2018

Background: Prognosis in light chain(AL) and transthyretin(ATTR) amyloidosis is influenced by car... more Background: Prognosis in light chain(AL) and transthyretin(ATTR) amyloidosis is influenced by cardiac involvement. ATTR has better prognosis than AL despite more amyloid infiltration, suggesting additional mechanisms of damage in AL amyloidosis. Objective: The aim of this study was to assess the presence and prognostic significance of myocardial edema in patients with amyloidosis. Methods: We recruited 286 patients (100 with systemic AL amyloidosis, 163 with cardiac ATTR amyloidosis, 12 with suspected cardiac ATTR amyloidosis (grade 1 on 99m Tc-DPD), 11 asymptomatic individuals with amyloidogenic transthyretin (TTR) mutations) and 30 healthy volunteers. All subjects underwent CMR with T1 and T2 mapping and 16 underwent endomyocardial biopsy. Results: Myocardial T2 was increased in amyloidosis with the degree of elevation being highest in untreated AL patients (AL untreated 56.6±5.1ms; AL treated 53.6±3.9ms; ATTR 54.2±4.1ms; each p<0.01 compared to controls: 48.9±2.0ms). Left ventricular (LV) mass and ECV were higher in ATTR compared to AL whilst LV ejection fraction was lower (p<0.001). Histological evidence of edema was present in 87.5% of biopsy samples ranging from 5% to 40% myocardial involvement. Using Cox regression models, T2 predicted death in AL amyloidosis (hazard ratio, HR,1.48, 95%CI 1.20-1.82) and remained significant after adjusting for ECV and NT-proBNP (HR 1.32, 95%CI 1.05-1.67). Conclusions: Myocardial edema is present in cardiac amyloidosis by histology and CMR T2 mapping. T2 is higher in untreated AL amyloidosis compared to treated AL and ATTR, and is a predictor of prognosis in AL amyloidosis. This suggests mechanisms additional to amyloid infiltration contributing to mortality in amyloidosis.

Journal of the American College of Cardiology, 2015

BACKGROUND The right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhy... more BACKGROUND The right ventricular outflow tract (RVOT) is acknowledged to be responsible for arrhythmogenesis in Brugada syndrome (BrS), but the pathophysiology remains controversial. OBJECTIVES This study assessed the substrate underlying BrS at post-mortem and in vivo, and the role for open thoracotomy ablation. METHODS Six whole hearts from male post-mortem cases of unexplained sudden death (mean age 23.2 years) with negative specialist cardiac autopsy and familial BrS were used and matched to 6 homograft control hearts by sex and age (within 3 years) by random risk set sampling. Cardiac autopsy sections from cases and control hearts were stained with picrosirius red for collagen. The RVOT was evaluated in detail, including immunofluorescent stain for connexin-43 (Cx43). Collagen and Cx43 were quantified digitally and compared. An in vivo study was undertaken on 6 consecutive BrS patients (mean age 39.8 years, all men) during epicardial RVOT ablation for arrhythmia via thoracotomy. Abnormal late and fractionated potentials indicative of slowed conduction were identified, and biopsies were taken before ablation. RESULTS Collagen was increased in BrS autopsy cases compared with control hearts (odds ratio [OR]: 1.42; p ¼ 0.026). Fibrosis was greatest in the RVOT (OR: 1.98; p ¼ 0.003) and the epicardium (OR: 2.00; p ¼ 0.001). The Cx43 signal was reduced in BrS RVOT (OR: 0.59; p ¼ 0.001). Autopsy and in vivo RVOT samples identified epicardial and interstitial fibrosis. This was collocated with abnormal potentials in vivo that, when ablated, abolished the type 1 Brugada electrocardiogram without ventricular arrhythmia over 24.6 AE 9.7 months. CONCLUSIONS BrS is associated with epicardial surface and interstitial fibrosis and reduced gap junction expression in the RVOT. This collocates to abnormal potentials, and their ablation abolishes the BrS phenotype and life-threatening arrhythmias. BrS is also associated with increased collagen throughout the heart. Abnormal myocardial structure and conduction are therefore responsible for BrS. (

Proceedings of the National Academy of Sciences, 2015

Significance Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease that is selectiv... more Significance Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disease that is selective to the right side of the heart and results in heart failure and sudden death. Genetic defects in desmosome components account for approximately 50% of human ARVC cases; in the other 50% of patients, however, the causes remain unknown. We show that inhibitor of apoptosis-stimulating protein of p53 (iASPP) is an important regulator of desmosomes. It interacts with desmoplakin and desmin in cardiomyocytes and regulates desmosome integrity and intermediate filaments. iASPP-deficient mice display pathological features of ARVC and die of sudden death. In human ARVC patients, cardiomyocytes exhibit reduced levels of iASPP at the cell junctions, suggesting that iASPP may be critical in ARVC pathogenesis.

Circulation. Arrhythmia and electrophysiology, 2013

The sudden death of young individuals is commonly attributed to inherited cardiac disorders, and ... more The sudden death of young individuals is commonly attributed to inherited cardiac disorders, and familial evaluation is advocated. The identification of pathognomonic histopathologic findings, or the absence of cardiac pathology (sudden arrhythmic death syndrome [SADS]) at postmortem, directs familial evaluation targeting structural disorders or primary arrhythmogenic syndromes, respectively. In a proportion of autopsies, structural abnormalities of uncertain significance are reported. We explored the hypothesis that such sudden cardiac deaths represent SADS. Families (n=340) of index cases of sudden cardiac deaths who underwent postmortem evaluation were evaluated in specialist cardiogenetics clinics. Families in whom the deceased exhibited structural abnormalities of uncertain significance (n=41), such as ventricular hypertrophy, myocardial fibrosis, and minor coronary artery disease, were included in the study. Results were compared with 163 families with normal postmortem (SADS)...

Journal of the American College of Cardiology, 2004

We sought to identify the histologic basis of myocardial late gadolinium enhancement cardiovascul... more We sought to identify the histologic basis of myocardial late gadolinium enhancement cardiovascular magnetic resonance (CMR) in hypertrophic cardiomyopathy (HCM). BACKGROUND The histologic basis of late gadolinium CMR in patients with HCM is unknown. METHODS A 28-year-old male patient with HCM and heart failure underwent late gadolinium enhancement CMR and, 49 days later, heart transplantation. The explanted heart was examined histologically for the extent of collagen and disarray, and the results were compared with a previous in vivo CMR scan. RESULTS Overall, 19% of the myocardium was collagen, but the amount per segment varied widely (SD Ϯ 19, range 0% to 71%). Both disarray and collagen were more likely to be found in the mesocardium than in the endo-or epicardium. There was a significant relationship between the extent of late gadolinium enhancement and collagen (r ϭ 0.7, p Ͻ 0.0001) but not myocardial disarray (p ϭ 0.58). Segments containing Ͼ15% collagen were more likely to have late gadolinium enhancement. Regional wall motion was inversely related to the extent of myocardial collagen and late gadolinium enhancement but not disarray (p ϭ 0.0003, 0.04, and NS, respectively). CONCLUSIONS In this patient with HCM and heart failure, regions of myocardial late gadolinium enhancement by CMR represented regions of increased myocardial collagen but not disarray.

Journal of Anatomy, 1999

This study was prompted by the prospect of transgenic pigs providing donor hearts for transplanta... more This study was prompted by the prospect of transgenic pigs providing donor hearts for transplantation in human recipients. Autonomic innervation is important for the control of cardiac dynamics, especially in the conduction system. Our objective was to assess the relative distribution of autonomic nerves in the pig heart, focusing initially on the conduction system but addressing also the myocardium, endocardium and epicardium (see Crick et al. 1999). Quantitative immunohistochemical and histochemical techniques were adopted. All regions of the conduction system possessed a significantly higher relative density of the total neural population immunoreactive for the general neuronal marker protein gene product 9.5 (PGP 9.5) than did the adjacent myocardium. A similar density of PGP 9.5‐immunoreactive innervation was observed between the sinus node, the transitional region of the atrioventricular node, and the penetrating atrioventricular bundle. A differential pattern of PGP 9.5‐immun...

Circulation, 2011

Background— Measurement of myocardial iron is key to the clinical management of patients at risk ... more Background— Measurement of myocardial iron is key to the clinical management of patients at risk of siderotic cardiomyopathy. The cardiovascular magnetic resonance relaxation parameter R2* (assessed clinically via its reciprocal, T2*) measured in the ventricular septum is used to assess cardiac iron, but iron calibration and distribution data in humans are limited. Methods and Results— Twelve human hearts were studied from transfusion-dependent patients after either death (heart failure, n=7; stroke, n=1) or transplantation for end-stage heart failure (n=4). After cardiovascular magnetic resonance R2* measurement, tissue iron concentration was measured in multiple samples of each heart with inductively coupled plasma atomic emission spectroscopy. Iron distribution throughout the heart showed no systematic variation between segments, but epicardial iron concentration was higher than in the endocardium. The mean±SD global myocardial iron causing severe heart failure in 10 patients was...

Cardiovascular Pathology, 2010

Cardiovascular Pathology, 2012

With the advent of molecular subclassification of diseases, much consideration should be given to... more With the advent of molecular subclassification of diseases, much consideration should be given to the proper processing of cardiovascular surgical pathology specimens to maximize patient care. Such specimens include endomyocardial biopsies, cardiac myectomy specimens, cardiac apical core segments, resected cardiac valves, pericardial biopsies, resected segments of aorta, cardiac tumors, vascular stents, vascular grafts, cardiac devices, resected veins, arterial biopsies including temporal artery biopsies and hearts removed during cardiac transplantation. In this report, the Standards and Definitions Committee of the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology present consensus guidelines for the gross description, sectioning, processing, and staining of these Cardiovascular Pathology 21 (2012) 2-16 There are no sources of external funding.

Circulation-cardiovascular Genetics, Aug 1, 2010

Background-Idiopathic dilated cardiomyopathy is a familial disorder in 25% to 50% of patients, bu... more Background-Idiopathic dilated cardiomyopathy is a familial disorder in 25% to 50% of patients, but the genetic basis in the majority of cases remains unknown. Genes encoding desmosomal proteins, currently regarded as synonymous with another disorder, arrhythmogenic right ventricular cardiomyopathy, are known to cause left ventricular dysfunction, but their importance in unselected patients with unequivocal dilated cardiomyopathy is unknown. The objective of this study was to determine the prevalence of mutations in 5 desmosomal protein genes in patients with dilated cardiomyopathy. Methods and Results-We studied 100 unrelated patients with idiopathic dilated cardiomyopathy consecutively referred to a dedicated cardiomyopathy unit. Patients underwent clinical evaluation, ECG, echocardiography, exercise testing, 24-hour ambulatory ECG monitoring, and mutation screening of 5 genes implicated in arrhythmogenic right ventricular cardiomyopathy: plakoglobin, desmoplakin, plakophilin-2, desmoglein-2, and desmocollin-2. Of the 100 patients (mean age at evaluation, 46.8Ϯ13.8 years; range, 17.0 to 72.8 years; male sex, 63%), 5 were found to carry pathogenic desmosomal protein gene mutations. An additional 13 patients had sequence variants of uncertain pathogenic significance and were excluded from further comparative analysis. Patients harboring desmosomal gene mutations had a phenotype indistinguishable from the 82 noncarriers, with the exception of exercise-induced ventricular ectopy, which was more frequent in the desmosomal mutation carriers (Pϭ0.033). None of the 5 carriers of desmosomal mutations fulfilled current diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy, but 1 had fibrofatty change in the left ventricle at autopsy. Conclusions-Heart failure caused by a dilated, poorly contracting left ventricle and arrhythmogenic right ventricular cardiomyopathy have been considered distinct clinicopathologic entities. This study suggests that both clinical presentations can be caused by mutations in desmosomal protein genes.

Circulation: Cardiovascular Genetics, 2010

Background— Idiopathic dilated cardiomyopathy is a familial disorder in 25% to 50% of patients, b... more Background— Idiopathic dilated cardiomyopathy is a familial disorder in 25% to 50% of patients, but the genetic basis in the majority of cases remains unknown. Genes encoding desmosomal proteins, currently regarded as synonymous with another disorder, arrhythmogenic right ventricular cardiomyopathy, are known to cause left ventricular dysfunction, but their importance in unselected patients with unequivocal dilated cardiomyopathy is unknown. The objective of this study was to determine the prevalence of mutations in 5 desmosomal protein genes in patients with dilated cardiomyopathy. Methods and Results— We studied 100 unrelated patients with idiopathic dilated cardiomyopathy consecutively referred to a dedicated cardiomyopathy unit. Patients underwent clinical evaluation, ECG, echocardiography, exercise testing, 24-hour ambulatory ECG monitoring, and mutation screening of 5 genes implicated in arrhythmogenic right ventricular cardiomyopathy: plakoglobin, desmoplakin, plakophilin-2, ...

Journal of the American College of Cardiology, 2002

OBJECTIVES This study characterizes the histology of myocardium predicted to be hibernating using... more OBJECTIVES This study characterizes the histology of myocardium predicted to be hibernating using three different imaging techniques to explain the discordance among them. BACKGROUND Both radionuclide and functional imaging techniques were used to assess myocardial hibernation. The former have high sensitivity and the latter high specificity for predicting functional recovery. METHODS Nineteen patients underwent thallium-201 and 99m-technetium tetrofosmin myocardial perfusion imaging, and dobutamine magnetic resonance imaging (MRI), prior to coronary bypass grafting. Criteria for predicted hibernation for each technique were defined before operation. Postoperative criteria for scar and true hibernation were also defined. Biopsies were analyzed for myocyte volume fraction (MVF), glycogen deposition and pathologic cell features. RESULTS Thallium was most sensitive in predicting hibernation (88%) and MRI most specific (84%); and, although there was good agreement between thallium and tetrofosmin (85%), agreement between MRI and thallium (59%) or tetrofosmin (59%) was poor. For each technique, MVF was higher in segments predicted to be hibernating rather than scar (p Ͻ 0.05). The MVF was higher where both thallium and MRI predicted hibernation (0.77 Ϯ 0.07) than in segments predicted by thallium alone (0.69 Ϯ 0.13, p Ͻ 0.05). Proven hibernating segments had a higher MVF than scar (0.72 Ϯ 0.11 vs. 0.6 Ϯ 0.26, p Ͻ 0.05). CONCLUSIONS Preservation of myocyte fraction is an important determinant of functional recovery after revascularization. A higher myocyte fraction is required to maintain contractile reserve than to achieve significant tracer uptake. This explains the higher sensitivity of radionuclide imaging compared with dobutamine MRI in the identification of myocardial hibernation.