An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins.

AIMS: Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients. METHODS AND RESULTS: For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates. CONCLUSION: A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.

Heart of glass: fatal hematemesis caused by bronchiole-cardiac fistula.

A 58-year old woman presented for autopsy after having been found unresponsive in a public bathroom surrounded by a pool of blood. During attempts at resuscitation, blood was noted in her airway. She had a past medical history that included surgical repair of Tetralogy of Fallot as a child. At autopsy, a shard of glass was identified projecting from the surface of the left lung, having formed densely fibrotic adhesions at the pleural surface. The glass also penetrated through a bronchiole lumen and into a previously surgically repaired bulging right ventricular outflow tract, forming a bronchiole-cardiac fistula, allowing for the massive hemoptysis that led to her death. After further inquiry, it was discovered that the decedent also had a history of seizure disorder and had fallen through a glass door during a seizure many years ago, requiring several shards of glass to be removed from her chest wall.

Evaluation of cardiac hypertrophy in the setting of sudden cardiac death.

Ventricular hypertrophy is a common pathological finding at autopsy that can act as a substrate for arrhythmogenesis. Pathologists grapple with the significance of ventricular hypertrophy when assessing the sudden and unexpected deaths of young people and what it could mean for surviving family members. The pathological spectrum of left ventricular hypertrophy (LVH) is reviewed herein. This article is oriented to the practicing autopsy pathologist to help make sense of various patterns of increased heart muscle, particularly those that are not clearly cardiomyopathic, yet present in the setting of sudden cardiac death. The article also reviews factors influencing arrhythmogenesis as well as genetic mutations most commonly associated with ventricular hypertrophy, especially those associated with hypertrophic cardiomyopathy (HCM).

Pathology of isolated atrial infarction: case report and review of the literature.

Infarction of the cardiac atria occurs more frequently than is commonly considered. Ischemic damage to the atrial myocardium is usually associated with infarction of cardiac ventricles, but isolated infarction of an atrium can occur and may be of clinical significance. We present an unusual case of an isolated right atrial infarct with an infarction-related endocardial thrombus that mimicked a mass lesion near the inferior vena cava. The presentation and causes of isolated atrial infarction are discussed.

A 10-year comparison of explanted Hancock-II and Carpentier-Edwards supraannular bioprostheses.

BACKGROUND: Bioprosthetic heart valves are more frequently being used in valve replacement procedures today. Although second-generation bioprosthetic valves have improved functionality over their first-generation counterparts, they still often fail due to primary tissue degeneration. METHODS: This study examines two second-generation porcine valves after surgical explantation, the Hancock-II (HAN; Medtronic Heart Valve Division, Irvine, CA, USA) and the Carpentier-Edwards supraannular (CE-SAV; Baxter Healthcare Corporation, now Edwards LifeSciences, Irvine, CA, USA), with special attention to morphological/histological changes and reasons for valve failure. A total of 98 HAN and 65 CE-SAV valves were explanted and seen over a 10-year period. RESULTS: CE-SAV valves had a longer average implant duration than HAN valves (13.9+/-3.9 years vs. 10.0+/-5.1 years). Compared with HAN valves, CE-SAV valves also had a higher incidence of stent deformation (41.5% vs. 14.3%), calcification (75.4% vs. 54.1%), and pannus (100% vs. 91.8%). CONCLUSIONS: The greater degenerative changes seen with CE-SAV valves over HAN valves may be due to the longer implant duration of CE-SAV valves in this series. To our knowledge, the present study is the first direct morphological comparison of these two valve models.

Inflammation and infection in nine surgically explanted Medtronic Freestyle stentless aortic valves.

BACKGROUND: The Medtronic Freestyle valve is fixed in glutaraldehyde at zero pressure on the cusps and treated with alpha-amino oleic acid. This valve reportedly has excellent clinical and hemodynamic results, but little has been reported about its long-term pathology. METHODS AND RESULTS: Nine Freestyle valves explanted between 2003 and 2005 were reviewed to assess the reasons for bioprosthesis failure (six implanted at our institution). All valves were examined in detail, using histochemistry and immunohistochemistry to identify the cellular response. One Freestyle valve, explanted for mitral valve endocarditis on the fifth postoperative day, was excluded from analysis. Average implant duration was 52.8+/-35.5 months. Four valves were explanted for infective endocarditis, three for aortic insufficiency, two for aortic stenosis with cusp calcification seen in five valves, pannus and thrombus in all valves and a chronic inflammatory reaction involving the xenograft arterial wall seen in eight of nine valves. This was associated with significant damage to the porcine aortic wall in seven cases, and cusp myocardial shelf damage in six cases. CONCLUSIONS: In this series of valves, we found (1) infective endocarditis; (2) pannus, thrombus, and calcification; and (3) unusual and significant inflammatory reaction and aortic tissue damage, which could by itself lead to aortic incompetence.

The Promise of Molecular Autopsy in Forensic Pathology Practice.

Molecular autopsy is changing the practice of forensic pathology. Under some circumstances, one must contemplate the involvement of genetic factors to help explain why someone has died unexpectedly. Such considerations most commonly occur when a young person dies by natural means. However, there are deaths that occur by nonnatural means that the forensic pathologist will be asked to investigate, which could involve natural disease that has a significant genetic underpinning. Elucidation of genetic mutations may not only further an understanding of the pathophysiology at hand, but also speak to underlying susceptibilities in an individual who dies that may not have been recognized. In addition, one may occasionally identify pathological findings that are confused for trauma that may actually be better explained by an underlying disease process. Using molecular medicine as a tool to explore such possibilities can improve the quality of death investigations and provide a new lens to probe challenging and contentious forensic cases that have proved resistant to traditional methods.

Fatty lesions of the atria and interatrial septum.

Lipomatous lesions of the heart involving the atria and interatrial septum are not well known. Most such lesions do not become clinically significant; however, intractable arrhythmias, blood flow obstruction, and valvular disruption may result from extensive fatty infiltration of the atrial wall or from the mass effect of benign or malignant lipomatous tumors. Some fatty lesions may be difficult to characterize radiologically, and misdiagnosis may lead to unnecessary surgical interventions. We describe the pathology of the most common fatty lesions and underscore some of the radiographic and surgical issues pertaining to the diagnosis and management of these masses.

A fatal case of atrioesophageal fistula following radiofrequency ablation of left atrium and pulmonary veins for atrial fibrillation.

Atrial fibrillation (AF) is associated with significant morbidity and mortality. Hemodynamic compromise and formation of thrombi within the fibrillating atrium or atrial appendage can occur. Surgical treatment aims to eliminate dysrhythmia-triggering foci in the pulmonary veins and posterior left atrium by radiofrequency ablation techniques using ohmic heat. As medical treatment may be ineffective, radiofrequency catheter ablation is increasingly being used by interventional cardiac electrophysiologists for AF. Serious complications have been observed among patients who have undergone radiofrequency ablation, atrioesophageal fistula being a very rare example. This case describes a 43-year-old man who died after the development of an atrioesophageal fistula following radiofrequency ablation of the left atrium and pulmonary veins for treatment of AF.

Pulmonary bacterial communities in surgically resected noncystic fibrosis bronchiectasis lungs are similar to those in cystic fibrosis.

Background. Recurrent bacterial infections play a key role in the pathogenesis of bronchiectasis, but conventional microbiologic methods may fail to identify pathogens in many cases. We characterized and compared the pulmonary bacterial communities of cystic fibrosis (CF) and non-CF bronchiectasis patients using a culture-independent molecular approach. Methods. Bacterial 16S rRNA gene libraries were constructed from lung tissue of 10 non-CF bronchiectasis and 21 CF patients, followed by DNA sequencing of isolates from each library. Community characteristics were analyzed and compared between the two groups. Results. A wide range of bacterial diversity was detected in both groups, with between 1 and 21 bacterial taxa found in each patient. Pseudomonas was the most common genus in both groups, comprising 49% of sequences detected and dominating numerically in 13 patients. Although Pseudomonas appeared to be dominant more often in CF patients than in non-CF patients, analysis of entire bacterial communities did not identify significant differences between these two groups. Conclusions. Our data indicate significant diversity in the pulmonary bacterial community of both CF and non-CF bronchiectasis patients and suggest that this community is similar in surgically resected lungs of CF and non-CF bronchiectasis patients.

CD10 is expressed in most epithelioid hemangioendotheliomas: a potential diagnostic pitfall.

CONTEXT: -Epithelioid hemangioendothelioma (EHE) is a vascular neoplasm that occasionally is difficult to distinguish from primary/metastatic carcinomas, particularly when EHEs express keratins. We recently encountered an EHE with strong CD10 positivity mimicking renal cell carcinoma. OBJECTIVE: -To examine sensitivity and specificity of CD10 in EHE. DESIGN: -Nine EHEs were stained with keratins, factor VIII, CD31, CD34, and CD10. Mimics of EHE were also retrieved and stained with CD10. RESULTS: -The EHE patients included 5 men and 4 women. Patients ranged in age from 24 to 74 years. Tumors were located in liver (3), skin (2), lung/pleura (2), and sternomastoid and mediastinum (1 each). Two had skin metastases. All EHEs were positive for vascular markers. A total of 7 of 9 primary tumors expressed cytoplasmic and intracytoplasmic luminal CD10. The 2 skin metastases were positive, whereas 2 primary skin EHEs were negative. Of the mimics, CD10 showed staining in 7 of 23 cases: 3 of 3 renal cell carcinomas, 1 of 7 other carcinomas, 2 of 3 epithelioid angiosarcomas, 1 of 3 melanomas, 0 of 3 mesotheliomas, and 0 of 4 epithelioid hemangiomas. CONCLUSIONS: -CD10 has a sensitivity of 78% (confidence interval, 63.6%-92.4%) and specificity of 70% (confidence interval, 54%-85.9%) for EHE. There is a growing list of tumors that show expression of CD10. Pathologists should be aware of this diagnostic pitfall.

Impact of tumor-infiltrating T cells on survival in patients with malignant pleural mesothelioma.

OBJECTIVE: The aim of the study was to determine the impact of tumor-infiltrating lymphocytes on survival in patients with malignant pleural mesothelioma treated with induction chemotherapy followed by extrapleural pneumonectomy. METHODS: We performed an immunohistochemical analysis of 32 extrapleural pneumonectomy specimens to assess the distribution of T-cell subtypes (CD3(+), CD4(+), and CD8(+)), regulatory subtypes (CD25(+) and FOXP3(+)), and memory subtype (CD45RO(+)) within the tumor. RESULTS: Patients with high levels of CD8(+) tumor-infiltrating lymphocytes demonstrated better survival than those with low levels (3-year survival: 83% vs 28%; P = .06). Moreover, high levels of CD8(+) tumor-infiltrating lymphocytes were associated with a lower incidence of mediastinal node disease (P = .004) and longer progression-free survival (P = .05). Higher levels of CD8(+) tumor-infiltrating lymphocytes were observed in patients treated with cisplatin and pemetrexed than in those treated with cisplatin and vinorelbine (P = .02). Patients presenting high levels of CD4(+) or CD25(+) tumor-infiltrating lymphocytes or low levels of CD45RO(+) also demonstrated a trend toward shorter survival. However, the presence of FOXP3(+) tumor-infiltrating lymphocytes did not affect survival. After multivariate adjustment, high levels of CD8(+) tumor-infiltrating lymphocytes remained an independent prognostic factor associated with delayed recurrence (hazard ratio = 0.38; confidence interval = 0.09-0.87; P = .02) and better survival (hazard ratio = 0.39; confidence interval = 0.09-0.89; P = .02). CONCLUSION: The presence of high levels of CD8(+) tumor-infiltrating lymphocytes is associated with better prognosis in patients undergoing extrapleural pneumonectomy for malignant pleural mesothelioma. The stimulation of CD8(+) lymphocytes can be a potential therapeutic strategy to improve outcome.

Early changes in bioprosthetic heart valves following ventricular assist device implantation.

Heart valve bioprostheses can undergo early post-implantation changes, including pannus and thrombus, which may be hastened by the presence of a left ventricular assist device (LVAD). We report the case of a 21 year-old male who was diagnosed with dilated cardiomyopathy and severe aortic insufficiency, and had his aortic valve replaced with a #25 BioPhysio valve (currently in clinical trials--Edwards Life Sciences, Irvine, CA, USA). His symptoms of congestive heart failure continued to worsen, and he received a Novacor LVAD (WorldHeart, Oakland, CA, USA), and subsequently, an orthotopic heart transplantation. The relevant pathologies of the heart, BioPhysio valve (in place for 4.5 months), and Novacor device are presented.

Serrated mucosal lesions of the colorectum.

PURPOSE OF REVIEW: To examine and clarify the nomenclature and histologic lesions identified as serrated mucosal lesions of the colorectum, including serrated adenomas, sessile serrated polyps (also known as sessile serrated adenomas) and hyperplastic polyps. This is timely given the significant confusion in ascribing a microscopic diagnosis and clinical utility of such a diagnosis. RECENT FINDINGS: The emergence of sessile serrated polyps (or adenomas) as distinct histomorphologic lesions from serrated adenomas, as well as the appreciation of the possibility of different modes of dysplasia exhibited in serrated lesions. SUMMARY: Clarification of the microscopic features, nomenclature and biology of serrated lesions are important for accurate histologic diagnosis, and in clinical terms for useful outcomes assessment, recommendations for follow-up and risk stratification.

A bicuspid pulmonary valve associated with tetralogy of fallot.

Congenitally bicuspid pulmonary valves are uncommon. When they occur, it is usually in association with other congenital cardiac lesions, most often a tetralogy of Fallot. We present a rare case of a patient with a congenitally bicuspid pulmonary valve who had pulmonary valve and RVOT reconstruction. The patient did well for 17 years, but needed further reconstruction when the pulmonary valve started getting stenosed and RV pressures went up significantly. The pulmonary valve showed fibroses, thickening, and focal calcification.

The role of shear stress in the pathogenesis of atherosclerosis.

Although the pathobiology of atherosclerosis is a complex multifactorial process, blood flow-induced shear stress has emerged as an essential feature of atherogenesis. This fluid drag force acting on the vessel wall is mechanotransduced into a biochemical signal that results in changes in vascular behavior. Maintenance of a physiologic, laminar shear stress is known to be crucial for normal vascular functioning, which includes the regulation of vascular caliber as well as inhibition of proliferation, thrombosis and inflammation of the vessel wall. Thus, shear stress is atheroprotective. It is also recognized that disturbed or oscillatory flows near arterial bifurcations, branch ostia and curvatures are associated with atheroma formation. Additionally, vascular endothelium has been shown to have different behavioral responses to altered flow patterns both at the molecular and cellular levels and these reactions are proposed to promote atherosclerosis in synergy with other well-defined systemic risk factors. Nonlaminar flow promotes changes to endothelial gene expression, cytoskeletal arrangement, wound repair, leukocyte adhesion as well as to the vasoreactive, oxidative and inflammatory states of the artery wall. Disturbed shear stress also influences the site selectivity of atherosclerotic plaque formation as well as its associated vessel wall remodeling, which can affect plaque vulnerability, stent restenosis and smooth muscle cell intimal hyperplasia in venous bypass grafts. Thus, shear stress is critically important in regulating the atheroprotective, normal physiology as well as the pathobiology and dysfunction of the vessel wall through complex molecular mechanisms that promote atherogenesis.