Cardiovascular Pathology - Articles in Press

Expression of hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN4) is increased in hypertrophic cardiomyopathy - Corrected Proof

Huang Wei-qing, Kong Qing-nuan, Xu Lin, Guo Cheng-hao, Zhang Qi-yi — 2010-03-08

Abstract: Objective: Hypertrophic cardiomyopathy (HCM) is a disease of the myocardium with uncertain etiology and often leads to sudden death as the result of arrhythmia. Pacemaker hyperpolarization-activated current If was altered in hypertrophic hearts and was probably responsible for arrhythmia. If channels are compose\d of four hyperpolarization-activated cyclic nucleotide-gated cation subunits (HCN1–4). A previous study found significantly high levels of HCN2 and HCN4 mRNA in hypertrophic hearts compared to control hearts in septum and left ventricles in rats. No studies, however, have investigated the HCN gene expression in the myocardium from human HCM heart.Methods: The left ventricular tissue from four patients who died of HCM and six healthy patients who died of motor vehicle accidents was included in this study. The fluorescent quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay was used to detect HCN4 mRNA. The expression of HCN4 mRNA of the two groups was detected on the assay.Results: In the HCM hearts, disorganization of the hypertrophic myofibers and interstitial fibrosis were observed in all four patients, although absent in healthy control hearts. By quantitative polymerase chain reaction, the mean copy number of HCN4 mRNA was 2.2×107 (range, 6.8×106 to 4.55×107) in HCM hearts and 8.17×103 (range, 8.76×101 to 3.5×104) in control hearts (P=.0318).Conclusion: Higher HCN4 mRNA levels in the HCM hearts suggest that up-regulation of HCN4 gene expression might be responsible for ventricular arrhythmia that leads to sudden death.

Ventricular septal defect complicating acute myocardial infarction—still an unsolved problem in the invasive treatment era - Corrected Proof

Anna Ledakowicz-Polak, Łukasz Polak, Marzenna Zielińska — 2010-02-26

Abstract: Background: Post-acute myocardial infarction (AMI) ventricular septal defect (VSD) is a rare but catastrophic complication. The aim of study was to delineate the incidence and risk factors of VSD in patients after AMI treated with successful primary percutaneous coronary intervention (pPCI).Methods and results: In the years 2004–2006, a total of 1835 patients with AMI underwent successful pPCI in our hospital. Thirteen patients (0.71%) developed VSD after pPCI. Mean time of occurrence of VSD was 24.46±9.32 h. Patients with VSD had longer time from the AMI onset to pPCI vs. patients without VSD (7.77±2.83 vs. 4.49±4.45, P 70 years (OR=4.66; P=.007), female gender (OR=5.73; P=.004), anterior infarction (OR=3.86; P=.04), single-vessel CAD (OR=3.74; P=.03), body mass index (BMI) <25 (OR=2.98; P=.04), and left ventricular wall hypertrophy (OR=3.39; P=.03).Conclusions: Our study demonstrated that the incidence of VSD after AMI appears to have declined in patients treated with pPCI. The pathomechanism of VSD in the invasive treatment era is the consequence of several processes and needs further investigation. Advanced age, female gender, anterior infarction, single-vessel CAD, left ventricular wall hypertrophy, and low BMI are strong risk factors of this complication after AMI, which remain invariable over the years.

Histopathologic correlates of myocardial improvement in patients supported by a left ventricular assist device - Corrected Proof

Ana Maria Segura, O.H. Frazier, Zumrut Demirozu, L. Maximilian Buja — 2010-02-26

Abstract: Background: Left ventricular assist devices unload the failing heart and improve hemodynamic function and tissue architecture. In some patients improvement allows for left ventricular assist device removal. We retrospectively compared histologic features in patients who were weaned off left ventricular assist device support with those who remained on support without evidence of clinical remission.Methods: We graded left ventricular core samples taken at implantation on a scale we designed for evaluating severity and extent of fibrosis and hypertrophy. We correlated the grades with a computerized semiquantitative analysis of picrosirius-red and Masson's trichrome-stained sections. We evaluated interstitial (10×), perivascular (20×), and replacement (4×) fibrosis. Hypertrophy was assessed by myocyte diameter, cytoplasmic area, and nuclear/cytoplasmic ratio.Results: All patients (N=17) underwent left ventricular assist device implantation for heart failure. In eight patients improvement allowed left ventricular assist device removal. The groups did not differ in age (24.1 vs. 25 years, P=.4) or mean time on left ventricular assist device support (506 vs. 414 days, P=.24). All mean measures showed significantly less hypertrophy in the left ventricular assist device-removal group than in the nonremoval group, respectively (cytoplasmic area, 58.00 vs. 77.18 μm2, P=.021; myocyte diameter, 20.32 vs. 25.35 μm, P=.004; nuclear/cytoplasmic ratio, 11.04 vs. 8.69, P=.053). Although not statistically significant, the left ventricular assist device-removal group tended toward less overall fibrosis than the nonremoval group (11.57 vs. 13.24, P=.214).Conclusions: Left ventricular assist device-removal patients had less hypertrophy and fibrosis overall than did nonremoval patients. These findings may help identify patients with a higher probability of left ventricular assist device removal and myocardial recovery.

Ischemic myocardial injuries after cardiac malformation repair in infants may be associated with oxidative stress mechanisms - Corrected Proof

2010-02-26

Abstract: Background: Despite advances in pediatric cardiac surgery, perioperative myocardial injury can be the major determinant of postoperative dysfunction after cardiac surgery. This study investigated the pathology-related differences in 29 infants with congenital heart disease that led to death. The infants were treated at the University Hospital of Ribeirão Preto, Brazil.Methods: The patients were divided into four groups: Group 1, 16 infants who underwent operations for congenital heart disease on cardiopulmonary bypass; Group 2, four infants who underwent off-cardiopulmonary bypass operations for congenital heart disease; Group 3, nine infants who died from congenital heart disease prior to surgical treatment; and Group 4 (control group), five infants with no congenital heart disease and who died from other causes. The myocardial injuries and oxidative stress mechanisms were assessed by histopathology and immunohistochemistry and were quantified by morphometrical analyses.Results: Contraction band necrosis and dystrophic calcification were found primarily in infants of Group 1. Coagulation necrosis and healing were prominent in Group 2, while infants without repair (Group 3) showed mainly colliquative myocytolysis. Apoptotic cells were more prominent in the operative groups. The control group showed no significant myocardial lesions. Lipid peroxidation was the principal mechanism of oxidative stress accounting for the myocardial lesions.Conclusion: The diversity of the lesions observed in these hearts seemed to indicate a large spectrum of cell damage due to inadequate myocardial perfusion, especially when these infants underwent surgery. Oxidative mechanisms could be a common mediator in the pathogenesis of myocardial injuries, mediated by peroxidation of the membrane phospholipids and resulting in changes in the permeability of the cell membrane, cell death, and intracellular calcium overload. Furthermore, an immature and often hypertrophied myocardium may promote unfavorable conditions, leading to heart failure and a lethal outcome.

Statin treatment of hypercholesterolemic-induced aortic valve sclerosis - Corrected Proof

Amanda M. Hamilton, Derek R. Boughner, Maria Drangova, Kem A. Rogers — 2010-02-19

Abstract: Background: Aortic valve sclerosis (AVS) is a common inflammatory heart valve disease prevalent in the population over the age of 65 years. Several published clinical and animal studies have examined the ability of statin treatment to modify disease progression. Clinical trials yielded conflicting results, and animal studies examined the effects of statins prior to the onset of disease. Our study assessed the effect of dietary modification and/or statin treatment on established aortic valve disease in a rabbit model of AVS to examine the tissue response to therapy.Methods: Aortic valve sclerosis was induced in male New Zealand White rabbits by dietary cholesterol supplementation. Rabbits were followed over 2.5 years, with the introduction of statins and/or dietary changes for the second half of the study. At end point, valve function was examined by magnetic resonance imaging. Excised aortic valve cusp tissue was surveyed for thickness, lipid accumulation, protein deposition, calcification, and cellular infiltration.Results: By 15 months, cholesterol-fed valves exhibited thickening due to significant lipid content, macrophage infiltration, and osteopontin expression. By 30 months, the untreated disease had progressed to include elevated collagen deposition, lymphocyte invasion, and calcification. With treatment, however, the valve cusps exhibited significant pathological changes including diminished immune cell infiltration and osteopontin expression. Unfortunately, lipid was retained and calcification persisted in all treated valves.Conclusions: In established AVS, the cellular response to statin therapy does not result in full regression of the sclerotic process.

Animal models of abdominal aortic aneurysm and their role in furthering management of human disease - Corrected Proof

Alexandra Trollope, Joseph V. Moxon, Corey S. Moran, Jonathan Golledge — 2010-02-05

Abstract: Abdominal aortic aneurysm is a common degenerative disorder associated with sudden death due to aortic rupture. Current therapy is limited to open surgical repair of the aorta or endovascular placement of covered stents to exclude the abdominal aortic aneurysm from the circulation. A number of different animal models have been developed in order to study abdominal aortic aneurysm in an effort to advance current management deficiencies. Large animal models have been mostly used to assist in developing novel methods to surgically treat abdominal aortic aneurysms. Small animal models, particularly those developed in rodents, have been employed to further the understanding of the mechanisms involved in abdominal aortic aneurysm in order to identify potential new medical treatments. It is expected that findings from these animal models will contribute importantly to new treatments for human abdominal aortic aneurysm. This review explores the animal models which are used in abdominal aortic aneurysm research and highlights their advantages and disadvantages.

Aortic aneurysms in systemic lupus erythematosus: a meta-analysis of 35 cases in the literature and two different pathogeneses - Corrected Proof

2010-02-05

Abstract: Background: Aortic aneurysms including dissection are uncommon complications of systemic lupus erythematosus, but the incidence has been increasing with an improved prognosis for this disease. However, the mechanisms contributing to aneurysm formation in systemic lupus erythematosus have not been fully clarified.Methods: A meta-analysis of published cases was conducted to clarify the patient characteristics that may contribute to aneurysm formation in systemic lupus erythematosus. A search of relevant studies published over the past 40 years (1969–2008) was carried out in the publications on aortic aneurysms with systemic lupus erythematosus, and 35 cases were identified. The contributing factors to aneurysm formation as well as the patient prognosis were searched for sex, age, duration of corticosteroid treatment, aneurysm site (thoracic and/or abdominal), mortality, evidence of atherosclerotic involvement, and presence or absence of an operation, rupture, dissection, cystic medial degeneration, vasculitis, and hypertension. Each of these factors was assigned to each point score. Based on the point scores, a statistical analysis of rank correlation was thereafter performed.Results: The factors correlating with the presence of thoracic or abdominal lesions differed significantly. The presence of thoracic aneurysms correlated with dissection and cystic medial degeneration, whereas abdominal lesions correlated with the finding of atherosclerosis. Thoracic lesions showed a high rate of death, while abdominal lesions were associated with a relatively favorable prognosis. Abdominal lesions were related to the duration of steroid therapy. The other correlations among the various factors were also evaluated, with the finding of cystic medial degeneration associated with vasculitis.Conclusion: Two principal patterns emerged from this analysis. One was the fatal nonatherosclerotic thoracic aneurysm which was associated with cystic medial degeneration and probably due to vasculitis. The other was atherosclerotic abdominal aneurysm which was complicated by long-term steroid treatment and it showed a relatively favorable prognosis.

The Society for Cardiovascular Pathology celebrating 25 disruptively exciting years - Corrected Proof

Bruce McManus — 2010-02-05

Abstract: It was 25 years ago when the Society for Cardiovascular Pathology was first organized. The Society has since devoted itself to the advancement of understanding about heart and blood vessel disorders, especially their diagnosis, and for the improvement of prevention, management, and treatment. In this 25 year span, the Society has accomplished many goals and met its initial commitments as an organization, dedication to education and learning, and to collegiality. With the many exciting steps the Society has taken in the first 25 years, it is sure to move to new and significantly transformative endeavours in the coming decades.

Congenital stridor and wheezing as harbingers of the del22q11.2 syndrome presenting cardiovascular malformations of right aortic arch, aberrant left subclavian artery, Kommerell's diverticulum, and left ligamentum arteriosum - Corrected Proof

2010-02-03

Abstract: A complete vascular ring composed of right aortic arch, aberrant left subclavian artery with Kommerell's diverticulum, and left ligamentum arteriosum was diagnosed by barium esophagography, echocardiography, angiography, and multidetector computed tomography of chest in an 18-day-old male neonate who presented with remarkable inspiratory stridor, expiratory wheezing, postprandial vomiting, and dysphagia since birth, and survived surgical division of the left ligamentum arteriosum, resection of the Kommerell's diverticulum, and reimplanation of the left subclavian artery to the left common carotid artery. Cytogenetic analysis and fluorescence in situ hybridization study of his blood revealed chromosome 22q11.2 deletion, with a karyotype of 46,XY.ish del(22)(q11.2 q11.2). A constellation of right aortic arch, aberrant left subclavian artery with Kommerell's diverticulum, and left ligamentum arteriosum in neonates may cause refractory stridor, wheezing, vomiting, and dysphagia, which can serve as harbingers of the del22q11.2 syndrome.

Aneurysms in the arteries of the upper extremity in a Kenyan population - Corrected Proof

Julius A. Ogeng'o, Beda Otieno — 2010-02-03

Abstract: Background: Aneurysms in the arteries of the upper extremity are rare but important in predicting aortic aneurysms and their potential to thromboembolize and cause limb loss. Their localization, age, and gender distribution vary between countries depending on ethnic background and cause. These data are valuable in the management of aneurysms, but are largely lacking from the Kenyan population.Objective: This study aimed at examining the pattern of these aneurysms in a Kenyan population.Study Design: Retrospective.Setting: Kenyatta National Hospital, Kenya.Patients and Methods: Hospital records of aneurysms in upper limb arteries over 10 years from January 1998 to December 2007 were examined. Ethical approval was given by the Kenyatta National Hospital Ethics and Research Committee. Site, age, gender, and risk factors were recorded. Unconfirmed diagnoses were excluded. Results were analyzed using SPSS 11.50 and presented using tables.Results: Aneurysms of the upper extremity arteries comprise 34 (35.4%) out of 96 peripheral aneurysms. Of these, brachial artery was the most common site (35.3%), followed by brachiocephalic (11, 32.4%), subclavian (9, 26.5%), radial (1, 2.9%), and anterior interosseous (1, 2.9%). Trauma was the commonest predisposing factor (41.2%), followed by atherosclerosis and related comorbidities (32.4%), infection (11.8%), and autoimmune disease (8.8%). The mean age was 39.5 years (range: 13–79) with a variable gender distribution.Conclusion: Aneurysms of the upper extremity arteries are not uncommon in the Kenyan population. They occur more commonly in individuals aged 50 years and less, and although most of them are traumatic, atherosclerosis constitutes a significant proportion. Prudent management of risk factors is recommended.

The infarcted cardiac microenvironment cannot selectively promote embryonic stem cell differentiation into cardiomyocytes - Corrected Proof

You-Ren Chen, Yang Li, Li Chen, Xin-Chun Yang, Pi-Xiong Su, Jun Cai — 2010-02-01

Abstract: Postinfarct congestive heart failure is one of the leading causes of morbidity and mortality in industrialized countries. It is controversial whether embryonic stem cells are feasible sources for in situ cardiac regeneration in infarcted hearts. In order to investigate whether the infarcted cardiac microenvironment could selectively promote embryonic stem cell differentiation into cardiomyocytes, we assessed the cardiac differentiation potential of mouse embryonic stem cells (mESCs) injected into normal (n=16) or acutely infarcted rat hearts (n=18). We found that the transplanted 4′,6-diamidino-2-phenylindole (DAPI)-labeled mESCs were able to survive and form stable intracardiac grafts both in normal and infarcted hearts, along with macrophages found specifically in the engraftment area. Two to four weeks after mESC transplantation, we found that more DAPI-positive mESCs differentiated into cardiomyocytes, marked by cardiac troponin T (cTnT), in normal than those in infarcted hearts (2.67±0.79% vs. 1.06±0.52%, P .05), when the transverse striation began to present in the mESCs-derived cardiomyocytes. In addition, mESCs differentiated into vimentin-positive cardiac fibroblasts in normal and infracted hearts. Our results indicated that transplanted mESCs cannot only survive but differentiate into cardiomyocytes in infarcted rat hearts. However, the infarcted cardiac microenvironment cannot selectively promote mESCs differentiation into cardiomyocytes.

Primary malignant mesothelioma of the pericardium - Corrected Proof

Junaid Patel, Mary N. Sheppard — 2010-02-01

Abstract: Primary malignant pericardial mesothelioma is an extremely rare tumor. One of the largest autopsy series gave an incidence of primary pericardial tumors of 0.0022%, of which mesothelioma is the most common type. A male predominance of the disease has been described, and the majority of cases occur in the fourth to seventh decades of life. Unlike peritoneal and pleural mesothelioma, there has been no definite correlation between asbestos exposure and pericardial disease. Malignant pericardial mesothelioma carries a poor prognosis with few successful treatment strategies and little benefit from radiation and chemotherapy. We report a case of a 66-year-old man who presented with shortness of breath, right shoulder pain, and peripheral edema of the lower limbs. A large pericardial effusion was seen on echocardiography, which was drained but the patient died the following day. A malignant tumor was found on autopsy and a final diagnosis of primary malignant pericardial mesothelioma was made following histopathological examination.

Proteome changes in CaMKIIδC-overexpressing cardiac myocytes - Corrected Proof

2010-01-21

Abstract: Recent studies have demonstrated that the expression as well as the activity of Ca/calmodulin-dependent protein kinase IIδC (CaMKIIδC) is increased in heart failure. Transgenic overexpression of CaMKIIδC in mouse hearts results in severe dilated cardiomyopathy. So far, little is known about CaMKIIδC-induced changes in gene expression and proteome alteration. We hypothesize that proteome changes similar to those found in advanced heart failure can be assessed even after short term overexpression of CaMKIIδC in an in vitro culture model. Thus, we designed a study using a proteomic approach combined with adenovirus-mediated gene transfer of CaMKIIδC to identify early CaMKIIδC-induced changes in cardiac myocyte phenotype on proteome level. CaMKIIδC was overexpressed by adenovirus-mediated gene transfer in isolated cardiac myocytes of adult rabbits for 48 h. Proteome changes were analyzed by two-dimensional gel electrophoresis and mass spectrometry (MS). Overexpression of CaMKIIδC resulted in a decreased expression of 21 proteins (at least twofold change of expression, P<.05, n=10). Using in-gel digest and MS, we identified 13 out of these 21 proteins. CaMKIIδC overexpression leads to a reduced abundance of NADH dehydrogenase, lactate dehydrogenase, pyruvate kinase, dihydrolipoamide succinyltransferase, creatine kinase M, heat shock protein 70, elongation factor Tu, and superoxide dismutase. The profile of the proteome changes induced by CaMKIIδC overexpression after 48 h displayed striking alterations of metabolic proteins, cell-protecting proteins including antioxidants, and proteins involved in protein synthesis. Interestingly, the observed proteome changes are in common with the phenotype of failing cardiac myocytes on the protein level. These altered proteins may act individually as contributors to heart failure, which is observed after overexpression of CaMKIIδC in genetically altered mice.

Remodeling of cardiac fibroblasts following myocardial infarction results in increased gap junction intercellular communication - Corrected Proof

Yan Zhang, Evelyn M. Kanter, Kathryn A. Yamada — 2010-01-21

Abstract: Background: We have recently shown that native murine ventricular fibroblasts express both connexin43 (Cx43) and Cx45, and that the level of Cx43 expression influences intercellular coupling and cell proliferation. Relatively little is known, however, about how myocardial infarction (MI) influences expression of Cx43, or how altered Cx43 expression may affect fibroblast function post-MI. Fibroblasts are critical for infarct healing and post-infarct ventricular remodeling. They can couple electrically with cardiac myocytes and influence myocardial activation patterns. Thus, Cx43 remodeling and the level of intercellular communication in fibroblasts expressed in the infarcted heart were the subject of the present investigation.Methods: Fibroblasts were isolated from both infarct scar and remote, noninfarcted regions of murine hearts 6 d after coronary ligation. Expression levels of Cx43, α-smooth muscle actin and N-cadherin were quantified by immunoblotting. Gap junctional intercellular communication was quantified by Lucifer yellow dye transfer.Results and Conclusions: Fibroblasts isolated from infarcted hearts exhibited marked up-regulation of Cx43 protein expression and enhanced intercellular coupling. Exogenous administration of transforming growth factor-β (TGF-β) to fibroblast cultures from normal, non-operated hearts produced comparable up-regulation of Cx43, suggesting that increased intercellular communication between fibroblasts in infarct and peri-infarct regions may be secondary to activation of a TGF-β pathway. Unlike cardiac myocytes that down-regulate Cx43, presumably to limit intercellular transmission of biochemical mediators of ischemic injury, fibroblasts may up-regulate Cx43 to maintain electrical and metabolic coupling at a time when intercellular communication is compromised.

DNA repair gene polymorphism is associated with the genetic basis of atherosclerotic coronary artery disease - Corrected Proof

2010-01-21

Abstract: Background: Atherosclerotic coronary artery disease (CAD) is a multifactorial process that appears to be caused by the interaction of environmental risk factors with multiple predisposing genes. It is nowadays accepted that increased levels of DNA damage induced by xenobiotics play an important role in the early phases of atherogenesis. Therefore, in this study, we focus on determining whether genetic variations in xenobiotic-metabolizing [glutathione-S-transferase theta 1 (GSTT1), glutathione-S-transferase mu 1 (GSTM1), cytochrome P450 IIEI (CYP2E1)] and DNA repair [X-ray cross-complementing group 1 (XRCC1)] genes might be associated with increased risk for CAD.Methods: A case-control study was conducted with 400 individuals who underwent subjected to coronary angiography. A total of 299 were patients diagnosed with effective coronary atherosclerosis (case group; >20% obstructive lesion), and 101 (control group) were individuals diagnosed as negative for CAD (<20% obstructive lesions). The polymorphism identifications for GSTM1 and GSTT1, and for CYP2E1 and XRCC1 genes were performed by polymerase chain reaction (PCR) amplification and by PCR-RFLP, respectively.Results and conclusions: The XRCC1 homozygous wild-type genotype Arg/Arg for codon 399 was statistically less pronounced in the case subjects (21.4%) than in controls (38.5%); individuals with the variant XRCC1 genotype had a 2.3-fold increased risk for coronary atherosclerosis than individuals with the wild-type genotype (OR=2.3, 95% CI=1.13–4.69). Conversely, no association between GSTM1, GSTT1, and CYP2E1gene polymorphisms and coronary atherosclerosis was detected. The results provide evidence of the role of DNA damage and repair in cardiovascular disease.

Collagen stimulates discoidin domain receptor 1-mediated migration of smooth muscle cells through Src - Corrected Proof

Katherine Kun Lu, Dan Trcka, Michelle P. Bendeck — 2010-01-21

Abstract: Background: Discoidin domain receptor 1 (DDR1) is a collagen-binding receptor tyrosine kinase which mediates the migration and proliferation of several cell types. DDR1 is expressed in vascular smooth muscle cells (SMCs) during atherosclerosis and following vascular injury, mediating cell migration and contributing to disease pathogenesis. However, very little is known about the signaling pathways activated by the DDR1 in SMCs. Therefore we have studied the involvement of Src and mitogen-activated protein kinase (MAPK) signaling pathways downstream of DDR1 in vascular SMCs.Methods: Cells harvested from DDR1−/−, DDR1+/+ mice, and DDR1+/+ cells overexpressing human DDR1b (O/hDDR1b) were used for these studies.Results: Stimulation of O/hDDR1b cells with type I collagen resulted in increased tyrosine phosphorylation of DDR1. The non-receptor kinase Src co-immunoprecipitated with DDR1, and the Src inhibitor PP2 inhibited type I collagen-induced tyrosine phosphorylation of DDR1. Stimulation of DDR1-expressing cells with collagen resulted in the activation of extracellular signal-regulated kinase 1/2 (ERK1/2); however, ERK1/2 was not activated in DDR1-deficient cells. By contrast, p38 MAPK (p38) was activated by collagen stimulation in both DDR1-expressing and DDR1-deficient cells. Treatment with PP2 attenuated DDR1-dependent ERK1/2 activation, but not p38 activation. Finally, treatment of SMCs with PP2, or the MEK inhibitor PD98059, inhibited migration toward type I collagen in a chemotaxis chamber. However, PP2 but not PD98059 had a greater effect in reducing the migration of DDR1+/+ cells compared to DDR1−/− cells, suggesting that Src but not ERK1/2 was important in regulating DDR1-dependent SMC migration.Conclusions: Type I collagen induces SMC migration through DDR1 and this is mediated via Src signaling.

Atrial myocardial nox2 containing NADPH oxidase activity contribution to oxidative stress in mitral regurgitation: potential mechanism for atrial remodeling - Corrected Proof

2010-01-18

Abstract: Background: Oxidative stress is linked with several cardiovascular diseases. However, the NADPH oxidase activity in severe mitral regurgitation patients with and without atrial fibrillation has not yet been explored.Methods: This study involved 16 adult patients (eight patients with persistent atrial fibrillation and eight with sinus rhythm) with severe mitral and moderate-to-severe tricuspid regurgitation and five control patients without mitral and tricuspid disease. Atrial tissues of the right and left atrial appendages were obtained during surgery. Superoxide anion production was measured by lucigenin-enhanced chemiluminescence, and the expression of nox2 containing NADPH oxidase mRNA was measured by quantitative real-time RT-PCR. Additionally, immunohistochemical study was performed.Results: NADPH-stimulated superoxide release was significantly higher than basal superoxide production from right [5671.9±3498.7 vs. 232.7±70.0 relative light units per second per milligram of protein (RLU s−1 mg protein−1), P=.008) and left atrial homogenates (6475.1±1890.8 vs. 229.0±79.6 RLU s−1 mg protein−1, P=.008) in atrial fibrillation patients. The NADPH-stimulated superoxide release from right atrial homogenates was also significantly higher than basal superoxide production in sinus patients (6809.1±1327.1 vs. 244.2±65.5 RLU s−1 mg protein−1, P=.008). Additionally, there was a borderline significant correlation between NADPH-stimulated superoxide production from left atrial homogenates and left atrial sizes (r=0.683, P=.062) in atrial fibrillation patients. Membrane-bound nox2 containing NADPH oxidase mRNA expression was increased and was similar in both the atrial fibrillation patients and sinus patients. The NADPH-stimulated superoxide production in right atrial homogenates in control atrial samples was 1863.7±137.2 RLU s−1 mg protein−1. Immunohistochemical study demonstrated increased expression of nox2 in myocytes with moderate-to-severe myolysis and hypertrophy.Conclusions: Results of this study demonstrate that membrane-bound nox2 containing NADPH oxidase activity and expression in the atrial myocardium is increased in patients with severe mitral regurgitation, possibly contributing to atrial remodeling in this clinical setting.

Cardiac infections: focus on molecular diagnosis - Corrected Proof

Fiorella Calabrese, Elisa Carturan, Gaetano Thiene — 2010-01-13

Abstract: The role of different types of infections in heart diseases is more important than commonly thought, with new and re-emerging infections (i.e., Mycobacterium tuberculosis).This review addresses the pathology of infective pericarditis, myocarditis, and endocarditis, mainly focusing on the significance of molecular techniques in the detection of infective agents. Molecular investigations represent important ancillary diagnostic tools and combined with other conventional approaches provide a more precise final diagnosis. A close collaboration and communication among cardiologists, cardiac surgeons, pathologists, and microbiologists is essential to ensure optimal diagnoses and management as well as a favorable impact on patient outcome.

AECVP and SCVP 2009 Recommendations for Training in Cardiovascular Pathology - Corrected Proof

2010-01-13

Abstract: Cardiovascular disease is of continuing importance as the result of a growing burden of risk factors in both developing and developed countries and the increasing number of elderly people worldwide. The recruitment and training of a new generation of Cardiovascular Pathologists is crucial to sustaining clinical excellence and to advancing our knowledge of cardiovascular disease. These pathologists will also have a key role in undergraduate and postgraduate training. In 2005 a task force of the Society for Cardiovascular Pathology published a document on the role of Cardiovascular Pathology as subspecialty of Anatomical Pathology (Pathological Anatomy). The 2005 report emphasized the need for a core curriculum and structured learning for residents and fellows in Cardiovascular Pathology. This new consensus statement on training is the result of collaboration between Cardiovascular Pathology Societies based in Europe and North America. It includes a detailed curriculum and describes three levels of expertise that can be developed.

Molecular basis and diagnosis of both inherited and acquired cardiovascular diseases: introduction - Corrected Proof

Gaetano Thiene — 2010-01-08

The long wave of molecular biology, since the discovery of DNA and the processing of genetic information to protein synthesis followed by the introduction of polymerase chain reaction, with the ability to clone DNA and RNA, has influenced cardiovascular medicine with major clinical impact.

Adult congenital heart disease—challenges and opportunities for pathologists - Corrected Proof

Bruce McManus — 2010-01-08

Abstract: Adults living with congenital heart disease (CHD) are numerous, at a prevalence of about four per 1000 population. Many of these patients are now over the age of 40 years. Typically, these adult CHD patients have had or require one or more invasive interventions, and thus most of them have modified anatomy and physiology. Despite professional education programs aimed at cardiologists, surgeons, radiologists, pathologists, and others to improve awareness of “grown-up kids” with CHD, there is still a paucity of caregivers who feel competent with these patients. An appreciation by pathologists of the main types of clinically modified congenital lesions seen in adult patients with CHD is of great importance in terms of helping clinicians understand why patients ultimately die (often prematurely) and in explaining the dysfunction and deterioration of biomaterials and devices required for care.Among the most common lesions observed in adults, atrial and ventricular septal defects, patent ductus arteriosus, coarctation of the aorta, tetralogy of Fallot, pulmonary atresia, transposition of the great arteries, single ventricle and Fontan circulation, and Ebstein anomaly are especially worthy of mention. General considerations needing attention for patients with adult CHD include tracking and follow-up, pregnancy guidance and counseling, noncardiac surgery risks, thrombosis, pulmonary hypertension, endocarditis risk, and arrhythmia management. Pathologists may contribute to supporting the families who are affected. As well, many of the adult patients with CHD now live long enough to develop atherosclerosis and all of its attendant morbidities and pathologies.

Protein kinase G activity prevents pathological-level nitric oxide-induced apoptosis and promotes DNA synthesis/cell proliferation in vascular smooth muscle cells - Corrected Proof

Janica C. Wong, Ronald R. Fiscus — 2010-01-08

Abstract: Background: Protein kinase G (PKG), a recognized downstream mediator of nitric oxide, is a key regulator of cardiovascular physiology and pathology. High-level stimulation of cyclic guanosine monophosphate/PKG signaling using high concentrations of nitric oxide donors, mimicking pathological conditions, induces apoptosis in vascular smooth muscle cells. In contrast, we have found that PKG at basal and moderately elevated activity prevents both spontaneous and toxin-induced apoptosis in many other cells. We hypothesized that PKG's apoptosis-regulatory role in vascular smooth muscle cells depends on PKG activation levels [low/basal-level activation prevents apoptosis, whereas high-level activation (hyperactivation) causes apoptosis]. Furthermore, we hypothesized that, although PKG hyperactivation inhibits vascular smooth muscle cell proliferation (potentially causing anti-atherogenic effects), basal PKG activity may promote vascular smooth muscle cell proliferation/atherogenesis.Methods: Involvement of PKG in apoptosis and proliferation was determined in unpassaged vascular smooth muscle cells from mouse aorta. Western blot analysis was used to determine PKG expression, and activators/inhibitors of PKG activity were used to determine involvement in apoptosis (Hoechst staining and DNA-fragmentation ELISAs) and proliferation (cell count, MTT assay, and BrdU incorporation).Results: Both PKG-Iα and PKG-Iβ isoforms were expressed. Lower-level stimulation of PKG using the nitric oxide donor S-nitroso-acetylpenacillamine (10, 50 μM) significantly (P<.05) lowered spontaneous apoptosis, whereas S-nitroso-acetylpenacillamine at higher concentrations (500, 1000 μM) elevated apoptosis. Twenty-four-hour pretreatment with atrial natriuretic peptide, a PKG activator, completely prevented high-concentration, nitric oxide-induced apoptosis. Inhibition of basal PKG activity using highly selective PKG inhibitors, DT-2 and DT-3, significantly (P<.001) increased apoptosis and inhibited DNA synthesis/proliferation.Conclusion: The data suggest that basal/moderately elevated PKG activity protects against high/pathological-level nitric oxide-induced apoptosis and promotes DNA synthesis/proliferation in vascular smooth muscle cells, potentially important for atherogenesis.

Immunohistochemical evaluation of three nitric oxide synthase isoforms in human saphenous vein exposed to different degrees of distension pressures - Corrected Proof

2010-01-08

Abstract: The effect of short duration and different degrees of distension pressures was investigated by means of immunohistochemistry of the three nitric oxide synthase isoforms in the human saphenous vein conventionally harvested from 20 patients submitted to coronary artery bypass graft. The human saphenous vein distal portion was divided into four segments, each one allocated to a different group. In Group I (control group), the human saphenous vein segment was not exposed to distension pressure. In Groups II, III, and IV, the human saphenous vein segment was exposed to 100, 200, and 300 mmHg of distension pressure, respectively. The distension pressures were applied and maintained with Krebs solution for 15 s. The human saphenous vein of the control group presented endothelial nitric oxide synthase and neuronal nitric oxide synthase in both endothelial and smooth muscle cells, while the inducible nitric oxide synthase appeared predominantly in the medial layer. Neither 100 nor 200 mmHg of pressurization affected the immunostaining of any nitric oxide synthase isoform. However, the human saphenous vein segments exposed to 300 mmHg of distension pressure showed a reduction in endothelial nitric oxide synthase content in the endothelium, but not in the tunica media. This lower endothelial nitric oxide synthase immunostaining in the intimal cells was associated with endothelial denudation. Therefore, we conclude that care should be taken when handling the human saphenous vein since just a few seconds of distension pressure above the normal systemic pressure can be sufficient to disrupt the endothelium reducing the amount of endothelial nitric oxide synthase and impairing the graft quality.

Primary cardiac tumors: a clinicopathologic evaluation of four cases - Corrected Proof

2010-01-08

Abstract: Introduction: We report the clinical, pathological, and immunohistochemical features of four primary malignant cardiac tumors identified at the Department of Pathology, Rigshospitalet, Denmark. A panel of immunohistochemical markers for classification is proposed.Methods: Between 2000 and 2008, four patients with malignant cardiac tumors were treated at our hospital. We retrospectively reviewed the medical records and evaluated the patient characteristics and treatment.Results: Three patients presented with severe dyspnea; one patient presented with chest pain. Transthoracic echocardiography demonstrated, in all four cases, abnormal masses in the atria. The cases were, based on morphological features and immunoprofile, classified as myogenic sarcoma (two cases), undifferentiated pleomorphic sarcoma, and leiomyosarcoma. Three of the patients received orthotopic heart transplantation. One patient survived 6.5 years after the diagnosis, and two patients are still alive 2 and 3 years after being diagnosed, respectively.Conclusions: All four cases were sarcomas. A limited number of immunohistochemical markers can be used in order to define a specific line of differentiation. In this small study, three of the patients were offered orthotopic heart transplantation, and the survival times were generally longer than in most series.

Arrhythmogenic right ventricular cardiomyopathy: new insights into mechanisms of disease - Corrected Proof

Jeffrey E. Saffitz, Angeliki Asimaki, Hayden Huang — 2010-01-06

Abstract: Arrhythmogenic right ventricular cardiomyopathy is a primary heart muscle disorder characterized by the early occurrence of arrhythmias often out of proportion to the extent of structural remodeling and contractile derangement. Approximately 40% of patients with arrhythmogenic right ventricular cardiomyopathy have one or more mutations in genes encoding proteins in desmosomes, intercellular adhesion junctions which, in cardiac myocytes, reside within intercalated disks. Some desmosomal proteins fulfill roles both as structural proteins in cell–cell adhesion junctions and as signaling molecules in pathways mediated by Wnt ligands. Evidence is increasing that mutations in desmosomal proteins can perturb the normal balance of critical proteins in junctions and the cytosol which, in turn, could alter gene expression by circumventing normal Wnt signaling pathways. This review highlights recent advances in understanding the pathogenesis of arrhythmogenic right ventricular cardiomyopathy and presents evidence suggesting that the disease is caused by a combination of altered cellular biomechanical behavior and altered signaling.

Aspergillus pancarditis manifesting as hospital-acquired infection: Report of two cases and review of literature - Corrected Proof

Pradeep Vaideeswar — 2009-12-17

Abstract: Nosocomial cardiac infections are most often related to interventions performed within the preceding one to two months of hospital admission and usually affect the endocardium or prosthetic devices. These can be sometimes caused by fungi, especially the molds. This is a report of rare fungal pancarditis seen as hospital-acquired infection in two patients who were admitted in the intensive care unit for leptospirosis. The cardiac manifestation was part of systemic mycosis; mechanical ventilation, administration of steroids and hepatorenal failure were the risk factors. Incidentally, both the patients had underlying intrinsic cardiac disease.

Common pathogenic features of atherosclerosis and calcific aortic stenosis: role of transforming growth factor-β - Corrected Proof

Songyi Xu, Amber C. Liu, Avrum I. Gotlieb — 2009-11-30

Abstract: Calcific aortic stenosis and atherosclerosis have been investigated separately in experimental in vitro and in vivo studies and in clinical studies. The similarities identified in both diseases suggest that similar pathogenic pathways are involved in both conditions. Most current therapeutic studies are focused on statins. The evidence suggests that statin effects on valves may, in large part, be independent of the lipid lowering effects of the drug. There are several molecules that play significant regulatory roles on the development and progression of valve sclerosis and calcification and on growth and complications of atherosclerotic plaques. The purpose of this review is to discuss the pathogenic features of the two conditions, highlight the important similarities, and then review the data that suggest that transforming growth factor-β may play a key regulatory role in both diseases and that this is worthy of study as a potential therapeutic target for both conditions.

Prosthetic valve endocarditis: clinicopathological correlates in 122 surgical specimens from 116 patients (1985–2004) - Corrected Proof

2009-11-20

Abstract: Background: Few studies have documented the clinicopathological features of prosthetic valve endocarditis independently of native valve endocarditis.Study Design: Retrospective analysis of patients undergoing cardiac surgery for prosthetic valve endocarditis at our institution (1985–2004).Methods: Medical records and microscopic slides were reviewed from 116 patients for demographics, infecting organisms, comorbidities, and pathologic features.Results: Patients were 12–86 years old (mean, 59 years). Among 122 valves, 64% were from men and 67% were purely regurgitant. Aortic prosthetic valve endocarditis frequently affected men (76%); mitral prosthetic valve endocarditis often affected women (62%). Embolization occurred in 35% and heart failure in 32%. Prevalent predisposing conditions were the prosthetic valve alone (43%) and diabetes mellitus (20%). Prosthetic valve endocarditis was aortic or mitral in 98% and was active in 70%. Annular abscess or paravalvular leak affected mechanical valves more frequently than bioprosthetic (89% vs. 65%; P=.001). Causative organisms (n=116) included Staphylococcus aureus (30%), coagulase-negative staphylococcus (22%), viridans streptococci (18%), enterococci (10%), other streptococci (8%), and other organisms (12%). S. aureus was the most prevalent cause of early-onset (38%) and late-onset (30%) prosthetic valve endocarditis. Coagulase-negative staphylococcus caused early-onset (31%) and most intermediate-onset (40%) disease and had a shorter median implantation-to-infection time than other organisms (6.5 vs. 61.3 months; P<.001). Viridans streptococci and enterococci primarily caused late-onset endocarditis. For active infections by cocci, most cases exhibited strong Gram staining, but four showed only strong Grocott methenamine silver staining.Conclusions: Cocci accounted for 83% of infections. Early-onset prosthetic valve endocarditis was primarily staphylococcal, and late-onset prosthetic valve endocarditis resembled native valve endocarditis. Both Gram and Grocott methenamine silver stains were necessary to reliably identify organisms microscopically.

Causes and histopathology of ascending aortic disease in children and young adults - Corrected Proof

2009-11-20

Abstract: Background: Ascending aortic diseases (aneurysms, dissections, and stenosis) and associated aortic valve disease are rare but important causes of morbidity and mortality in children and young adults. Certain genetic causes, such as Marfan syndrome and congenital bicuspid aortic valve disease, are well known. However, other rarer genetic and nongenetic causes of aortic disease exist.Methods: We performed an extensive literature search to identify known causes of ascending aortic pathology in children and young adults. We catalogued both aortic pathologies and other defining systemic features of these diseases.Results: We describe 17 predominantly genetic entities that have been associated with thoracic aortic disease in this age group.Conclusions: While extensive literature on the common causes of ascending aortic disease exists, there is a need for better histologic documentation of aortic pathology in rarer diseases.

Sally Patricia Allwork (June 14, 1938–July 12, 2009) - Corrected Proof

Robert H. Anderson, Stephanie Taylor, Gaetano Thiene — 2009-11-20

After a short illness of rapid onset, Sally Allwork passed away on the July 12, 2009. Sally achieved her ultimate position as a morphologist despite the lack of an initial traditional university education. Her mother was Italian in origin. She left school at the age of 16 after taking her 'O' level examinations. She became an Almoners' Clerk at The Central Middlesex Hospital, continuing her studies in the evenings so as to obtain the necessary qualifications to become a laboratory technician. She was appointed as a student technician at The Hammersmith Hospital and eventually achieved a position as a technician working in the operating rooms. It was there that she met her life-long mentor, Professor Hugh Bentall. Under his subsequent tutelage, she began to prepare homograft heart valves, but technical work did not satisfy her inquiring mind. So, encouraged by Hugh, she studied anatomy under Professor Tony Glenister at The Charing Cross Hospital Medical School, passing an examination on basic anatomy and laboratory procedures which made her eligible to complete further studies. These produced a thesis qualifying for the degree of Master of Philosophy, and following this, another thesis on the functionally univentricular heart, which resulted in the award of Doctor of Philosophy from the University of London.

Heterogeneity of atherosclerosis in mesenteric arteries and outgrowth remodeling - Corrected Proof

2009-11-19

Abstract: Background: In patients with acute mesenteric ischemia by occlusive thrombo-embolism, the superior mesenteric artery (SMA) is more affected than the inferior mesenteric artery (IMA).Methods: This study investigated postmortem mesenteric arteries from aged subjects (n=21). Four atherosclerotic stages were defined by signs of degeneration and inflammation in sections stained with Elastica-van-Gieson and immunohistology, respectively.Results: In females and males, Stages 3 and 4 were found in 62% of the SMA and 24% of the IMA. Lumenal areas based on diameter measurements remained essentially unchanged between Stages 1 and 4. Compared to a Stage 1 reference, remodeling was associated with thinning of the media below the plaque base and with pronounced thickening below the shoulder in the IMA. In Stages 3 and 4, the adventitia of the IMA had more vasa vasorum and a higher number of CD45-positive leukocytes than the adventitia of the SMA. During atherosclerotic progression, a stable fraction of leukocytes represented mast cells (6%) and CD117-positive cells as potential progenitor cells (1%).Conclusions: Outgrowth remodeling occurred in both the SMA and the IMA. Less severe atherosclerosis in the IMA than in the SMA was associated with stronger signs of inflammation.

Activator protein-1 in carotid plaques is related to cerebrovascular symptoms and cholesteryl ester content - Corrected Proof

2009-11-18

Abstract: Introduction: Transcription factor activator protein-1 regulates genes involved in inflammation and repair. The aim of this study was to determine whether transcription factor activator protein-1 activity in carotid plaques is related to symptoms, lipid accumulation, or extracellular matrix composition.Methods: Twenty-eight atherosclerotic carotid plaques were removed by endarterectomy and divided into two groups based on the presence or absence of ipsilateral symptoms (<1 month ago). Activator protein-1 DNA binding activity was assessed, and subunit (c-Jun, JunD, JunB, c-Fos, FosB, Fra-1, Fra-2) protein levels analyzed by immunoblotting. Distribution of c-Jun in plaques was analyzed by immunohistochemistry.Results: Plaques associated with symptoms had increased activator protein-1 activity and increased expression of c-Jun and JunD, as compared to asymptomatic plaques. Fra-1 and Fra-2 were present in equal amounts in both groups, whereas JunB, FosB, and c-Fos were undetectable. Activator protein-1 activity correlated with cholesteryl ester and elastin in plaques and decreased with age. Activator protein-1 activity did not correlate with collagen, calcified tissue, or proteoglycan content.Conclusions: Activator protein-1 is increased in plaques associated with symptoms. The correlation between activator protein-1 and cholesteryl esters suggests that high activator protein-1 is a marker of plaque vulnerability. Activator protein-1 expression can also reflect the activation of repair processes.

The heart in Fabry's disease - Corrected Proof

Mary N. Sheppard — 2009-11-18

Abstract: Fabry's disease (FD) is a rare X-linked recessive genetic disorder that leads to premature mortality as a result of renal, cardiovascular, or cerebrovascular complications. FD is caused by a deficiency of α-galactosidase A (alpha-Gal A), due to mutations in the GLA gene. There is an inability to catabolize lipids which results in cellular accumulation of its most abundant substrate, globotriaosylceramide (Gb3), and other neutral glycosphingolipids in vascular endothelium and other tissues throughout the body. This progressive glycosphingolipid accumulation leads to life-threatening clinical sequelae in renal, cardiac, and cerebrovascular systems. In males who carry the mutation (1/40,000), severe multisystem disease develops in childhood or adolescence. Hemizygous male patients have no detectable alpha-Gal activity in tests on plasma and leukocytes confirming the diagnosis. Stroke, seizures, cardiac disorders (conduction disturbances, valve disease, heart failure), and kidney disorders (proteinuria and chronic renal failure) develop in the third or fourth decade of life.Heterozygous FD is less well studied. Women who are heterozygous for the GLA gene can transmit the disease to their sons but may be free of symptoms. They may have moderate or severe disease related to uneven chromosome X inactivation with development of symptoms usually about 15 to 20 years later than males. Due to random X-chromosomal inactivation, enzymatic detection in carriers is often inconclusive with most affected females having normal levels of alpha-Gal A. Late-onset variants with predominant neurological, cardiac, or renal manifestations have been described. Until recently, FD management was symptomatic, but this has changed dramatically with the availability of enzyme replacement therapy (ERT) since 2001. They have been reported to improve clinical symptoms and quality of life. However, limited and controversial data on their efficacy in cardiac involvement have been published with reports of cardiac damage already present in older patients with FD despite use of ERT. There has been a growing awareness that the first signs and symptoms of FD may develop in childhood. Interest is now focused on whether ERT can slow or prevent the onset of these disease manifestations with earlier diagnosis and treatment. This review highlights the cardiac damage in FD and results of ERT use on cardiac disease and function.

A comparative study of myocardial function and morphology during fasting/refeeding and food restriction in rats - Corrected Proof

2009-11-16

Abstract: Background: This study compared the influence of fasting/refeeding cycles and food restriction on rat myocardial performance and morphology.Methods: Sixty-day-old male Wistar rats were submitted to food ad libitum (C), 50% food restriction (R50), and fasting/refeeding cycles (RF) for 12 weeks. Myocardial function was evaluated under baseline conditions and after progressive increase in calcium and isoproterenol. Myocardium ultrastructure was examined in the papillary muscle.Results: Fasting/refeeding cycles maintained rat body weight and left ventricle weight between control and food-restricted rats. Under baseline conditions, the time to peak tension (TPT) was more prolonged in R50 than in RF and C rats. Furthermore, the maximum tension decline rate (−dT/dt) increased less in R50 than in RF with calcium elevation. While the R50 group showed focal changes in many muscle fibers, such as the disorganization or loss of myofilaments, polymorphic mitochondria with disrupted cristae, and irregular appearance or infolding of the plasma membrane, the RF rats displayed few alterations such as loss or disorganization of myofibrils.Conclusion: Food restriction promotes myocardial dysfunction, not observed in RF rats, and higher morphological damage than with fasting/refeeding. The increase in TPT may be attributed possibly to the disorganization and loss of myofibrils; however, the mechanisms responsible for the alteration in −dT/dt in R50 needs to be further clarified.

Post-irradiation pericardial malignant mesothelioma: an autopsy case and review of the literature - Corrected Proof

Matyas Bendek, Miroslaw Ferenc, Nikolaus Freudenberg — 2009-11-16

Abstract: We report a case of a malignant pericardial mesothelioma of the epithelioid type in a 39-year-old man. He had a history of nodular sclerosing Hodgkin's disease treated with irradiation of the cervical and mediastinal regions 24 years before, and of infarction of the anterior wall of the left ventricle, after which a percutaneous coronary intervention was carried out 7 years previously. He was admitted to a cardiology unit with progressive dyspnea. On examination, a hemorrhagic pericardial fluid collection of 600 ml was detected which was successfully drained. On the next day, the patient developed an electromechanical dissociation suggesting a pericardial tamponade, which was followed by circulatory arrest. At autopsy, the pericardial sac was found to contain 300 ml of partly clotted blood. The epicardial surface showed a diffuse thickening, suggesting a chronic fibrous pericarditis without a macroscopically evident distinct tumor mass. A rupture measuring 0.4 cm in diameter was detected in the right ventricular free wall, 1 cm below the level of the tricuspid valve. The diagnosis of a diffusely growing, malignant mesothelioma of the epithelioid type was made on the basis of histological and immunohistochemical examination of the thickened pericardium.

The diameter of liver sinusoidal fenestrae is not a major determinant of lipoprotein levels and atherosclerosis in cholesterol-fed rabbits - Corrected Proof

Frank Jacobs, Eline Van Craeyveld, Yingmei Feng, Bart De Geest — 2009-11-16

Abstract: Background: The liver is a key organ in lipid and lipoprotein metabolism. It has been postulated that a small diameter of sinusoidal fenestrae retards clearance of chylomicron remnants, resulting in hypercholesterolemia and atherosclerosis. However, this hypothesis has not been rigorously tested hitherto.Methods: In the current study, we compared plasma levels of proatherogenic lipoproteins and assessed the development of atherosclerosis at distinct locations throughout the arterial tree in heterozygous New Zealand White and Dutch Belt rabbits that are deficient in low-density lipoprotein receptor and with an average fenestrae size of 103 and 124 nm, respectively.Results: Feeding of a 0.15% cholesterol diet for 4 months resulted in similar total plasma cholesterol levels in New Zealand White (420±20 mg/dl) and Dutch Belt (380±30 mg/dl) rabbits. Following isolation of lipoproteins by ultracentrifugation, no biologically significant differences in very-low-density lipoprotein, intermediate-density lipoprotein, and low-density lipoprotein cholesterol levels were observed between cholesterol-fed New Zealand White and Dutch Belt rabbits. Furthermore, the relative amount of intestinally derived apolipoprotein-B48-containing lipoproteins did not differ significantly between both strains (7.3±0.42% vs. 8.0±0.54%). Atherosclerosis was more pronounced in the thoracic aorta in New Zealand White rabbits than in Dutch Belt rabbits, but the reverse was observed with the abdominal aorta. These topographic differences cannot be explained by circulating lipoprotein levels.Conclusions: The data presented in this study do not support the hypothesis that the diameter of fenestrae is an important determinant of chylomicron remnant levels, diet-induced hypercholesterolemia, and atherosclerosis in cholesterol-fed rabbits.

Impact of intimal pathogen burden in acute coronary syndromes—correlation with inflammation, thrombosis, and autoimmunity - Corrected Proof

2009-11-16

Abstract: Background: Increasing evidence supports a link between serological evidence of pathogen burden (PB) and the risk for future cardiovascular events. Our study evaluates the intimal presence of 4 pathogens in atheroma, clinically associated with acute coronary syndromes (ACS) and stable angina (SA), and the effect on the expression of intimal C-reactive protein (CRP), tissue factor (TF) and human heat-shock protein 60 (hHSP60).Methods: Coronary atherectomy specimens retrieved from 60 primary lesions of patients with ACS (n=35) or SA (n=25) were assessed immunohistochemically for the presence of Chlamydia pneumoniae (Cpn), Helicobacter pylori (HP), Cytomegalovirus (CMV) and Epstein–Barr Virus (EBV) and for the expression of CRP, TF, and hHSP60.Results: Analysis revealed eight lesions without, 22 lesions with one, 19 lesions with two, seven lesions with three, and four lesions with four pathogens. Cpn was present in 73%, HP in 31%, CMV in 16%, and EBV in 40%. Mean value of PB in ACS-lesions was significantly increased. Expressions of CRP, TF, and hHSP60 were significantly higher in ACS lesions. The number of infectious pathogens correlated significant with the expressions of CRP, TF, and hHSP60.Conclusions: Our data demonstrate the impact of PB in plaque instability and suggest local proinflammatory, prothrombotic, and proimmunogenic effects.

Blocking the CD40–CD40L interaction by CD40-Ig reduces disease progress in murine myocarditis induced by CVB3 - Corrected Proof

Han Bo, Liu Zhenhu, Zhao Lijian — 2009-11-16

Abstract: Introduction: CD40 and CD40L, as costimulatory molecules, are reported to play a critical role for cytokine production and antigen-specific T-cell activation in acute viral myocarditis (VMC). The purpose of this study was to probe the therapeutic effect of CD40-Ig in coxsackievirus B3 (CVB3)-induced myocarditis.Methods: Adolescent male Balb/c mice were infected with cardiovirulent CVB3 and then injected with CD40-Ig (0.1 mg/kg) at 6 h and 3 days postinfection (pi), with IgG (0.1 mg/kg) as control. The surviving mice were sacrificed on the seventh day. The copies of CVB3 mRNA in the myocardium were detected by real-time PCR and the expression of CD40 protein and CD4+ T cell was assessed by immunohistochemistry method. The serum level of IL-4 and IFN-γ and their transcriptions in the myocardium were determined by ELISA and real-time PCR.Results: The mortality was low in VMC model mice receiving CD40-Ig treatment with relived inflammation and reduced transcription of CVB3 in the myocardium. The expression pattern of IFN-γ (Th1-related cytokine) and IL-4 (Th2-related cytokine) was altered to Th1 prevalence in the acute phase of VMC. Intervention of CD40-Ig switched the balance of Th1/Th2.Conclusions: Our findings suggest that intervention of CD40-Ig can relieve the myocardial injury and inhibit viral replication of CVB3 in VMC. Its mechanism may involve blocking the interaction between CD40 and CD40L and regulating the Th1/Th2 balance.

Sudden coronary death caused by pathologic intimal thickening without atheromatous plaque formation - Corrected Proof

2009-11-13

Abstract: Background: Atherosclerotic plaques progress from early lesions with little free cholesterol and lipid to late fibroatheromas with necrotic cores that may rupture. The frequency of severe coronary atherosclerosis without core formation in any artery in sudden coronary death is not known.Methods: We studied 314 hearts from 253 men and 61 women who died suddenly from severe coronary stenosis (≥1 epicardial artery with ≥75% luminal area narrowing) and with no other cause of death. If no section demonstrated any necrotic core, the designation was nonatheromatous atherosclerosis; if there was ≥1 necrotic core, the designation was atheromatous atherosclerosis. Plaques were scored for the presence of calcification, intimal inflammation, and neovasculature on a 5-point scale. Plaque burden was estimated semiquantitatively.Results: In 22 men (9%) and 14 women (23%), there were no necrotic cores in any plaque (nonatheromatous atherosclerosis). Fourteen of these 36 nonatheromatous atherosclerosis cases had focal acute thrombus due to erosion (39%). Of the remaining 278 cases (atheromatous atherosclerosis), acute erosions were present in 25 (9%; P 10% of sudden coronary deaths and is more frequent in young Black women. Nonatheromatous atherosclerosis is a relatively infrequent pathway for coronary plaque progression, leading to severe disease and sudden death that may involve plaque erosion.

In memoriam: Margaret E. Billingham, M.D. (1930–2009) - Corrected Proof

Gayle L. Winters — 2009-11-13

The cardiovascular pathology and cardiac transplant communities mourn the death of our dear friend and colleague, Dr. Margaret Billingham, who died of kidney cancer on July 14, 2009, at the age of 78. Dr. Billingham, professor of pathology emeritus and director of cardiac pathology emeritus at Stanford University Medical Center, is best known for her pioneering work in cardiac transplant pathology. Working with Dr. Norman Shumway and Dr. Philip Caves, Dr. Billingham developed criteria for monitoring rejection in heart transplant recipients through pathologic interpretation of endomyocardial biopsies. Her grading system was the basis for the International Society for Heart and Lung Transplantation standardized grading system, formulated in 1990 and revised in 2004, which is used today worldwide to guide immunosuppressive therapy after cardiac transplantation.

A dangerous myxoma - Corrected Proof

Hector I. Michelena, Dylan V. Miller, Hartzell V. Schaff — 2009-10-15

A 38-year-old female presented with worsening migraines complicated by one episode of transient global aphasia. Brain magnetic resonance imaging was suggestive of previous cerebral infarction. Echocardiogram demonstrated a mass in the left atrium suggestive of myxoma, and the patient was referred to our clinic for surgery. Intraoperative transesophageal echocardiogram confirmed a 3.8×1.8-cm echogenic mass in the left atrium (, Panel 1), with prominent frond-like projections (, Panel 2), prolapsing into the left ventricle in diastole (, Panel 3). The mass was attached to the left atrial septum and was excised with its stalk and underlying atrial endocardium; pathologic evaluation confirmed villous/friable atrial myxoma with gelatinous consistency grossly (A). Histologically, there was sparse cellularity and abundant myxoid matrix and the cytoarchitecture showed prominent branching and finger-like projections (H and E, ×12.5) (B and C). Neurologic symptoms as the presenting feature in left atrial myxomas have been reported in 12% of myxoma patients . Myxomas with these tissue characteristics are not common representing 35% of all myxomas and more prone to embolization and thrombus formation which explains the clinical presentation of our patient, with neurologic instead of typical cardiac symptoms. The patient was discharged on the fifth postoperative day and had no new neurologic symptoms at 4-month follow-up.

Extranodal Rosai–Dorfman disease involving the heart: report of two cases - Corrected Proof

Joseph J. Maleszewski, Alexandra C. Hristov, Marc K. Halushka, Dylan V. Miller — 2009-10-12

Abstract: Sinus histiocytosis with massive lymphadenopathy (Rosai–Dorfman disease) is a rare disease that typically occurs in lymph nodes. While many body sites have been reported to be involved in extranodal manifestations of the disease, the cardiovascular system has been largely absent in this literature. We report two cases of Rosai–Dorfman disease that involves the heart. Case 1 was a 40-year-old man with chronic myelomonocytic leukemia who was incidentally noted to have Rosai–Dorfman disease on autopsy after succumbing to respiratory failure in the setting of adult respiratory distress syndrome. Case 2 was a 57-year-old woman known to have Rosai–Dorfman disease involving mediastinal lymph nodes and found to have a right atrial mass on workup for atypical chest pain. Both cases showed a similar histologic picture of large, multinucleated histiocytes with immunoreactivity to S100, emperipolesis, and marked plamacytosis. This study expands our knowledge of organs involved in extranodal Rosai–Dorfman disease.

Detection of nanobacteria-like material from calcified cardiac valves with rheumatic heart disease - Corrected Proof

2009-09-11

Abstract: Background: Nanobacterium contributes to pathological calcification in human renal stones and psammoma bodies in ovarian cancer. Pathological calcification is also present in cardiac valves with rheumatic heart disease. The aim of this study was to detect, isolate, culture, and characterize nanobacteria-like material from human calcified cardiac valves with rheumatic heart disease.Methods: Normal and calcified cardiac valve groups, as well as positive (nanobacteria strain Se90) and negative (serum radiated with 30 kGy of γ-ray) control groups, were included in this study. Part of each valve was immunostained with nanobacterial antibody 8D10, and the remaining parts were homogenized, filtered, and maintained in culture. The cultures were checked with a microscope weekly. Culture medium at different time points was analyzed with a spectrophotometer. The cultures maintained for 3 weeks were further examined with immunofluorescence double staining and transmission electron microscopy.Results: While 26 of 29 calcified valves stained positive for 8D10 antibody, all normal valves stained negative. Mobile tiny particles were observed under a microscope in the calcified valve group and the Se90 group. Optical densities were significantly different among groups (P<.001). Immunofluorescence double staining displayed tiny green fluorescence particles in the calcified valve group, in the Se90 group, and in two samples of the normal valve group. Transmission electron microscopy analysis indicated that cultured particles from calcified valves ranging in size from 88 to 341 nm had an obvious cell membrane structure similar to that of Se90.Conclusions: The nanobacteria-like material has been isolated and cultured from calcified cardiac valves with rheumatic heart disease, and its characteristics are similar to those of Se90.

Respiratory chain deficiency precedes the disrupted calcium homeostasis in chronic doxorubicin cardiomyopathy - Corrected Proof

2009-09-11

Abstract: Background: Doxorubicin causes a chronic cardiomyopathy in which genetic and functional lesions of mitochondria accumulate in the long-term. A disrupted Ca2+ homeostasis is also implicated in doxorubicin cardiotoxicity. We investigated if the alterations in myocellular Ca2+ are primary or secondary to the respiratory chain dysfunction in chronic doxorubicin cardiomyopathy.Methods and Results: A “long-observation group” of rats was treated with intravenous doxorubicin (1 mg/kg per week) for 7 weeks, starting at 11 weeks of age. Controls received equivalents of saline. A “short-observation group” received seven injections of doxorubicin, starting at 41 weeks of age. All rats were euthanized at 48 weeks of age. Only the long-observation rats developed a significant clinical, macroscopic, histological, and ultrastructural cardiomyopathy. Their intramyocardial cytochrome c oxidase (COX) activity was lowest; they had the highest loss of mitochondrial DNA (mtDNA) and its encoded respiratory chain subunit COX I, and the highest amount of ultrastructural and intracellular calcium accumulation resembling hydroxyapatite. The short-term-group hearts had fewer alterations of the cardiomyopathy score, COX-activity, and mtDNA-content than the long-observation group. Despite a measurable loss of mtDNA and its encoded respiratory chain activity, however, there was virtually no detectable calcium accumulation in the hearts of the short-term group.Conclusions: mtDNA depletion and secondary respiratory chain dysfunction precedes the precipitation of mitochondrial calcium deposits in chronic doxorubicin cardiotoxicity.

Molecular mechanisms of congenital heart disease - Corrected Proof

Huang Jing-bin, Liu Ying-long, Sun Pei-wu, Lv Xiao-dong, Du Ming, Fan Xiang-ming — 2009-09-11

Abstract: Background: Congenital heart disease (CHD) is the most common type of birth defect. Despite the many advances in our understanding of cardiac development and many genes related to cardiac development identified, the fundamental etiology for the majority of cases of congenital heart disease remains unknown.Methods: This review summarizes normal cardiac development, outlines the recent discoveries of the genetic causes of CHD, and provides possible strategies for exploring them.Results: CHD is a multifactorial complex disease, with environmental and genetic factors playing important roles. A number of causative genes of selected congenital heart defects and genetic syndromes have been found. The molecular mechanisms of CHD may include mutations in components of the cardiac gene network, altered haemodynamics, regulatory pathway of cardiac genes, micro-RNA dysfunction, epigenetics, adult congenital heart diseases, and so on.Conclusions: The molecular basis of CHD is an exciting and rapidly evolving field. The continuing advances in the understanding of the molecular mechanisms of CHD will hopefully result in improved genetic counseling and care of affected individuals and their families.

Ghrelin inhibits foam cell formation via simultaneously down-regulating the expression of acyl-coenzyme A:cholesterol acyltransferase 1 and up-regulating adenosine triphosphate-binding cassette transporter A1 - Corrected Proof

Bei Cheng, Jingjing Wan, Yanfu Wang, Chunli Mei, Wei Liu, Li Ke, Ping He — 2009-09-11

Abstract: Background: Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), revealed cardioprotective effects in both experimental models and human. There is far less information on the mechanisms that produce antiatherogenic effects. We assessed the expression of acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT-1) and adenosine triphosphate (ATP)-binding cassette transporter A1 (ABCA1), which have been implicated in regulating cellular cholesterol homeostasis and therefore play critical roles in foam cell formation, in THP-1-derived foam cells in the presence of various concentration of ghrelin.Methods: After 48 h of culture in the presence of phorbol myristate acetate, THP-1 monocytes differentiated to macrophages. After another 24 h of culture with ox-LDL, the differentiated cells transformed to foam cells. Different concentrations of ghrelin and other intervention factors were added, respectively. The expression of ACAT-1 and ABCA1 was detected by a technique in molecular biology. The content of cellular cholesterol was measured by zymochemistry via a fluorospectrophotometer.Results: Ghrelin could down-regulate the expression of ACAT-1 and up-regulate the expression of ABCA1 in a dose-dependent manner simultaneously. Ghrelin also decreased cellular cholesterol content and increased cholesterol efflux. These effects could be abolished by the specific antagonist of GHS-R and a peroxisome proliferator-activated receptor γ (PPARγ)-specific inhibitor, respectively.Conclusions: The results suggest that ghrelin inhibited foam cell formation via simultaneously down-regulating the expression of ACAT-1 and up-regulating ABCA1. Those effects may be achieved via pathways involving GHS-R and PPARγ.

Inducibility of atrial fibrillation depends not on inflammation but on atrial structural remodeling in rat experimental autoimmune myocarditis - Corrected Proof

2009-09-11

Abstract: Introduction: There is increasing evidence to support a link between inflammation and atrial fibrillation (AF). However, the role of inflammation on new-onset AF is still to be elucidated.Methods: Rats underwent induction of experimental autoimmune myocarditis (EAM). Atrial structural change was evaluated by echocardiography and histological analysis. Electrophysiological data and the in vivo atrial response to burst atrial pacing were evaluated in the acute (2 weeks after EAM induction) and chronic phases (8 weeks after induction). In addition, atrial pacing after 2, 4, and 6 h after lipopolysaccharide (LPS) infusion, when the expression of gap junctions was modified, were challenged with young healthy rats.Results: AF was induced in 11 of 15 chronic phase EAM rats but not in either acute phase EAM rats or LPS infusion rats (P<.01). Echocardiography showed dilatation of both atrium and ventricle and a decrease in the ejection fraction in the chronic phase. Histology revealed severe inflammatory lesions only in the acute phase. Interstitial atrial fibrosis as well as the area of atrial myocyte increased in the chronic phase but not in the acute phase.Conclusions: AF could be induced in the chronic phase of myocarditis rats, but not in the acute phase of myocarditis rats or in rats with LPS infusion. Acute inflammation per se did not increase the occurrence of AF induction. Atrial structural remodeling caused by inflammation and hemodynamic effects is necessary to induce AF.

Chronic type 1 diabetes in spontaneously hypertensive rats leads to exacerbated cardiac fibrosis - Corrected Proof

2009-09-11

Abstract: Introduction: Diabetes in human subjects is often associated with hypertension. The aim of this study was to examine the development of cardiac fibrosis following induction of type 1 diabetes in genetically hypertensive rats.Methods: Diabetes was induced by streptozotocin (STZ) injection in 8-week-old normotensive Wistar–Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) for a duration of 16 or 24 weeks. Aged-matched, nondiabetic WKY and SHRs were used as controls. At termination of treatment, the rats were anaesthetized, hearts arrested in diastole and perfusion fixed. A comprehensive examination of cardiac fibrosis throughout the right and left ventricles was undertaken in picrosirius red-stained sections, using image analysis and by undertaking collagen type I and type III immunohistochemistry.Results: Induction of diabetes in the SHRs led to a marked increase in the levels of interstitial fibrosis in the left ventricle plus septum (LV+S) at both 16 and 24 weeks duration (59% and 43% increase, respectively) and also in the right ventricle after 24 weeks duration of diabetes (35% increase compared to the nondiabetic SHR). Exacerbated perivascular fibrosis was also observed in the LV+S in the diabetic-hypertensive rats at the later time point. These effects of induction of diabetes were not observed in the normotensive strain.Conclusions/Interpretation: Our findings clearly demonstrate elevations in cardiac fibrosis when type 1 diabetes is combined with hypertension. Our findings thus stress the importance of closely monitoring both blood pressure and glucose levels in type 1 diabetic patients in order to prevent myocardial collagen deposition.

Pathology of late-onset anthracycline cardiomyopathy - Corrected Proof

Bob N. Bernaba, Jessica B. Chan, Chi K. Lai, Michael C. Fishbein — 2009-09-11

Abstract: Introduction: Anthracyclines are known to have acute cardiotoxicity. Anthracycline-induced dilated cardiomyopathy may have late onset and present years after administration of the drug. Several studies have described the clinical findings in patients with late-onset cardiomyopathy, including electrocardiography, exercise testing, echocardiography, and histological findings in endomyocardial biopsies; however, there is little information on the pathological changes that are found in explanted or autopsy hearts.Methods: We reviewed the medical records and microscopic slides of heart tissue from one patient who had an autopsy and from nine patients who had cardiac transplants between 2001 and 2008. Heart weights were compared to historic controls (heart weights normalized for the patient's heights). Hematoxylin and eosin (H&E)-stained slides were semiquantitated for evidence of necrosis, myocytolysis, interstitial fibrosis, replacement fibrosis, and the presence of inflammation.Results: The average heart weight ranged from 231 to 470 g (mean=317±65 g, median=303 g). Review of the histological sections revealed no evidence of significant necrosis or myocytolysis. Interstitial fibrosis was identified in all 10 patients, with six patients showing multifocal fibrosis, three patients showing diffuse fibrosis, and only one patient showing focal fibrosis. Replacement fibrosis was identified in six patients, with two patients displaying multifocal and four patients displaying focal replacement fibrosis.Conclusion: Late-onset cardiomyopathy is a serious consequence of anthracycline therapy resulting in death or the need for cardiac transplantation in some patients. Unlike most other forms of dilated cardiomyopathy, the major pathological changes appear to be interstitial and/or replacement fibrosis without significant cardiac hypertrophy.

Apoptosis-regulated survival of primarily extravascular cells in proliferative active poststent neointima - Corrected Proof

2009-09-11

Abstract: Background: Increased proliferation, mitigated apoptosis, and recruitment of primarily extravascular cells to injured vessels are important processes during neointima formation. Therefore, the goal of this study was to assess the spatiotemporal balance between proliferation and apoptosis and the influence of apoptosis on the survival of primarily extravascular cells in in-stent neointima.Methods: Minipigs underwent stent implantation to abdominal aortic segments. At Days 1, 7, 14, 30, 60, and 90 after injury, arterial cross sections were analyzed by TUNEL assay to detect apoptotic cells. For immunohistochemical detection of Ki67+/proliferating cell nuclear antigen (PCNA)+ proliferative, caspase3+ apoptotic, S100+/fascin+ dendritic, GFAP+ neural crest-derived cells and CD14+ monocytes/macrophages, the alkaline phosphatase–anti-alkaline phosphatase (APAAP) method was used.Results: In the incipient cell-rich neointima, both frequency of proliferation and apoptosis was maximal (Ki67, 28.5±2.2%; PCNA, 25.4±3.8%; TUNEL, 8.6±0.4%; caspase3, 7.9±4.3%). With time, parallel to the decline in the neointima cellularity, signaling for proliferation and apoptosis decreased. Throughout the time course of neointima development, the apoptotic activity was detected in primarily extravascular cells.Conclusions: Imbalance between proliferation and apoptosis and recruitment of dendritic cells, monocytes/macrophages, and neural crest-derived cells to the injured vessels may partly explain the formation of the hypercellular in-stent neointima. Herein, apoptosis is an important factor that regulates survival of primarily extravascular neointimal cells.