Cardiovascular Pathology - Articles in Press

Clear cells in the atrioventricular valves of infants with severe human mucopolysaccharidosis (Hurler syndrome) are activated valvular interstitial cells - Corrected Proof

2010-07-12

Abstract: Background: Severe mucopolysaccharidosis type I (Hurler syndrome) is an autosomal recessive lysosomal storage disease of childhood that results in accumulation of glycosaminoglycans within cardiac valves and consequent valve dysfunction. Valve thickening in mucopolysaccharidosis type I (Hurler syndrome) is due, in part, to the presence of glycosaminoglycan-laden cells (the so-called “clear” or “Hurler” cells) within the valve that remain largely unstudied with respect to identity, origin, and function. We hypothesized that the “clear” or “Hurler” cells within the atrioventricular valves from individuals with untreated mucopolysaccharidosis type I are activated valvular interstitial cells.Methods: We performed routine and immunohistochemical staining on atrioventricular valves from two infants with untreated severe mucopolysaccharidosis type I (Hurler syndrome) and compared them to atrioventricular valve tissue from two age-matched and gender-matched normal infants.Results: Despite the marked differences in their histological appearances, mucopolysaccharidosis type I valve cells have an immunohistochemical fingerprint identical to that of normal infant valvular interstitial cells. Both mucopolysaccharidosis type I valvular interstitial cells and normal infant valvular interstitial cells have the phenotype of activated myofibroblasts, as evidenced by positive staining for vimentin, smooth muscle actin, and metalloproteinase-9. However, the number of mucopolysaccharidosis type I valvular interstitial cells is significantly increased when compared to that of normal cells (P<.0031). Both mucopolysaccharidosis type I (Hurler syndrome) cells and normal valvular interstitial cells express CD34+, a hematopoietic and capillary endothelial progenitor cell marker, suggesting a common response to activation.Conclusions: We conclude that “clear” or “Hurler” cells are valvular interstitial cells with the immunohistochemical phenotype of activated myofibroblasts and may be engaged, albeit ineffectively, in valve repair.

Pathology of explanted polytetrafluoroethylene vascular grafts - Corrected Proof

Rupal I. Mehta, Arnob K. Mukherjee, Tyler D. Patterson, Michael C. Fishbein — 2010-07-12

Abstract: Introduction: Graft occlusion is a well-documented etiology for arteriovenous fistulae failure. However, there is little morphologic information elucidating why synthetic vascular grafts fail. The purpose of this study was to examine the tissue responses occurring within and adjacent to explanted polytetrafluoroethylene grafts that were utilized during cardiovascular procedures and subsequently removed.Methods: Forty explanted polytetrafluoroethylene grafts (including 32 failed vascular grafts) originating from 18 females and 22 males who ranged in age from 6 to 82 years (mean age, 36 years) were evaluated. Duration of engraftment varied from 1 to 255 months (mean engraftment period, 64 months).Results: In addition to neointimal hyperplasia, foreign body reaction, and thrombosis, an unexpected finding was calcification involving the graft material, as well as luminal thrombus and adjacent soft tissues. Twenty-seven of forty cases (68%) showed evidence of calcification, either within or adjacent to polytetrafluoroethylene grafts. Histologic examination revealed variable degrees and patterns of calcification within and adjacent to explanted polytetrafluoroethylene membranes and conduits (arterial, arteriovenous, or cardiac grafts). A significantly longer duration of engraftment (P=.015) was identified in calcified versus noncalcified polytetrafluoroethylene materials. Patient age, serum calcium, creatinine level, and blood urea nitrogen level showed no statistically significant differences between patients with calcified grafts and patients without calcified grafts.Conclusions: Interstitial calcification is frequently found within explanted polytetrafluoroethylene grafts and is associated with graft disruption. These findings suggest that calcification of polytetrafluoroethylene biomaterials may play a role in eventual graft failure. A better understanding of the process of polytetrafluoroethylene graft calcification may lead to novel therapies that aid in the prevention of polytetrafluoroethylene vascular graft failure.

What a pity the master cannot admire his pupil's work: the autopsy of the anatomist Antonio Cocchi (1695–1758) performed by his pupil Saverio Manetti - Corrected Proof

Raffaella Santi, Andrea A. Conti, Gabriella Nesi — 2010-07-09

Abstract: Antonio Cocchi (1695–1758) was a physician, sanitary administrator, and Professor of Anatomy at the University of Florence. Wide-ranging in his interests, he was also a philologist, botanist, and a cultured traveler through 18th-century Europe.After Cocchi died, his pupil Saverio Manetti (1723–1785) reported in a private letter on the state of health of his renowned master the circumstances of his death and the autopsy findings. In an endeavour to determine the cause of death, Manetti accurately described the symptoms and clinical signs preceding the exitus of Antonio Cocchi and related them to the autopsy results. Interestingly, his lifestyle habits, past medical history, and family diseases were all considered when making the diagnosis. This handling of the matter clearly proceeds from Cocchi's teachings. As an anatomist, Cocchi believed autopsy to be a fundamental tool in achieving new insights into medicine while, as a professor, he emphasized the didactic relevance of autopsy in medical education. Manetti's letter appears as a surprisingly modern example of clinicopathological practice. Based on this informative document, we present an interpretation of the possible cause of the death of Antonio Cocchi, namely, congestive heart failure.

Sudden coronary death in children - Corrected Proof

Fabio Tavora, Ling Li, Allen Burke — 2010-07-09

Abstract: Coronary disease is an uncommon cause of severe morbidity and death in the young. The great majority of lesions are congenital, and anomalous origins and courses of the coronary arteries are the most common groups of diseases in the age group. Intimal proliferation and coronary arteritis are even less common causes of death in this age population. For this review, we retrospectively studied cases of coronary cardiac death in children and adolescents, from 2004 to 2007, from a statewide medical examiner's office. There were 197 natural deaths in children ages ≤16 years and 58 deaths from sudden infant death syndrome. Of these, the largest group of deaths showed no morphologic abnormalities and was attributed to arrhythmias. The next largest group of deaths comprised complex congenital heart disease (n=13; 20%), followed by myocarditis (n=11; 17%), coronary disease (n=9; 14%), cardiomyopathy (n=8; 12%), valve disease (n=4; 6%), and cardiac fibroma (n=1). Nine coronary deaths occurred in seven boys and two girls, ranging from 14 days to 16 years of age (mean, 8 years). An anomalous course of the coronaries was seen in seven of the nine coronary deaths, and the other two casualties were examples of intimal proliferations involving the coronaries. The rare examples of coronary lesions in the young are discussed in this article.

iNOS induction and PARP-1 activation in human atherosclerotic lesions: an immunohistochemical and ultrastructural approach - Corrected Proof

2010-07-09

Abstract: Background: Several lines of clinical and experimental evidence have demonstrated that reactive oxygen species and nitrogen species are generated in unregulated amounts during diverse cardiovascular disorders. It has been previously reported by our group and others that augmented expression of nitric oxide synthase isoforms is associated with human atherogenesis and that the activity of the enzymes in an atherosclerotic environment may promote the formation of peroxynitrite. Among the downstream mechanisms triggered by oxidants, poly(ADP-ribose) polymerase-1 activation has recently been implicated in the pathogenesis of acute and chronic myocardial dysfunction, diabetes, hypertension, aging, and various forms of shock.Methods: Based on these observations, we performed immunohistochemical and immunogold labeling analyses to evaluate the expression profile and the subcellular localization of inducible nitric oxide synthase and poly(ADP-ribose) polymerase-1 in healthy and atherosclerotic human aortae.Results: We have demonstrated that inducible nitric oxide synthase colocalizes with poly(ADP-ribose) polymerase-1 within vascular cells of atherosclerotic human aortae. We have reported for the first time, to our knowledge, the ultrastructural localization of poly(ADP-ribose) polymerase-1 within the nuclei of lesional smooth muscle cells. Finally, we have evidenced that poly(ADP-ribose) polymerase-1 induction within cells of the diseased aorta strongly correlates with alterations in mitochondrial morphology.Conclusions: Our data imply the possibility of a significant role for cross-talk between inducible nitric oxide synthase and poly(ADP-ribose) polymerase-1 in human atherosclerotic lesions. We conclude that the prooxidant milieu of the plaque might exert damaging effects on mitochondria via a poly(ADP-ribose) polymerase-1-mediated mechanism since the absence of the enzyme results in a corresponding lack of changes in mitochondrial morphology. The present report may open avenues for further researches that could have important therapeutic consequences for the treatment of atherosclerosis and its clinical sequelae.

Dr. Groven M. Hutchins - Corrected Proof

G. William Moore, Ralph H. Hruban — 2010-07-09

Dr. Grover M. Hutchins died on April 27, 2010, following an accident while traveling abroad with his wife Loretta Hutchins. He was 77.

Idiopathic massive myocardial calcification: a case report and review of the literature - Corrected Proof

2010-07-05

Abstract: We report a rare case of massive myocardial calcification in a 42-year-old male who presented with symptoms of congestive heart failure and arrhythmia. Myocardial calcification is most commonly associated with myocardial infarction or, less commonly, hypercalcemia. This case is particularly unusual due to the lack of any known predisposing risk factors, including normal coronary arteries, normal renal function, and normal serum calcium levels. Alternative etiologies are discussed accompanied by a review of the literature.

Early obstruction of decellularized xenogenic valves in pediatric patients: involvement of inflammatory and fibroproliferative processes - Corrected Proof

2010-07-05

Abstract: Background: Decellularization of pulmonary valve substitutes is believed to eliminate immunogenicity and improve conduit durability. This study focused on a detailed histopathological and immunohistochemical analysis of explanted Matrix P plus valves, following their early obstruction in pediatric patients.Methods: Occurrence of fibrosis, scar formation, neovascularization, and inflammatory infiltrates were determined in longitudinal sections of four valve specimens explanted after 12–15 months. Valves were immunohistochemically analyzed for presence of different subtypes of inflammatory cells. The expression of smooth muscle actin and connective tissue growth factor was determined.Results: We observed a foreign body-type reaction accompanied by severe fibrosis and massive neointima formation around decellularized porcine valve wall, whereas the equine pericardial patch remained separated from porcine layer and acellular. Re-cellularization of decellularized matrix was low, and neovascularization was observed only in the neointima and scar tissue. Inflammatory infiltrates, composed mainly of T cells, B cells, and plasma cells, as well as the presence of dendritic cells, macrophages, and mast cells were detected in the tissue surrounding the porcine matrix. In the fibrous tissue, overexpression of connective tissue growth factor was observed. The leaflets remained functional, with normal endothelialization and no degenerative changes. Control pre-implant samples of Matrix P plus valve revealed incomplete decellularization of porcine matrix, which may have contributed to increased immunogenicity of these conduits.Conclusions: Early obstruction of decellularized Matrix P plus valve is associated with massive inflammatory reaction and exaggerated fibrotic scaring around porcine conduit wall. Detailed studies will be necessary to determine factors that contribute to remnant immunogenicity of decellularized grafts.

Fenestrations and lipoproteins - Corrected Proof

David G. Le Couteur, Victoria C. Cogger, Bruce Dobbs, Robin Fraser — 2010-07-05

In their recent article, Jacobs et al. have provided an elegant set of experiments from which they conclude that fenestration diameter does not influence circulating lipoprotein concentrations and, hence, is unlikely to influence atherosclerosis. Fenestrations are pores in the liver sinusoidal endothelial cell with a diameter 50 to 200 nm. Fraser et al. and Wisse et al postulated that some lipoproteins traverse the fenestrations and, hence, that the diameter of fenestrations impacts on the concentration of circulating lipoproteins. In particular, it was hypothesized that because the average diameter of fenestrations is about 100 nm, their major influence will be on the blood levels of chylomicron remnants (diameter, 50–150 nm) and, hence, postprandial hypertriglyceridemia . It should be noted that the diameter of intermediate-density lipoproteins (IDLs) is 30 to 80 nm and for very-low-density lipoproteins (VLDLs) is 25 to 50 nm; therefore, these particles are less likely to be influenced by changes in fenestration diameter in comparison to the larger chylomicron remnants. It should also be noted that chylomicron remnants are primarily of intestinal origin, while the smaller IDLs and VLDLs are produced by the hepatocytes, which has obvious implications for the direction of their transfer across the liver sinusoidal endothelium.

Introduction to congenital heart disease articles in Cardiovascular Pathology - Corrected Proof

Frederick J. Schoen — 2010-07-05

Congenital heart disease is common and causes substantial consequences for patients, their families, their communities and the health care system. Congenital heart defects occur in nearly 1% of live births and comprise at least 18 distinct types (most commonly ventricular septal defect, tetralogy of Fallot, transposition of the great arteries, and atrioventricular septal defect). They range in severity from minute holes between chambers, which may resolve spontaneously, to major malformations that can require multiple surgical procedures (frequently in the first years of life) and may result in death in infancy, childhood, or as a young adult.

Why the diameter of sinusoidal fenestrae unlikely matters for lipoprotein metabolism and atherosclerosis susceptibility - Corrected Proof

Frank Jacobs, Eline Van Craeyveld, Bart De Geest — 2010-07-05

In their Letter to the Editor, Le Couteur et al. provide a series of interesting comments on our manuscript entitled “The diameter of liver sinusoidal fenestrae is not a major determinant of lipoprotein levels and atherosclerosis in cholesterol-fed rabbits” . We thank them for their ad hoc analysis. Here, we provide a detailed response to their specific comments.

Perivascular mantle cell lymphoma affecting a temporal artery—a highly unusual cause of temporal headache - Corrected Proof

Imran Masood, Ben While, Hardeep S. Mudhar — 2010-07-05

Abstract: Introduction: Temporal artery biopsy is a widely performed procedure for clinically suspected temporal arteritis. We the report the case of a 79-year-old male with mantle cell non-Hodgkin's lymphoma previously treated with chemotherapy under follow-up with right-sided orbital recurrence, who developed right temporal headache, tenderness, and visual symptoms in the right eye. His symptoms were unresponsive to steroid treatment and he underwent a temporal artery biopsy.Methods: The temporal artery was fixed in standard 10% buffered formalin, processed to paraffin wax, 4 micron sections cut through the entire artery and stained with standard haematoxylin and eosin. Some sections were exposed to CD20, CD5, and cyclin D1 immunohistochemistry.Results: Histology showed a perivascular, nodular lymphoid infiltrate composed of small centrocyte-type lymphocytes around the main artery and identical lymphocytes within the wall of a main artery branch. Additionally, the lymphocytes were located around a peripheral nerve in the peri-artery connective soft tissues. These lymphocytes were positive for CD5, CD20, and cyclin D1 indicating a diagnosis of peri-neural, peri-vascular mantle cell non-Hodgkin's lymphoma of identical appearance to that in the index biopsy.Conclusions: This report describes a highly unusual histological and clinical scenario of peri-temporal artery Mantle cell lymphoma causing temporal headache from peripheral nerve and artery side branch involvement by the lymphoma immediately adjacent to the temporal artery. We propose that involvement of a temporal artery by lymphoma be considered in the differential diagnosis, in patients with an established diagnosis of lymphoma, if presenting with “temporal arteritis” type headache symptoms.

Phenotypic modulation and turnover of bone marrow-derived cells after myocardial infarction in rats - Corrected Proof

2010-06-01

Abstract: Background: Bone marrow-derived cells (BMCs) are critically involved in inflammation and regeneration after myocardial infarction (MI). However, the participation of BMCs in the reconstruction of infarcted myocardium remains unclear. In this study, we investigated phenotypic modulation of BMCs and their turnover in the heart following MI.Methods and results: MI was produced in rats with intra-bone marrow-bone marrow transplantation from the syngenic rats expressing green fluorescence protein (GFP). The number of GFP-positive BMCs recruited to the infarcted myocardium peaked at 3 days after MI, and the majority of BMCs recruited to the heart after MI underwent turnover within 2 weeks. This turnover rate was unchanged for up to 16 weeks after MI, although the number of BMCs recruited to the infarcted myocardium rapidly decreased between 2 and 8 weeks after MI. A small number of BMCs recruited to the heart were positive for CD31 and α-smooth muscle actin, and the majority of these were positive for Vimentin at 3 days and 4 weeks after MI. None of BMCs expressed α-actinin or von Willebrand factor 4 weeks after MI.Conclusions: These results suggest that BMCs recruited to the heart underwent phenotypic modulation to a fibroblastic cell type and turnover within 2 weeks after MI without differentiating into cardiomyocytes or endothelial cells, and that although the number of BMCs in the infarcted myocardium decreased over time, the rate of turnover remained relatively constant during the chronic phase of MI.

Association between AT C573T polymorphism and cardiovascular risk factors in myocardial infarction - Corrected Proof

2010-06-01

Abstract: Background: Polymorphisms in the AT1 gene have been associated with various parameters related to the pathogenesis of cardiovascular diseases and to myocardial infarction. This study analyzed the relationship between two polymorphisms of the angiotensin II AT-1 receptor gene (AT1_1166 and AT1_573) and the risk of ischemic heart disease by studying their association with several cardiovascular risk factors.Methods: The sample population comprised 356 subjects: 174 patients who had survived myocardial infarction (61.01±8.15 years), and 182 age- and gender-matched controls (mean age of 60.25±9.43). The polymorphisms of the angiotensin II AT1-receptor gene (C573T and A1166C) were studied by polymerase chain reaction and DNA restriction analysis. We compared the patients' genetic polymorphism with their risk of ischemic heart disease.Results: The A1166C polymorphism did not show any significant differences between the groups. However, with respect to C573T, genotypes tended to differ significantly between cases and controls in the CC and TT types, remaining significant when the CC and CT+TT were grouped. Through analysis of the fit of various multivariate models, we found that the CC genotype is a risk factor for myocardial infarction. This risk remains significant after being adjusted for gender, age, homeostasis model assessment, and anthropometric variables.Conclusions: There is a relationship between the C573T polymorphism and the pathogenesis of myocardial infarction that seems to be due to its relationship with some risk factors. However, given the multifactorial nature of this pathology, further studies are needed to confirm the evidence that we report herein.

Smooth muscle cells in porcine vein graft intimal hyperplasia are derived from the local vessel wall - Corrected Proof

2010-06-01

Abstract: Background: Accelerated intimal hyperplasia (IH) is an important cause of morbidity and mortality in patients with atherosclerotic vascular disease treated with bypass vein grafts. We used an interposition vein graft model to determine the source of neointimal cells in a clinically relevant large animal model.Methods: Jugular vein segments from sex-mismatched, MHC-in-bred pigs were implanted into common carotid arteries bilaterally and harvested up to 8 weeks postsurgery for stereological, histological, and immunofluorescence analyses.Results: Progressive IH lesions contained macrophages and smooth muscle cells (SMC). Fluorescent in situ hybridization following grafting of female veins into male arteries revealed that only ∼10% of the SMC were male, confirming that the majority of intimal SMC derived from the local vessel wall.Conclusions: The majority of neointimal SMC in the IH seen after interposition vein grafting derive from the engrafted local vessel wall. These are the first results from a clinically relevant large animal model that confirm data from rodent models. They have implications for the utility of therapeutic stem cells in this type of intimal hyperplasia.

Single measurement of troponin T for early prediction of infarct size, congestive heart failure, and pulmonary hypertension in an animal model of myocardial infarction - Corrected Proof

2010-06-01

Abstract: Background: Early prediction of infarct size and of the subsequent development of congestive heart failure (CHF) and pulmonary hypertension (PH) would be useful in therapeutic trials using the rat myocardial infarction (MI) model.Methods: A total of 194 rats were subjected to MI or sham surgery, and plasma cardiac troponin T (cTnT) was measured 24 h after surgery in rats. Echocardiography was performed after 2 and 5 weeks. Hemodynamic and morphometric parameters were evaluated 5 weeks after MI.Results: cTnT had strong positive correlations with left ventricular (LV) wall motion abnormalities at 2 and 5 weeks (R=.85 and .89; P<.0001), and with histological infarct size (R=.87, P<.0001). cTnT≥5.1 μg/l predicted LV wall motion abnormalities ≥30% with a sensitivity of 90.9% and specificity of 84.0%. Rats with cTnT≥5.1 μg/l developed PH [right ventricular (RV) systolic pressure 37±3 vs. 23±0.6 mmHg], RV hypertrophy (RV/LV+septum weight 42±4% vs. 24±0.5%), and lung structural remodeling (all P<.01).Conclusion: Early single cTnT measurement correlates with infarct size in rats, and a cutoff value of 5.1 μg/l provides good sensitivity and specificity to predict CHF with secondary PH. cTnT could be used for treatment allocations in therapeutic trials of secondary pulmonary hypertension using this model.

Anatomical and pathophysiological classification of congenital heart disease - Corrected Proof

Gaetano Thiene, Carla Frescura — 2010-05-13

Abstract: Congenital heart diseases (CHD) consist of defects of the cardiac architecture which interfere with the venous drainage, septation of the cardiac segments and their sequences and regular function of the valve apparatuses. In the normal heart the segments are disposed in such a way to allow deoxygenated venous blood to go to the lungs through the pulmonary artery and the oxygenated venous blood to go to the systemic organs through the aorta without mixing. Small and great circulations are in sequence, with no communication to each other. Establishing the sequence of cardiac segments is the prerequisite for planning a surgical repair. We propose a pathyphysiological classification of CHD based upon the clinical consequence of structural defects on the physiology of blood circulation. We divided cardiac anomalies in: (1) CHD with increased pulmonary blood flow (septal defects without pulmonary obstruction and with left-to-right shunt); (2) CHD with decreased pulmonary flow (septal defects with pulmonary obstruction and with right-to-left shunt); (3) CHD with obstruction to blood progression and no septal defects (no shunt); (4) CHD so severe as to be incompatible with postnatal blood circulation; and (5) CHD silent until adult age.

Opposing roles of PARP-1 in MMP-9 and TIMP-2 expression and mast cell degranulation in dyslipidemic dilated cardiomyopathy - Corrected Proof

2010-04-30

Abstract: Introduction: Previously, we demonstrated that inhibition of poly(ADP-ribose) polymerase (PARP) exerts protective effects against high-fat (HF) diet-induced atherogenesis in part by increasing tissue inhibitor of metalloproteinase (TIMP)-2 expression. Given that characteristics of dilated cardiomyopathy closely associate with atherosclerosis and are mediated by an imbalance between matrix metalloproteinases (MMPs) and TIMPs, we hypothesized that PARP-1 gene deletion may protect against HF-induced cardiac hypertrophy and dilatations by altering TIMP-2/MMPs balance in favor of a maintenance of tissue homeostasis.Methods and results: Hemodynamic parameters determined by echocardiography were similar in ApoE−/− mice and PARP-1-deficient ApoE−/− mice (DKO) fed a regular diet (RD). However, histological analysis revealed that cardiomyocytes of ApoE−/− mice on RD were hypertrophied, displaying an enlarged cell body and nucleus, traits that were absent in DKO animals. HF diet-fed ApoE−/− mice exhibited increased interventricular septum, left ventricular (LV) internal dimension, LV volume, and LV mass in addition to a separation of myocardial fibers suggestive of dilated cardiomyopathy. PARP-1 gene deletion protected against these degenerative changes. MMP activity was dramatically increased in hearts of ApoE−/− mice on HF diet and was accompanied by increased collagen degradation, mast cell degranulation, and increased myocyte cell death. PARP-1 gene knockout was associated with increased TIMP-2 expression antagonizing, as a result, the damaging effects of active MMPs.Conclusions: The present study demonstrates that PARP-1 gene deletion exerts protective effects against HF diet-induced dilated cardiomyopathy by maintaining increased expression of TIMP-2. With additional protective effects against cell death and inflammation, PARP-1 deficiency preserves cardiac tissue homeostasis.

Does inducible NOS have a protective role against hypoxia/reoxygenation injury in rat heart? - Corrected Proof

Alma Rus, Maria Luisa del Moral, Francisco Molina, Maria Angeles Peinado — 2010-04-26

Abstract: Purpose: The present study analyzes the role of the nitric oxide (NO) derived from inducible NO synthase (iNOS) under cardiac hypoxia/reoxygenation situations.Methods: For this, we have designed a follow-up study of different parameters of cell and tissue damage in the heart of Wistar rats submitted for 30 min to acute hypobaric hypoxia, with or without prior treatment with the selective iNOS inhibitor N-(3-(aminomethyl)benzyl) acetamidine or 1400W (10 mg/kg). The rats were studied at 0 h, 12 h, and 5 days of reoxygenation, analyzing NO production (NOx), lipid peroxidation, apoptosis, and protein nitration expression and location. This is the first time-course study which analyzes the effects of the iNOS inhibition by 1400W during hypoxia/reoxygenation in the adult rat heart.Results: The results show that when 1400W was administered before the hypoxic episode, NOx levels fell, while both the lipid peroxidation level and the percentage of apoptotic cells rose throughout the reoxygenation period. Levels of nitrated proteins expression fell only at 12 h post-hypoxia.Conclusions: The inhibition of iNOS raises the peroxidative and apoptotic level in the hypoxic heart indicating that this isoform may have a protective effect on this organ against hypoxia/reoxygenation injuries, and challenging the conventional wisdom that iNOS is deleterious under these conditions. These findings could help in the design of new treatments based on NO pharmacology against hypoxia/reoxygenation dysfunctions.

Survey of North American pathologist practices regarding antibody-mediated rejection in cardiac transplant biopsies - Corrected Proof

Lauren M. Kucirka, Joseph J. Maleszewski, Dorry L. Segev, Marc K. Halushka — 2010-04-26

Abstract: Background: The 2004 International Society for Heart and Lung Transplantation consensus report specified an entity of histopathologic antibody-mediated rejection (hAMR) but did not define specific histologic criteria. Therefore, there is no gold standard for hAMR diagnosis.Methods: In May 2009 we performed a survey of pathologists from cardiac transplant centers in the United States and Canada assessing practices regarding hAMR investigation.Results: Of 94 centers who responded to our survey (77% response rate), 90% reported investigating for hAMR, and 80% of those reported having a defined protocol. Of centers with a defined protocol, 23% investigated all biopsies for hAMR. Of those who investigated for hAMR selectively, the most common triggers were clinical suspicion (61%) or suggestive histologic findings (36%). Sixteen different stains were used for hAMR investigation, the most common being C4d by immunofluorescence (38%), immunohistochemistry (38%) or both (21%).Conclusions: We found wide variation in pathologists' practices regarding hAMR diagnosis. A consensus document regarding hAMR is needed to better align our collective protocols, understand this disease process and to optimize patient care.

Sudden death due to isolated right ventricular infarction: a case report - Corrected Proof

2010-04-26

Abstract: Introduction: Isolated right ventricular infarction (RVI) is a rare phenomenon associated with atherosclerotic disease of the acute marginal vessels or of a non-dominant right coronary artery. It may happen in the absence of coronary disease when substantial right ventricular hypertrophy is present. The prognosis is usually good, although sudden collapse can occur due to ventricular fibrillation, rupture of the right ventricular free wall, or a massive pulmonary embolism. In this report, a case of sudden death in a patient with an isolated RVI due to an acute thrombosis of a non-dominant right coronary artery is presented.Methods: A 46-year-old man without previous cardiopulmonary disease died suddenly at home. A medicolegal autopsy was performed within 72 h in order to clarify the circumstances that suddenly led the man to an unexpected death. Samples were collected for histological, immunohistochemical, and toxicological examination.Results: The postmortem investigation revealed central cyanosis, polyvisceral stasis, and pulmonary oedema. The macroscopic examination of the heart showed left and right ventricular hypertrophy. A fresh thrombus located in the right coronary artery accompanied by a haemorrhagic infiltration of the posterolateral right ventricular wall was found.Microscopic findings confirmed the observations from the autopsy and showed miliary necrosis of the right ventricular wall. Toxicology was negative for drugs and alcohol.Conclusions: On the basis of morphologic and microscopic data, the cause of death was determined to be an isolated RVI. The autopsy findings of both right and left ventricular hypertrophy associated with a nondominant right coronary artery thrombosis were observed. In cases like this, the authors would like to underline the importance of a complete postmortem examination and a full pathological approach.

Sudden cardiac death with normal heart: Molecular autopsy - Corrected Proof

2010-04-12

Abstract: Several culprits may be identified at postmortem in sudden death (SD) victims, including coronary artery, myocardial, valve, conduction system, and congenital heart diseases. However, particularly in young people, the heart can be found grossly and histologically normal in a not-so-minor amount of cases (the so-called unexplained SD or “mors sine materia”) and inherited ion channel diseases are implicated (long and short QT syndromes, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia). These channelopathies are due to defective genes encoding for proteins of sodium and potassium ion channels at the sarcolemma level or for receptors regulating intracellular calcium release at the sarcoplasmic reticulum level. Postmortem investigation may still represent the first opportunity to make the proper diagnosis also in the setting of a structurally normal heart and the employment of molecular biology techniques is of help to solve the puzzle of such “silent” autopsies. For these reasons, autopsy investigation of cardiac SD should always include sampling for genetic testing to search for the invisible inherited arrhythmogenic disorders, as recommended in the recent guidelines by the Association for European Cardiovascular Pathology.

Calcification after myocardial infarction is independent of amniotic fluid stem cell injection - Corrected Proof

2010-04-12

Abstract: Ischemic heart disease remains one of the most common causes of mortality in developed countries. Recently, stem cell therapy is being considered for treating ischemic heart diseases. On the other hand, there has been evidence of chondro-osteogenic mass formation after stem cell injection in the heart. In a recent publication, Chiavegato et al. (J Mol Cell Cardiol. 42 (2007) 746–759) has suggested that amniotic fluid-derived stem (AFS) cells cause chondro-osteogenic masses in the infarcted heart. The goal of the current study was to further examine the formation of such masses, specifically, the role of AFS cells in this process. Our results confirm the presence of similar bone-like masses in the left ventricular wall of infarcted rats; however, this phenomenon occurred independent of AFS cell injection into the myocardium. Moreover, AFS cell injection did not increase the presence of chondro-osteogenic masses. Echocardiographic analysis of large infarctions in rats frequently revealed the presence of echogenic structures in the left ventricular wall. We further demonstrated a significant relationship between the infarction size and chondro-osteogenic formation and subsequent decrease in cardiac function. Collectively, our study indicates that chondro-osteogenic differentiation can take place in infarcted rat heart independent of cell injection. These results have significant implications for future design and testing of stem cell therapy for treatment of cardiac muscle diseases.

Can sudden cardiac death be prevented? - Corrected Proof

Barry J. Maron — 2010-04-09

Abstract: Hypertrophic cardiomyopathy is regarded as the most common cause of sudden cardiac death in young people (including trained athletes). Introduction of implantable cardioverter-defibrillators to the hypertrophic cardiomyopathy patient population represents a new paradigm for clinical practice and perhaps the most significant advance in the management of this disease to date. Implantable defibrillators offer the only proven protection against sudden death by virtue of effectively terminating ventricular tachycardia/fibrillation and, in the process, altering the natural history of hypertrophic cardiomyopathy and providing the potential opportunity of normal or near-normal longevity for many patients. However, targeting the most appropriate candidates for prophylactic device therapy can be complex, compounded by the unpredictability of the underlying arrhythmogenic substrate, absence of a single dominant and quantitative risk marker in this heterogeneous disease, and the historical difficulty in assembling sufficiently powered prospective and randomized trials in large patient populations. Nevertheless, the current risk factor algorithm, when combined with a measure of individual physician judgment, is an effective strategy for identifying high-risk patients. Indeed, prevention of sudden death has now become an integral, albeit challenging, component of overall hypertrophic cardiomyopathy management.

Postoperative pathology of congenital heart disease - Corrected Proof

William D. Edwards — 2010-04-08

Abstract: The evaluation of congenitally malformed hearts that have been subjected to operative and nonoperative interventions includes not only a categorization of the underlying anomalies and various procedures but also an assessment of interventional complications, postprocedural changes in chamber, valvular, and vascular sizes, presence of ischemia or fibrosis, presence of cardiac or extracardiac infections, and evidence of regression or progression of hypertensive pulmonary vascular disease. Input from clinicians or surgeons may be helpful, but biases should be avoided. Referral of cardiopulmonary specimens to experienced pathologists may also be considered.

PTX3 expression in the heart tissues of patients with myocardial infarction and infectious myocarditis - Corrected Proof

2010-03-31

Abstract: Introduction: The long pentraxin 3 is involved in innate resistance to pathogens, controlling inflammation and extracellular matrix remodeling. Moreover, pentraxin 3 plays a nonredundant role in the regulation of cardiac tissue damage in mice and, recently, it has been proposed as a new candidate marker for acute and chronic heart diseases. However, the actual localization and cellular sources of pentraxin 3 in ischemic and infectious cardiac pathology have not been carefully defined.Methods: In this study, using immunohistochemistry, we analyzed pentraxin 3 expression in the heart tissues of patients with acute myocardial infarction at different time points after the ischemic event. In addition, we studied the heart tissues of patients with infectious myocarditis (fungi, bacteria, and protozoa) and patients who died of noncardiac events with normal heart histology.Results: In acute myocardial infarction cases, we observed pentraxin 3 localized within and around ischemic lesions. On the contrary, no pentraxin 3 was observed in normal heart areas. In early ischemic lesions, pentraxin 3 was localized primarily in granulocytes; in more advanced acute myocardial infarction, pentraxin 3 positivity was found in the interstitium and in the cytoplasm of macrophages and the endothelium, whereas most granulocytes did not express pentraxin 3, presumably as a consequence of degranulation. In infectious myocarditis, pentraxin 3 was present and localized within and around histological lesions, associated with macrophage, endothelial cell, and, more rarely, myocardiocyte and granulocyte positivities. As observed in acute myocardial infarction patients, no pentraxin 3 staining was found in normal heart areas.Conclusions: Thus, neutrophils are an early source of pentraxin 3 in acute myocardial infarction and presumably other inflammatory heart disorders. Subsequently, in acute myocardial infarction and infectious myocarditis, pentraxin 3 is produced by macrophages, the endothelium, and, to a lesser extent, myocardiocytes, and localized in the interstitium.

Elevated oxidative stress is associated with ventricular fibrillation episodes in patients with Brugada-type electrocardiogram without SCN5A mutation - Corrected Proof

2010-03-11

Abstract: Background: Brugada syndrome is a disease known to cause ventricular fibrillation with a structurally normal heart and is linked to SCN5A gene mutation. However, the mechanism by which ventricular fibrillation develops in cases of Brugada-type electrocardiogram without SCN5A mutation has remained unclear. Recently, oxidative stress has been implicated in the pathophysiology of cardiac arrhythmia. We also investigated oxidative stress levels in the myocardia of patients with Brugada-type electrocardiogram.Methods: Endomyocardial biopsy samples were obtained from 68 patients with Brugada-type electrocardiogram (66 males and two females). We performed histological and immunohistochemical analyses for CD45, CD68, and 4-hydroxy-2-nonenal-modified protein, which is a major lipid peroxidation product.Results: SCN5A mutation was detected in 14 patients. Ventricular fibrillation was documented in three patients with SCN5A mutation and in 11 without SCN5A mutation. In patients with SCN5A mutation, 4-hydroxy-2-nonenal-modified protein-positive area was not significantly different between the documented ventricular fibrillation (VF) group (VF+ group) and the group without documented VF (VF− group). However, in patients without SCN5A, the area was significantly larger in the VF+ group than that in the VF− group (P<.05). All other parameters (fibrosis area, CD45, and CD68) were not different between the VF+ and VF− group in both SCN5A+ and SCN5A− patients.Conclusion: Oxidative stress is elevated in the myocardium of patients with Brugada-type electrocardiogram who have VF episodes and do not have SCN5A gene mutations. Oxidative stress may be associated with the occurrence of VF in patients with Brugada-type electrocardiogram without SCN5A mutation.

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.

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.

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.

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.

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.