Cardiovascular Pathology - Articles in Press

Regional variations in canine descending aortic tissue mechanical properties change with formalin fixation - Corrected Proof

2012-02-02

Abstract: Background/introduction: Diseases of the aorta can alter the local mechanical properties of the tissue, leading to aneurysms and plaque instability. Local tissue properties are best evaluated from surgical samples or autopsy tissue using mechanical testing ex vivo. We examined whether formalin-fixed tissues preserve regional and local variations in tissue properties when compared to fresh tissues in order to determine if fixed tissue can be used to infer mechanical changes associated with tissue remodeling.Methods: Equibiaxial mechanical tests were performed on canine descending thoracic aorta to quantify the regional and local tissue stiffness. Samples were taken from four locations along the aorta and from the lateral and medial side at each location. Half of the samples were randomly formalin fixed and used to measure the effect of fixation on local thickness, stiffness, and anisotropy.Results: In fresh tissue, regional differences in tissue stiffness and thickness are present. Aortic tissue stiffens and thins along the aorta. Fixation did not alter thickness, significantly increased tissue stiffness, and altered the directional dependency of the mechanical properties (anisotropy) at low strain. Formalin fixation altered local stiffness of the aorta near the aortic arch.Conclusion: The changes in mechanical properties along the aorta were preserved in formalin-fixed samples. However, our results show that formalin fixation can change the variation in tissue stiffness and significantly affects the anisotropic properties of vascular tissues. Formalin fixation introduces spurious changes in mechanical properties, and we therefore strongly recommend the use of fresh aortic tissues for biomechanical analysis.

Primary and metastatic cardiac tumors: imaging characteristics, surgical treatment, and histopathological spectrum: a 10-year-experience at a German heart center - Corrected Proof

Thomas Strecker, Johannes Rösch, Michael Weyand, Abbas Agaimy — 2012-02-02

Abstract: Background: Tumors of the heart are rare compared to other cardiac diseases. Their clinical symptoms vary from absent to nonspecific. This great variation and general paucity of symptoms related to cardiac tumors often result in delayed diagnosis and treatment.Methods: We retrospectively evaluated all patients who underwent cardiac surgery for a space-occupying lesion in the observation period between 2000 and 2010 at our hospital. Clinicopathological features, imaging characteristics, and disease outcomes were analyzed, and the results were compared with the available English literature.Results: During the last 10 years, 84 patients underwent resection of a cardiac mass at our center, i.e., 0.85% of the total number (n=9829) of all cardiac surgical operations performed in that period. The part of primary cardiac tumors was 73.8% (n=62; 59 benign and 3 malign tumors). In nine cases (10.7%), secondary cardiac tumors represented metastases of malignant tumors from different extracardiac locations. In 13 cases (15.5%), the mass represented cardiac thrombus. The majority of cardiac tumors were benign, and most of them were cardiac myxomas (n=48). Papillary fibroelastoma was the second most common primary tumor.Conclusions: Our data in this study were comparable to the literature regarding the frequency and allocation of the different cardiac tumors. Our data are in line with previous reports that patients with benign cardiac tumors profit from surgical resection compared to those subjected to conservative treatment with the risk of central or peripheral embolisms. Concerning malignant primary cardiac tumors and cardiac metastases, surgery represents only a palliative strategy in most of the cases.

Deletion of tenascin-C gene exacerbates atherosclerosis and induces intraplaque hemorrhage in Apo-E-deficient mice - Corrected Proof

Lai Wang, Wei Wang, Prediman K. Shah, Lei Song, Mingjie Yang, Behrooz G. Sharifi — 2012-02-02

Abstract: Aims: Tenascin-C (TNC), a matricellular protein, is up-regulated in atherosclerotic plaques. We investigated whether the deletion of TNC gene affects the development of atherosclerosis in a murine model.Methods: TNC−/−/apo E−/− mice were generated and used for atherosclerosis studies. We compared these results to those observed in control groups of apo E−/− mice.Results: The en face analysis of aortic area showed that the mean aortic lesion area of the double knockout (KO) mice was significantly higher than that of control mice at different times after feeding of atherogenic diet; the accumulation of lesional macrophages and lipids was significantly higher. Analysis of cell adhesion molecules revealed that vascular cell adhesion molecule-1 (VCAM-1), but not intercellular adhesion molecule-1, was up-regulated 1 week after feeding of atherogenic diet in the double KO mouse as compared to apo E−/− mouse. Cell culture studies revealed that the expression of VCAM-1 in endothelial cells isolated from the double KO mouse is more sensitive to the tumor necrosis factor α stimulation than the cells isolated from apo E−/− mice. Cell adhesion studies showed that the adherence of RAW monocytic cells to the endothelial cells was significantly enhanced in the cultured endothelial cells from the TNC gene-deleted cells. Following the prolonged feeding of an atherogenic diet (28–30 weeks), the aortic and carotid atherosclerotic lesions frequently demonstrated large grossly visible areas of intraplaque hemorrhage in the double KO mice compared to control.Conclusions: These data unveil a protective role for TNC in atherosclerosis and suggest that TNC signaling may have the potential to reduce atherosclerosis, in part by modulating VCAM-1 expression.

Increased myocardial prevalence of C-reactive protein in human coronary heart disease: direct effects on microvessel density and endothelial cell survival - Corrected Proof

2012-01-30

Abstract: Background: Elevated plasma C-reactive protein (CRP) is a biomarker of cardiovascular diseases (CVDs), but its potential roles as a participant of the disease process are not well defined. Although early endothelial cell injury and dysfunction are recognized events in CVD, the initiating events are not well established. Here we investigated the local myocardial CRP levels and cardiac microvessel densities in control and CVD tissue samples. Using in vitro methodologies, we investigated the direct effects of CRP on human endothelial cells.Methods: Cardiac specimens were collected at autopsy within 4 h of death and were classified as normal controls or documented evidence of CVD. The regional prevalence of CRP and the cardiac microvessels (<40 μm) were investigated using immunohistochemistry. For in vitro experiments, human umbilical vein endothelial cells were incubated with CRP. Intracellular oxidant levels were assessed using 2′,7′-dichlorofluorescein diacetate fluorescence microscopy, and cell survival was concurrently determined. Effects of chemical antioxidants on endothelial cell survival were also tested.Results: Myocardial CRP levels were elevated in CVD specimens. This was associated with reduced cardiac microvessels, and this rarefaction was inversely correlated to adjacent myocardial CRP prevalence. CRP caused concentration-dependent increases in oxidant production and cell apoptosis.Conclusions: These findings provide evidence supporting myocardial CRP as a locally produced inflammatory marker and as a potential participant in endothelial toxicity and microvascular rarefaction.

Neuregulin-1/ErbB signaling is impaired in the rat model of diabetic cardiomyopathy - Corrected Proof

Chun Gui, Liguang Zhu, Ming Hu, Lei Lei, Qicheng Long — 2012-01-30

Abstract: Background: Diabetic cardiomyopathy (DCP) is one of the leading causes of increased morbidity and mortality in the diabetic population. The neuregulin-1(NRG1)/ErbB signal system plays a critical role in maintenance of adult heart function. But little is known about the changes of NRG1/ErbB signal system in DCP. The aim of this study was to investigate the changes of the NRG1/ErbB signal system in DCP.Methods: A rat model of DCP was established using a single intraperitoneal injection of streptozotocin (STZ). Cardiac function was assessed using echocardiography. The left ventricle fibrosis was evaluated using Masson's trichrome staining. The mRNA expression profiles of ErbB2 and ErbB4 receptors were evaluated using real-time polymerase chain reaction. The protein expression of NRG1 and the phosphorylation of ErbB2 and ErbB4 receptors were assessed using Western blot analysis.Results: The results showed dramatic left ventricle fibrosis and impaired left ventricle systolic function at 12 weeks after STZ-induced diabetes. This study also showed that ErbB2 andErbB4 mRNA expression and NRG1 protein expression in the left ventricular myocardium were significantly decreased. In addition, weobserved decreased phosphorylation of the ErbB2 and ErbB4 receptors at 12 weeks after the induction of diabetes.Conclusions: These findings suggest that NRG1/ErbB signaling is impaired in DCP, which may play some roles in the pathogenesis of DCP.

Characterization of atrial morphology and sinus node morphology in heterotaxy syndrome: an autopsy-based study of 41 cases (1950–2008) - Corrected Proof

Adam L. Ware, Dylan V. Miller, Co-burn J. Porter, William D. Edwards — 2012-01-30

Abstract: Background: Heterotaxy syndrome affects the sidedness of heart, lungs, and abdominal viscera, and is associated with complex congenital heart disease. Cardiac sidedness is defined by the position of the morphological right atrium and may be normal, mirror-image, or isomeric. The sinus node has been reported to be present bilaterally in right isomerism and absent bilaterally in left isomerism, although exceptions may occur.Objective: Our aim was to evaluate bilaterally the presence or absence of sinus node tissue in autopsy-derived hearts from patients with heterotaxy and to correlate the findings with the sidedness of the two atria.Methods: Autopsy and clinical records were reviewed from 41 cases with heterotaxy. From the cardiac specimens, tissue was collected bilaterally from expected sinus node sites. Sinus node tissue was categorized microscopically as normal, hypoplastic, indeterminate, or absent.Results: In hearts thought to show right atrial isomerism, sinus node tissue was detected bilaterally in 54%, was absent on one side in 43%, and was absent on both sides in 3%. For cases with apparent left atrial isomerism, a single sinus node was present in the left-sided atrium in 75% of cases and was absent bilaterally in 25%.Conclusions: Bilateral sinus nodes were observed in only 54% of cases with right isomerism, and bilateral absence of sinus nodes was documented in only 25% of cases with left isomerism. Thus, our findings indicate that the sinus node is not a morphologically right-sided structure, and its presence therefore is not consistently related to the sidedness of the atria.

The pathophysiology of heart failure - Corrected Proof

Clinton D. Kemp, John V. Conte — 2012-01-09

Abstract: Heart failure is a clinical syndrome that results when the heart is unable to provide sufficient blood flow to meet metabolic requirements or accommodate systemic venous return. This common condition affects over 5 million people in the United States at a cost of $10–38 billion per year.Heart failure results from injury to the myocardium from a variety of causes including ischemic heart disease, hypertension, and diabetes. Less common etiologies include cardiomyopathies, valvular disease, myocarditis, infections, systemic toxins, and cardiotoxic drugs. As the heart fails, patients develop symptoms which include dyspnea from pulmonary congestion, and peripheral edema and ascites from impaired venous return. Constitutional symptoms such as nausea, lack of appetite, and fatigue are also common.There are several compensatory mechanisms that occur as the failing heart attempts to maintain adequate function. These include increasing cardiac output via the Frank–Starling mechanism, increasing ventricular volume and wall thickness through ventricular remodeling, and maintaining tissue perfusion with augmented mean arterial pressure through activation of neurohormonal systems. Although initially beneficial in the early stages of heart failure, all of these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure.Treatment strategies have been developed based upon the understanding of these compensatory mechanisms. Medical therapy includes diuresis, suppression of the overactive neurohormonal systems, and augmentation of contractility. Surgical options include ventricular resynchronization therapy, surgical ventricular remodeling, ventricular assist device implantation, and heart transplantation. Despite significant understanding of the underlying pathophysiological mechanisms in heart failure, this disease causes significant morbidity and carries a 50% 5-year mortality.

Fibroblast growth factor-2 promotes in vitro heart valve interstitial cell repair through the Akt1 pathway - Corrected Proof

Li Han, Avrum I. Gotlieb — 2012-01-09

Abstract: Background: Fibroblast growth factor-2 promotes in vitro heart valve interstitial cell repair. Fibroblast growth factor-2 acts through betaglycan which is known to bind both transforming growth factor-β and fibroblast growth factor-2 at different locations on the molecule. When fibroblast growth factor-2 binds to betaglycan, transforming growth factor-β binding to betaglycan is reduced, allowing for more transforming growth factor-β to be available to activate pSmad2/3 which then promotes repair. This study investigates another pathway through which fibroblast growth factor-2 regulates valve interstitial cell repair.Methods: We used an in vitro model of cell culture disruption. Confluent valve interstitial cell monolayers were disrupted, creating an experimental wound in the confluent monolayer, and incubated in treatments of exogenous fibroblast growth factor-2, anti-fibroblast growth factor receptor antibody, active Akt1, and Akt inhibitor. Valve interstitial cell monolayers were immunohistochemically stained and quantified for nuclear pSmad2/3 at the wound edge. The extent of closure was measured up to 96 h after disruption.Results: Anti-fibroblast growth factor receptor antibody significantly increased both nuclear pSmad2/3 staining at the wound edge and wound closure compared to nontreated control. This increase was less than that seen when valve interstitial cells were treated with fibroblast growth factor-2 and combined treatments of fibroblast growth factor-2 and anti-fibroblast growth factor receptor antibody did not further increase nuclear pSmad2/3 staining compared to fibroblast growth factor-2 alone. This suggested that the regulation of wound closure by fibroblast growth factor-2 also involved pathways other than transforming growth factor-β/Smad signaling. Treatment with Akt1 significantly increased wound closure, while Akt inhibitor reduced closure as compared to nontreated valve interstitial cells. Fibroblast growth factor-2 and fibroblast growth factor-2 neutralizing antibody up-regulated and down-regulated phosphorylated Akt1 expression in valve interstitial cells, respectively.Conclusion: Fibroblast growth factor-2 promotes valve interstitial cell repair in two ways: the fibroblast growth factor-2/fibroblast growth factor-2 receptor interaction through the activation of Akt1 independent of the transforming growth factor-β/Smad2/3 signaling pathway and the previously described transforming growth factor-β/Smad signaling.

Unicommissural aortic valves: gross, histological, and immunohistochemical analysis of 52 cases (1978-2008) - Corrected Proof

Michael E. Fealey, William D. Edwards, Dylan V. Miller, Joseph J. Maleszewski — 2011-12-29

Abstract: Background: Unicommissural aortic valves (UAVs) are rare anomalies in which adjacent cusps of two commissures are congenitally fused. Currently, features of UAVs are poorly characterized.Methods: Fifty-two surgical and autopsy cases of UAV at Mayo Clinic were evaluated for various clinicopathologic features. Histology and immunohistochemistry (IHC) were used in 30 UAVs to identify biomarkers important to developing aortic stenosis.Results: In 52 UAV patients (58% were male, 42% were female), their ages ranged from 18 weeks' gestation to 80 years (mean, 28 years). Functional status was pure stenosis in 20, pure regurgitation in 9, combined in 22, and normal in 1. Common additional cardiovascular disorders included left ventricular hypertrophy (56%) and ascending aortopathies (42%). The position of the true commissure was determined in 30 UAVs and was left posterior in 73%. Gross calcification increased exponentially with age, starting as early as 16 years. Microscopically, the values of the 3 youngest patients showed dysplasia. Other UAVs exhibited fibrous thickening (93%), ventricular pads (89%), aortic pads (81%), and thickened spongy layer (74%). Macrophages were the most common leukocyte by IHC. Bone morphogenetic protein-2 was positive in 27 IHC cases; osteopontin was positive in 15, and matrix metalloproteinase (MMP) 2, MMP-9, and MMP-14 were positive in 1, 6, and 4 cases, respectively.Conclusion: The functional status of UAVs typically involves stenosis but can vary in type and degree or rarely be normal. In early stenosis (<16 years), the pathology is primarily fibrosis with minimal calcification. UAVs show more calcification compared with age-matched bicuspid or tricuspid aortic valves. The molecular mechanisms of calcification and fibrosis in UAVs remain incompletely understood.

Stereological characterization of left ventricular cardiomyocytes, capillaries, and innervation in the nondiabetic, obese mouse - Corrected Proof

2011-12-26

Abstract: Background: Obesity is associated with left ventricular hypertrophy and dysfunction, but little is known about the structural remodeling of cardiomyocytes, capillaries, and nerve fibers in this state. We hypothesized that all three compartments should show quantitative structural alterations.Methods: Ten C57Bl6 mice were randomly assigned to a control or obesity group. Lean mice received standard chow, whereas obese mice received a high-fat Western diet. After 28 weeks, the mice were sacrificed, and the hearts were prepared for design-based stereology using light and electron microscopy.Results: Body mass and left ventricular mass were significantly elevated in obese vs. control mice. The left ventricular hypertrophy was accompanied by a significant increase in cardiomyocyte lipid droplets and total myocyte volume. The volume fractions of myofibrils, free sarcoplasm, and mitochondria did not differ between the groups. The total length of capillaries was significantly enhanced in obese vs. control mice, whereas the total length of axons ramifying between cardiomyocytes was not different.Conclusions: Obesity is associated with significant structural alterations in cardiomyocytes and capillaries, whereas no structural changes in the myocardial innervation were observed. The structural characteristics in obese mice do not provide a clear basis for functional changes observed in obesity-related cardiac hypertrophy.

Intracardiac thrombi in extracardiac disorders: an autopsy study - Corrected Proof

Pradeep Vaideeswar, Smita Divate, Megha Harke — 2011-12-26

Abstract: Introduction: Intracardiac thrombi (ICT), more commonly encountered at autopsy, are well documented with underlying cardiovascular disease. Occurrence of ICT in systemic diseases without an intrinsic cardiac disorder is rare. The aim of this autopsy study was to highlight such an occurrence.Methods: From 1996 to 2010, cases with ICT unrelated to primary cardiac disorders were selected at autopsy and analyzed. Clinical and investigational data were obtained from the medical records. The location, morphology, size, and histological appearance of the thrombi were noted. The thrombi were then classified on the basis of their location, nature, and histology (fresh and/or organized); this was correlated with the clinical setting.Results: Among a total of 11,724 autopsies performed in 15 years, 276 patients (2.4%) had ICT. Of these, 45 patients (0.4%) had ICT that were unrelated to primary cardiac diseases. There were 25 men and 20 women with a mean age of 46.1 years. Antemortem diagnosis was not made in any of these patients. Eight patients each (35.6%) showed isolated left-sided and multichambered involvement, while the rest of the hearts (64.4%) had thrombi in the right-sided chamber(s). The recognizable risk factors were underlying cancers (24.4%), prolonged immobilization (20%), systemic lupus erythematosus (6.7%), pregnancy (4.4%), nephropathy (4.4%), primary antiphospholipid antibody syndrome (2.2%), and ulcerative colitis (2.2%). However, 16 patients (35.7%) had no obvious predisposing factor, although investigations for prothrombotic markers had not been done. Diabetes mellitus, chronic alcoholism, and deep vein thrombosis of the lower limbs had been clinically documented in some of them. The cause of death in most patients (73.3%) had been related to pulmonary and/or systemic thromboembolism.Conclusions: This autopsy study emphasizes the great need for a higher index of suspicion of in situ thrombosis in the heart in hypercoagulable states so as to curtail the morbidity and mortality of the primary disease process.

Mycobacterium fortuitum prosthetic valve endocarditis: a case for the pathogenetic role of biofilms - Corrected Proof

2011-12-23

Abstract: Background: Prosthetic valve endocarditis presents unique challenges for both diagnosis and treatment. A potential role of biofilm has been hypothesized in the pathogenesis of these infections.Methods: A patient with infective endocarditis involving a stentless (Freestyle) porcine prosthetic aortic valve with annular abscess and paravalvular leak 8 months after implantation is reported.Results: The infected valve did not show vegetations or perforations, but histiocytic inflammation was seen along the endocardial surfaces of the valve. Auramine–rhodamine staining revealed many acid-fast organisms associated with the inflammation. There was also an acellular matrix material with ultrastructural features of biofilm. Blood cultures grew Mycobacterium fortuitum, a biofilm-associated microbe.Conclusions: The role of biofilm in prosthetic valve endocarditis is discussed. The importance of microscopy for prosthetic valves, even when no vegetations are present, is highlighted along with correlation of pathologic findings with culture results.

The first cardiac transplant experience in a patient with mucopolysaccharidosis - Corrected Proof

2011-12-08

Abstract: Hunter syndrome (MPSII) is a rare X-linked lysosomal storage disorder that can affect multiple systems but primarily affects the heart. We report the case of a previously asymptomatic 23-year-old patient who had an attenuated form of MPSII and presented with refractory heart failure that required a heart transplant. The diagnosis was confirmed by detection of an increase in urinary excretion of glycosaminoglycans, a deficiency in enzymatic activity, and molecular analysis. A myocardial biopsy revealed hypertrophic cardiomyocytes, mild fibrosis, and lysosomal storage in interstitial cells. Molecular analysis identified a novel mutation in the iduronate-2-sulfatase gene. Although the clinical outcome was not favorable, we believe that this approach may be valid in end-stage heart failure.

Increased lipofuscin on endomyocardial biopsy predicts greater cardiac improvement in adolescents and young adults - Corrected Proof

2011-12-08

Abstract: Background: The presence of interstitial fibrosis and lipofuscin in endomyocardial biopsies may indicate the chronicity of heart failure. Fibrosis is known to increase in the failing heart. Lipofuscin increases with age, but its relationship to heart function is unknown. This study investigated whether lipofuscin or fibrosis had predictive utility in indicating function or adverse event (death, transplant, assist device placement) at 1 year postbiopsy in adolescents and young adults.Methods: A retrospective analysis was performed on nontransplant endomyocardial biopsies between 2000 and 2009 from individuals aged 10–40 years. Clinical and demographic information including ejection fraction (EF), EF at 1 year, and adverse events were obtained as available. Lipofuscin and fibrosis were scored retrospectively in a blinded fashion for 201 biopsies. Linear regression and Cox proportional hazard models were used for multivariable analysis.Results: Increasing lipofuscin strongly correlated with patient age (P<.0001). Higher lipofuscin levels were correlated with a better EF at 1 year (P=.02). This remained significant (P=.04) after adjusting for age. The degree of fibrosis did not associate with any clinical variable and had no predictive capabilities in this study.Conclusions: This is the first study to incorporate lipofuscin in predicting future heart function. We found that more lipofuscin correlates with better EFs at 1 year, suggesting that lipofuscin is a marker for improved cardiac compensation. This information can help clinicians devise treatment plans for individuals in this age group.

2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology - Corrected Proof

2011-12-05

Abstract: The Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology have produced this position paper concerning the current role of endomyocardial biopsy (EMB) for the diagnosis of cardiac diseases and its contribution to patient management, focusing on pathological issues, with these aims:

Solitary atrial myocardial metastasis revealing ileal neuroendocrine carcinoma - Corrected Proof

2011-12-05

Abstract: A previously healthy 56-year-old man presented with chest pain. Echocardiography and cardiac magnetic resonance imaging revealed minimal pericardial effusion associated with an isolated myocardial mass, protruding into the left atrium. The tumor was surgically removed. Cardiac valve morphology was strictly normal. Histology revealed a well-differentiated neuroendocrine carcinoma. Positron emission tomography scan and thin-slice abdominal computed tomography demonstrated ileal tumor, without evidence of liver metastasis. Histological study of the removed ileal tumor confirmed a neuroendocrine carcinoma, and histology of liver biopsy was negative. Somatostatin analogue treatment was started. No tumoral recurrence was observed after 1 year of follow-up. In conclusion, we report an unusual presentation of neuroendocrine carcinoma, revealed by a large solitary atrial metastasis, in the absence of liver involvement or carcinoid syndrome.

Development of a mathematical model to describe the transport of monocyte chemoattractant protein-1 through a three-dimensional collagen matrix - Corrected Proof

Krisada Leemasawatdigul, Heather Gappa-Fahlenkamp — 2011-11-21

Abstract: Introduction: Monocyte chemoattractant protein-1 is a bioactive molecule that is expressed in significant amounts in all stages of atherosclerosis. The role of monocyte chemoattractant protein-1 in this disease is to recruit monocytes across the endothelium and into the arterial tissue. Eventually, the monocytes differentiate into cholesterol-engorged macrophages called “foam cells” that result in atherosclerotic plaque formation. The mechanism that monocyte chemoattractant protein-1 uses to mediate monocyte transendothelial migration is believed to be via its concentration gradient. However, the formation of the monocyte chemoattractant protein-1 concentration gradient in the extracellular matrix is still poorly understood.Methods: A three-dimensional in vitro vascular tissue model has been developed to study the cellular mechanisms involved in the early stages of atherosclerosis. In the present study, a mathematical model is used to determine the gradient of monocyte chemoattractant protein-1 in the collagen matrix of the three-dimensional in vitro vascular tissue model. Experiments were performed to investigate the stability of monocyte chemoattractant protein-1 and the interaction between monocyte chemoattractant protein-1 and the collagen matrix.Results and conclusions: Monocyte chemoattractant protein-1 is stable for at least 24 h under experimental conditions and monocyte chemoattractant protein-1 interacts with the collagen matrix. The diffusion coefficient for the transport of monocyte chemoattractant protein-1 in the collagen matrix and the rate constant for the binding of monocyte chemoattractant protein-1 to collagen were determined to be 0.108 mm2 h−1 and 0.858 h−1, respectively. Numerical results from the model indicate that the concentration gradients of both soluble and matrix-bound (or static) monocyte chemoattractant protein-1 are formed inside the collagen matrix.

Transfection by eukaryotic expression vector pcDNA3-HERG inhibits the cultured neonatal rabbit ventricular myocyte hypertrophy induced by phenylephrine - Corrected Proof

Yonghui Zhao, Yu Xu, Changcong Cui, Yu Li, Yanjun Zeng — 2011-11-21

Abstract: Objective: Prolonged action potential and decreased outward K+ currents are consistent findings in hypertrophic myocardium. The relation between action potential prolongation and myocyte hypertrophy has remained unclear. The present study investigated the temporal relation between action potential prolongation and myocyte hypertrophy, and the effect of enhancing repolarization on myocyte hypertrophy induced by phenylephrine.Methods: Neonatal rabbit ventricular myocytes were cultured and treated with 10 μmol/l phenylephrine. At 6 and 48 h after phenylephrine stimulation, myocyte hypertrophic parameters (including myocyte volume, total protein content, and membrane capacitance), action potential duration (APD), and calcineurin activity were measured; meanwhile, the effect of human-ether-a-go-go–related gene (HERG; encoding the αsubunit of rapidly activating delayed rectifier potassium channel) transfection on the above parameters at 48 h of phenylephrine stimulation was also measured.Results: At 6 h after phenylephrine treatment, APD at 90% repolarization of neonatal rabbit ventricular myocytes was prolonged by 14.3% (P<.05), but myocyte hypertrophy was not found. At 48 h after phenylephrine stimulation, APD at 90% repolarization of neonatal rabbit ventricular myocytes was furthermore prolonged by 18.8% (P<.05); at the same time, myocyte volume, total protein content, membrane capacitance, and calcineurin activity were increased by 40.0%, 41.8%, 36.4%, and 124.1%, respectively (P<.01). Neonatal rabbit ventricular myocytes transfected by pcDNA3-HERG overexpressed IHERG,tail current, which was about fourfold higher than IKr (rapidly activating delayed rectifier K+ current) of neonatal rabbit ventricular myocytes without transfection of HERG. HERG overexpression could accelerate repolarization and shorten APD at 90% repolarization prolonged by phenylephrine and partially inhibit myocyte hypertrophy and calcineurin activation.Conclusions: During the myocyte hypertrophy induced by phenylephrine, prolongation of APD at 90% repolarization is not secondary to but precedes myocyte hypertrophy. HERG overexpression could enhance the repolarization and inhibit the calcineurin activation and myocyte hypertrophy induced by phenylephrine.

Cardiac myxoma with oncocytic change—cardiac oncocytoma? - Corrected Proof

Skye Puskarz-Thomas, Andrew Dettrick, Peter G. Pohlner — 2011-11-21

Abstract: We report the case of an incidental cardiac myxoma that was remarkable for the presence of extensive oncocytic change, a feature that has not be reported previously. The oncocytes most likely represent part of a spectrum of degenerative changes present in the tumor, but the possibility that they are neoplastic is also discussed.

Serum proteomics in patients with diagnosis of abdominal aortic aneurysm - Corrected Proof

2011-11-21

Abstract: Background: Molecular mechanisms underlying abdominal aneurysm (AAA) formation and rupture are not well understood. Early detection and repair of AAA may reduce the high mortality rates associated with rupture. Serum proteomics allows the detection of alterations in the expression of proteins, guiding further studies on these target molecules as potential markers.Analysis of proteomic profile of asymptomatic patients with AAA allows the identification of reliable predictors or markers of disease presence or progression.Methods: A proteomics approach based on two-dimensional electrophoresis and mass spectrometry was used to compare serum proteomic profiles of patients with AAA who are candidates for surgical repair compared with healthy controls. We analyzed in parallel the proteomic profile of subjects with cardiac heart failure to discriminate these two pathologies, which show similar pattern of systemic inflammation process.Results: We identified in AAA subjects four serum proteins that show altered expression profile and that could be specifically linked to AAA pathology. We discuss the role of our identified proteins with their possible implications in disease outcome.Conclusions: This approach could provide an initial screening tool that may drive the basis for further research in the field of cardiovascular diseases. These results need to be validated in larger studies to find potential markers of AAA presence or progression to use in clinical settings.Summary: A proteomics approach was used to compare serum proteomic profiles of patients with abdominal aortic aneurysm who are candidates for surgical repair compared with healthy controls. Four serum proteins showed altered expression profile that could be correlated with the pathology. This approach could provide an initial screening tool that may drive the basis for further research in the field of cardiovascular diseases.

Integrin expression during reverse remodeling in the myocardium of heart failure patients - Corrected Proof

2011-11-21

Abstract: Background: The main anchoring proteins of myocardial cells with each other and with the extracellular matrix are integrins present in the membranes of myocardial cells. These integrins are important for maintaining the architecture of the myocardial tissue and the mechanotransduction in the heart. Heart failure leads to various alterations in the myocardium, such as changes in morphology, and in expression of mRNAs, miRNAs, and proteins. Left ventricular assist device (LVAD) support in heart failure patients has been described to induce reverse remodeling of the myocardium and thus to (some degree of) reversal of the aforementioned alterations. In this study, we evaluated whether changes in expression of integrins α-1, -3, -5, -6, -7, -10, -11 and β-1, -3, -5 and -6 play a role during reverse remodeling.Methods: Three-step immunoperoxidase staining procedures were applied on frozen heart tissue sections to locate the various integrins tested. Integrin mRNA expression was established by standard Q-PCR procedures.Results: It was shown that mRNA expression of several integrins changes significantly during LVAD support, however without subsequent changes in immunohistochemical detectable quantities. Various integrins showed different locations within the myocardium.Conclusion: LVAD-induced reversed remodeling did not result in significant integrin protein expression, although changes in integrin mRNA expression suggested an adaptation to unloading.

Histological analysis of clipped human intracranial aneurysms and parent arteries with short-term follow-up - Corrected Proof

2011-11-21

Abstract: Background: Surgical clipping of intracranial aneurysms is the gold standard for the prevention of rupture. However, the biological processes that occur following clipping are poorly understood. To better understand these effects, retrieved and clipped human intracranial aneurysms were examined histologically.Methods: At autopsy, 17 aneurysms from 10 patients were retrieved 3–21 days after clipping. The tissues were embedded in paraffin, and microtome sections were stained using hematoxylin–eosin and Movat pentachrome. Using light microscopy, clip placement relative to the internal elastic lamina of the parent artery, endothelialization of the aneurysm neck, thrombus organization inside the aneurysm sac, inflammation in the sac, wall, and parent artery, and atherosclerotic changes were determined.Results: Despite complete reconstruction of the artery with the clip, diseased vessel wall was frequently observed outside the clip. By 10 days postsurgery, the beginnings of endothelialization and neointima formation were observed at the neck. However, the neck coverage was variable and incomplete at these early time points. Thrombus organization inside the aneurysm sac was rarely observed, and inflammatory cells were not present inside the aneurysm sac. Inflammatory cells were commonly observed in the aneurysm wall, and atherosclerotic change was present in each sample.Conclusions: Complete aneurysm exclusion and apposition of healthy arterial wall occurred infrequently in our series. Endothelialization and neointima formation at the aneurysm neck take some time to complete and are often incomplete. The effectiveness of aneurysm clipping is related to the mechanics of aneurysm exclusion rather than the processes of endothelialization and neointima formation.Summary: Complete aneurysm exclusion and apposition of healthy arterial wall occurred infrequently in our series. Endothelialization and neointima formation at the aneurysm neck take some time to complete and are often incomplete. The effectiveness of aneurysm clipping is related to the mechanics of aneurysm exclusion rather than the processes of endothelialization and neointima formation.

Helicobacter species in the atherosclerotic plaques of patients with coronary artery disease - Corrected Proof

2011-11-21

Abstract: Introduction: Several epidemiological studies have proposed an association between Helicobacter pylori infection and coronary artery disease. In the current study, we aimed to evaluate the prevalence and relevance of H. pylori infection, using polymerase chain reaction (PCR) methods, in the coronary arterial wall of Iranian patients who have already undergone coronary bypass grafting (CABG).Methods: A total of 105 consecutive patients who underwent CABG at the Department of Cardiovascular Surgery of Baqiyatallah University of Medical Sciences were included in the study, and biopsy specimens from their coronary plaques were taken and analyzed using the PCR methods for detecting Helicobacter species (H Spp.). Fifty-three specimens from biopsies of the left internal mamillary artery in the same patients were also collected and tested.Results: H. Spp. PCR test result was positive for 31 (29.5%) specimens from coronary artery atherosclerotic plaques. Serologic test results also showed 25 (23.8%) positive cases for H. pylrori immunoglobulin A (IgA) and 56 (53.3%) positive for anti-H. pylori immunoglobulin G. None of the specimens from the mamillary artery were positive for H Spp. genome when it was evaluated using PCR (P<.0001). Patients with positive test result for H. pylori IgA were significantly more likely to have higher total cholesterol and low-density lipoprotein (LDL) levels than IgA-negative patients.Conclusion: H Spp. infection replication in the coronary arterial wall is associated with atherosclerotic plaque formation. Seropositivity for H. pylori IgA may also enhance blood values of total cholesterol and LDL in these patients.

Arrhythmogenic cardiomyopathy: from autopsy to genes and transgenic mice (SCVP Achievement Award Lecture, San Antonio, TX, February 27, 2011) - Corrected Proof

Gaetano Thiene — 2011-11-21

Abstract: We present the history of arrhythmogenic cardiomyopathy since its discovery in the 1980s at autopsy of young subjects, who died suddenly during effort as a first manifestation of the disease and in whom the right ventricle was found as the source of lethal arrhythmias. Most of the contributions have come from the Padua as well as from the Paris and London schools.Investigations were then developed to arrive at the diagnosis, and these include electrocardiography, angiography, echocardiography, electroanatomic mapping, endomyocardial biopsy, and magnetic resonance imaging. Disqualification from sport activity and implantable cardioverter defibrillator proved to be life-saving.Genetic investigations have confirmed that arrhythmogenic cardiomyopathy is a hereditary Mendelian disease, either dominant or recessive, with mutations of genes encoding intercellular proteins (desmosome disease).The disease was recently reproduced in transgenic mice, with electrocardiographic and morphologic features overlapping the human disease.Cardiomyocyte cell death occurs with time as a genetically determined injury. The challenge now is to find ways to prevent onset and progression of the disease.

Cardiac hypertrophy in deceased users of anabolic androgenic steroids: an investigation of autopsy findings - Corrected Proof

Hamid Reza Mobini Far, Greta Ågren, Ingemar Thiblin — 2011-11-21

Abstract: Background: The use of anabolic androgenic steroids (AASs) has been associated with hypertrophy of the left cardiac ventricle (LVH) as diagnosed by echocardiography. Case reports suggest that AAS-related LVH may lead to sudden death. We performed an investigation of the gross cardiac pathological findings in deceased male AAS users in order to further elucidate the proposed role of AAS in cardiac hypertrophy.Methods: Eighty-seven deceased males who tested positive for AAS at autopsy and 173 age-adjusted control deceased males without suspected AAS use were studied for cardiac hypertrophy. The AAS-positive subjects had been examined at any of the six departments of forensic medicine in Sweden during the period from 1989 to 2009. Data were assessed employing multivariate analyses controlling for body weight, height, age, bleeding after trauma, and the impact of weight training.Results: The analysis of the logarithm of heart mass by multivariate statistics implied that strong correlations existed between body mass and heart mass (P<.00001), height and heart mass (P<.02), age and heart mass (P<.00001), and trauma (bleeding) and heart mass (P=.00001). After controlling for these factors, a significantly higher heart mass (P=.0001) was found among the AAS-positive males.Conclusion: Our findings suggest that use of AAS may lead to cardiac hypertrophy with a direct cardiotropic effect.

Segmental arterial mediolysis—an iatrogenic vascular disorder induced by ractopamine - Corrected Proof

Richard E. Slavin, Micheal J. Yaeger — 2011-10-31

Abstract: Background: Segmental arterial mediolysis, an uncommon arterial disorder most often occurring in the splanchnic muscular arteries of the abdomen, is a cause of catastrophic hemorrhages. Its histology and initial clinical presentations suggested that it represented a localized norepinephrine-induced vasospastic response to perturbations in vascular tone and blood volume distribution caused by coexisting vasoconstrictor conditions. However, later presentations were at odds with some aspects of this hypothesis.Methods: Nine greyhound dogs were administered a single dose of ractopamine. Two dogs developing persistent conduction abnormalities with biochemical evidence of heart injury were euthanized and necropsied—one 4 days and the other 17 days after dosage This report is based on findings and comparisons of the canine abdominal and coronary arteries to segmental arterial mediolysis.Results: Lesions having features of early-injurious-stage segmental arterial mediolysis were identified in the canine arteries 4 days postractopamine, and arteries examined after 17 days showed alterations typically occurring in reparative-stage segmental arterial mediolysis. It is suspected that ractopamine, a Beta-2 adrenergic agonist, created segmental arterial mediolysis by neuromodulating the peripheral sympathetic nervous system to release norepinephrine from varicosities of efferent nerves serving splanchnic arteries that stimulate alpha-1 receptors to induce injury at the adventitial medial junction and medial muscle apoptosis.Conclusion: This finding and other cited examples suggest that segmental arterial mediolysis may be a disorder principally caused by iatrogenic or accidental exposure to alpha-1 adrenergic receptor agonists or Beta-2 agonists able to release norepinephrine from the peripheral nervous system.

Single gene disorders of the aortic wall - Corrected Proof

Marc K. Halushka — 2011-10-31

Abstract: Genetic diseases that affect the vasculature primarily affect the aortic root and ascending aorta. These conditions lead to aortic root dilatation, which, if not treated, will result in dissection and death. Often, aortic disease is just one manifestation of a syndrome with diverse findings. Some of these diseases were described over 100 years ago based on physical manifestations, and their causative genes are among the first described Mendelian causes of cardiovascular disease.Within the pediatric and young adult population, there are over 15 causes of ascending aortic disease. Previously, these diverse diseases, along with their histopathology, have been extensively characterized. Most genetic causes of root aneurysm are extremely rare. Amongst these, five diseases are relatively common with known genetic mutations for which pathologists should be familiar. These are Marfan syndrome, vascular Ehlers–Danlos syndrome, Loeys–Dietz syndrome, Turner syndrome, and familial thoracic aneurysm and dissection.This review will focus on these important causes of genetic aortic disease. The aim is to briefly describe the historical record and physical manifestations and then focus on cardiovascular complications, the causative genes, and current research into these entities.

Molecular changes in the heart of a severe case of arrhythmogenic right ventricular cardiomyopathy caused by a desmoglein-2 null allele - Corrected Proof

2011-10-31

Abstract: Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder caused by mutations in desmosomal genes. It is often associated with life-threatening arrhythmias. Some affected individuals develop progressive heart failure and may require cardiac transplantation.Methods: The explanted heart of a young adult with end-stage heart failure due to a null allele in desmoglein-2 was studied at macroscopic, microscopic, and molecular level. Myocardial samples were probed for junctional localization of desmosomal components and the gap junction protein connexin43 by immunohistochemical staining. In addition, the protein content of desmosomal and adherens junction markers as well as connexin43 was assessed by Western blotting.Results: Histological analysis confirmed ARVC. Despite the loss of specific immunoreactive signal for desmosomal components at the cardiac intercalated disks (shown for plakoglobin, desmoplakin, and plakophilin-2), these proteins could be detected by Western blotting. Only for desmoglein-2, desmocollin-2, and plakoglobin were reduced protein levels observed. Adherens junction proteins were not affected. Lower phosphorylation levels were observed for connexin43; however, localization of the gap junction protein displayed regional differences. At the molecular level, disease progression was more severe in the right ventricle compared to the left ventricle.Conclusion: Our data suggest that, in the ARVC heart, plakoglobin is mainly redistributed from the junctions to other cellular pools and that protein degradation only plays a secondary role. Homogenous changes in the phosphorylation status of connexin43 were observed in multiple ARVC samples, suggesting that this might be a general feature of the disease.

Adhesion molecule expression and ventricular remodeling in chronic rheumatic heart disease: a cause or effect in the disease progression — a pilot study - Corrected Proof

2011-10-17

Abstract: Background: Rheumatic fever and chronic rheumatic heart disease (RHD) remains one of the most important causes of cardiovascular morbidity leading to a major public health problem, especially in developing countries. This was a pilot study to assess the presence of inflammation and expression of adhesion molecules by immunohistochemistry (IHC) in endomyocardial biopsy specimens of patients with chronic RHD.Methods: Endomyocardial biopsy was obtained from 14 patients of chronic RHD with no features of activity clinically. Biopsies were processed for histology and IHC. IHC was carried using monoclonal antibodies against CD3, CD4, CD8, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1.Results: Histomorphologically, varying degree of interstitial and perivascular fibrosis was seen in all the 13 patients (100%). Mild fibrosis (1+) was seen in five patients (38.5%); moderate interstitial fibrosis (2+) was present in four patients (30.8%).There was no Aschoff nodule or evidence of active myocarditis in any of the biopsy specimens.Immunohistochemistry: Moderate positivity of (2+) and intense positivity of (3+) for intercellular adhesion molecule-1 was seen in 11 and 2 patients, respectively. With vascular cell adhesion molecule-1, four showed mild positivity (1+), and three showed intense positivity (3+). The phenotypic analysis of the inflammatory cells in our study revealed CD8+ cells in 77%, CD4+ in 23.1%, and CD3+ in 38.5% of total patients, which suggests chronicity.Conclusion: The nonspecific histomorphological changes and increased adhesion molecules expression could be a part of the ventricular remodeling due to the hemodynamic stress by the stenotic or regurgitant lesions of RHD itself.

Acute myocardial infarction induces bilateral stellate ganglia neural remodeling in rabbits - Corrected Proof

2011-10-17

Abstract: Introduction: Myocardial infarction (MI) results in cardiac nerve sprouting in the myocardium. Whether or not similar neural remodeling occurs in the stellate ganglia (SGs) is unknown. We aimed to test the hypothesis that MI induces bilateral SG nerve sprouting.Methods: Acute MI was created by coronary artery ligation in rabbits (n=12). Serum nerve growth factor (NGF) level was measured by enzyme-linked immunosorbent assay. The hearts and bilateral SGs were harvested for immunohistochemistry after 1 week in six rabbits and after 1 month in six rabbits. Immunostaining for tyrosine hydroxylase (TH), growth-associated protein 43 (GAP43), choline acetyltransferase (ChAT), and synaptophysin (SYN) was performed to determine the magnitude of nerve sprouting. Tissues from six normal rabbits were used as controls. Nerve density was determined by computerized morphometry.Results: Myocardial infarction results in increased serum NGF levels at 1 week (1519.8±632.2 ng/ml) that persist up to 1 month (1361.2±176.3 ng/ml) as compared to controls (89.6±34.9 ng/ml) (P=.0002 and P=.0001, respectively). Immunostaining demonstrated nerve sprouting and hyperinnervation in both SGs after MI. The nerve densities (μm2/ganglion cell) in SG 1 week after MI and 1 month after MI and those in control groups, respectively, were as follows: GAP43: 278±96, 225±39, and 149±57 (P=.01); SYN: 244±152, 268±115, and 102±60 (P=.02); TH: 233±71, 180±50, and 135±68 (P=.047); ChAT: 244±100, 208±46, and 130±41 μm2/cell (P=.01).Conclusions: Myocardial infarction increases serum NGF levels and induces nerve sprouting and hyperinnervation in bilateral SGs for at least 1 month after MI. The hyperinnervation includes both adrenergic axons and cholinergic axons in the SG.

Histological correlate of a cardiac magnetic resonance imaged microvascular obstruction in a porcine model of ischemia–reperfusion - Corrected Proof

2011-09-23

Abstract: Background: Microvascular obstruction after reperfusion therapy of acute myocardial infarction is reported as an adverse promoter of left ventricular remodeling and is an important target to prevent deterioration into heart failure. In this study, we illustrate the early onset of a magnetic resonance imaged microvascular obstruction in a porcine model of acute myocardial infarction with the exact histological correlate.Methods: Occlusion of the left anterior descending coronary artery followed by 3-h reperfusion was performed in 10 pigs. Microvascular obstruction was assessed by contrast-enhanced magnetic resonance imaging (MRI). After sacrifice, serial sectioned slices of the hearts matching the MRI were stained with Triphenyl tetrazolium chloride (TTC). Biopsies were fixed, embedded in paraffin, and stained for hematoxylin–eosin.Results: Microvascular obstruction was defined with MRI as a hypoenhanced no-reflow area within the hyperenhanced infarct region. Erythrocyte plugging was consistently observed in the no-reflow area and was completely absent in the adjacent hyperenhanced infarct region.Conclusion: This model of acute ischemia–reperfusion contributes to the histological comprehension of contrast-enhanced MRI during the early stages of myocardial infarction.

Elevated cyclic stretch and serotonin result in altered aortic valve remodeling via a mechanosensitive 5-HT2A receptor-dependent pathway - Corrected Proof

2011-08-24

Abstract: Introduction: Serotonin/5-hydroxytryptamine (5-HT) has been implicated in valve disease and in the modulation of valve mechanical properties. Several 5-HT receptor subtypes are also known to be mechanosensitive in other cell types, but this has not been studied in the context of the valve. In this study, we sought to understand the effects of elevated 5-HT levels and stretch overload on aortic valve remodeling and the dominant 5-HT receptor subtype that regulates these processes.Methods and results: Collagen biosynthesis and tissue mechanical properties of porcine aortic valve cusps were evaluated after 10% (physiologic) and 15% (pathologic) dynamic stretch. These studies were performed in normal medium or medium supplemented with 5-HT (1, 10, 100 μM) in the absence and presence of 5-HT2A or 5-HT2B receptor antagonists. Fresh valves served as controls. Valve collagen content was maximal at the 10-μM 5-HT concentration for both 10% and 15% stretch. The 5-HT2A receptor antagonist reduced collagen synthesis, cell proliferation, and hsp47 expression under elevated and normal stretch, whereas the 5-HT2B receptor antagonist was effective only at normal stretch. The pretransition stiffness of the valve cusps was also increased in response to 5-HT via a stretch-sensitive 5-HT2A mechanism, with the post-transition stiffness unaltered.Conclusions: Combined elevated stretch and 5-HT resulted in increased valve collagen biosynthesis, cell proliferation, and tissue stiffness. These responses were inhibited by a 5-HT2A antagonist. This strongly suggests that the 5-HT2A receptor subtype is sensitive to elevated stretch.

Deletion of discoidin domain receptor 2 does not affect smooth muscle cell adhesion, migration, or proliferation in response to type I collagen - Corrected Proof

Guangpei Hou, David Wang, Michelle P. Bendeck — 2011-08-24

Abstract: Collagen receptors expressed on vascular smooth muscle cells include the discoidin domain receptors (DDR1 and DDR2). DDR1 is known to play important roles in mediating smooth muscle cell responses to vascular injury, including neointimal hyperplasia, but much less is known about the function of DDR2. In this study, we harvested smooth muscle cells from DDR2 wild-type and knockout mice and studied the cells using in vitro models of migration and growth. There were no significant differences in the ability of Ddr2+/+ or Ddr2−/− smooth muscle cells to attach to, migrate, or proliferate on type I collagen. Furthermore, neither matrix metalloproteinase (MMP) 2 nor MMP-9 activity nor type I collagen expression was different between the cell types. We conclude that in vitro, endogenous DDR2 is not required for smooth muscle cell hyperplastic responses to collagen.

Sudden death and coronary intimal thickening - Corrected Proof

Fabio Rocha Tavora, Allen Burke — 2011-08-22

We agree completely with Ottaviani's comments that intimal thickening has been observed in human coronary arteries in infants and children and that our study should have placed our findings in this broader context. The point of our study, in part, was to distinguish intimal thickening with extracellular lipid deposits from intimal thickening composed solely of smooth muscle cells and proteoglycan ground substance. The former has been termed “pathologic intimal thickening,” as initially coined by Virmani et al . Pathologic intimal thickening was originally described as a substrate for plaque erosion, a major type of coronary thrombosis that does not necessarily occur after formation of a necrotic core. As we state in our study, plaque erosion has been associated with coronary events in young individuals and seem more common in females . Pathologic intimal thickening has subsequently been described to occur in late childhood and young adults and may be considered a possible transition lesion between “adaptive” or “diffuse” intimal thickening, to which Ottaviani is referring, and fibroatheroma. The coronary wall changes, mainly intimal modifications, described in the studies by Milei et al and Matturri et al are quite similar to the ones seen in the figures of our study. It remains to be studied if the in utero environment that yields the coronary abnormalities share similar pathogenesis in adult plaques without a necrotic core. Our study was the first, we believe, to emphasize that pathologic intimal thickening may, in addition to providing a substrate for plaque erosion or a pathway to atheroma, result in coronary occlusion and sudden death.

Sudden death and coronary intimal thickening - Corrected Proof

Giulia Ottaviani — 2011-08-22

I read with great interest the report of Tavora et al. , who accurately studied sudden coronary death caused by pathologic intimal thickening without atheromatous plaque formation. In a large institution, over 300 hearts from patients experiencing a sudden unexpected death were studied retrospectively; the authors found that nonatheromatous atherosclerosis accounts for over 10% of sudden coronary death and is significantly more frequent at younger age, in female gender, and in black race .

Age is a risk factor for maladaptive changes of the pulmonary root in rats exposed to increased pressure loading - Corrected Proof

2011-08-18

Abstract: Introduction: Pulmonary artery root does not adapt properly when exposed to increased pressure stress, with progressive dilatation. The aim of this study was to evaluate, in an animal model, the histologic changes of the pulmonary root wall under increased pressure load.Methods and Results: To increase the systolic pressure in the pulmonary root, a banding of the pulmonary artery (PAB) was performed in 10 adult Sprague–Dawley rats and in 10 weanlings, using 7 adults and 8 weanlings as controls. We analyzed the structural changes of the pulmonary artery root after 30 days of increased pressure load.The mean pressure gradient across the banded pulmonary trunk was 53.57 ± 10 mmHg in the adult rats and 86.73 ± 15 mmHg in the weanlings. The pulmonary artery wall was significantly thicker in both age groups of PAB rats when compared to age-matched controls, showing also architectural structural changes, as a higher degree of mucoid degeneration, medionecrosis, and fibrosis as well as elastic fibers fragmentation. The apoptotic index was also increased in both PAB age groups. We also confirmed the physiologic higher degree of elastic fibers disarray in adult rats when compared to weanlings.Conclusions: The pulmonary artery wall seems to present maladaptive architectural changes in the media when exposed to systemic pressure. The PAB-related increase of the apoptotic index seems to reflect an accelerated involution of the pulmonary root's media. The physiologic higher degree of elastic fibers disarray in adult rats can possibly influence the worst adaptation of the pulmonary arterial wall to a systemic pressure load.

Granulation tissue is altered after intramyocardial and intracoronary bone marrow-derived cell transfer for experimental acute myocardial infarction - Corrected Proof

2011-08-12

Abstract: Background: Bone marrow-derived mononuclear cell (BMMC) treatment in acute myocardial infarction (AMI) has been shown to have a beneficial effect. Our objective was to study in detail the histopathological process after the cell therapy after intramyocardial (IM) or intracoronary (IC) administration of BMMCs following experimental AMI.Methods: Twenty-fours pigs were randomized to the IM group (n=8), the IC group (n=8), and the control group (n=8).After 90 min of transient occlusion of the circumflex coronary artery, BMMCs were injected either intramyocardially or by a transfemoral catheter into the circumflex coronary artery. Echocardiography was performed preoperatively, postoperatively, and after a 21-day recovery period. The heart biopsies were examined histopathologically. Volumetric ex vivo CT scan was performed to evaluate calcification of the infarcted myocardium.Results: The ejection fraction (EF) showed significant recovery in the IM group compared to the control group at Day 21 (P=.05). Despite beneficial histological changes in the infarction site in the IC group, compared to the control group, EF failed to recover. Reduction of collagen density that depicts scar formation was seen in both cell therapy groups compared to the control (P<.001). The number of mitotic cells was higher in the control group compared to the cell therapy groups (P<.001). The IC and IM groups differed significantly from each other in muscle-specific actin staining (P<.001) and smooth muscle actin staining (P<.004). The IM therapy group showed higher density for both stainings. Additionally, macrophage density was higher in the IC group compared to the IM and control groups (P<.002). Both cell therapy regimens substantially diminished tissue calcification; due to the large variation, the effect was not statistically significant.Conclusion: BMMC therapy launches cellular changes that affect mostly the repair process in the granulation tissue. The cell transplantation method might have some effect on the magnitude of the effect.

Atypical cardiac myxomas: a clinicopathologic analysis and their comparison to 64 typical myxomas - Corrected Proof

Pradeep Vaideeswar, Rajib Gupta, Prashant Mishra, Charan Lanjewar, Abhijit Raut — 2011-08-12

Abstract: Introduction: Myxomas are the most common among the primary cardiac neoplasms, seen mainly in adult population, and are typically attached to the interatrial septum, on the left side. Myxomas arising from other sites are designated as “atypical myxomas.” In this article, we describe the clinicopathologic features of 28 such lesions, resected in 20 patients.Methods: A 15-year study (1995–2009) of all cardiac myxomas, received as surgical excisions in our institution, was performed. Atypical myxomas were selected on the basis of their atypical sites of origin, and a systematic review and comparison of their clinicopathologic features with all typical myxomas excised during the same period were done.Results: Among a total of 84 patients who had undergone cardiac myxoma excisions in this 15-year duration, 64 patients had typical myxomas, while atypical myxomas (30 tumors) were diagnosed in 20 patients (23.8%). None of them had a family history of similar symptoms. There were six children. In the atypical subset, there were 12 males and eight females; the mean age of diagnosis was 33.7 years. This demography differed from the typical myxoma group where there were more females than males and the mean age of diagnosis being 40.8 years. The symptoms of dyspnea, episodic chest pain, and palpitation were common in both cohorts of patients, and all showed a mass lesion with varying degrees of valvular regurgitation and obstruction on echocardiography. Five of the 20 patients with atypical myxomas had multifocal or multicentric tumors. Grossly, like typical myxomas, the atypical ones also exhibited solid and papillary patterns with the usual histological features. Four patients had recurrence of the disease.Conclusions: Atypical myxomas are rare lesions having clinical and pathological features, not entirely different from those of typical myxomas. With the advent of modern diagnostics, it is now imperative to do genetic studies and screen the relatives of patients having atypical myxomas to rule out additional occult familial cases as they are now known to occur more in this “atypical” group.

Onchocerca armillata contamination of a bovine pericardial xenograft in a human patient with repaired tetralogy of Fallot - Corrected Proof

Cheryl Mather, Piper Treuting — 2011-08-10

Abstract: Background: Bovine pericardial patches are used for many purposes, including facilitating right ventricular outflow tract reconstruction in patients with congenital heart disease. Here we present a case of parasitic contamination of a bovine pericardium used as a transannular patch during repair of tetralogy of Fallot 28 years prior at a hospital in China.Methods: The patient presented to the University of Washington Medical Center for congestive heart failure and pulmonic regurgitation, and heart tissues including the xenograft pericardial patch were submitted to the Pathology Department and subsequently to the Comparative Pathology Program.Results: The pericardial parasitic nodules with intralesional adult nematodes and microfilaria in the bovine tissues were preserved at harvest by (presumed) glutaraldehyde fixation.Conclusion: Onchocerca armillata parasitic pericardiopathy was diagnosed in the xenograft tissue based on the characteristic nematode morphology and the presumed geographic location of the donor bovine. This resulted in O. armillata contamination of the pericardial xenograft in a human patient with repaired tetralogy of Fallot.

Cystic tumor of the atrioventricular node: rare antemortem diagnosis - Corrected Proof

Kelsey B. Law, Tianshu Feng, Vidhya Nair, Robert James Cusimano, Jagdish Butany — 2011-08-05

Abstract: Background: The cystic tumor of the atrioventricular node (TAV) is a rare, congenital cardiac tumor, typically located at the base of the atrial septum. Histologically benign, this multicystic mass is a tumor of the conduction system and is considered the smallest tumor capable of causing sudden and unexpected death. TAV has shown a predilection for women with a mean age at presentation of 38 years. The majority of cases are diagnosed incidentally at autopsy, while antemortem surgical excision is rare, with ours being the firth and sixth reported cases in the medical literature.Methods: We present two cases, in 33- and 29-year-old women who were admitted for complaints of dyspnea, dizziness, palpitation or numbness, along with a review of the literature. One was known to have complete congenital heart block and ventricular septal defect, where an intraoperative transesophageal echocardiogram revealed a right atrial mass. The other patient had a right atrial mass visible on magnetic resonance imaging, which led to surgical resection and permanent pacemaker insertion.Results: Histopathological examination revealed a tumor composed of cysts, some lined by squamous epithelium, and others by transitional epithelium. Irregular proliferation of glandular structures with squamoid nests within a fibrous stroma, with sebaceous-type differentiation, was also observed. A chronic inflammatory component with secondary lymphoid follicles was also noted.Conclusion: These cases are presented, along with a review of the four previously reported cases of TAV diagnosed antemortem. Awareness regarding this lesion could improve gross and microscopic characterization of TAV and increase antemortem diagnoses.

Characterizing the inflammatory reaction in explanted Medtronic Freestyle stentless porcine aortic bioprosthesis over a 6-year period - Corrected Proof

2011-08-04

Abstract: Background: The Medtronic Freestyle valve is a stentless porcine valve with reportedly excellent clinical and hemodynamic results, but little has been reported about its long-term pathology.Methods: Seventeen Freestyle valves were explanted (from 2003 to 2009) and reviewed to assess reasons for bioprosthesis failure. All valves were examined in detail, using histochemistry and immunohistochemistry to identify morphological changes, as well as cellular and humoral responses.Results: One Freestyle valve, explanted for mitral valve endocarditis on the fifth postoperative day, was excluded from analysis. The average implant duration was 71.1±35.2 months. Six valves were explanted for infective endocarditis, six for aortic insufficiency, and four for aortic stenosis. Calcification was seen in 11 explants, pannus in 15, thrombus in 12, cusp tears in 9, and 10 explants showed needle tract-like injuries. A chronic inflammatory reaction involving the xenograft arterial wall was seen in 15 of 16 valves. The cells were composed of macrophages and lymphocytes, including T cells (CD8 positive) and B cells. Significant damage to the porcine aortic wall was seen in 15 cases, and cusp myocardial shelf damage in 7 cases. All cases stained positively for IgG and C4dpar.Conclusions: The porcine aortic tissue showed T cell-mediated rejection and significant aortic medial damage, consistent with dilatation of the porcine aortic root. The demonstration of IgG suggests the likelihood of humoral rejection, in addition to cellular rejection. One of the underlying possibilities is that the porcine aortic tissues are inadequately fixed, hence the retained antigenicity.

Congenital left main coronary artery aneurysm - Corrected Proof

Roberto Andrés Guerri-Guttenberg, Gabriela Celeste Francos, José Milei — 2011-08-01

Abstract: We report a rare case of a congenital left main coronary artery aneurysm in a 2-year-old patient with concomitant intimal hyperplasia and strong intimal apolipoprotein B expression.

Resistin is independently associated with abdominal aortic aneurysm in severe coronary artery disease patients - Corrected Proof

2011-07-28

Abdominal aortic aneurysm (AAA) is primarily characterized by chronic transmural inflammation associated with the monocyte/macrophage lineage as well as matrix metalloproteinases (MMPs)-mediated aortic wall degradation. Moreover, prevalence of AAA is higher in patients with atherosclerosis, and both entities share some but not all risk factors . The adipokine resistin, primarily synthesized by macrophages in humans, is known to modulate inflammation, a pathophysiologic process underlying both AAA and atherosclerosis . In a population-based study, serum resistin concentrations were independently associated with AAA and infrarenal aortic diameters . We aimed at assessing this association in patients with severe atherosclerosis.

Variable phenotype in murine transverse aortic constriction - Corrected Proof

2011-07-18

Abstract: Background: In mice, transverse aortic constriction (TAC) is variably characterized as a model of pressure overload-induced hypertrophy (left ventricular [LV] hypertrophy, or LVH) or heart failure (HF). While commonly used, variability in the TAC model is poorly defined. The objectives of this study were to characterize the variability in the TAC model and to define a simple, noninvasive method of prospectively identifying mice with HF versus compensated LVH after TAC.Methods: Eight-week-old male C57BL/6J mice underwent TAC or sham and then echocardiography at 3 weeks post-TAC. A group of sham and TAC mice were euthanized after the 3-week echocardiogram, while the remainder underwent repeat echocardiography and were euthanized at 9 weeks post-TAC. The presence of TAC was assessed with two-dimensional echocardiography, anatomic aortic m-mode and color flow, and pulsed-wave Doppler examination of the transverse aorta (TA) and by LV systolic pressure (LVP). Trans-TAC pressure gradient was assessed invasively in a subset of mice. HF was defined as lung/body weight>upper limit in sham-operated mice.Results: As compared with sham, TAC mice had higher TA velocity, LVP and LV weight, and lower ejection fraction (EF) at 3 or 9 weeks post-TAC. Only a subset of TAC mice (28%) developed HF. As compared with compensated LVH, HF mice were characterized by similar TA velocity and higher percent TA stenosis, but lower LVP, higher LV weight, larger LV cavity, lower EF and stress-corrected midwall fiber shortening, and more fibrosis. Both EF and LV mass measured by echocardiography at 3 weeks post-TAC were predictive of the presence of HF at 3 or 9 weeks post-TAC.Conclusions: In wild-type mice, TAC produces a variable cardiac phenotype. Marked abnormalities in LV mass and EF at echocardiography 3 weeks post-TAC identify mice with HF at autopsy. These data are relevant to appropriate design and interpretation of murine studies.

Degeneration of sensory afferent nerves enhances pulmonary inflammatory alterations in acute myocardial infarction in rats - Corrected Proof

Jie Wu, Zheng Guo, Li-Li Wang, Rui-Lin Zhang — 2011-06-13

Abstract: Background: Evidence suggests proinflammatory changes in the lungs during acute myocardial infarction and a participation of neural mechanisms and substance P in the pathology. This study was undertaken to investigate the role and the mechanisms by which sensory afferent degeneration at neonatal stages exacerbates the pulmonary inflammatory responses to acute myocardial infarction in the adult rats.Methods: The degeneration of capsaicin-sensitive afferent nerves was induced by administration of capsaicin to neonatal rats. The pulmonary inflammatory changes following coronary artery occlusion (CAO) were assessed by the analysis of the infiltration of neutrophils and tissue morphology in the lungs.Results: Significant increases in the pulmonary infiltration of neutrophils, up to 240% and 218% of the sham controls at 3 and 6 h, respectively, after CAO (P<.05) and marked pulmonary edema were observed. Degeneration of capsaicin-sensitive afferent nerves or antagonism of endogenous neurokinin (NK)-1 receptor exacerbated the pulmonary infiltration of neutrophils (up to 214% and 254% of the controls, respectively) and pulmonary tissue edema following the CAO.Conclusion: The findings indicate that degeneration of sensory afferent nerves enhances the pulmonary inflammatory changes in acute myocardial infarction, in which the endogenous NK may play a role.

Myocardial infarction quantification with late gadolinium-enhanced magnetic resonance imaging in rats using a 7-T scanner - Corrected Proof

2011-06-08

Abstract: Aims: The objective of this study was to noninvasively measure the volume of myocardial infarction in rats, using delayed enhancement magnetic resonance imaging (MRI) in a coronary occlusion/reperfusion model on a 7-T scanner.Methods: At 24 h after cardiac ischemia, contrast-enhanced MRI was performed. Two distinct experimental groups were compared: one was subjected to permanent ischemia (PL) and the other was subjected to 30 min of ischemia followed by 24 h of reperfusion (IR). The sizes of enhanced regions were compared to triphenyltetrazolium chloride (TTC)-stained sections of the excised rat heart. Cardiomyocyte apoptosis was analyzed by TUNEL methods, and neutrophils and macrophages were quantitated after histology and immunohistochemical staining.Results: Twenty-four hours after ischemia, delayed hyperenhancement imaging was clearly visualized in the anterior left ventricular walls corresponding to the infarcted myocardium. In the PL group, infarct size was 37.2±9.8% (LV %) as measured by MRI and 38.8±9% (LV %) by TTC (P=NS). In the IR group, infarct size was 23.2±8.8% (LV %) as measured by MRI and 24.4±9.2% (LV %) by TTC (P=NS). Infarction volume measured with MRI was strongly correlated to TTC staining (R=0.82 for PL, R=0.973 for IR). Increased inflammatory cell infiltration was detected in the infarct area of the heart after reperfusion compared to permanent ligation (P<.01). The ratio of TUNEL-positive cardiomyocytes to total number of cardiomyocytes in the IR group was significantly reduced as compared to the PL group (P<.01).Conclusions: MRI can accurately assess infarct size in intact rats early after MI. After transient arterial occlusion, the size of the myocardial infarct was found to be significantly smaller as compared to permanent occlusion.

An unusual association of endomyocardial fibrosis and hypertrophic cardiomyopathy in a patient with heart failure - Corrected Proof

2011-06-06

Abstract: A 69-year-old female patient presented heart failure with preserved ejection fraction and atrial fibrillation. Echocardiography and late gadolinium enhancement magnetic resonance imaging were suggestive of endomyocardial fibrosis (EMF). The patient underwent cardiac surgery, and after surgery, she developed low cardiac output syndrome and died. Postmortem examination revealed residual fibrosis of the left ventricle (LV), mild endocardial fibrous deposition of the right ventricle, and severe concentric, symmetrical LV hypertrophy. Histological examination of the surgically resected material from the LV confirmed EMF. Histopathology of the interventricular septum disclosed myocardial hypertrophy and disarray plus fine interstitial fibrosis, typical of hypertrophic cardiomyopathy. The present case illustrates the association of two different patterns of cardiomyopathies in the same patient.

Effects of nicotinic acid on endothelial cells and platelets - Corrected Proof

2011-06-01

Abstract: Background: Interactions between platelets and endothelial cells under inflammatory conditions lead to an increased expression of various activity markers of atherosclerosis in the vessel wall. The purpose of this study was to investigate possible protective effects of nicotinic acid in an in vitro endothelial cell model.Methods: After a 24-hour incubation period with nicotinic acid (1 mmol/l), human umbilical vein endothelial cells were stimulated for 1 h with lipopolysaccharide and were then incubated in direct contact with activated platelets. Following this incubation, the expression of CD40L and CD62P on platelets and the expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, uPAR, and MT1-MMP on endothelial cells were measured by flow cytometry. Supernatants were analyzed by ELISA for soluble MCP-1 and MMP-1.Results: The increased expression of VCAM-1 on endothelial cells by proinflammatory stimulation with activated platelets was significantly reduced through preincubation with nicotinic acid (P<.05). Furthermore, platelets in direct contact with preincubated endothelial cells showed a significant reduction in their CD62P and CD40L expression when compared to platelets incubated with untreated endothelial cells (P<.05). Treatment with nicotinic acid did not have a significant effect on ICAM-1, uPAR, and MT1-MMP expression on endothelial cells. Levels of soluble MCP-1 and MMP-1 in supernatants were lower after preincubation with nicotinic acid.Conclusion: Nicotinic acid inhibits platelet activation after platelets contacted nicotinic acid treated endothelial cells and inhibits VCAM-1 expression on human endothelial cells under inflammatory conditions. These findings suggest a possible pleiotropic therapeutic relevance of nicotinic acid in atherosclerosis.

Altered melusin pathways involved in cardiac remodeling following acute myocardial infarction - Corrected Proof

Rong Gu, Di Zheng, Jian Bai, Jun Xie, Qing Dai, Biao Xu — 2011-05-06

Abstract: Background: Melusin, a muscle-specific integrin-linked protein, has been reported to be a biomechanical sensor and to protect the heart from pressure overload. In the present study, we investigated the possible role that melusin plays during cardiac remodeling after myocardial infarction (MI).Methods: We constructed a heart failure model of rats induced by left anterior descending coronary artery ligation. At different time points (1, 2, 3, 4, 6, and 8 weeks) following the operation, cardiac function was monitored by echocardiography and hemodynamic assessment; cardiac morphology was measured using hematoxylin–eosin-stained sections. Melusin expression, as well as p-Akt, Akt, and one of the Rho small GTPase family members, CDC42, was determined dynamically by Western blotting analysis during the postinfarction cardiac remodeling.Results: Progressive increase in left ventricular (LV) end-systolic dimension and LV end-diastolic dimension and decrease in percent LV fractional shortening (%FS) and LVdp/dtmax demonstrated gradually deteriorated cardiac function in rats following MI operation. Morphological analysis revealed cardiac remodeling in MI animals, including increased LV diameter and decreased border zone thickness. We also showed a dynamic change in melusin during heart failure progression; it had an initial decline which was evident at 3 weeks and increased subsequently, reaching peak levels at 6 weeks. This dynamic change in melusin was significantly correlated with %FS and LVdp/dtmax. p-Akt/Akt and CDC42 protein expression was correlated with melusin content.Conclusions: The altered melusin pathways and CDC42 parallel the cardiac function progression during cardiac remodeling post-MI. The dynamic change of them during this procedure may represent an important molecular mechanism underlying postinfarction cardiac remodeling and provide potential therapeutic targets.

Versican and CD44 in in vitro valvular interstitial cell injury and repair - Corrected Proof

Jon M. Carthy, Seti Boroomand, Bruce M. McManus — 2011-05-06

Abstract: Background: Versican is one of the key components of the extracellular matrix (ECM) that is expressed during injury, inflammatory, and repair processes. The current study evaluated the relationship between versican and the membrane receptor CD44 during in vitro valvular interstitial cell (VIC) injury and repair.Methods: Subconfluent, confluent, and wounded cultures of human VICs were fixed and immunostained to detect versican and the membrane receptor CD44. To examine the relationship between versican and CD44, a blocking antibody to CD44 was added to cultured VICs, and in vitro wound repair along with pericellular versican organization and stress fiber formation were examined.Results: Immunohistochemistry demonstrated that versican is prominent intracellularly, as well as extracellularly, in actively proliferating VICs. In contrast, versican was only localized to fibrils in the extracellular space in between cells in confluent (quiescent) cultures. Following wounding, versican expression was up-regulated, and it was secreted as ECM at the trailing edge of migrating cells. The staining for CD44 was similarly localized to the trailing edge of migrating VICs in wounded cultures. Treatment of VICs with a CD44-blocking antibody disrupted the organization of versican in the pericellular matrix and inhibited stress fiber formation in these cells. Functionally, blocking CD44 significantly inhibited VIC-mediated contraction of type I collagen gels (35.7%±0.7% vs. 23.3%±1.4% of initial gel area, P<.01).Conclusions: Versican is a key component of the provisional wound repair ECM that is expressed following injury to VICs. The receptor CD44 plays an important role in organizing the provisional ECM.Summary: Our data suggests VICs synthesize and secrete versican following injury. These cells also up-regulate CD44, a receptor that binds versican. Blocking CD44 disrupted the organization of versican and inhibited stress fiber formation. Functionally, blocking CD44 inhibited cell-mediated contraction of a collagen matrix. Collectively, these data suggest versican expression and organization are important to valve cell injury and repair.