Molecular differences between arterial and venous grafts in the first year after coronary artery bypass grafting.

Despite commonly used for coronary artery bypass surgery, saphenous vein (SV) grafts have significantly lower patency rates in comparison to internal thoracic artery (ITA) grafts, which might be due to the structural characteristics of the vessel wall but also due to differences in oxidative stress adaptation and molecular signaling and regulation. This human post mortem study included a total of 150 human bypass grafts (75 SV grafts and 75 ITA grafts) obtained from 60 patients divided into five groups due to the time period of implantation: group 1: baseline group without grafting; group 2: 1 day; group 3: > 1 day-1 week; group 4: > 1 week-1 month; group 5: > 1 month-1 year. Pieces of 3 mm length were fixed with formaldehyde, dehydrated, wax embedded, cut into sections of 3 µm thickness, and histologically and immunohistochemically examined. Over the whole time period, we observed a lower neointima formation and a better preserved media in ITA grafts with a higher percentage of TNF-α, PDGFR-α, and VEGF-A in nearly all vessel wall layers, a higher amount of MMP-7, MMP-9, EGFR, and bFGF positive cells in SV grafts and a timely different peak not only between ITA and SV grafts but also within the various vessel wall layers of both graft types. Since most of the examined growth factors, growth factor receptors and cytokines are regulated by MAPKs, our results suggest an activation of different pathways in both vessel graft types immediately after bypass grafting.

Gene therapy with antisense oligonucleotides silencing c-myc reduces neointima formation and vessel wall thickness in a mouse model of vein graft disease.

Gene therapy for avoiding intimal hyperplasia of vein grafts after coronary artery bypass grafting is still discussed controversially. A promising application of gene therapy in vein grafts is the use of antisense oligonucleotides to block the expression of genes encoding cell cycle regulatory proteins in vascular smooth muscle cells. C-myc, either directly or by regulating the expression of other proteins, controls cell proliferation, apoptosis and cell survival, tissue remodeling, angiogenesis, cell metabolism, production of inflammatory and anti-inflammatory cytokines, and also participates in cell transformation. Forty C57BL/6J mice underwent interposition of the inferior vena cava from isogenic donor mice into the common carotid artery using a previously described cuff technique. Twenty mice received periadventitial administration of antisense oligonucleotides directed against c-myc (treatment group), the other twenty mice received no treatment (control group). All vein grafts were harvested two weeks after surgery, dehydrated, wax embedded, cut into slides of 2 µm thickness, stained and histologically and immunohistochemically examined under light microscope. In our study, we could show the promising effects of antisense oligonucleotide treatment in a mouse model of vein graft disease including the significant reduction of neointimal, media and total vessel wall thickness with a significantly lower percentage of SMA positive cells, elastic fibres and acid mucopolysaccharides in the neointima and media, a decreased vascularization, and a lower expression of PDGFR ß, MMP-9 and VEGF-A positive cells throughout the whole vein graft wall.

Stem cell therapy with skeletal myoblasts accelerates neointima formation in a mouse model of vein graft disease.

Although still a matter of controversial discussion, skeletal myoblasts are one of the options for stem cell transplantation improving cardiac function after myocardial infarction, exhibiting several advantages including the availability, the ability of self-renewal and differentiation, and the lack of ethical and immunological problems. The aim of this study was to investigate the impact of stem cell therapy with skeletal myoblasts on experimental venous bypass grafts in a mouse model of vein graft disease. Forty C57BL/6J mice underwent bypass grafting interposing a venous bypass graft of the donor mouse into the carotid artery of the recipient mouse. Twenty mice received periadventitially treatment with 1 million fluorescence labeled skeletal myoblasts suspended in culture medium (treatment group), the other twenty mice received only culture medium without myoblasts (control group). Two weeks after bypass surgery, the vein grafts of all 40 mice were harvested, stained and histologically investigated under light and immunofluorescence microscope. Against our expectations, skeletal myoblasts stayed in place and were still located in the adventitia after bypass grafting. Additionally, vein grafts of the myoblast group revealed a 2fold increased neoneointima formation, a decreased media thickness, a slightly increased neovascularization, a higher percentage of reendothelialization and also a slightly higher percentage of PDGFR ɑ, PDGFR ß, MMP-7 and MMP-9 positive cells, suggesting a paracrine mechanism responsible for accelerated neointima formation. In conclusion, the results of our study do not support the use of skeletal myoblast for the treatment of vein graft disease after coronary artery bypass surgery.

Vein graft disease in a knockout mouse model of hyperhomocysteinaemia.

A major reason for vein graft failure after coronary artery bypass grafting is neointimal hyperplasia and thrombosis. Elevated serum levels of homocysteine (Hcy) are associated with higher incidence of cardiovascular disease, but homocysteine levels also tend to increase during the first weeks or months after cardiac surgery. To investigate this further, C57BL/6J mice (WT) and cystathionine-beta-synthase heterozygous knockout mice (CBS+/-), a mouse model for hyperhomocysteinaemia, underwent interposition of the vena cava of donor mice into the carotid artery of recipient mice. Two experimental groups were examined: 20 mice of each group underwent bypass surgery (group 1: WT donor and WT recipient; group 2: CBS+/- donor and CBS+/- recipient). After 4 weeks, the veins were harvested, dehydrated, paraffin-embedded, stained and analysed by histomorphology and immunohistochemistry. Additionally, serum Hcy levels in CBS knockout animals and in WT animals before and after bypass surgery were measured. At 4 weeks postoperatively, group 2 mice showed a higher percentage of thrombosis compared to controls, a threefold increase in neointima formation, higher general vascularization, a lower percentage of elastic fibres with shortage and fragmentation in the neointima, a lower percentage of acid mucopolysaccharides in the neointima and a more intense fibrosis in the neointima and media. In conclusion, hyperhomocysteinaemic cystathionine-beta-synthase knockout mice can play an important role in the study of mechanisms of vein graft failure. But further in vitro and in vivo studies are necessary to answer the question whether or not homocysteine itself or a related metabolic factor is the key aetiologic agent for accelerated vein graft disease.

Histologic pathologies of the myocardium in septic shock: a prospective observational study.

Myocardial depression in septic shock is well known, but its pathophysiological genesis is incompletely understood. To assess the incidence and extent of stress-induced histologic myocardial alterations in septic shock, a prospective, observational, combined clinical and postmortem study was conducted, and 20 patients dying from septic shock were included. Exclusion criteria were younger than 18 years, pregnancy, open heart surgery or cardiopulmonary resuscitation, acute neurologic diseases, pheochromocytoma, and forensic autopsy. A systematic macropathologic evaluation was performed. Nine predefined heart sections were histologically screened for myocytolysis, interstitial fibrosis, contraction band necrosis, mononuclear infiltrates, interstitial edema, and tissue hemorrhage. Stress-induced pathologies were found in 90% to 100% of patients in all heart sections (myocytolysis, 100%; interstitial fibrosis, 100%; contraction band necrosis, 95%; mononuclear infiltrates, 90%; interstitial edema, 90%; tissue hemorrhage, 30%). The incidence and extent of contraction band necrosis, mononuclear infiltrates, and myocytolysis did not differ between sexes; patients with or without chronic ß-blocker, calcium antagonist, and/or statin premedication; or between the binary use of different catecholamine agents (all comparisons P > 0.05). The maximum epinephrine dose correlated with the overall extent of mononuclear infiltrates (Spearman-Rho, r = 0.704; P = 0.05) and myocytolysis (Spearman-Rho, r = 0.933; P = 0.001). Maximum norepinephrine doses correlated with the extent of mononuclear infiltrates in the left ventricular anterior wall (Spearman-Rho, r = 0.519; P = 0.02). The total duration of catecholamine therapy was correlated with the extent of mononuclear infiltrates in the apex (Spearman-Rho, r = 0.571; P = 0.009) and right atrium (Spearman-Rho, r = 0.535; P = 0.02). In conclusion, our results suggest that histologic lesions potentially indicative of stress-induced cardiotoxicity can be observed in most patients dying from septic shock.

The angiogenic factor secretoneurin induces coronary angiogenesis in a model of myocardial infarction by stimulation of vascular endothelial growth factor signaling in endothelial cells.

BACKGROUND: Secretoneurin is a neuropeptide located in nerve fibers along blood vessels, is upregulated by hypoxia, and induces angiogenesis. We tested the hypothesis that secretoneurin gene therapy exerts beneficial effects in a rat model of myocardial infarction and evaluated the mechanism of action on coronary endothelial cells. METHODS AND RESULTS: In vivo secretoneurin improved left ventricular function, inhibited remodeling, and reduced scar formation. In the infarct border zone, secretoneurin induced coronary angiogenesis, as shown by increased density of capillaries and arteries. In vitro secretoneurin induced capillary tubes, stimulated proliferation, inhibited apoptosis, and activated Akt and extracellular signal-regulated kinase in coronary endothelial cells. Effects were abrogated by a vascular endothelial growth factor (VEGF) antibody, and secretoneurin stimulated VEGF receptors in these cells. Secretoneurin furthermore increased binding of VEGF to endothelial cells, and binding was blocked by heparinase, indicating that secretoneurin stimulates binding of VEGF to heparan sulfate proteoglycan binding sites. Additionally, secretoneurin increased binding of VEGF to its coreceptor neuropilin-1. In endothelial cells, secretoneurin also stimulated fibroblast growth factor receptor-3 and insulin-like growth factor-1 receptor, and in coronary vascular smooth muscle cells, we observed stimulation of VEGF receptor-1 and fibroblast growth factor receptor-3. Exposure of cardiac myocytes to hypoxia and ischemic heart after myocardial infarction revealed increased secretoneurin messenger RNA and protein. CONCLUSIONS: Our data show that secretoneurin acts as an endogenous stimulator of VEGF signaling in coronary endothelial cells by enhancing binding of VEGF to low-affinity binding sites and neuropilin-1 and stimulates further growth factor receptors like fibroblast growth factor receptor-3. Our in vivo findings indicate that secretoneurin may be a promising therapeutic tool in ischemic heart disease.

The impact of distension pressure on acute endothelial cell loss and neointimal proliferation in saphenous vein grafts.

OBJECTIVES: We aimed to determine the extent of acute endothelial cell loss and neointimal proliferation in the long-term in saphenous vein grafts (SVGs) exposed to defined distension pressures. METHODS: During routine competence testing of SVGs for coronary artery bypass grafting (CABG), blinded peak pressure measurements were performed in 10 patients. In an experimental set-up, distension pressure-related endothelial damage was studied in the SVGs of 20 patients. In a subgroup (n = 10), each patient's SVG was divided into segments and subjected to four constant pressures (50, 100, 150 and 300 mmHg) for 30 min each. In another subgroup (n = 10), SVGs were exposed to a short phase of high pressure (low pressure followed by 300 mmHg for 5 min). Acute endothelial cell loss was quantified by CD31-immunostaining. After 2 weeks of organ culture, the neointimal proliferation was evaluated using histomorphometry. Pressure-related damage was compared with damage at baseline (0 mmHg). RESULTS: During routine competence testing for CABG, we revealed a median peak pressure of 355 mmHg (range: 240-639 mmHg). In the experimental set-up, significant acute endothelial cell loss occurred at all tested distension pressures: at 50 mmHg, the median endothelial cell loss was 29% (range: 20-51%, P = 0.015), at 100 mmHg 54% (range: 37-69%, P < 0.001), at 150 mmHg 75% (range: 41-88%, P < 0.001), at 300 mmHg 91% (range: 63-100%, P < 0.001) and at short high-pressure exposure 65% (range: 49-82%, P < 0.001) in comparison with 20% (range: 0-44%) at baseline. Significant neointimal proliferation occurred when a distension pressure of 50 mmHg was exceeded: at 50 mmHg, median neointimal proliferation was 97 µm (range: 60-380 µm, P = 0.176), at 100 mmHg 168 µm (range: 100-600 µm, P = 0.001), at 150 mmHg 183 µm (range: 160-440 µm, P < 0.001) at 300 mmHg 347 µm (range: 190-590 µm, P < 0.001) and at short high-pressure exposure 130 µm (range: 60-410 µm, P = 0.02) in comparison with 90 µm (range: 60-170 µm) at baseline. CONCLUSIONS: In vitro exposure of SVGs to low distension pressure ranges causes significant acute endothelial cell loss and crucial long-term damage, namely neointimal proliferation.

Primary cardiac tumours: a single-center 41-year experience.

Primary cardiac tumours are extremely rare with the most commonest being left atrial myxomas. In general, surgical resection is indicated, whenever the tumour formation is mobile and embolization can be suspected. Within 17280 patients receiving heart surgery at the Innsbruck Medical University, 78 patients (0.45%) underwent tumourectomy of primary cardiac tumours. The majority of patients (63) suffered from a left or right atrial myxoma, 12 showed a papillary fibroelastoma of the valves at echocardiographical or histological examination, 1 suffered from a hemangioma, 1 from a chemodectoma, and another one from a rhabdomyosarcoma. The mean age of cardiac tumour patients was 54.29 ± 13.28 years (ranging from 18 to 83 years). 67.95% of the patients were female and 32.05% were male. The majority of tumours were found incidentally; 97.44% of the patients showed no tumour recurrence.

Alternative valve-in-root concepts for redo procedures.

Since aortic root reoperations are challenging procedures, alternative lower-risk procedures should be considered in certain cases. Herein are presented two different approaches to high-risk root reoperations. The first patient, a 59-year-old male who had undergone root replacement 11 years previously with an Edwards Prima stentless valve, presented with severe aortic regurgitation and a heavily calcified aortic root. An open implantation of an Edwards Sapien valve was performed via an aortotomy distal to the calcified aortic root. The second patient, a 60-year-old female, underwent transapical implantation of an Edwards Sapien transcatheter valve for stenosis of the aortic valve in an aortic homograft implanted 11 years previously. The long-term durability of these implants has yet to be evaluated.

Chromosomal imbalances in carcinoma showing thymus-like elements (CASTLE).

Carcinoma showing thymus-like elements (CASTLE) is a rare neoplasm of the thyroid gland resembling lymphoepithelioma-like and squamous cell carcinoma of the thymus and is thought to arise from ectopic thymic tissue within the thyroid gland or rudimentary branchial pouches along the thymic line. Using comparative genomic hybridization (CGH), chromosomal imbalances have been detected in several types of thymomas and thymic carcinomas. To evaluate whether there are hints of an underlying sequence in the pathogenesis of CASTLE analogue to those found in thymomas and thymic carcinomas, we evaluated four of these rare neoplasms for chromosomal imbalances using CGH. The most frequent gains were seen on chromosomal arm 1q (3/4), and losses were most frequently detected on 6p (4/4), 6q (3/4) and 16q (3/4). These CGH data show that CASTLE is characterized by chromosomal imbalances similar to those found in thymomas and thymic carcinomas and indicate a similar sequence in tumour development.

Aortic valve ochronosis: a rare manifestation of alkaptonuria.

Alkaptonuric ochronosis is a heritable disorder of tyrosine metabolism, with various systemic abnormalities related to pigment deposition and degeneration of collagen and other tissues, including the heart and aorta. A 65-year-old woman with alkaptonuric ochronosis and a history of four joint replacements required aortic valve replacement for severe aortic stenosis. Operative findings included ochronosis of a partly calcified aortic valve and the aortic intima. The aortic valve was removed at surgery and histologically investigated. Light microscopic examination of the aortic valve revealed intracellular and extracellular deposits of ochronotic pigment and a chronic inflammatory infiltrate. Beside the case representation, the disease history, aetiology, pathogenesis, clinical presentation and treatment of aortic valve ochronosis are reviewed.

Thymic hyperplasia after lung transplantation imitating posttransplant lymphoproliferative disorder.

Thymic hyperplasia is usually associated with the treatment of malignant tumours and is sometimes linked with endocrine diseases. For the first time, we report a case of thymic hyperplasia in a patient 2 years after bilateral lung transplantation. Contrast-enhanced chest CT scan was highly suspicious for a posttransplant lymphoma or thymoma. Therefore, the patient received total thymectomy. Excised specimens were sent to the Department of Pathology. Unexpectedly, the histological examination revealed hyperplastic thymic tissue without evidence for a posttransplant lymphoproliferative disorder or malignancy.

Primary liposarcoma of the heart.

The author reports a case of a 64-year-old man, who presented with a 4-week history of dyspnoea and dizziness suffering from a large mass in the pericardium. CT of the chest showed a lobulated mass in the pericardial sac located between the pulmonary veins and the ascending aorta reaching the superior vena cava. The tumour was completely resected and histopathological analysis revealed the tumour to be a well-differentiated lipoma-like and focal sclerosing liposarcoma, which was composed predominantly of adipocytes with hyperchromatic nuclei and eosinophilic-to-vacuolated cytoplasm disrupted by fibrous septa. Two years after initial tumour diagnosis the patient is still alive without signs of tumour recurrence.

A typical thymic carcinoid tumour within a thymolipoma: report of a case and review of combined tumours of the thymus.

Thymolipomas are rare tumours located in the anterior mediastinum. Sometimes these tumours may be combined with thymomas or lymphomas. We present a unique case of a thymic carcinoid arising within a thymolipoma. A 68-year-old patient presented with chronic chest and neck pain, which was initially thought to be caused by coronary artery disease. A chest x-ray, exercise tolerance test and coronary angiography were unremarkable. The following CT scan of the neck and chest showed a small tumour in the anterior mediastinum. A robotic-assisted thymectomy was performed and histological examination revealed a neuroendocrine tumour of the thymus within a thymolipoma. The patient was discharged 3 days after surgery in good general condition.

Myopathy, left ventricular noncompaction, and tetralogy of fallot.

Left ventricular hypertrabeculation, also termed noncompaction (LVHT) is a cardiac abnormality characterized by excessive trabeculations of the left ventricular cavity. LVHT may be associated with extracardiac abnormalities, most frequently neuromuscular disorders (NMDs). LVHT associated with tetralogy of Fallot (ToF), so far, has been reported in 2 cases, but no indication for the presence of NMDs are given.We present a 47-year old female who underwent 2 cardiac surgeries because of ToF, and was admitted because of heart failure. She was diagnosed with echocardiographic LVHT. A myopathy was diagnosed by biopsy.

Cardiac sarcoidosis mimicking arrhythmogenic right ventricular dysplasia.

Isolated manifestation of sarcoidosis in the heart is very rare. The present work describes the case of a 41-year-old woman with ventricular tachycardia and severe symptoms of heart failure in June 2006. Clinical, MRI and echocardiographic findings revealed the diagnosis of an arrhythmogenic right ventricular dysplasia. Due to the severe progression of the disease, cardiac transplantation was performed in August 2007. Histopathological examination of the explanted heart, however, revealed numerous non-necrotising granulomas with giant cells, lymphocytic infiltration and interstitial fibrosis, finally confirming the diagnosis of a myocardial sarcoidosis.

CASTLE tumour of the neck: a rare location of a malignant tumour of the thymus.

We present the case of a 62-year-old woman who consulted her physician in December 2005, suffering from a mass at the left lower anterior neck with rapid enlargement. Intraoperative frozen section was highly suspicious of a CASTLE tumour (carcinomas showing thymus-like differentiation). Finally, immunohistochemical investigation revealing positivity for CK5/6, c-kit (CD117) and CD5 as well as negativity for thyroglobulin, calcitonin, vimentin and TTF-1 confirmed the diagnosis. Due to lymph node metastases, radiochemotherapy was performed. Fifteen months after the initial diagnosis disseminated pulmonary metastases were found and treated with cisplatin based chemotherapy, which led to a stabilisation of the disease. In June 2008, computed tomography showed progress of the pulmonary metastases, making further chemotherapeutical treatment necessary. Although treatment was changed in October 2008, the staging evaluation in January 2009 revealed further progress of the metastatic disease. Currently, the patient is still alive, but receives no medical treatment at the moment.