Heike Goebel

Tissue Endothelin-1 Immunoreactivity in the Active Coronary Atherosclerotic Plaque A Clue to the Mechanism of Increased Vasoreactivity of the Culprit Lesion in Unstable Angina

BACKGROUND The pathomorphological substrate of complicated coronary atherosclerotic lesions underlying unstable angina is characterized by a localized chronic inflammatory process. Functionally, coronary lesions associated with unstable angina demonstrate an enhanced vasoreactivity. Endothelin-1 is a potent vasoconstrictor peptide produced not only by endothelial cells but also by macrophages and polymorphonuclear leukocytes, the cell types characteristic of inflammation. METHODS AND RESULTS By use of immunohistochemical techniques, we examined the presence of endothelin-1 in coronary atherosclerotic plaque tissue obtained by directional coronary atherectomy of primary lesions from 50 consecutive patients. The tissue specimens of 43 of 50 patients (86%) demonstrated endothelin-1-like immunoreactivity. Endothelin-1-like immunoreactivity preferentially localized to macrophage-rich areas, to hypercellular regions rich in microvessels, and to plaque areas with evidence of prior hemorrhage. Double-immunolabeling revealed that both macrophages (HAM56 positive) and intimal smooth muscle cells (alpha-actin positive) demonstrated cytoplasmic immunostaining for endothelin-1. Semiquantitative analysis of endothelin-1-like immunostaining revealed significantly (P < .005) higher staining grades in active (1.86 +/- 0.15, n = 40) compared with nonactive lesions (0.78 +/- 0.35, n = 10): endothelin-1 staining grades were significantly (P < .001) lower in patients with stable angina (0.69 +/- 0.19, n = 13) than in patients with crescendo angina (1.82 +/- 0.30, n = 11), with angina at rest (2.08 +/- 0.21, n = 12), or with angina after myocardial infarction (2.0 +/- 0.26, n = 14). CONCLUSIONS Endothelin-1 immunostaining of atherosclerotic tissue localizes predominantly with plaque components indicative of chronic inflammatory processes. The increased tissue endothelin-1-like immunoreactivity in active coronary atherosclerotic lesions may provide a clue to the mechanisms of increased vasoreactivity of the culprit lesion in acute ischemic syndromes, which is the clinical substrate of the active coronary atherosclerotic plaque.

Expression of Macrophage Migration Inhibitory Factor in Different Stages of Human Atherosclerosis

Background—Atherosclerosis is a chronic inflammatory response of the arterial wall to injury. Macrophage migration inhibitory factor (MIF), a cytokine with potent inflammatory functions, was thus considered to be important in atherosclerotic lesion evolution. Methods and Results—We studied the presence and distribution of MIF immunoreactivity (MIF-IR) and MIF mRNA in internal mammary arteries with a normal histology and arteries with plaques in different stages of human atherosclerosis. To address a potential role for the coactivator Jab1 as a cellular mediator of MIF effects in vascular tissue, we correlated the expression of MIF to that of Jab1 by using immunohistochemistry and coimmunoprecipitation. We further sought to determine a potential functional role for endothelium-derived MIF in early atherogenesis by studying the effects of oxidized LDL on MIF expression in cultured human umbilical vascular endothelial cells. The results showed that MIF-IR and Jab1-IR are found in all cell types present in atherosclerotic lesions, that MIF-IR is upregulated during progression of atherosclerosis, that MIF is produced locally in the arterial wall, and that all MIF+ cells are simultaneously Jab1+. Coimmunoprecipitation experiments demonstrated in vivo complex formation between MIF and Jab1 in plaques. MIF expression in human umbilical vascular endothelial cells and a macrophage line was upregulated after stimulation with oxidized LDL. Conclusions—MIF is produced abundantly by various cells in all types of human atherosclerotic lesions and thus may play an important role in early plaque development and advanced complicated lesions. MIF-Jab1 complexes could serve critical regulatory functions in atherosclerotic lesion evolution.

Thoracic endovascular stent grafting inhibits aortic growth: an experimental study.

OBJECTIVE Dilatation of the aorta at the landing zone site may be exaggerated by the radial force of stent grafts potentially limiting long-term results of endovascular therapy. We evaluated growth patterns and morphology of the thoracic aorta in young piglets after thoracic stent-graft placement. METHODS Eight domestic piglets (37+/-2 kg) had an endovascular stent graft placed in the proximal descending thoracic aorta using retroperitoneal access. At implantation, the stent was oversized by 10%. Aortic size was documented after thoracotomy by intraoperative measurement and angiography. Subsequently the piglets were grown to adult size (181+/-42 kg). At explantation 6-15 months later, CT scan and surgical evaluation for endoleaks, defined as perigraft flow, was performed. Histopathological assessment of the explanted aorta was performed in stented and non-stented segments and compared to five normal porcine aortas. RESULTS No endoleak (perigraft flow) or stent migration occurred even in 230kg pigs. The stent grafts expanded to full size, but there was no further growth in the stented area. The aortic diameter increased significantly by 32+/-9% 1cm proximal to the stents (p=0.0012) and by 45+/-13% 1cm distal to the stents (p=0.0033). The stented area grew less than the proximal (p=0.0011) and distal aorta (p<0.0001). In all pigs, the distal aorta was larger than the proximal overstented segment. Histology of the stented aorta showed significant thickening of the intima (p=0.018) and media (p=0.006) with neointimal formation and segmental fibrosis of the inner 1/3 of the media with loss of smooth muscle cells and compression of the elastic fibers but normal architecture in the outer 2/3 of the media. CONCLUSIONS Endovascular stent grafting may inhibit growth of the nonatherosclerotic normal aorta and lead to intimal hyperplasia and focal fibrosis in the inner media part adjacent to the stent. Stent-graft interaction with aortic tissue over time is important and should receive more detailed evaluation. Testing this interaction in an animal model of nonatherosclerotic dilative aortic disease could be of great interest.

Development of a Special Balloon Occlusion Device to Prevent Adverse Events in High-Risk Patients during Open Aortic Surgery

Objective: To prevent clamp injury that may occur during aortic surgery, we aimed to develop a special balloon occlusion (BO) device to lower the thromboembolic risk in patients with severe atherosclerosis during aortic aneurysm repair. Methods: The study comprised two test phases: a laboratory-testing series focussing on flexible artificial aortas, and an experimental series conducted on 10 pigs. Results: The device proved to be effective during the laboratory tests and the experiments on pigs. No complications such as intraoperative balloon rupture, dislocation, or occlusion leaks occurred. No damage to the aortic vessels was observed in further histological examinations. Conclusions: This BO device has the potential to become an alternative to cross-clamping for vascular surgeons in patients with severely atherosclerotic vessels.

A case of pericoronary pseudotumor due to localized Castleman's disease

BACKGROUND A 59-year-old male had a latent epicardial mass discovered at cardiovascular imaging during the assessment of an aortic murmur. RESULTS The resected mass surrounded the left anterior descending coronary artery. It was a well-limited pericoronary cellular lesion. It was made of a mixture of polytypic plasma cells, lymphocytes with lymphoid follicles, hyaline vascular hyperplasia, and focal eosinophils. No immunoglobulin and TCR-gamma gene rearrangements were detected. In this immunocompetent patient, HHV-8 was negative. CONCLUSION The pattern was consistent with a pericoronary localized Castlemans disease of composite histologic subtype.

Entwicklung eines neuen Ballonokklusions-Device alternativ zur Gefäßklemme bei offenen Eingriffen an der Aorta

ZusammenfassungHintergrundSchwere atherosklerotische Veränderungen der Aorta und anderer großer Gefäße stellen eine besondere Herausforderung für den Gefäßchirurgen dar. Das Abklemmen eines Gefäßes mittels einer herkömmlichen Gefäßklemme kann Schäden am Gefäß verursachen und atheromatöse Plaques aufbrechen, die wiederum zu arteriellen Embolien in der peripheren Strombahn führen können. Um dies zu vermeiden, haben wir ein neues Ballonokklusions (BO-)Device als Alternative zur Gefäßklemme entwickelt.MethodenDie vorliegende Studie umfasste zwei Testphasen. In der In-vitro-Phase wurde an künstlichen, flexiblen Aortenbogenmodellen, das ideale Cuffvolumen des BO-Device bestimmt. In der In-vivo-Phase wurden Untersuchungen unter physiologischen Bedingungen mit dem BO-Device an zehn Hausschweinen durchgeführt. Abschließende histologische Untersuchungen, der mit dem BO-Device geblockten Aortenwände, vervollständigten die Untersuchungen.ErgebnisseDas BO-Device absolvierte die experimentelle In-vitro-Phase problemlos und konnte kontinuierlich weiterentwickelt werden, so dass wir nach kurzer Zeit in der Lage waren, die Aorten im Tierversuch effektiv zu okkludieren. Es traten keine Komplikationen, wie intraoperative Ballonruptur, Dislokation oder Undichtigkeiten, auf. Desweiteren fanden sich keine Dissektionen oder andere Gefäßschäden bei den postoperativen histologischen Nachuntersuchungen.SchlussfolgerungDas BO-Device hat in der experimentellen In-vitro- und In-vivo-Testphase alle Anforderungen erfüllt und gezeigt, dass es dazu beitragen kann Gefäßschäden zu minimieren. Das BO-Device ist jetzt soweit um im klinischen Alltag erprobt zu werden und hat das Potential eine Alternative zur konventionellen Gefäßklemme, bei Patienten mit schwer atherosklerotisch veränderten Gefäßen, zu werden.SummaryBackgroundSevere atherosclerosis of the aorta and the great vessels presents a huge challenge for vascular surgeons. Cross-clamping may cause vessel damage and result in atheromatous degeneration, which can lead to arterial embolism in the terminal vessels. In order to prevent these complications, we developed a new balloon occlusion (BO) device as an alternative to aortic cross-clamping.MethodsThis study comprised two test phases. In the in vitro phase, which focused on flexible artificial aortas, the ideal occlusion volume of the BO device was determined. During in vivo phase the BO device was tested under physiological conditions on ten pigs. Subsequent histological tests of the aortic walls, which were occluded by the BO device, completed the study.ResultsThe BO device met the laboratory test requirements relating to experimental application and material properties and was enhanced successfully, which allowed us in the aftermath to occlude the aortas effectively during the animal experiments. No complications such as intraoperative balloon rupture, dislocation or occlusion leaks occurred. In none of the histological examinations were dissections or other damage to the aortic vessels observed.ConclusionsThe BO device not only meets in vitro and in vivo requirements, it also helps to prevent vessel damage. This BO device is ready to be proved during operations and has the potential to become an operative alternative to conventional vessel clamps on patients with severe atherosclerotic vessels.

Full viability of the myocardium after twenty-four hour organ conservation

Background: Orthotopic heart transplantation following ischemic times beyond 4 hrs is associated with an increased risk of early graft failure. The use of modern myocardial preservation strategies could enable safe transplantation after long-term conservation. Methods: Orthotopic heart transplantations (n 5) were performed in a pig model. Donor hearts were flushed with Bretschneider solution, excised, and stored for 24 hours at 4 °C. During implantation controlled reperfusions with substrate-enriched leukocyte-depleted blood cardioplegia were performed after each anastomosis. Blood cardioplegia contained 1 mmol/l of the NHE inhibitor HOE 642 and 100 mg/l of adenosine. Controlled reperfusion was maintained with leukocytedepleted blood for 20 min. To prevent right heart failure a microaxial pump was inserted after heart transplantation and circulatory assistance was maintained for 5 hours. Results: All hearts could be weaned from ECC and subsequent right ventricular support. Hemodynamics remained stable after removal of the right ventricular assist system with epinephrine at 0.1 g/kg/min. Myocardial oxygen consumption 20 min after start of reperfusion (5.2 2.3 ml/100 g/min) did not differ significantly versus baseline (6.8 2.2 ml/100g/min). Oxygen extraction 6 hours after heart transplantation was also well preserved compared to baseline (59 6 % versus 50 8%). Histological examination after transplantation using luxol fast blue staining revealed that only 1.0 % of the myocytes were damaged irreversibly. Conclusion: The data indicatate full viability of the myocardium after 24 hour heart conservation. The described preservation technique could contribute to the extention of conservation times in heart transplantation and enable safe transplantation of marginal donor hearts.