Untersuchungen über die Expression von Early-Response Genen und intrazelluläre Signalübertragungswege nach Verletzung humaner vaskulärer Endothelzellmonolayer in vitro

Perkutane Interventionsverfahren stellen ein etabliertes und wichtiges Behandlungskonzept der Arteriosklerose dar. Ihr Ergebnis wird getrübt durch hohe Restenoseraten nach z.B. Ballon-Angioplastie. Wesentlich für die Ausbildung und den Grad einer postinterventionellen Restenose ist die Reendothelialisierung der zerstörten Intima, weshalb es von besonderem Interesse ist, intrazelluläre Signalübertragungswege, welche nach Zerstörung eines Endothelzellmonolayers in den überlebenden Zellen ablaufen, zu untersuchen, um potentielle Angriffspunkte z.B. für eine pharmakologische Modulation der Endothelzellantwort nach Angioplastie zu finden. In der vorliegenden Arbeit wurden diese Signalübertragungswege an einem Modell zur Verletzung vaskulärer Endothelzellmonolayer in vitro untersucht. Das Hauptaugenmerk lag dabei auf Untersuchung des an der Regulation der Zellproliferation beteiligten Transkriptionsfaktors und Proto-Oncogens AP-1 bzw. dessen mRNA-Vorstufe c-fos. An humanen vaskulären Endothelzellen (HUVEC) wurde in Zellkultur mittels Northern-Blot Analysen und Electrophoretic mobility shift assays untersucht, ob c-fos und AP-1 nach Endothelzellverletzung exprimiert bzw. aktiviert werden. Es konnte gezeigt werden, dass die Endothelzellverletzung im vorliegenden Modell eine starke Expression von c-fos sowie die Aktivierung des korrespondierenden Transkriptionsfaktors AP-1 bewirkt. Diese Aktivierung wird gesteuert durch einen Anstieg der intrazellulären Calcium-Konzentration sowie unter Beteiligung negativ regulierender G-Protein, der Proteinkinase C sowie von Protein-Tyrosinkinasen. Keine Beteiligung konnte nachgewiesen werden für MAPKinasen, Proteinkinase A sowie die CamKinasen. Die Ergebnisse dieser Arbeit liefern in Zusammenschau mit publizierten Ergebnissen anderer Arbeitsgruppen wichtige Erkenntnisse für eine weiterführende Untersuchung der Signalübertragungswege in huamnen Endothelzellen nach z.B. perkutaner Angioplastie und führen in Zukunft zu neuen Ansatzpunkten für die Pharmakotherapie vaskulärer Läsionen, z.b. durch drug-eluting Stents

Embolic Protection in Complex Femoropopliteal Interventions: Safety, Efficacy and Predictors of Filter Macroembolization

Objectives. To evaluate the safety and efficacy of a filter embolic protection device (FEPD) in endovascular interventions of the femoropopliteal arteries. Methods. Patients who underwent endovascular interventions of the femoropopliteal arteries between 2008 and 2016 and in whom the SpiderFXTM FEPD was applied were included in this retrospective study. Clinical and angiographic characteristics, filter macroembolization (FME), device-related complications, distal embolization, as well as the early clinical and hemodynamic outcome, were assessed. Potential risk factors for FME were evaluated by multivariate analysis. Results. A total of 244 cases were identified (203 patients, claudication 60.4%, critical limb ischaemia 39.6%, mean lesion length 13.2 ± 12.9 cm, complete occlusions in 72.7%). Balloon angioplasty ± stenting (BAP), directional atherectomy ± balloon angioplasty ± stenting (DA) and rotational thrombectomy ± balloon angioplasty±stenting (RT) were performed in 141, 61 and 42 cases, respectively. FEPD placement and retrieval were successful in all but one case each. Permanent filter-related vessel damage was not observed. The rate of FME was 37.3% (BAP 36.2%, DA 32.8%, RT 47.7%). Risk factors for FME in the BAP- and DA-group were total occlusion, lesion length > 19 cm, visible thrombus and diabetes mellitus. The distal embolization rate despite filter protection was 4.1 % (BAP 4.9%, DA 1.6%, RT 4.8%) and was higher in cases with FME compared with those without FME (8.7% vs. 1.5%, p = 0.02). Conclusion. The Spider FXTM device is safe and effective in capturing embolic debris during femoropopliteal interventions. A residual risk of peripheral embolization remains

Visceral embolus protection by catheters with balloon-inflatable tips during hybrid repair of thoracoabdominal aortic aneurysm

Thoracoabdominal aortic aneurysms (TAAA) are associated with high rupture rates and poor outcome in patients who do not have surgical repair. Endovascular and hybrid techniques have gained increasing acceptance for the treatment of TAAA in patients with multiple comorbidities and an increased anesthetic risk. One of the complications of endovascular repair in TAAA is procedurally related embolism to visceral vessels. Visceral embolism causes bowel ischemia and is a potentially lethal complication. This report illustrates the intermittent use of catheters with balloon-inflatable tips as visceral embolus protection systems. These catheters are easy to apply and demonstrated perfect prevention of visceral embolization. To date, 10 patients have undergone operations at our clinic using this protection system, and no embolic complications were observed at the visceral vessels. Therefore, catheters with balloon-inflatable tips for visceral embolous protection should be considered in patients undergoing a two-stage hybrid TAAA repair to avoid embolus-associated morbidity and mortality

A pitfall of bilateral inferior petrosal sinus sampling in cyclic Cushing's syndrome

Background: Clinical care of patients with cyclic Cushing's syndrome (CS) is challenging. Classical pitfalls include incorrect subtyping, unnecessary surgical procedures and delayed definite treatment. Case presentation: A 43-year-old female suffered from a rapidly cycling ectopic CS. She experienced six cycles of severe hypercortisolism within a 2 year period (maximum plasma cortisol 5316 nmol/L, normal range 124.2-662.4 nmol/L; maximum urinary free cortisol 79,469 nmol/24 h, normal range < 414 nmol/24 h) lasting 2-9 weeks. The episodes were associated with pronounced hypokalemia (lowest K+ value recorded 2.4 mmol/l) and progressive signs and symptoms of CS. A bilateral inferior petrosal sinus sampling (BIPSS) performed during a trough phase was false positive for pituitary ACTH overproduction resulting in unnecessary transsphenoidal surgery while a second BIPSS performed during an active phase was indicative for ectopic CS. The 18F-DOPA PET/CT showed a pancreatic lesion, which was subsequently partially removed. Surprisingly, the histopathology was conclusive for ACTH-positive lymph node metastasis located in the retro-duodenal tissue of an occult neuroendocrine tumor WHO grade II. The primary tumor has not been identified so far and, because of the persistent hypercortisolism, the patient underwent bilateral adrenalectomy. Two years later, ACTH levels started to increase progressively. Percutaneous biopsy of a newly identified suspected lesion in the fifth thoracic vertebra revealed a metastasis with positive staining for ACTH, synaptophysin and chromogranin A. Therapy with carboplatin and etoposide was started and, since then, the patient underwent 12 cycles of chemotherapy. Conclusions: We report the challenging case of a rapidly cycling CS secondary to ACTH-secreting neuroendocrine intestinal tumor of unknown primary. We highlight the importance of performing diagnostic tests only during the phases of active cortisol secretion and as soon as first symptoms appear to avoid pitfalls

Cortisol excess in patients with primary aldosteronism impacts on left ventricular hypertrophy

Context Primary aldosteronism (PA) represents the most frequent form of endocrine hypertension. Hyperaldosteronism and hypercortisolism both induce excessive left ventricular hypertrophy (LVH) compared to matched essential hypertensives. In recent studies frequent co-secretion of cortisol and aldosterone has been reported in PA patients. Objective Our aim was to investigate the impact of cortisol co-secretion on left ventricular hypertrophy in PA patients. We determined 24-h excretion of mineralocorticoids and glucocorticoids by gas chromatography-mass spectrometry and assessed cardiac remodeling using echocardiography initially and one year after initiation of treatment for PA. Patients We included 73 patients from the Munich center of the German Conn's registry; 45 with unilateral aldosterone-producing adenoma and 28 with bilateral adrenal hyperplasia. Results At the time of diagnosis, 85% of PA patients showed left ventricular hypertrophy according to left ventricular mass index (LVMI, median 62.4 g/m2.). LVMI correlated positively with total glucocorticoid excretion (r2=0.076, p=0.018) as well as with tetrahydroaldosterone excretion (r2=0.070, p=0.024). Adrenalectomy led to significantly reduced LVMI in aldosterone-producing adenoma (p<0.001) while mineralocorticoid receptor antagonist therapy in bilateral adrenal hyperplasia patients reduced LVMI to a lesser degree (p=0.024). In multivariate analysis, the decrease in LVMI was positively correlated with total glucocorticoid excretion and systolic 24-hour blood pressure, but not with tetrahydroaldosterone excretion. Conclusion Cortisol excess appears to have an additional impact on cardiac remodeling in patients with PA. Treatment of PA by either adrenalectomy or mineralocorticoid receptor antagonist improves LVMI. This effect was most pronounced in patients with high total glucocorticoid excretion

Schnitzler's Disease as an Important Differential Diagnosis of Chronic Recurrent Multifocal Osteomyelitis: A Case Report

Introduction. At first sight, chronic recurrent multifocal osteomyelitis (CRMO) and Schnitzler's disease are diagnoses of exclusion and can be similar in their manifestation. Methods. In this paper we present the reevaluation of the 13-year-old diagnosis of chronic recurrent osteomyelitis of a 58-year-old man with chronic ostealgia, night sweat, and pruritic urticarial lesions on the extremities and trunk. For further examination, we performed blood analysis, bone and skin biopsies, CT scans, and magnetic resonance imaging. Results. Laboratory findings showed increased inflammation parameters. Magnetic resonance imaging (MRI) revealed a diffuse bone marrow infiltration. A bone and skin biopsy showed a sclerotic bone marrow involvement and a superficial dermal and perivascular infiltrate of neutrophils. Based on these findings, the diagnosis of Schnitzler’s disease was made. Conclusion. Here, we want to present Schnitzler's disease as an important differential diagnosis to CRMO in adults presenting with signs suggestive of CRMO

Primary and Secondary Hyperparathyroidism in Patients with Primary Aldosteronism - Findings From the German Conn's Registry

CONTEXT Recent studies support a bidirectional interaction between aldosterone and parathyroid hormone (PTH), possibly increasing the individual cardiovascular risk. Primary aldosteronism (PA) and primary hyperparathyroidism can occur simultaneously. OBJECTIVE Our aim was to investigate the prevalence of hyperparathyroidism in PA. PATIENTS We performed a case finding of primary hyperparathyroidism in a retrospective series of 503 patients with PA (cohort 1). We analysed primary and secondary hyperparathyroidism in 141 prospective PA patients who underwent PTH, serum calcium and phosphate measurements at time of diagnosis of PA (cohort 2). RESULTS The prevalence for primary hyperparathyroidism was 1.2% in cohort 1, and 2.1% in cohort 2. Secondary hyperparathyroidism was found in 54.6% of the patients. Patients with secondary hyperparathyroidism had significantly higher aldosterone and lower potassium levels and took more antihypertensive medications compared to those with normal PTH levels. In multivariate analysis, aldosterone and 25-hydroxyvitamin D levels were significantly correlated with serum PTH levels. There was a nonsignificant trend to a higher cardiovascular morbidity in patients with secondary hyperparathyroidism. Patients with aldosterone producing adenoma had significantly higher PTH levels compared to patients with bilateral adrenal hyperplasia. After treatment, there was a significant decrease of PTH levels in both groups. CONCLUSION Patients with PA frequently have primary or secondary hyperparathyroidism, which is alleviated by correction of PA by surgical or medical means. Patients affected by secondary hyperparathyroidism seem to have a more severe phenotype of PA and have a trend towards more cardiovascular co-morbidities

Patients with primary aldosteronism respond to unilateral adrenalectomy with long-term reduction in salt intake

CONTEXT High dietary salt intake is known to aggravate arterial hypertension. This effect could be of particular relevance in the setting of primary aldosteronism (PA), which is associated with cardiovascular damage independent of blood pressure levels. The aim of this study was to determine the impact of therapy on salt intake in PA patients. PATIENTS AND METHODS 148 consecutive PA patients (66 with unilateral and 82 with bilateral PA) from the database of the German Conn's Registry were included. Salt intake was quantified by 24-hour urinary sodium excretion before and after initiation of PA treatment. STUDY DESIGN Observational longitudinal cohort study. SETTING Tertiary care hospital. RESULTS At baseline, unilateral PA patients had a significantly higher urinary sodium excretion than patients with bilateral disease (205 vs. 178 mmol/d, p= 0.047). Higher urinary sodium excretion correlated with an increased cardiovascular risk profile including proteinuria, impaired lipid and glucose metabolism and was associated with higher daily doses of antihypertensive drugs to achieve blood pressure control. In unilateral disease, urinary sodium excretion dropped spontaneously to 176 mmol/d (p= 0.012) one year after unilateral adrenalectomy and remained low at three year of follow-up (174 mmol/d). In contrast, treatment with mineralocorticoid receptor antagonists (MRA) in bilateral PA patients was not associated with a significant change in urinary sodium excretion at follow-up (179 mmol/d vs. 183 mmol/d). CONCLUSION PA patients consuming a high salt diet, estimated based on urinary sodium excretion, respond to adrenalectomy with a significant reduction of salt intake, in contrast to MRA treatment