Gabriele Plenz

Introduction: Cogan's syndrome is a rare disorder of unknown origin characterized by inflammatory ocular disease and vestibuloauditory symptoms. Systemic vasculitis is found in about 10% of cases. Methods and results: We report a case of a 46-year-old female with Cogans's syndrome. The patient presented with severe chest pain. Aortic angiography revealed an aortic arch syndrome with occlusion of both subclavian and vertrebral arteries. Ultrasound showed a fusiform abdominal aortic aneurysm and axial computed tomography demonstrated an aneurysm of the ascending aorta with a dissection membrane located a few centimeters distal from the aortic root. Immunohistochemistry of the resected tissue specimen demonstrated an occult inflammatory process with massive inflammatory infiltration and loss of smooth muscle cells particularly at the intima-media border. Elastic lamellae and collagenous matrix were degraded. Foci of matrix deterioration in deeper medial areas collocated with clusters of inflammatory cells. Matrix metalloproteinase 1 (MMP1) and MMP9 as studied by immunohistochemistry and RT-PCR were strongly expressed at the intima-media border and in deeper areas of the media. Thus, histopathological analysis revealed that vascular matrix integrity and expression of the major matrix molecules was characterized by elastolysis and collagenolysis and a dramatic loss of structural integrity. Remarkably, exceeding matrix deterioration was associated with massively increased levels of granulocyte macrophage colony stimulating factor (GM-CSF). Conclusion: Our data suggest that the persistently increased secretion of the inflammatory mediator GM-CSF by resident inflammatory cells but also by smooth muscle cells may be the trigger of aortic wall structural deterioration.

Background: Cogan's syndrome is a rare disorder of unknown origin characterized by inflammatory ocular disease and vestibuloauditory symptoms. Systemic vasculitis is found in about 10% of cases. Case presentation: A 46-year-old female with Cogans's syndrome and a history of arterial hypertension presented with severe chest pain caused by an aneurysm of the ascending aorta with a dissection membrane located a few centimeters distal from the aortic root. After surgery, histopathological analysis revealed that vascular matrix integrity and expression of the major matrix molecules was characterized by elastolysis and collagenolysis and thus a dramatic loss of structural integrity. Remarkably, exceeding matrix deterioration was associated with massively increased levels of granulocyte macrophage colony stimulating factor (GM-CSF). Conclusion: Our data suggest that the persistently increased secretion of the inflammatory mediator GM-CSF by resident inflammatory cells but also by SMC may be the trigger of aortic wall structural deterioration.

GM‐CSF takes part in the cytokine network regulating the metabolism of extracellular matrix (ECM) during atherogenesis. Since data also point to an effect of GM‐CSF on the vascular ECM in general, the vascular collagenous matrix was studied in wild‐type and GM‐CSF‐deficient mice. Histological examination revealed a disorganized vascular ECM in GM‐CSF‐deficient mice involving the collagenous matrix and elastic fiber system. As shown by electron microscopy, collagen bundles were disrupted and reduced. The diameter of fibrils varied widely. mRNA expression of collagens and related molecules was studied. Fibrillar collagens were markedly reduced, α1(I)procollagen to 16.5% of control levels α1(III)procollagen was abolished whereas the expression level of network‐forming α1(VIII)procollagen was not altered. As shown by in situ hybridization, the number of collagen‐expressing cells was reduced. Matrix metalloproteinases and their inhibitor 1 were not affected by GM‐CSF deficiency. Our studies demonstrate that GM‐CSF plays a major role in the cytokine network regulating the metabolism of vascular collagens. GM‐CSF deficiency leads to an altered composition of the vascular collagenous matrix, i.e., reduced amount of fibrillar collagen, altered ratio of fibrillar and network‐forming collagen, and failures in the fibrillogenesis. We suggest that GM‐CSF is a basic requirement for the maintenance of vessel wall integrity and resilience.—Plenz, G., Eschert, H., Beissert, S., Arps, V., Sindermann, J. R., Robenek, H., Völker, W. Alterations in the vascular extracellular matrix of granulocyte macrophage colony‐stimulating factor (GM‐CSF) ‐deficient mice, FASEB J. 17, 1451–1457 (2003)

Objectives: The study objective was to assess the cardiac expression of interleukin-6 (IL6) and its receptor (IL6R) in advanced heart failure. Background: While IL6 plasma levels are elevated and associated with an impaired prognosis in advanced heart failure, little is known about the intracardiac expression of the IL6 system. Methods: Heart tissue was obtained from 20 patients (n - 10, idiopathic dilated cardiomyopathy, age 44±15 years; n - 10, ischemic cardiomyopathy, age 55±8 years) at the time of transplantation. Left and right ventricular tissue was subjected to in situ hybridization, Northern blot analysis, and RT-PCR. Signals were quantified by densitometric scanning and corrected for G3PDH-mRNA levels. Right ventricular biopsy specimens (n - 11) of patients with arrhythmias and normal cardiac function served as controls. In addition, data were correlated with cardiac catheterization and echocardiography data obtained at transplant evaluation. Results: Ventricular IL6 and IL6R transcripts were detected in all explant specimens examined. Expression of both mRNA species was higher than in controls (P - 0.001). Left ventricular IL6 mRNA levels correlated positively with heart rate (r - 0.77; P - 0.009), pulmonary capillary wedge pressure (r - 0.53; P - 0.03), right atrial pressure (r - 0.77; P - 0.003), and inversely with left ventricular ejection fraction (r - −0.61; P - 0.03). Right ventricular IL6 mRNA levels correlated inversely with cardiac index (r - −0.48; P - 0.05). IL6R expression did not correlate with hemodynamic data. Conclusions: In advanced heart failure, cardiac IL6/IL6R mRNA expression is increased and may play a role in the pathophysiology of advanced heart failure.