Uric acid stimulates proliferative pathways in vascular smooth muscle cells through the activation of p38 MAPK, p44/42 MAPK and PDGFRß.

Hyperuricemia and angiotensin II (Ang II) may have a pathogenetic role in the development of hypertension and atherosclerosis as well as cardiovascular disease (CVD) and its prognosis. The purpose of this study was to investigate whether uric acid can induce proliferative pathways of vascular smooth muscle cell (VSMC) that are thought to be responsible for the development of CVD. The phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), p44/42 mitogen-activated protein kinase (p44/42 MAPK) and platelet-derived growth factor receptor ß (PDGFRß) was measured by Elisa and Western blot techniques to determine the activation of proliferative pathways in primary cultured VSMCs from rat aorta. Results demonstrated that uric acid can stimulate p38 MAPK, p44/42 MAPK and PDGFRß phosphorylation in a time- and concentration-dependent manner. Furthermore, treatment of VSMCs with the angiotensin II type I receptor (AT1R) inhibitor losartan suppressed p38 MAPK and p44/42 MAPK induction by uric acid. The stimulatory effect of uric acid on p38 MAPK was higher compared to that of Ang II. The results of this study show for the first time that uric acid-induced PDGFRß phosphorylation plays a crucial role in the development of CVDs and that elevated uric acid levels could be a potential therapeutical target in CVD patients.

Importance of preimplantation procedures in candidates for an implantable atrial defibrillator.

INTRODUCTION: Due to the limited efficacy of antiarrhythmic drugs for the treatment of atrial fibrillation, several nonpharmacologic therapeutic options have been developed. One of these options is an implantable atrial defibrillator for patients with severe symptoms and infrequent drug-refractory episodes of atrial fibrillation. The purposes of this study were: (1) to evaluate how many patients with atrial fibrillation are possible candidates for an implantable atrial defibrillator; and (2) to report the results and findings of preimplantation testing in a single center. METHODS AND RESULTS: From our atrial fibrillation outpatient clinic, we evaluated the number of possible candidates for an atrial defibrillator using the following criteria: (1) recurrent persistent atrial fibrillation; (2) long-lasting but infrequent episodes; (3) refractory to antiarrhythmic drugs; (4) capability of maintaining normal sinus rhythm; and (5) no factors increasing proarrhythmic risk. In those patients eligible for an atrial defibrillator, a separate preimplantation test was performed to evaluate atrial defibrillation limits and patient acceptance. Thirty-one of 196 patients were possible candidates for an atrial defibrillator. Fourteen of these 31 patients agreed to participate in the METRIX clinical study phase I on atrial defibrillators. Six of these patients met implantation criteria; two patients refused permanent implantation because of intolerable pain. Implantation was performed in four patients; however, one patient could not be cardioverted intraoperatively despite a successful preimplantation test. CONCLUSION: About 16% of selected patients with atrial fibrillation are possible candidates for an atrial defibrillator. However, successful preimplantation testing does not exclude implantation failure.

Apolipoprotein E polymorphism is associated with both senile plaque load and Alzheimer-type neurofibrillary tangle formation.

Recent work provided evidence that the apolipoprotein (apo) E polymorphism is associated with late-onset sporadic Alzheimer's disease. The major histological hallmarks of Alzheimer's disease are the extraneuronal deposition of A4/beta-amyloid and the intraneuronal formation of neurofibrillary tangles, the latter correlating strongly with the psychometric status. We examined the relationship between the apo E polymorphism and Alzheimer's disease-related histological changes using a staging system which accounts for the progression of the disease over time and correlates well with the cognitive decline ante mortem. We observed a significant positive correlation between both neurofibrillary changes and A4/beta-amyloid deposits and the epsilon 4 gene dose. We estimated that the presence of one apo E4 allele leads to an earlier onset of the histopathological process of about one decade. The association of both types of Alzheimer's disease-related changes with the prevalence of the epsilon 4-allele suggests that the apo E polymorphism causally contributes to the development of Alzheimer's disease.

Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation.

Only recently, evidence was provided that apolipoprotein E allele epsilon 4 located on Chromosome 19 is associated with late onset (i.e. senile) sporadic Alzheimer's disease. Histologically, Alzheimer's disease is associated with intraneuronal neurofibrillary changes and extraneuronal A4/beta-amyloid deposition. We set out with a histological staging system which considers the gradual development of Alzheimer's disease-related histological changes over time and correlates highly with the cognitive decline ante mortem. Our analysis revealed that both the mean stage for A4/beta-amyloid deposits and the mean stage for neurofibrillary tangles get significantly shifted upwards in epsilon 4-carriers. This represents an earlier onset of the histopathological process of about one decade. The fact that both types of Alzheimer's disease-related changes correlate positively with the prevalence of the epsilon 4-allele suggests for a causal relationship between the apolipoprotein E polymorphism and the development of Alzheimer's disease.