A new mitochondrial point mutation in the transfer RNA(Lys) gene associated with progressive external ophthalmoplegia with impaired respiratory regulation.

We report a novel heteroplasmic point mutation G8299A in the gene for mitochondrial tRNA(Lys) in a patient with progressive external ophthalmoplegia complicated by recurrent respiratory insufficiency. Biochemical analysis of respiratory chain complexes in muscle homogenate showed a combined complex I and IV deficiency. The transition does not represent a known neutral polymorphism and affects a position in the tRNA acceptor stem which is conserved in primates, leading to a destabilization of this functionally important domain. In vitro analysis of an essential maturation step of the tRNA transcript indicates the probable pathogenicity of this mutation. We hypothesize that there is a causal relationship between the novel G8299A transition and progressive external ophthalmoplegia with recurrent respiratory failure due to a depressed respiratory drive.

Beta-blocker treatment of chronic systolic heart failure improves prognosis even in patients meeting one or more exclusion criteria of the MERIT-HF study.

AIMS: Improved prognosis of patients with chronic systolic heart failure by treatment with beta-blockers has been shown in several randomized controlled multicentre trials. However, in clinical practice only a part of heart failure patients meet the inclusion criteria of these trials. The present study evaluates whether reduction of mortality by beta-blockers also can be achieved in patients presenting one or more exclusion criteria of the MERIT-HF trial. METHODS AND RESULTS: From the Ludwigshafen Heart Failure Registry 675 patients with chronic systolic heart failure consecutively enrolled between January 1995 and June 2004 were divided in two groups either meeting the inclusion criteria of the MERIT-HF trial ('trial patients': n = 278, 60% treated with beta-blockers) or not ('non-trial patients': n = 397; 51% treated with beta-blockers). The distribution of the MERIT-HF exclusion criteria in the group of 'non-trial patients' was as follows: acute myocardial infarction 9.6%; systolic blood pressure <100 mmHg 7.5%; chronic obstructive lung disease 33.2%; other serious diseases potentially limiting prognosis 16.9%; acutely performed or planned ICD, bypass surgery, PCI, heart transplantation: 17.1, 15.9, 7.8, and 4.8%, respectively. Median follow-up was 31.3 months (upper/lower quartile 16.3/50.0 months). All-cause mortality was significantly reduced by beta-blocker treatment not only in 'trial patients' (adjusted hazard ratio 0.57, 95% CI 0.38-0.86) but also in 'non-trial patients' (adjusted hazard ratio 0.72, 95% CI 0.53-0.97). CONCLUSION: In clinical practice only the smaller part of the population to be treated for chronic systolic heart failure meets the inclusion criteria of the MERIT-HF study. However, beta-blocker treatment is associated with a significantly reduced long-term mortality even in patients meeting one or more exclusion criteria of the MERIT-HF study.

Cytokine response after percutaneous coronary intervention in stable angina: effect of selective glycoprotein IIb/IIIa receptor antagonism.

BACKGROUND: It is unclear whether modulation of inflammatory markers by glycoprotein IIb/IIIa receptor inhibition after percutaneous coronary intervention (PCI) is caused by an interaction with the alpha(v)beta3 and alpha(M)beta2 receptor or it correlates with ischemic events during PCI. This study investigates the inflammatory profile after elective, nonacute PCI and whether and how administration of the glycoprotein IIb/IIIa receptor antagonist tirofiban modulates the postinterventional inflammatory myocardial response. METHODS: The time course of inflammatory parameters (C-reactive protein [CRP], interleukin-1 [IL-1], interleukin-6 [IL-6], and tumor necrosis factor alpha [TNF-alpha]) of patients receiving peri- and postinterventional placebo (n = 46) or tirofiban infusion (n = 50) was analyzed by use of enzyme-linked immuno assays. Samples were collected before and 30 minutes, 2.5 hours, 6.5 hours, 12 hours, 24 hours, and 48 hours after elective PCI. RESULTS: Among the inflammatory markers analyzed, TNF-alpha, IL-6, and CRP levels increased significantly. However, the latter markers followed individual time courses in patients given placebo and patients treated with tirofiban after PCI, compared with pre-PCI levels (P <.01), with no significant differences between the placebo and tirofiban-treated groups. However, by subgroup analysis, significant differences were revealed in TNF-alpha, IL-6, and CRP levels of patients who were troponin T-positive versus patients who were troponin T-negative after PCI. CONCLUSIONS: The administration of the selective glycoprotein IIb/IIIa receptor antagonist tirofiban has no direct impact on the inflammatory profile after elective PCI. Change of the inflammatory profile was only related to the presence or absence of postinterventional troponin.

Cyclooxygenase-2 in myocardium stimulation by angiotensin-II in cultured cardiac fibroblasts and role at acute myocardial infarction.

Myocardial infarction is followed by a complex repair process that includes a significant role for inflammatory cells. Cyclooxygenase-2 (COX-2) plays a key role in mediating inflammation. Contribution of COX-2 to inflammatory response following myocardial infarction is less certain. In an effort to evaluate the function of COX-2 and prostaglandin E(2)(PGE(2)) in myocardial infarction, we examined the role of COX-2 after angiotensin II (Ang II) stimulation in cardiac fibroblasts and in rats with experimental myocardial infarction (MI). We combined Western blot analysis and enzyme immunoassay to demonstrate COX-2 expression and PGE(2)release in cardiac fibroblasts. Isolated cardiac fibroblasts were stimulated with Ang II. Unstimulated fibroblasts showed no COX-2 protein expression. Fibroblasts stimulated with Ang II showed a strong time-dependent expression of COX-2 protein. The p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 but not the p42/44 MAPK-inhibitor PD98059 suppressed Ang II-induced COX-2 protein expression. COX-2 expression correlated with a significantly increased PGE(2)release from cardiac fibroblasts. The COX-2 specific inhibitor NS-398 suppressed the Ang II-stimulated PGE(2)production. We then investigated COX-2 expression and inflammatory cell infiltration in our rat model of myocardial infarction. MI was produced by coronary artery ligation in adult female Wistar rats. The period of coronary artery occlusion was 96 h. The selective COX-2 inhibitor rofecoxib (3 mg/kg/d), administered orally, was given one day before MI and continued for four days. Western blotting showed expression of COX-2 protein in the area of necrosis and the infarct border zone. Immunofluorescence analysis showed macrophage infiltration as well as fibroblast proliferation in the infarct border zone of 4-d infarcted tissue and a significantly reduced cell invasion and fibroblast proliferation in infarcted tissue of rats treated with rofecoxib. MI size at day 4 was comparable in untreated and treated rats. In conclusion, we demonstrate that pharmacological interference with prostaglandin synthesis in myocardial infarction is associated with reduced myocardial invasion of inflammatory cells.