Determinants of thromboxane biosynthesis in rheumatoid arthritis: Role of RAGE and oxidant stress.

Thromboxane (TX) biosynthesis by platelets and other cells in response to inflammatory triggers may provide a link between chronic inflammatory disease and atherothrombosis in rheumatoid arthritis (RA). In this study, we investigated the determinants of TX biosynthesis in RA, with particular reference to enhanced oxidative stress, receptor for advanced glycation end-products (RAGE) hyperactivity, and anti-tumor necrosis factor (TNF) treatment. Fifty-four patients with RA and 20 healthy subjects were recruited and a cross-sectional comparison of urinary 11-dehydro-TXB(2), 8-iso-PGF(2alpha), and plasma endogenous secretory RAGE (esRAGE) levels was performed between patients and controls. Urinary 11-dehydro-TXB(2) was significantly higher in RA patients than in healthy controls [425 (309-592) vs 233 (158-327) pg/mg creatinine, P<0.0001]. Furthermore, urinary 8-iso-PGF(2alpha) [323 (221-515) vs 172 (91-292) pg/mg creatinine, P<0.0001] and plasma esRAGE [155 (100-240) vs 377 (195-486) pg/ml, P=0.001] were higher and lower, respectively, in patients than in controls. A direct correlation was found between urinary 11-dehydro-TXB(2) and 8-iso-PGF(2alpha) only in patients not on anti-TNF therapy (r=0.420, P=0.021). Conversely, patients on anti-TNF therapy showed significantly lower urinary 8-iso-PGF(2alpha) [284 (201-373) vs 404 (241-539) pg/mg creatinine, P=0.043] but not 11-dehydro-TXB(2) than anti-TNF-treated subjects, with esRAGE as the only independent predictor of 11-dehydro-TXB(2) in this group of patients (adjusted R(2)=0.496, beta=-0.725, SEM=0.025, P=0.001). In conclusion, we provide biochemical evidence of enhanced TX biosynthesis in patients with RA, driven, at least in part, by lipid peroxidation. Treatment with anti-TNF agents may blunt isoprostane generation in the absence of significant effects on TX biosynthesis. We suggest that RAGE hyperactivity may escape TNF blockade, thus contributing to persistent TX biosynthesis in this setting.

Transthoracic versus transesophageal cardioversion of atrial fibrillation under light sedation: a prospective randomized trial.

BACKGROUND: Electrical cardioversion (ECV) of atrial fibrillation (AF) is limited by a 5-10% failure rate and by the expense arising from a perceived need for general anesthesia. A transesophageal approach using light sedation has been proposed as a means of augmenting the success rate and avoiding the need for general anesthesia. We hypothesized that the high rate of success and the lower energy requirement associated with biphasic cardioversion might eliminate any advantage of the transesophageal approach. METHODS: We randomly assigned 60 patients attending for ECV of persistent AF to a transesophageal or a transthoracic approach. Sedation of moderate depth was achieved with intravenous midazolam. The dose of midazolam was titrated in the same manner in both groups. RESULTS: Sinus rhythm was restored in 29/30 patients (97%) in each group using a similar number of shocks for both groups (1.3 +/- 0.6 transesophageal vs 1.4 +/- 0.7 transthoracic, P = NS) with a similar procedure duration (14.1 +/- 8.2 minutes vs 13.8 +/- 7.5 minutes, P = NS). Both groups received similar doses of midazolam (4.2 +/- 2.7 mg vs 4.4 +/- 2.8 mg, P = NS) and both reported a similar discomfort score in (0.9 +/- 1.3 vs 1.1 +/- 1.8, P = NS). No complication occurred in either group. CONCLUSION: AF may be cardioverted safely and effectively by either a transthoracic or a transesophageal approach. The use of sedation of moderate depth renders cardioversion by either approach acceptable. As transesophageal ECV shows no clear advantage, transthoracic cardioversion should remain the approach of first choice.