Adrenomedullin-induced dilation of human placental arteries is modulated by an endothelium-derived constricting factor.

Adrenomedullin is synthesized and secreted by fetoplacental tissues. Given that the placenta lacks autonomic innervation, we proposed that adrenomedullin acts locally to control blood flow in the placental vasculature through a balance of dilatory and constrictive pathways. Placental stem villous arteries (200 microm) from normotensive human pregnancies were dissected and mounted on a wire myograph. The vessels were preconstricted with the thromboxane A(2) mimetic U46619 (EC(80) concentration), and exposed to cumulative concentrations of adrenomedullin (1 x 10(-9) to 3 x 10(-7) mol/L). Adrenomedullin caused concentration-dependent vasorelaxation which, in endothelium-intact vessels, was attenuated in the presence of the nitric oxide synthase inhibitor L-NMMA. This suggested that the vasodilation was mediated, at least in part, through nitric oxide. However, removal of the endothelium did not similarly alter the response. Nor did L-NMMA have any effect in endothelium-denuded vessels. We hypothesized that adrenomedullin must induce release of both endothelium-derived relaxing (nitric oxide) and constricting factors. When we blocked the two major pathways through which adrenomedullin is known to induce vasodilation, by incubating the vessels with L-NMMA (nitric oxide synthase inhibitor) and Rp-cAMPS (cAMP-dependent protein kinase inhibitor), adrenomedullin induced concentration-dependent vasoconstriction. This was not mediated through endothelin, since addition of the non-specific endothelin receptor antagonist PD142893 failed to alter the response to adrenomedullin. We conclude that, in addition to increasing endothelial nitric oxide biosynthesis in placental stem villous arteries, adrenomedullin induces release of an endothelium-derived constricting factor.

Approaching a decade of cryo catheter ablation for type 1 atrial flutter-a meta-analysis and systematic review.

PURPOSE: Despite increasingly widespread use of cryo catheter ablation (CCA) in clinical practice, current ACC/AHA/ESC guidelines for management of supraventricular arrhythmias cite only radiofrequency catheter ablation (RFCA) as first-line treatment for type 1 atrial flutter (AFL). We performed a meta-analysis of efficacy and procedure outcomes from randomized controlled clinical trials comparing CCA with RFCA for type 1 AFL. A systematic review of non-randomized, single-arm clinical studies of CCA for type 1 AFL was also done. METHODS: An English language search of Medline, Cochrane, Embase, and an extensive bibliography search from January 2000 to May 2010 was conducted. Inclusion/exclusion criteria were met by six randomized clinical trials for meta-analysis (n = 341) and 13 non-randomized, single-arm clinical studies for systematic review (n = 763). Four primary outcomes were analyzed, namely, percent of patients with bidirectional conduction block (BCB) at procedure, proportion of patients who were asymptomatic during follow-up, procedure time, and fluoroscopy time. RESULTS: Random effect analyses for CCA versus RFCA favored the latter ablation modality for percent of patients with BCB at procedure (84.3% vs. 93.3%; OR = 0.51; p = 0.14). A similar proportion of patients were asymptomatic during follow-up (85.5% vs. 87.3%; OR = 0.68; p = 0.53). A significantly longer procedure time was determined for CCA (171.7 min vs. 134.5 min; Std diff means = 0.57; p < 0.001), but fluoroscopy time was similar for both (27.5 vs. 27.3 min; Std diff means = 0.12; p = 0.28). Sensitivity analyses revealed a shift in favor of CCA with large tip size catheters only versus RFCA for long-term effectiveness (OR = 1.5; p = 0.09). CONCLUSIONS: Results from this meta-analysis and systematic review do not generally favor one ablation modality over another for treatment of type 1 AFL. Indeed, there is higher percent BCB at procedure and shorter procedure time with RFCA. However, chronic success and fluoroscopy time were similar for both ablation modalities. Ultimately, investigator experience, catheter costs, and patient preference may sway device selection in clinical practice.