Background-Endothelial function is known to be impaired in subjects with chronic heart failure (CHF), but the association between endothelial function and subsequent mortality risk in CHF has not been previously reported. Methods and Results-Biomarkers of endothelial function in the systemic arterial circulation (flow-mediated dilation [FMD] in the brachial artery) and the pulmonary circulation (exhaled nitric oxide [NO] production during submaximal exercise) were prospectively assessed in 259 subjects with New York Heart Association class II-III CHF. In subjects with FMD measurements (nϭ149), there were 12 deaths and 5 urgent transplantations over a median follow-up period of 841 days. In subjects with exhaled NO production measurements (nϭ110), there were 18 deaths and 1 urgent transplantation over a median follow-up period of 396 days. Both decreased FMD and decreased exhaled NO production were associated with increased risk of death or urgent transplantation after adjustment for other known CHF prognostic

These findings support an independent role of Lp(a) in atherogenesis, an effect that is particularly evident in African Americans. The proatherogenic property of Lp(a) can be attributed in part to its apo(a) component.

ACE (angiotensin-converting enzyme) inhibitors and PDE5 (phosphodiesterase type 5) inhibitors have each been reported to improve endothelial function in cardiovascular disease patients, but the comparative and combined effects of these two classes have not been studied previously. We sought to characterize the acute effects of ramipril alone, sildenafil alone, or their combination on endothelial function in patients with CHF (chronic heart failure). CHF subjects (n=64) were randomized to receive placebo, 10 mg of ramipril alone, 50 mg of sildenafil alone or a combination of ramipril and sildenafil in a double-blind manner. FMD (flow-mediated dilation) of the brachial artery was determined by high-resolution ultrasound imaging before and at 1, 2 and 4 h after administration of the study drug. Ramipril alone increased FMD at 4 h compared with placebo (+2.3+/-1.3%, P=0.02). Sildenafil alone increased FMD at 1, 2 and 4 h compared with placebo (+3.9+/-1.4, +4.6+/-1.8 and +3.7+/-1.3% respectively, all P<0.02). Sildenafil in combination with ramipril increased FMD at 1, 2 and 4 h when compared with placebo (+3.5+/-1.5, +4.5+/-1.8 and +4.8+/-1.3% respectively, all P<0.03). Ramipril and sildenafil both acutely improved FMD in patients with CHF, with additive effects evident at 4 h during combination therapy. Therefore further work to characterize chronic effects of combined ACE and PDE5 inhibition on endothelial function are warranted.

Objective-Dexrazoxane is an antioxidant prodrug that on hydrolysis is converted into an intracellular iron chelator. We hypothesized that the antioxidant effects of dexrazoxane would prevent homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. Methods and Results-Ten healthy volunteers completed a randomized, double-blind, crossover study. Plasma homocysteine levels and brachial artery endothelium-dependent (flow-mediated dilation [FMD]) and endothelium-independent (sublingual nitroglycerin) responses were measured before and 4 hours after ingestion of L-methionine (100 mg/kg), preceded by intravenous administration of dexrazoxane (500 mg/m 2 ) or placebo over 30 minutes. After placebo, oral methionine increased plasma homocysteine (from 5.1Ϯ0.4 mol/L at baseline to 14.2Ϯ1.3 mol/L at 4 hours, PϽ0.001) and decreased FMD (from 3.8Ϯ0.7% at baseline to 1.2Ϯ0.5% at 4 hours, Pϭ0.02). Dexrazoxane did not change homocysteine concentrations after methionine administration (14.9Ϯ1.1 mol/L at 4 hours, Pϭ0.29 versus placebo) but did completely abrogate the homocysteine-induced reduction in FMD (from 3.5Ϯ0.5% at baseline to 5.9Ϯ1.1% at 4 hours, PϽ0.01 versus placebo). Endothelium-independent responses to sublingual nitroglycerin did not differ after the administration of placebo and dexrazoxane. Key Words: methionine Ⅲ vascular endothelium Ⅲ oxidative stress Ⅲ chelation Ⅲ iron L ow molecular weight ferrous iron (LMW-Fe 2ϩ ) catalyzes the production of hydroxyl radicals from hydrogen peroxide in the Fenton reaction. 1 The hydroxyl radical is a highly reactive species that leads to lipid peroxidation, oxidative damage of DNA, cell dysfunction, and death. 2 Dexrazoxane (ICFR-187), a cyclic derivative of the chelating agent EDTA, is approved by the Federal Drug Administration for the prevention of anthracycline cardiotoxicity in humans. In contrast to EDTA and deferoxamine, dexrazoxane is membrane permeable and chelates LMW-Fe 2ϩ in the intracellular space, where hydrolysis of 2 imide bonds activates its binding sites. 3 The cardioprotective action of dexrazoxane is due to its high-affinity binding of intracellular LMW-Fe 2ϩ , which reduces the formation of anthracycline-iron complexes and the consequent generation of hydroxyl radical and other toxic reactive oxygen species. 4,5 Hyperhomocysteinemia induced by oral methionine ingestion in normal subjects is associated with increased oxidant stress and transient vascular endothelial dysfunction. 6 -8 The present study was undertaken to test the hypothesis that the antioxidant effects of dexrazoxane would prevent vascular endothelial dysfunction induced by homocysteine in the brachial artery of normal human subjects in a double-blind, placebo-controlled, crossover study. Methods Study PopulationEight men and 2 women were studied. All subjects were normotensive nonsmokers with no history of chronic illness or chronic medication use. Criteria for exclusion were LDL Ͼ160 mg/dL, fasting blood sugar Ͼ110 mg/dL, plasma homocysteine Ͼ10 mol/L, an...