Background Endothelial function is impaired in coronary artery disease and may contribute to its clinical manifestations. Increased oxidative stress has been linked to impaired endothelial function in atherosclerosis and may play a role in the pathogenesis of cardiovascular events. This study was designed to determine whether endothelial dysfunction and vascular oxidative stress have prognostic impact on cardiovascular event rates in patients with coronary artery disease. Methods and Results Endothelium-dependent and -independent vasodilation was determined in 281 patients with documented coronary artery disease by measuring forearm blood flow responses to acetylcholine and sodium nitroprusside using venous occlusion plethysmography. The effect of the coadministration of vitamin C (24 mg/min) was assessed in a subgroup of 179 patients. Cardiovascular events, including death from cardiovascular causes, myocardial infarction, ischemic stroke, coronary angioplasty, and coronary or peripheral bypass operation, were studied during a mean follow-up period of 4.5 years. Patients experiencing cardiovascular events (n=91) had lower vasodilator responses to acetylcholine ( P <0.001) and sodium nitroprusside ( P <0.05), but greater benefit from vitamin C ( P <0.01). The Cox proportional regression analysis for conventional risk factors demonstrated that blunted acetylcholine-induced vasodilation ( P =0.001), the effect of vitamin C ( P =0.001), and age ( P =0.016) remained independent predictors of cardiovascular events. Conclusions Endothelial dysfunction and increased vascular oxidative stress predict the risk of cardiovascular events in patients with coronary artery disease. These data support the concept that oxidative stress may contribute not only to endothelial dysfunction but also to coronary artery disease activity.

A cute pulmonary embolism (PE) is a potentially lifethreatening disease, spanning a wide spectrum of clinical outcomes.1 Hemodynamically stable patients with preserved right ventricular (RV) size and function are classified as lowrisk patients and have an excellent short-term prognosis once therapeutic levels of anticoagulation therapy are established. 2In contrast, hemodynamically unstable patients are at high risk of death from worsening RV failure and cardiogenic shock, with a hospital mortality rate >15%. 3,4 Approximately one quarter of hemodynamically stable patients with PE are at intermediate risk, with mortality rates ranging from 3% to 15% if imaging or biomarker evidence of RV dilatation or dysfunction is present. 5,6 Editorial see p 420 Clinical Perspective on p 486Systemic thrombolysis improves hemodynamic parameters 7 and reverses RV dilatation and dysfunction 8,9 but is associated with rates of major bleeding complications in up to 20% and intracranial hemorrhage in up to 3%.10,11 Systemic thrombolysis is standard treatment for high-risk PE 2,11 ; however, it is withheld in more than two thirds of such patients. 4,12 The use of systemicBackground-In patients with acute pulmonary embolism, systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized, controlled trial investigated whether ultrasound-assisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients. Methods and Results-Fifty-nine patients (63±14 years) with acute main or lower lobe pulmonary embolism and echocardiographic RV to left ventricular dimension (RV/LV) ratio ≥1.0 were randomized to receive unfractionated heparin and an USAT regimen of 10 to 20 mg recombinant tissue plasminogen activator over 15 hours (n=30; USAT group) or unfractionated heparin alone (n=29; heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes included death, major and minor bleeding, and recurrent venous thromboembolism at 90 days. In the USAT group, the mean RV/LV ratio was reduced from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours (P<0.001); in the heparin group, mean RV/LV ratios were 1.20±0.14 and 1.17±0.20, respectively (P=0.31). The mean decrease in RV/LV ratio from baseline to 24 hours was 0.30±0.20 versus 0.03±0.16 (P<0.001), respectively. At 90 days, there was 1 death (in the heparin group), no major bleeding, 4 minor bleeding episodes (3 in the USAT group and 1 in the heparin group; P=0.61), and no recurrent venous thromboembolism. Conclusions-In