Endothelium-dependent vasodilation is impaired in humans with diabetes mellitus. Inactivation of endotheliumderived nitric oxide by oxygen-derived free radicals contributes to abnormal vascular reactivity in experimental models of diabetes. To determine whether this observation is relevant to humans, we tested the hypothesis that the antioxidant, vitamin C, could improve endothelium-dependent vasodilation in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus. We studied 10 diabetic subjects and 10 age-matched, nondiabetic control subjects. Forearm blood flow was determined by venous occlusion plethysmography. Endothelium-dependent vasodilation was assessed by intraarterial infusion of methacholine (0.3-10 g/min). Endothelium-independent vasodilation was measured by intraarterial infusion of nitroprusside (0.3-10 g/min) and verapamil (10-300 g/min). Forearm blood flow dose-response curves were determined for each drug before and during concomitant intraarterial administration of vitamin C (24 mg/min). In diabetic subjects, endothelium-dependent vasodilation to methacholine was augmented by simultaneous infusion of vitamin C ( P ϭ 0.002); in contrast, endothelium-independent vasodilation to nitroprusside and to verapamil were not affected by concomitant infusion of vitamin C ( P ϭ 0.9 and P ϭ 0.4, respectively). In nondiabetic subjects, vitamin C administration did not alter endothelium-dependent vasodilation ( P ϭ 0.8). We conclude that endothelial dysfunction in forearm resistance vessels of patients with non-insulin-dependent diabetes mellitus can be improved by administration of the antioxidant, vitamin C. These findings support the hypothesis that nitric oxide inactivation by oxygen-derived free radicals contributes to abnormal vascular reactivity in diabetes. ( J. Clin. Invest. 1996. 97:22-28.) Key words: ascorbate • antioxidants • free radicals • endothelium-derived relaxing factor • vascular

Nitric oxide forms complexes with an array of biomolecular carriers that retain biological activity. This reactivity of nitric oxide in physiological systems has led to some dispute as to whether endothelium-derived relaxing factors nitric oxide or a closely related adduct thereof, such as a nitrosothiol. In vitro bioassays used to address this question are limited by the exclusion of biological thiols that are requisite for nitrosothiol formation. Thus, the purpose of this study was to obtain insight into the identity of endothelium-derived relaxing factor in vivo. We reasoned that if endothelium-derived relaxing factor in nitric oxide, infusion of physiological concentrations of thiol would potentiate its bioactivity by analogy with effects seen in vitro, whereas nitrosothiol would be resistant to such modulation. We used venous-occlusion plethysmography to study forearm blood flow in normal subjects. Methacholine (0.3 to 10 micrograms/min) and nitroglycerin (1 to 30 micrograms/min) were infused via the brachial artery to elicit endothelium-dependent and endothelium-independent vasodilation, respectively. Dose-response determinations were made for each drug before and after an intra-arterial infusion of the reduced thiol, N-acetylcysteine, at rates estimated to achieve a physiological concentration of 1 mmol/L. Methacholine increased forearm blood flow in a dose-dependent manner. Infusion of N-acetylcysteine did not change the sensitivity (ED50, 1.7 versus 1.7 micrograms/min, P = NS) or maximal response to methacholine. In contrast, thiol increased the sensitivity to nitroglycerin (ED50, 4.7 versus 2.8 micrograms/min, P < .01). Thus, conflicting with reports in vitro, thiol does not modulate endothelium-derived relaxing factor responses in vivo. These data indicate that sulfhydryl groups are not a limiting factor for endothelium-derived relaxing factor responses in forearm resistance vessels in normal humans and are in keeping with reports that nitrosothiol contributes to endothelium-derived relaxing factor bioactivity in plasma and vascular smooth muscle. Potentiation of the effects of nitroglycerin by N-acetylcysteine can be attributed to its enhanced biotransformation to an endothelium-derived relaxing factor equivalent, such as nitrosothiol. These observations support the notion of an equilibrium between nitric oxide and nitrosothiol in biological systems that may be influenced by redox state.

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Background: A variety of devices exist for endovascular aneurysm repair (EVAR) of abdominal aneurysms. Device-specific instructions for use (IFU) detail anatomic constraints to application and deployment of devices and are developed from rigorous bench testing. Nonadherence to IFU occurs frequently to avoid open surgery. The purpose of this study was to determine if IFU violations are associated with increased risk of device failure during follow-up.Methods: This multicenter retrospective observational study included patients undergoing elective endovascular repair for abdominal aneurysmal disease with up to six different devices. Demographics, anatomic data, and follow-up data were collected on all patients from 2005 to 2014. IFU violations were device specific and included neck diameter, length, and angulation and iliac diameter and length. Device failure included a composite outcome of reintervention, migration, endoleak (type II excluded), rupture, limb occlusion, sac growth, and aneurysm-related mortality during the followup period. Kaplan-Meier survival analysis and Cox proportional hazard modeling were performed. Any IFU violations as well as neck-specific IFU violations were analyzed.Results: In 468 patients undergoing EVAR, 49% had at least one IFU violation. Patients with IFU violations appeared to be older (age >80 years, 41.8% vs 31.1%), were more likely to have peripheral vascular disease (13.8% vs 5.9%), and were less likely to be male (78.9% vs 92%). The most frequent IFU violations included diameter deviations of the neck (16.3%) and of the iliac (22.1%), whereas length violation of the neck and the iliac occurred with less frequency, 5.8% and 3.2%, respectively. Overall device failure rate was 12.9%. Mean follow-up time was 1.9 and 2.1 years for patients with and without an IFU violation, respectively. Kaplan-Meier survival analysis revealed a significant association between the presence of an IFU violation and device failure (log-rank, P ¼ .02; Fig). When adjusted for clinical variables through Cox hazard modeling, the association remained significant (hazard ratio, 1.7; 95% confidence interval, 1.0-2.9). When neck-specific violations were considered independently, Kaplan-Meier survival analysis and Cox modeling revealed a significant association between neck-specific IFU violation and device failure (log-rank, P ¼ .0005; hazard ratio, 1.9; 95% confidence interval, 1. Fig).Conclusions: Almost half of the patients undergoing EVAR had a device-specific IFU violation, indicating that implanters are pushing the boundaries of device capabilities. Our study identified that any IFU violation was significantly associated with device failure over time. Caution should be applied to patients being considered for EVAR where IFU deviations exist.