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Background. Endothelial cells produce a number of substances, collectively termed endothelium-derived relaxing factor (EDRF), that promote local relaxation of vascular smooth muscle. Although studies have demonstrated defects in endothelium-dependent vasodilation in animal models of hypertension, atherosclerosis, and heart failure, there are only limited data from human subjects because of the difficulty in obtaining fresh vascular segments.Methods and Results. To address the hypothesis that endothelium-dependent vasodilation is attenuated in patients with heart failure, we measured forearm blood flow responses to the intra-arterial administration of methacholine, a known stimulus of EDRF release through muscarinic receptors. In 14 normal subjects, a dosage range of methacholine increased forearm blood flow by 5.26±+0.63, 10.50±0.63, and 13.22±0.86 ml/min/100 ml forearm volume (FAV); these responses were 1.98+±0.46, 5.48±0.79, and 8.50±+1.53 ml/min/100 ml FAV in 14 patients with heart failure. When pooled over all doses, the responses were strikingly less in the patients with heart failure (5.32+±0.31 versus 9.52+±0.60 ml/min/100 ml FAV; p=0.0003). In a second study, the average difference in forearm blood flow responses between patients with heart failure and normal subjects with methacholine was significantly greater than the average difference between the groups with nitroprusside (4.04±1.10 versus 2.20±0.71 ml/min/100 ml FAV; p=0.04). The decreased methacholine responses in the patients with heart failure were not related to age (r= 0.39; p=NS) or etiology because there was no difference in the responses between patients with ischemic heart disease and those with idiopathic cardiomyopathy.Conclusions. These data suggest that endothelium-dependent vasodilation is attenuated in patients with heart failure. Although the mechanisms of the decreased endothelium-dependent responses in heart failure are not known, this impaired local vasodilation may contribute to characteristic of heart failure. (Circulation

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Chronic open-loop ART via left- or right-side VNS is feasible and well tolerated in HFrEF patients. Safety and efficacy measures are encouraging and warrant further study.

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