Aims Continuous‐flow left ventricular assist device (CF‐LVAD) implantation is associated with improved quality of life, but the effect on exercise capacity is less well documented. It is uncertain whether a fixed CF‐LVAD pump speed, which allows for sufficient circulatory support at rest, remains adequate during exercise. The aim of this study was to evaluate the effects of fixed versus incremental pump speed on peak oxygen uptake (peak VO2) during a maximal exercise test. Methods and results In CF‐LVAD (HeartMate II) patients exercise testing measuring peak oxygen uptake (VO2) was performed on an ergometer bike twice in one day: once with fixed pump speed (testfix) and once with incremental pump speed (testinc). The order of testfix and testinc in each patient was determined by randomization. During testinc pump speed was increased from the baseline value by 400 rpm/2 min. Fourteen patients (aged 23–69 years) were included with a mean support duration of 465 ± 483 days. Baseline CF‐LVAD speed was 9357 ± 238 rpm and during testinc speed was increased by a mean of 1486 ± 775 rpm. Mean peak VO2 was significantly higher in testinc compared with testfix (15.4 ± 5.9 mL/kg/min vs. 14.1 ± 6.3 mL/kg/min; P = 0.012), corresponding to a 9.2% increase. All exercise tests (n = 28) were adequately performed with RER > 1. Conclusion Increasing pump speed during exercise augments peak VO2 in patients supported with CF‐LVADs. An automatic speed‐change function in future generations of CF‐LVADs might improve functional capacity.

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Results from in vitro experiments suggest that development of nitrate tolerance is due to a depletion of vascular thiol compounds (ie, cysteine and glutathione [GSH]) necessary for the bioconversion of organic nitrates. However, it is unknown whether in vivo tolerance development is associated with changes in thiol levels. This study measures plasma and vessel tissue GSH and cysteine levels in nontolerant rats, nitratetolerant rats, and rats treated with the two characteristically different thiol donors N-acetyl-L-cysteine and L-2-oxothiazolidine-4-carboxylic acid (OXO). Chronically catheterized conscious rats received an intravenous infusion of either nitroglycerin (NTG, 0.2 mg/h) or matching placebo for 3 days. At day 3, the hypotensive effect of 2.5 mg NTG/kg was decreased by 74+6% (mean±SEM, P<.05) (n=6, P>.05). Hemodynamic tolerance is not associated with changes in aorta cysteine or GSH levels as compared with the placebo group (cysteine, 77±14 versus 57±11 [mean+SEM] nmol/g; GSH, 414±62 versus 399±89 nmol/g; P>.05). However, the increase in vascular thiol levels seen after OXO treatment in nontolerant rats is completely absent in nitratetolerant animals. The results suggest that (1) depletion of vascular cysteine and/or GSH is apparently not the mechanism underlying development of nitrate tolerance in vivo, and (2) the metabolic handling of thiol compounds and/or the activity of enzymes that act on these thiols is altered during the development of nitrate tolerance in vivo. (Circ Res. 1994;74: 115-120.) Key Words * nitroglycerin * cysteine * glutathionenitrate tolerance known whether "thiol depletion" occurs during the development of tolerance in vivo.The present study was carried out to determine whether or not tolerance to NTG is associated with changes in thiol levels in vivo. Plasma and vascular cysteine and GSH levels in normal and nitrate-tolerant rats were compared. In addition, the effects of two potent, but characteristically different, thiol donors on thiol levels and NTG hemodynamics were also investigated. Material and Methods GSH and Thiol MetabolismGSH is found almost exclusively intracellularly, where it constitutes the major nonprotein thiol pool. GSH is synthesized intracellularly from cysteine, glutamate, and glycine by the consecutive actions of y-glutamylcysteine synthetase and GSH synthetase.9 Cysteine is rapidly metabolized, and GSH serves as a storage and transport form of cysteine.10 y-Glutamylcysteine synthetase is the rate-limiting step in GSH synthesis and is feedback-inhibited by the product of the pathway, GSH.9,11 Availability of substrates, especially cysteine, may also regulate cellular GSH levels.Cysteine and GSH levels may be increased by several methods. N-Acetyl-L-cysteine (NAC) leads to increased plasma and cellular cysteine levels after deacetylation.9'12 L-2-Oxothiazolidine-4-carboxylic acid (OXO) is a nonthiol nontoxic cysteine delivery drug that is readily transported into cells and converted into cysteine by 5-oxoprolinase.9 13Thus, whereas NAC has both intra...