Ideal MHD Limited Electron Temperature in Spherical Tokamaks.

It is well documented that the central electron temperature in the national spherical torus experiment (NSTX) remains largely unchanged as the external heating power, and hence the normalized volume averaged plasma pressure ß increases [Stutman, Phys. Rev. Lett. 102, 115002 (2009)PRLTAO0031-900710.1103/PhysRevLett.102.115002]. Here we present a hypothesis that low n, pressure driven ideal magnetohydrodynamic (MHD) instabilities that are nondisruptive, can break magnetic surfaces in the central region and thereby flatten the electron temperature profiles. We demonstrate this mechanism in a 3D resistive MHD simulation of a NSTX discharge. By varying the toroidal magnetic field strength, and/or the heating power, we show that there is a critical value of ß, above which the central temperature profile no longer peaks on axis.

Macrophage Transcriptional Profile Identifies Lipid Catabolic Pathways That Can Be Therapeutically Targeted after Spinal Cord Injury.

Although infiltrating macrophages influence many pathological processes after spinal cord injury (SCI), the intrinsic molecular mechanisms that regulate their function are poorly understood. A major hurdle has been dissecting macrophage-specific functions from those in other cell types as well as understanding how their functions change over time. Therefore, we used the RiboTag method to obtain macrophage-specific mRNA directly from the injured spinal cord in mice and performed RNA sequencing to investigate their transcriptional profile. Our data show that at 7 d after SCI, macrophages are best described as foam cells, with lipid catabolism representing the main biological process, and canonical nuclear receptor pathways as their potential mediators. Genetic deletion of a lipoprotein receptor, CD36, reduces macrophage lipid content and improves lesion size and locomotor recovery. Therefore, we report the first macrophage-specific transcriptional profile after SCI and highlight the lipid catabolic pathway as an important macrophage function that can be therapeutically targeted after SCI.SIGNIFICANCE STATEMENT The intrinsic molecular mechanisms that regulate macrophage function after spinal cord injury (SCI) are poorly understood. We obtained macrophage-specific mRNA directly from the injured spinal cord and performed RNA sequencing to investigate their transcriptional profile. Our data show that at 7 d after SCI, macrophages are best described as foam cells, with lipid catabolism representing the main biological process and canonical nuclear receptor pathways as their potential mediators. Genetic deletion of a lipoprotein receptor, CD36, reduces macrophage lipid content and improves lesion size and locomotor recovery. Therefore, we report the first macrophage-specific transcriptional profile after SCI and highlight the lipid catabolic pathway as an important macrophage function that can be therapeutically targeted after SCI.

Evidence of Toroidally Localized Turbulence with Applied 3D Fields in the DIII-D Tokamak.

New evidence indicates that there is significant 3D variation in density fluctuations near the boundary of weakly 3D tokamak plasmas when resonant magnetic perturbations are applied to suppress transient edge instabilities. The increase in fluctuations is concomitant with an increase in the measured density gradient, suggesting that this toroidally localized gradient increase could be a mechanism for turbulence destabilization in localized flux tubes. Two-fluid magnetohydrodynamic simulations find that, although changes to the magnetic field topology are small, there is a significant 3D variation of the density gradient within the flux surfaces that is extended along field lines. This modeling agrees qualitatively with the measurements. The observed gradient and fluctuation asymmetries are proposed as a mechanism by which global profile gradients in the pedestal could be relaxed due to a local change in the 3D equilibrium. These processes may play an important role in pedestal and scrape-off layer transport in ITER and other future tokamak devices with small applied 3D fields.

Self-Organized Stationary States of Tokamaks.

We demonstrate that in a 3D resistive magnetohydrodynamic simulation, for some parameters it is possible to form a stationary state in a tokamak where a saturated interchange mode in the center of the discharge drives a near helical flow pattern that acts to nonlinearly sustain the configuration by adjusting the central loop voltage through a dynamo action. This could explain the physical mechanism for maintaining stationary nonsawtoothing "hybrid" discharges, often referred to as "flux pumping."

Observation of a multimode plasma response and its relationship to density pumpout and edge-localized mode suppression.

Density pumpout and edge-localized mode (ELM) suppression by applied n=2 magnetic fields in low-collisionality DIII-D plasmas are shown to be correlated with the magnitude of the plasma response driven on the high-field side (HFS) of the magnetic axis but not the low-field side (LFS) midplane. These distinct responses are a direct measurement of a multimodal magnetic plasma response, with each structure preferentially excited by a different n=2 applied spectrum and preferentially detected on the LFS or HFS. Ideal and resistive magneto-hydrodynamic (MHD) calculations find that the LFS measurement is primarily sensitive to the excitation of stable kink modes, while the HFS measurement is primarily sensitive to resonant currents (whether fully shielding or partially penetrated). The resonant currents are themselves strongly modified by kink excitation, with the optimal applied field pitch for pumpout and ELM suppression significantly differing from equilibrium field alignment.

Pedestal bifurcation and resonant field penetration at the threshold of edge-localized mode suppression in the DIII-D Tokamak.

Rapid bifurcations in the plasma response to slowly varying n=2 magnetic fields are observed as the plasma transitions into and out of edge-localized mode (ELM) suppression. The rapid transition to ELM suppression is characterized by an increase in the toroidal rotation and a reduction in the electron pressure gradient at the top of the pedestal that reduces the perpendicular electron flow there to near zero. These events occur simultaneously with an increase in the inner-wall magnetic response. These observations are consistent with strong resonant field penetration of n=2 fields at the onset of ELM suppression, based on extended MHD simulations using measured plasma profiles. Spontaneous transitions into (and out of) ELM suppression with a static applied n=2 field indicate competing mechanisms of screening and penetration of resonant fields near threshold conditions. Magnetic measurements reveal evidence for the unlocking and rotation of tearinglike structures as the plasma transitions out of ELM suppression.

Tokamak operation with safety factor q95 < 2 via control of MHD stability.

Magnetic feedback control of the resistive-wall mode has enabled the DIII-D tokamak to access stable operation at safety factor q(95) = 1.9 in divertor plasmas for 150 instability growth times. Magnetohydrodynamic stability sets a hard, disruptive limit on the minimum edge safety factor achievable in a tokamak, or on the maximum plasma current at a given toroidal magnetic field. In tokamaks with a divertor, the limit occurs at q(95) = 2, as confirmed in DIII-D. Since the energy confinement time scales linearly with current, this also bounds the performance of a fusion reactor. DIII-D has overcome this limit, opening a whole new high-current regime not accessible before. This result brings significant possible benefits in terms of fusion performance, but it also extends resistive-wall mode physics and its control to conditions never explored before. In present experiments, the q(95) < 2 operation is eventually halted by voltage limits reached in the feedback power supplies, not by intrinsic physics issues. Improvements to power supplies and to control algorithms have the potential to further extend this regime.

Observations of heteroclinic bifurcations in resistive magnetohydrodynamic simulations of the plasma response to resonant magnetic perturbations.

A class of topological magnetic island bifurcations that has not previously been observed in toroidal plasmas is described. Increasing an externally applied three-dimensional magnetic field in resistive magnetohydrodynamic simulations results in the asymmetric elongation of resonant island flux surfaces followed by a sequence of heteroclinic bifurcations. These bifurcations produce new sets of hyperbolic-elliptic fixed points as predicted by the Poincaré-Birkoff fixed point theorem. Field line calculations verify that the new fixed points do not connect to those of the prebifurcated islands as required for heteroclinic bifurcations on a torus with winding numbers composed of common integer factors.

Independent risk factors for long-term skeletal relapse after mandibular advancement with bilateral sagittal split osteotomy.

The purpose of this retrospective cohort study was to identify the independent risk factors for long-term skeletal relapse following mandibular advancement with bilateral sagittal split osteotomy. Univariate and multivariate linear regression analyses were performed including nine common risk factors for relapse as independent variables and horizontal/vertical long-term (≥2 years) skeletal relapse as dependent variables. Ninety-six patients were analyzed; 66 were female (68.8%) and the average age of the patients was 29.7±10.5 years. Over an average follow-up of 3.8±1.8 years after an initial mandibular advancement of 8.8±2.4 mm, long-term skeletal relapse of 1.6±1.0 mm horizontal and 0.9±0.7 mm vertical was found. Multivariate analysis identified age, preoperative mandibular plane angle (MPA), bimaxillary surgery, counterclockwise mandibular rotation, and the magnitude of mandibular advancement to be significantly associated with horizontal long-term skeletal relapse. Preoperative MPA, counterclockwise mandibular rotation, and the magnitude of mandibular advancement were significantly associated with vertical long-term skeletal relapse. Thus preoperative MPA, the magnitude of mandibular advancement, and counterclockwise mandibular rotation of the mandible were found to be independent risk factors for both horizontal and vertical long-term skeletal relapse. Although long-term skeletal relapse cannot be avoided entirely, understanding the independent risk factors and their contributions will optimize treatment planning and long-term stability.

Effect of the renin-angiotensin system on limb circulation and metabolism during exercise in patients with heart failure.

The maximal aerobic exercise capacity of patients with chronic heart failure is frequently decreased because of inadequate blood flow to working skeletal muscle. To investigate whether this reduced flow is in part due to interference by angiotensin II with arteriolar dilation in working muscle, the effect of the angiotensin-converting enzyme inhibitor captopril on leg blood flow, leg vascular resistance, leg oxygen consumption (VO2) and leg lactate release during maximal upright bicycle exercise was examined in 12 patients with heart failure (maximal VO2 10.7 +/- 3.1 ml/min per kg). Captopril decreased leg resistance at rest (258 +/- 115 to 173 +/- 67 U, p less than 0.01) and maximal exercise (68 +/- 69 to 45 +/- 29 U, p less than 0.01) associated with proportionately similar decreases in systemic vascular resistance. However, maximal exercise duration and maximal VO2 were unchanged and, at identical peak exercise work times, there was no improvement in leg blood flow (2.0 +/- 0.9 to 2.0 +/- 1.1 liters/min, p = NS), leg VO2 (261 +/- 104 to 281 +/- 157 ml/min, p = NS) or leg lactate release (269 +/- 149 to 227 +/- 151 mg/min, p = NS). These data suggest that, during exercise in patients with heart failure, angiotensin II does not interfere with blood flow to working skeletal muscle.

Respiratory muscle deoxygenation during exercise in patients with heart failure demonstrated with near-infrared spectroscopy.

Exertional dyspnea in patients with heart failure may be due, in part, to respiratory muscle underperfusion. Near-infrared spectroscopy is a new technique that permits noninvasive assessment of skeletal muscle oxygenation by monitoring changes in near-infrared light absorption. With use of near-infrared spectroscopy, serratus anterior muscle oxygenation during maximal bicycle exercise was compared in 10 patients with heart failure (ejection fraction 16 +/- 5%) and 7 age-matched normal subjects. Oxygen consumption (VO2), minute ventilation (VE) and arterial saturation were also measured. Changes in difference in absorption between 760 and 800 nm, expressed in arbitrary units, were used to detect muscle deoxygenation. Minimal change in this difference in absorption occurred in normal subjects during exercise, whereas patients with heart failure exhibited progressive changes throughout exercise consistent with respiratory muscle deoxygenation (peak exercise: normal 3 +/- 6, heart failure 12 +/- 4 near-infrared arbitrary units, p less than 0.001). At comparable work loads patients with heart failure had significantly greater minute ventilation and respiratory rate but similar tidal volume when contrasted with normal subjects. However, at peak exercise normal subjects achieved significantly greater minute ventilation and tidal volume with a comparable respiratory rate. No significant arterial desaturation occurred during exercise in either group. These findings indicate that respiratory muscle deoxygenation occurs in patients with heart failure during exercise. This deoxygenation may contribute to the exertional dyspnea experienced by such patients.

Effect on peripheral arterioles of chronic fluid and sodium retention in heart failure.

To determine whether chronic fluid and sodium retention in heart failure adversely affects peripheral arteriolar behavior, systemic vascular resistance and skeletal muscle vasodilation were compared in eight control dogs and nine dogs with chronic fluid and sodium retention (ascites = 2.3 +/- 2.3 liters) induced by rapid ventricular pacing for 2 months. At rest, both groups exhibited comparable systemic vascular resistance (control 45 +/- 14 versus heart failure 40 +/- 7 U) and femoral bed vascular resistance (control 18.7 +/- 6.9 versus heart failure 19.0 +/- 7.2 x 10(2) U) (both p = NS). Femoral bed resistance also decreased similarly in both groups during treadmill exercise (resistance at peak exercise: control 4.7 +/- 3.0 versus heart failure 4.9 +/- 0.9 x 10(2) U [p = NS]). In isolated gracilis muscle, vascular resistance was also comparable in both groups at rest (control 7.3 +/- 3.3 versus heart failure 10.2 +/- 3.6 x 10(3) U/100 g), at peak exercise (control 1.6 +/- 0.5 versus heart failure 1.8 +/- 0.9 x 10(3) U/100 g) and after maximal vasodilation with papaverine (control 0.7 +/- 0.3 versus heart failure 0.9 +/- 0.3 x 10(3) U/100 g) (all p = NS). These data suggest that chronic fluid and sodium retention in heart failure does not alter peripheral arteriolar behavior.

Effect of dichloroacetate on the exercise performance of patients with heart failure.

The reduced maximal exercise capacity of patients with heart failure has been attributed to skeletal muscle underperfusion with resultant intramuscular lactic acidosis and muscular fatigue. To investigate this hypothesis, the effect of dichloroacetate, a drug that decreases lactate formation by increasing pyruvate oxidation, on the maximal exercise performance of 18 patients with heart failure and reduced ejection fraction (25 +/- 9%) was examined. Exercise tests after parenteral dextrose (control) and dichloroacetate were performed 1 week apart. The sequence of interventions was randomized in a double-blind manner. Dichloroacetate decreased blood lactate at rest (control 8.0 +/- 2.5 versus dichloroacetate 5.6 +/- 2.9 mg/dl), throughout exercise and at peak exercise (control 26.0 +/- 14.3 versus dichloroacetate 19.4 +/- 10.8) (all p less than 0.05). In contrast, dichloroacetate had no effect on exercise time (control 15.2 +/- 6.0 versus dichloroacetate 15.9 +/- 6.2 min) or peak exercise oxygen consumption (control 1,280 +/- 498 ml/min versus dichloroacetate 1,312 +/- 530 ml/min) (both p = NS). In six subjects, dichloroacetate also had no effect at peak exercise on leg blood flow (control 2.8 +/- 1.1 versus dichloroacetate 3.0 +/- 0.6 liters/min) or femoral oxygen vein saturation (control 12.7 +/- 4.1% versus dichloroacetate 12.5 +/- 5.7%). These data suggest that intramuscular lactate accumulation is not responsible for muscular fatigue during exercise in patients with heart failure.

Effect of hydralazine on nutritive flow to working canine gracilis skeletal muscle.

The direct smooth muscle vasodilator hydralazine has been used to treat exertional fatigue in patients with chronic heart failure. However, prior studies suggest that arteriolar vasodilators such as hydralazine may actually impair nutritive flow to working skeletal muscle by interfering with the distribution of blood flow within muscle. To investigate this possibility, tension development and metabolism were measured in nine vascularly isolated gracilis muscle preparations perfused at 90 mm Hg and stimulated to contract progressively at rates of 1, 3 and 6/s with each stage lasting 3 minutes. Studies were then repeated after 30 minutes of intraarterial hydralazine (0.02 to 0.12 mg/min). At rest, hydralazine decreased mean vascular resistance (+/- SEM) from 15.1 +/- 1.4 to 8.6 +/- 0.9 X 10(2) units (p less than 0.001) and increased blood flow from 6.4 +/- 0.7 to 11.4 +/- 1.2 ml/min (p less than 0.001), but did not change oxygen consumption (VO2) control, 18 +/- 1 versus hydralazine, 17 +/- 2 microliter/min). Hydralazine also decreased vascular resistance and increased flow at a contraction rate of 1/s, but not at 3 and 6/s. Hydralazine had no effect on maximal VO2 (control, 254 +/- 18 versus hydralazine, 236 +/- 19 microliter/min), maximal developed tension (control, 353 +/- 90 versus hydralazine, 334 +/- 74 kg X min) or the response in venous lactate (control, 20.6 +/- 2.3 versus hydralazine, 18.1 +/- 2.0 mg/dl). Hydralazine also did not change muscle metabolism and function at contraction rates of 1 and 3/s. These data suggest that hydralazine does not adversely affect nutritive flow to working skeletal muscle.

Effect of atrial pacing on intracoronary thromboxane production in coronary artery disease.

The effect of atrial pacing on intracoronary thromboxane production was investigated in 35 patients with stable (n = 19) or unstable (n = 16) angina. Arterial and coronary sinus thromboxane B2, the stable metabolite of thromboxane A2, myocardial lactate extraction and thermodilution coronary sinus flow were measured before, during and immediately after atrial pacing until the onset of angina. Pacing did not significantly increase coronary sinus thromboxane B2 (rest, 233 +/- 107 pg/ml; pacing, 249 +/- 154 pg/ml; postpacing, 330 +/- 309 pg/ml) (mean +/- standard deviation) despite a moderate increase in arterial thromboxane B2 (rest, 270 +/- 170 pg/ml; pacing, 387 +/- 364 pg/ml; postpacing, 446 +/- 420 pg/ml) (all changes probability [p] less than 0.05). A positive transmyocardial thromboxane B2 gradient, suggesting intracoronary thromboxane A2 production, occurred in only five patients at rest (gradient = 60 +/- 35 pg/ml). During pacing, a transmyocardial thromboxane B2 gradient was not observed despite myocardial lactate production in 18 patients. A postpacing gradient was observed in eight patients (gradient = 284 +/- 349 pg/ml). These gradients were significantly more frequent in patients who produced lactate during pacing (7 of 18) than in patients without lactate production (1 of 17) (p less than 0.05). In patients with and without a postpacing gradient, coronary vascular resistance decreased with pacing and returned to rest levels immediately after pacing, suggesting that a postpacing thromboxane gradient does not significantly alter coronary tone. These data suggest that: 1) pacing-induced angina is usually not associated with substantial intracoronary thromboxane A2 production; 2) in a minority of patients who develop intracoronary thromboxane A2 production, the amount is small and does not produce significant coronary vasoconstriction.

Circulatory improvement after hydralazine or isosorbide dinitrate administration in patients with heart failure. Effect on metabolic responses to submaximal exercise.

Hydralazine and isosorbide dinitrate can increase the cardiac output during submaximal exercise in patients with heart failure but whether this increase improves oxygen delivery to underperfused exercising muscle is uncertain. To investigate this question, we measured three systemic markers of skeletal muscle oxygen availability--exercise VO2, mixed venous lactate concentration and oxygen debt--during submaximal exercise in 15 patients with heart failure both before after hydralazine (nine patients) or isosorbide dinitrate (eight patients) administration. Hydralazine increased the cardiac output during exercise from 4.9 +/- 1.2 liter/min to 6.5 +/- 1.8 liter/min (p less than 0.01) but had no effect on exercise VO2 (control, 531 +/- 135 ml/min; hydralazine, 489 +/- 102 ml/min), peak lactate concentration (control, 18.3 +/- 4.2 mg/dl; hydralazine, 17.9 +/- 3.6 mg/dl) or oxygen debt (control, 474 +/- 213 ml; hydralazine, 465 +/- 170 ml) (all p greater than 0.10). Isosorbide dinitrate increased the cardiac output during exercise from 4.6 +/- 0.9 liter/min to 5.3 +/- 0.8 liter/min (p less than 0.01) but also did not change exercise VO2 (control, 488 +/- 62 ml/min; isosorbide, 473 +/- 44 ml/min), peak lactate concentration (control, 19.2 +/- 6.0 mg/dl; isosorbide, 21.4 +/- 8.2 mg/dl) or oxygen debt (control, 522 +/- 154 ml; isosorbide, 445 +/- 147 ml) (all p less than 0.10). We conclude that short-term administration of hydralazine or nitrates to patients with heart failure can substantially improve circulatory function during exercise but that this improvement probably does not enhance skeletal muscle nutritional flow.

Exercise intolerance in patients with chronic left heart failure: relation to oxygen transport and ventilatory abnormalities.

Circulatory, metabolic, and ventilatory responses to maximal and submaximal symptom-limited exercise were studied in 13 patients with chronic stable heart failure. Maximal exercise was sustained 6.5 +/- 0.6 minutes (mean +/- standard error of the mean) and increased minute oxygen consumption (VO2) to 940 +/- 65 ml/min, whereas submaximal exercise was sustained for 15.4 +/- 2.3 minutes and increased VO2 to 825 +/- 49 ml/min (both p less than 0.01 compared with maximal exercise). Both exercise protocols were terminated because of fatigue and both were associated with reduced cardiac output relative to VO2, marked systemic oxygen extraction (80 +/- 2% maximal versus 78 +/- 2% submaximal) and similarly elevated blood lactate concentrations (37 +/- 4 mg/dl maximal versus 36 +/- 4 mg/dl submaximal), suggesting inadequate oxygen delivery to working muscle. Minute ventilation during both types of exercise was also more than twice normal relative to carbon dioxide production. However, during submaximal exercise, dyspnea was noted in only 3 patients despite these ventilatory abnormalities. During maximal exercise, dyspnea was noted in 11 patients but did not force termination of exercise or preclude achievement of marked systemic oxygen extraction and lactate production. These data suggest that patients with chronic stable cardiac failure are limited during both maximal and submaximal exercise primarily by inadequate oxygen transport to working muscle.

Exercise ventilation and pulmonary artery wedge pressure in chronic stable congestive heart failure.

In patients with chronic heart failure (CHF), physical exertion frequently is associated with higher than normal ventilatory levels and dyspnea. To determine the prevalence of such excessive ventilatory responses in CHF and whether this excessive ventilation is a result of acute increases in intrapulmonary pressure during exercise, minute ventilation (VE) and pulmonary artery (PA) wedge pressure were measured during maximal bicycle exercise in 38 patients with chronic CHF. It was then determined whether reducing the PA wedge pressure during exercise with prazosin (9 patients) or dobutamine (6 patients) reduced ventilatory levels toward normal. To compare ventilation between patients, VE was correlated with minute carbon dioxide production (VCO2) (r greater than or equal to 0.90); the calculated VE at a VCO2 of 1 liter/min (VE-CO2) was derived from this relation and used as a normalized index of ventilation. During exercise, VE-CO2 ranged from 27 to 71 liters/min, exceeding the normal range in 37 of 38 patients (normal 33 liters/min or less). VE-CO2 did not correlate with peak exercise PA wedge pressure and correlated only weakly with PA wedge pressure at rest (r = 0.48). Acute reduction in the PA wedge pressure during exercise with prazosin or dobutamine did not significantly reduce VE-CO2. These data suggest that ventilatory levels are frequently excessive during exercise in patients with CHF and therefore may provide a useful, objective index of their altered pulmonary function. In addition, our data suggest that this excessive ventilation is not a result of acute changes in intrapulmonary pressure during exercise.

Respiratory gas analysis during exercise as a noninvasive measure of lactate concentration in chronic congestive heart failure.

Measurement of blood lactate during exercise in patients with chronic congestive heart failure provides a useful index of oxygen (O2) availability in working muscle. Bicarbonate buffering of lactate produces carbon dioxide (CO2) in excess of that resulting from oxidative metabolism. Therefore, calculation of excess CO2 production from measured CO2 production and O2 uptake may offer a noninvasive quantitative index of changes in blood lactate during exercise in these patients. To investigate this possibility, 22 patients with congestive heart failure and depressed left ventricular function were studied during progressive maximal upright bicycle exercise. Oxygen uptake, expired carbon dioxide, arterial lactate, O2 extraction, and cardiac output were measured at each 20 W incremental work load and peak exercise. Exercise increased VO2 from 3.5 +/- 0.9 ml/min/kg at rest to 13.1 +/- 2.9 ml/min/kg, O2 extraction from 49 +/- 9% at rest to 78 +/- 6%, lactate from 12 +/- 5 mg/dl at rest to 41 +/- 15 mg/dl, and cardiac index from 1.7 +/- 0.4 at rest to 3.8 +/- 1.2 liters/min/m2. The increase in lactate at each work load was linearly related to excess CO2 production (r = 0.92, p less than 0.01). Exercise was repeated the following day in 10 patients; measurements of excess CO2 production was highly reproducible (r = 0.98, p less than 0.01). Excess CO2 production also correlated with the decrease in bicarbonate produced by exercise (r = 0.81), supporting the hypothesis that excess CO2 is produced by bicarbonate buffering of lactate. Thus, calculation of excess carbon dioxide production from noninvasive measurement of respiratory gas exchange provides a reliable and reproducible method of continuously assessing alterations in lactate throughout bicycle exercise in patients with chronic congestive heart failure.

Impaired skeletal muscle nutritive flow during exercise in patients with congestive heart failure: role of cardiac pump dysfunction as determined by the effect of dobutamine.

The maximal exercise capacity of patients with congestive heart failure (CHF) is frequently reduced, partly because of inadequate skeletal muscle nutritive flow. To investigate whether this altered muscle nutritive flow is a result of inability of the heart to increase cardiac output normally during exercise, the effect of dobutamine on systemic and leg blood flow and metabolism during maximal exercise was examined in 11 patients with CHF. At maximal exercise before dobutamine, all patients were limited by fatigue and had reduced maximal systemic oxygen uptake (11.9 +/- 1.1 ml/min/kg) (+/- standard error of the mean), markedly elevated leg oxygen extraction (85 +/- 2%) and elevated femoral venous lactate (53 +/- 5 mg/dl), consistent with impaired nutritive flow to working muscle. Dobutamine increased the peak cardiac output from (6.5 +/- 0.9 0.74 +/- 0.7 liters/min, p less than 0.01) and peak leg flow (from 1.7 +/- 0.3 to 2.1 +/- 0.3 liters/min, p less than 0.05) during exercise. In contrast, no change occurred in maximal exercise duration (5.5 +/- 0.8 vs 5.8 +/- 0.8 min), peak systemic VO2 (829 +/- 97 vs 869 +/- 77 ml/min), peak arterial lactate (34 +/- 2 vs 35 +/- 4 mg/dl) or peak leg lactate output (248 +/- 39 vs 275 +/- 53 mg/min), whereas peak leg oxygen extraction decreased (85 +/- 2 to 80 +/- 2%, p less than 0.01), suggesting no improvement in muscle nutritive flow. These data suggest that nutritive flow to working skeletal muscle is impaired in patients with CHF and that this impairment is not due simply to an inability of the heart to increase the cardiac output normally during exercise.