Evidence of reduced respiratory muscle endurance in patients with heart failure.

OBJECTIVES: We sought to investigate whether reduced respiratory muscle endurance contributes to increased dyspnea and decreased exercise capacity in patients with chronic heart failure. BACKGROUND: In patients with heart failure, the sensation of dyspnea may be related to abnormalities of respiratory muscle function, such as diminished strength or endurance, or both. METHODS: Respiratory muscle endurance was assessed by measuring maximal sustainable ventilatory capacity in 15 patients with congestive heart failure and 8 normal subjects using progressive isocapnic hyperpnea. Near-infrared spectroscopy of an accessory respiratory muscle, Borg scale recordings of perceived dyspnea, time in inspiration, time per breath and minute ventilation were measured. Exercise testing with measurement of oxygen consumption was also performed. RESULTS: Maximal voluntary ventilation (normal subjects 167 +/- 40, heart failure group 89 +/- 31 liters/min) and maximal sustainable ventilatory capacity (normal subjects 90 +/- 23, heart failure group 53 +/- 22 liters/min) were significantly reduced in patients with heart failure (both p < 0.05). No significant accessory respiratory muscle deoxygenation was observed in either group. Borg scale recordings at maximal sustainable ventilatory capacity were comparable in both groups. At rest, the inspiratory duty cycle (i.e., time in inspiration divided by the time per breath) was comparable in the two groups (normal subjects 0.34 +/- 0.09, heart failure group 0.37 +/- 0.12, p = NS). However at maximal sustainable ventilatory capacity, only normal subjects had a significant increase in the inspiratory duty cycle (normal subjects 0.49 +/- 0.04, heart failure group 0.36 +/- 0.10, p < 0.05). This finding suggests obstruction to airflow in patients with congestive heart failure. Values for peak exercise minute ventilation did not differ significantly from values in maximal sustainable ventilatory capacity in either group and were significantly correlated (r = 0.84, p < 0.0001). CONCLUSION: Respiratory muscle endurance as assessed by maximal sustainable ventilatory capacity is reduced in patients with heart failure.

Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome.

PURPOSE: To evaluate the aerobic power (as maximum volume of oxygen consumed [VO2 max]) of women with chronic fatigue syndrome (CFS). PATIENTS AND METHODS: Twenty-one women with CFS and 22 sedentary healthy controls (CON) were studied at the CFS Cooperative Research Center Exercise Laboratory at the VA Medical Center, East Orange, New Jersey. Performance was measured on an incremental treadmill protocol walking to exhaustion. Expired gases were analyzed by a metabolic system, heart rate was recorded continuously, and ratings of perceived exertion (RPE) were taken at each workload. The groups were divided into those who achieved VO2 max (CFS-MAX and CON-MAX) and those who stopped at a submaximal level (CFS-NOMAX and CON-NOMAX) by using standard criteria. RESULTS: Seventeen CON and 10 CFS subjects achieved VO2 max. The VO2 max (mL/kg/min) of the CFS-MAX (28.1 +/- 5.1) was lower than that of the CON-MAX (32.1 +/- 4.3, P = 0.05). The CFS-MAX achieved 98 +/- 11% of predicted VO2 max. The CFS group had a higher RPE at the same absolute workloads as controls (P < 0.01) but not the same relative workloads. CONCLUSION: Compared with normal controls, women with CFS have an aerobic power indicating a low normal fitness level with no indication of cardiopulmonary abnormality. Our CFS group could withstand a maximal treadmill exercise test without a major exacerbation in either fatigue or other symptoms of their illness.

Immunologic parameters in chronic fatigue syndrome, major depression, and multiple sclerosis.

The purpose of this study was to evaluate the immune dysfunction hypothesis of chronic fatigue syndrome (CFS) by comparing immunologic data from patients with CFS with data from patients with other fatiguing illnesses--major depression and multiple sclerosis (MS)--and with data from healthy sedentary controls. The subjects were 65 healthy sedentary controls, 71 CFS patients (41 with no axis-I diagnosis), 23 patients with mild MS, and 21 patients with major depression. Blood was sampled and assayed for the following: (1) immunologic serologic variables--circulating immune complexes (i.e., Raji cell and C1q binding), immunoglobulins A, E, G, and M, and IgG subclasses; (2) cell surface activation markers--the proportion of CD4+ cells expressing CD45RA+ and CD45RO+ and the proportion of CD8+ cells expressing CD38+, CD11b-, HLA-DR+ and CD28+; and (3) natural killer (NK) total cell count as well as the proportion of lymphocytes expressing NK cell surface markers (i.e., CD3-/CD16+ and CD56+. Of the 18 variables studied, differences between CFS patients and controls were found only for IgG1 and IgG3. When CFS patients were stratified by the presence or absence of concurrent axis-I disease, it was the group with axis-I disorder that had the lowest IgG1 values-contrary to expectation. When data from patients with MS and major depression were also evaluated, the subclass deficiency was no longer significant. The one group to show evidence for immune activation (i.e., an elevated proportion of CD4+ cells expressing the CD45RA+ activation marker) was the group with mild MS. These data support neither immune dysfunction nor immune activation in CFS or in major depression, for the variables studied. The reductions in IgG subclasses may be an epiphenomenon of patient or control subject composition. In contrast, MS, even in the mild and early stages, as in the patients studied here, is associated with immune activation.

Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome.

The purpose of this study was to determine the effect of exhaustive exercise on cognitive performance of patients with chronic fatigue syndrome (CFS) and sedentary healthy controls (CON). Subjects were 19 women with CFS and 20 CON. A test battery consisting of 4 cognitive tests (CTB) was given pre-, immediately post-, and 24 hours post-treadmill exercise to exhaustion. No differences were seen on the CTB pre-exercise. CFS patients improved at a slower rate than CON on the Symbol Digit Modalities Test (SDMT), Stroop Word Test (SWT), and Stroop Color Test (SCT). When compared with CON, a lower number of correct responses was seen for the CFS immediately postexercise on the SDMT (61 +/- 3 vs 66 +/- 2), SWT (137 +/- 6 vs 146 +/- 6), and SCT (99 +/- 4 vs 107 +/- 3), and 24 hours postexercise on the SDMT (64 +/- 3 vs 69 +/- 2), SWT (134 +/- 7 vs 148 +/- 5), and SCT (101 +/- 4 vs 106 +/- 3). We conclude that after physically demanding exercise, CFS subjects demonstrated impaired cognitive processing compared with healthy individuals.

Use of a triaxial magnetometer for respiratory measurements.

We describe a triaxial magnetometer (Tri-mag) system, which consists of a transmitter, four sensors, a processing unit, and a personal computer (PC). The Tri-mag processing unit outputs the position of each sensor relative to the transmitter in three orthogonal coordinates, and this information is communicated to the PC. First, we demonstrated that within a defined octant of a sphere in which the center is the transmitter, we can measure radial distances with an accuracy of +/- 1 mm over a range extending from 10 to 70 cm from the transmitter. Second, we recorded the three-dimensional movement of sensors on the anterior and posterior surfaces of the chest wall during maximum voluntary ventilation in four normal men; all sensors were placed in the midsagittal plane of the body. Anterior sensors were located on the sternum at the level of the third intercostal space and at 2 cm above the umbilicus, whereas posterior sensors were located on the posterior spine at the same vertical levels as the anterior sensors. In all subjects the following was found. 1) Both anterior sensors moved anterior and cephalad during inspiration. The anterior thoracic sensor showed greater vertical than anteroposterior (A-P) movement, whereas the anterior abdominal sensor showed greater A-P than vertical movement. 2) Inspiration was associated with spinal extension, whereas expiration was associated with spinal flexion. Third, we used Tri-mag information to 1) measure tidal volume (VT) over a range extending from 500 ml to inspiratory capacity and 2) measure the change in end-expiratory lung volume (EELV) over a range extending from FRC to FRC plus a minimum of 1.5 liters. Our results indicate that greater than 96% of the changes in VT and greater than 82% of the changes in EELV can be accounted for by changes in A-P, vertical, and lateral dimensions of the chest wall.

Growth hormone does not prevent corticosteroid-induced changes in rat diaphragm structure and function.

The present study tested the hypothesis that growth hormone (GH), an anabolic agent, could prevent the abnormalities of diaphragm structure and function associated with short-term administration of the corticosteroid triamcinolone (TR). During a 10-day period, male rats (n = 33) were assigned to control (CTL), TR (1 mg.kg-1.day-1 im), and TR-GH (2 mg.kg-1.day-1 im) groups. Diaphragm weight was significantly reduced in the TR and TR-GH animals compared with the CTL animals, but there was no difference in the diaphragm-to-body weight ratio. Fiber type (I, IIa, and IIx/b) proportions did not differ among the three groups. However, in TR rats there was a significant reduction in the contribution of type IIx/b fibers to total diaphragm cross-sectional area due to marked atrophy (approximately 42% decrease in mean fiber cross-sectional area). There was no significant reversal of TR-induced type IIx/b fiber atrophy by concomitant GH administration. TR and TR-GH groups both exhibited a left-ward shift of the force-frequency relationship and enhanced in vitro fatigue resistance, whereas maximal specific force was unaltered. We conclude that GH does not prevent corticosteroid-induced effects on the diaphragm under these conditions, possibly as a result of reduced nutritional intake associated with TR administration.

Physical activity before and after exercise in women with chronic fatigue syndrome.

We measured physical activity after strenuous exercise in 20 women with chronic fatigue syndrome (CFS), compared to 20 sedentary healthy volunteers who exercised no more than once per week. Activity was measured for 2 weeks using a portable waist-worn vertical accelerometer. After the first week of activity monitoring, all participants returned for a maximal treadmill test, followed by continued activity monitoring for the second week. Five activity measures were derived from the data: (i) average activity; (ii) total activity; (iii) duration of waking day; (iv) duration; and (v) number of daily rests. A repeated measures ANCOVA was used to determine post-treadmill group differences accounting for pre-treadmill differences. There was a significant reduction in overall average activity after the treadmill test, with the greatest decrease on days 12 through 14. This reduction was accompanied by a significant increase in the duration of the waking day and number of daily rests. Thus, marked exertion does produce changes in activity, but later than self-report would suggest, and are apparently not so severe that CFS patients cannot compensate.

Is depression associated with immune activation?

BACKGROUND: Some research immunologists have suggested that major depression amd chronic fatigue syndrome (CFS) are characterized by immune activation. To test this hypothesis, we compared immunological function in patients with major depression and in patients with CFS who developed major depression after the onset of CFS to that of sedentary healthy controls. METHODS: Subjects completed the Centers for Epidemiological Study-Depression (CES-D) questionnaire and allowed venisection. We performed flow cytometric analysis on 13 groups of white blood cells and used a reverse transcriptase PCR method to assay m-RNA of eight cytokines. RESULTS: CES-D scores were high in both patient groups and did not differ significantly. We found no evidence for immune activation in either patient group. Instead the data suggested immunological downregulation in depression. LIMITATIONS: Not all the subjects in the two patient groups were off antidepressants. CONCLUSIONS: The data indicate that immune activation is not necessary in depression--either alone or with CFS.

Mouse running activity is lowered by Brucella abortus treatment: a potential model to study chronic fatigue.

Chronic fatigue syndrome, which can occur after acute infection and last for years, is characterized by severe and persistent fatigue. Others have reported decreases in mouse running activity following infection and have suggested this may provide an animal model for studying chronic fatigue. Voluntary running is a highly motivated activity in mice, which will often run 5-7 mi/day in our laboratory. Following 2 weeks of acclimation to running wheels with food and water available ad lib, female BALB/c mice received 0.2-mL tail vein injections of killed Brucella abortus (BA) or saline vehicle. Subsequently the effects on voluntary running and grooming behavior were determined. Injection of BA caused an immediate large decrease in running and a lack of grooming. Vehicle injections produced no changes in behavior. After the first several days of reduced running behavior, levels of running and grooming slowly returned back to normal over the next 2-4 weeks, with substantial individual differences in the rate of recovery. The pattern of running during recovery was intriguing in that BA mice first ran at normal levels just after the lights went out, but they stopped after only 1-2 h. As recovery proceeded, they gradually increased the duration of the running bout during the night. Because this model uses voluntary exertion and the ability to run for longer periods of time characterizes recovery, the model may be a good one for studying the biologic underpinnings of chronic fatigue.

Effects of iron repletion on VO2max, endurance, and blood lactate in women.

To determine the effects of an 8-wk dietary iron supplementation (100 mg.d-1) on low plasma ferritin concentration (< 20 ng.ml-1) and endurance, 20 active women (19-35 yr) were studied while performing a VO2max test and an endurance test (80% VO2max) on a cycle ergometer. Subjects were randomly placed in an iron supplement (IG) or a placebo group (PG) using a double-blind method. After treatment in the IG, ferritin levels were higher (22.5 +/- 3.4 vs 14.3 +/- 2.2 ng.ml-1; P < 0.05), Hb increased (12.8 +/- 0.4 to 14.1 +/- 0.2 g.dl-1; P < 0.05), and TIBC decreased (366.2 +/- 24.8 to 293.8 +/- 14.0 micrograms.dl-1; P < 0.05). Also after treatment the IG's VO2max was significantly greater (P < 0.05) than the PG value and their postendurance blood lactate decreased (5.03 +/- 0.44 to 3.85 +/- 0.6 mM.l-1; P < 0.05). Endurance time to exhaustion increased 38% (37.28 +/- 5.03 to 51.4 +/- 7.45 min) following iron treatment; however, this change was not statistically significant. The results suggest that this level of iron supplementation can reverse mild anemia, increase VO2max, and reduce blood lactate concentration after submaximal exercise.

Effects of low ferritin concentration on endurance performance.

To determine the effects of depleted iron stores on endurance performance and blood lactate concentration, eight active women with normal (> 26 ng/ml) and eight with low (< 12 ng/ml) plasma ferritin concentrations were studied while performing a VO2max and an endurance test (80% VO2max) on a cycle ergometer. The low ferritin group had significantly lower serum iron concentration and transferrin saturation and higher TIBC than the normal ferritin group. Mean VO2max was not significantly different between groups. No significant difference was found in total time to exhaustion during the endurance test for low (23.2 min) and normal (27.0 min) ferritin groups; however, the normal ferritin group exercised 14% longer. Blood lactate concentrations following the VO2max and endurance test did not differ significantly between groups. Food diaries revealed lower daily absorbable iron intake by the low ferritin group compared to the normal ferritin group. Ferritin concentration was significantly related to absorbable iron (r = .72) and total iron (r = .70) intake. The results suggest that women with depleted iron stores who are not anemic may have less endurance, but do not have higher blood lactate during exercise than women with normal iron stores.

Respiratory muscle function and dyspnea in patients with chronic congestive heart failure.

BACKGROUND: Patients with heart failure (HF) frequently experience exertional dyspnea. Using near-infrared spectroscopy, we have previously demonstrated accessory respiratory muscle deoxygenation during exercise in these patients by monitoring changes in light absorption at 760-800 nm. METHODS AND RESULTS: To investigate whether low-frequency respiratory muscle fatigue occurs, we performed supramaximal bilateral transcutaneous phrenic nerve stimulation before and after maximal bicycle exercise in 10 patients with HF (age, 62 +/- 10 years; ejection fraction, 18 +/- 7%) and six normal subjects (age, 50 +/- 8 years). Maximal rates of contraction and relaxation, peak twitch tension, and maximal transdiaphragmatic pressure (Pdi) were derived before and after exercise from analysis of six to 12 twitches obtained at functional residual capacity. Pdi, time in inspiration (Ti), time per breath (TTOT), respiratory gases, ratings of perceived dyspnea and fatigue, and 760-800 nm near-infrared spectroscopy absorbency changes of the serratus anterior muscle were measured throughout exercise. The tension time index (TTdi) of the diaphragm was derived. In both normal and HF subjects, all parameters of diaphragmatic function (i.e., maximal rates of contraction and relaxation, peak twitch tension, and maximal Pdi) were unchanged before and after exercise. Mean Pdi was comparable at rest (normal, 3.7 +/- 1; HF, 5.8 +/- 2.9 cm H2O; p = NS) but significantly greater in patients with HF at peak exercise (normal, 12.1 +/- 3; HF, 18.3 +/- 6.6 cm H2O; p less than 0.05). Ti/TTOT of both groups was similar at rest and throughout exercise. TTdi was significantly greater at rest (normal, 0.01 +/- 0.01; HF, 0.03 +/- 0.02; p less than 0.05) and at peak exercise (normal, 0.03 +/- 0.02; HF, 0.10 +/- 0.03; p less than 0.04) in patients with HF. Significant accessory respiration muscle deoxygenation was noted only in patients with HF (peak exercise; normal, -1 +/- 13; HF, 28 +/- 15 arbitrary units; p less than 0.01). Linear correlation analysis was performed between ratings of perceived dyspnea and parameters of pulmonary and diaphragmatic function. Significant correlations were observed between ratings of perceived dyspnea and maximal inspiratory and expiratory pressure, the TTdi of the diaphragm, near-infrared absorption changes, and forced expiratory volume in 1 second (FEV1) (all r greater than 0.5; p less than 0.05). Thus, respiratory muscle strength, work, and oxygenation were significantly correlated with the degree of dyspnea. CONCLUSIONS: We conclude that low-frequency diaphragmatic muscle fatigue does not occur despite accessory respiratory muscle deoxygenation during exercise in patients with HF. However, diaphragmatic work as assessed by the TTdi is dramatically increased in patients with HF and approaches levels previously shown to generate fatigue. The sensation of dyspnea appears closely related to respiratory muscle function.

Creatine depletion elicits structural, biochemical, and physiological adaptations in rat costal diaphragm.

To elucidate adaptations elicited by creatine (Cr) depletion in the costal diaphragm (Dia), 16 12-wk-old male Fisher 344 rats had 2% beta-guanidinopropionic acid (beta-GPA), a competitive inhibitor of Cr transport into muscle, added to their food; a control group (Con) of 16 rats ate normal rat chow. After 18 wk, beta-GPA and Con Dia did not differ histochemically with respect to fiber-type distribution; however, the cross-sectional area of type II(b + x) fibers was 33% less in beta-GPA than Con Dia. Biochemically, the proportion of myosin heavy chain IIb in beta-GPA Dia was decreased 42% from Con Dia, whereas the proportions of myosin heavy chains I and IIa were increased. Physiologically, both peak twitch tension and tetanic tension in beta-GPA Dia were decreased 40% from Con. To assess fatigability, we used the protocol of Kelsen and Nochomovitz (J. Appl. Physiol. 53; 440-447, 1982) for 2-6 min duration; the percentage of initial force exhibited by beta-GPA Dia was approximately twice that of Con Dia. We conclude that these structural, biochemical, and physiological adaptations elicited by Cr depletion can all be explained by selective atrophy of IIb muscle fibers in the Dia.

Sweat iron loss of male and female runners during exercise.

Male (n = 9) and female (n = 8) collegiate cross-country runners were studied during a training session to determine the amount of iron lost in the sweat. Sweat samples were collected from the arm using polyethylene bags. Total sweat loss was determined by weighing subjects before and after the runs. Average time of sweat collection was 42 min for males and 39 min for females. Sweat rate for the males (717.5 +/- 145.9 g/m2/h) was significantly greater than for the females (460.1 +/- 142.9 g/m2/h); however, the sweat rate per km was not significantly different. Females had a significantly greater sweat iron concentration (0.417 +/- 0.024 mg/l) than males (0.179 +/- 0.011 mg/l). Rate of sweat iron loss was not significantly different for females (0.276 +/- 0.140 mg/h) and males (0.21 +/- 0.13 mg/h). Sweat iron concentration was inversely related with sweat rate (r = -0.64). Our data suggest that although males lose more total sweat than females, the higher sweat iron concentration of females leads to similar rates of iron loss. For female runners, sweat iron loss coupled with a low dietary iron intake may result in a negative iron balance.

Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise.

OBJECTIVE: The purpose of this study was to compare the cardiovascular responses of patients with chronic fatigue syndrome (CFS) to healthy control subjects when performing stressful cognitive tasks before and after strenuous exercise. METHOD: Beat-by-beat blood pressure and electrocardiogram were recorded on 19 women with CFS and 20 healthy nonexercising (ie, sedentary) women while they performed cognitive tests before, immediately after, and 24 hours after incremental exercise to exhaustion. RESULTS: Diminished heart rate (p <.01) and systolic (p <.01) and diastolic (p <.01) blood pressure responses to stressful cognitive testing were seen in patients with CFS when compared with healthy, sedentary controls. This diminished stress response was seen consistently in patients with CFS across three separate cognitive testing sessions. Also, significant negative correlations between self-ratings of CFS symptom severity and cardiovascular responses were seen (r = -0.62, p <.01). CONCLUSIONS: Women with CFS have a diminished cardiovascular response to cognitive stress; however, exercise did not magnify this effect. Also, the data showed that the patients with the lowest cardiovascular reactivity had the highest ratings of CFS symptom severity, which suggests that the individual response of the patient with CFS to stress plays a role in the common complaint of symptoms worsening after stress.

Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome.

The purpose of this study was to determine if patients with the chronic fatigue syndrome have less vagal power during walking and rest periods following walking, in comparison to a group of healthy controls. Eleven patients (ten women and one man) who fulfilled the case definition for chronic fatigue syndrome modified to reduce heterogeneity and eleven healthy, but sedentary, age- and sex-matched controls walked on a treadmill at 2.5 mph four times each for 4 min duration. Between each period of walking, subjects were given a 4-min seated rest period. Vagal power, a Fourier-based measure of cardiac, parasympathetic activity in the frequency range of 0.15 to 1.0 Hz, was computed. In each period of walking and in one period of rest, patients had significantly less vagal power than the control subjects despite there being no significant group-wise differences in mean heart rate, tidal volume, minute volume, respiratory rate, oxygen consumption or total spectrum power. Further, patients had a significant decline in resting vagal power after periods of walking. These results suggest a subtle abnormality in vagal activity to the heart in patients with the chronic fatigue syndrome and may explain, in part, their post-exertional symptom exacerbation.

A simple biofeedback digital data collection instrument to control ventilation during autonomic investigations.

Autonomic evaluation using the heart rate spectrum is sensitive to changes in breathing parameters, but few studies using this technique have controlled both the rate and depth of breathing. Fewer still have also measured or controlled inspiration and expiration times, or end-tidal carbon dioxide. This study describes the development of a digital instrument that can be used to alter tidal volume, ventilation rate and the time of inspiration and expiration with paced breathing visual templates displayed on a computer monitor. The digital instrument runs during data acquisition and displays the ventilatory signal from the subject superimposed on the paced breathing templates. Thus, adjustment of ventilatory parameters is achieved by matching the actual breathing signal to the target template. By regulating the ventilation rate and the tidal volume, end-tidal carbon dioxide could be increased or decreased in small increments. This instrument provided ventilatory control to investigate the effects on the heart rate spectrum of breathing depth, ventilation rate, end-tidal carbon dioxide and the time of expiration.

Cardiovascular response during head-up tilt in chronic fatigue syndrome.

This study examined the cardiovascular response to orthostatic challenge, and incidence and mechanisms of neurally mediated hypotension in chronic fatigue syndrome (CFS) during a head-up tilt test. Stoke volume was obtained by a thoracic impedance cardiograph, and continuous heart rate and blood pressure were recorded during a 45-min 70 degrees head-up tilt test. Thirty-nine CFS patients and 31 healthy physically inactive control subjects were studied. A positive tilt, i.e. a drop in systolic blood pressure of > 25 mmHg, no concurrent increase in heart rate and/or development of presyncopal symptoms, was seen in 11 CFS patients and 12 control subjects (P > 0.05). During baseline and the first 5 min of head-up tilt, CFS patients had higher heart rate and smaller pulsatile-systolic area than control subjects (P < 0.05). Among subjects who completed the test, those with CFS had higher heart rate and smaller stroke volume (P < 0.05) than corresponding control subjects. When comparing those who had a positive test outcome in each group, CFS patients had higher heart rates and lower pulse pressure and pulsatile-systolic areas during the last 4 min before being returned to supine (P < 0.05). These data show that there are baseline differences in the cardiovascular profiles of CFS patients when compared with control subjects and that this profile is maintained during head-up tilt. However, the frequency of positive tilts and the haemodynamic adjustments made to this orthostatic challenge are not different between groups.