Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are chronic multisymptom illnesses with substantial clinical and diagnostic overlap. The primary complaint of CFS patients, predictably, is debilitating fatigue, whereas the primary complaint of FM patients is chronic widespread pain. The two conditions are highly comorbid; up to 70% of CFS patients fulfill the American College of Rheumatology criteria for diagnosis of FM (4,5,15,38).
Commonly, CFS patients report an exacerbation of their symptom complex as a result of even minimal exertion. Accordingly, acute exercise has been used as a stressor to determine whether abnormalities in cardiorespiratory and metabolic systems might underlie the patients’ poor exercise tolerance and worsening of symptoms after exercise. Results from these studies have been equivocal (2,8,10,20). Our previous work highlighted the importance of controlling for aerobic fitness and accounting for FM status on cardiorespiratory and perceptual responses to exercise in CFS (8). In that work, initial analysis of the data indicated that CFS patients had lower cardiorespiratory responses and enhanced exertion and pain responses to maximal exercise compared to healthy, sedentary controls—data that seemed consistent with prior works (20,29). However, when the data were analyzed while controlling for aerobic fitness and accounting for the presence of comorbid FM (CFS + FM), group differences for cardiorespiratory responses were eliminated, and the only remaining differences between the groups was that the CFS + FM group reported greater exertion and pain during exercise compared to healthy control subjects (8). Our results suggested that the equivocal findings of previous CFS research were likely due to a failure to effectively control for differences in aerobic capacity between patients and controls and/or to account for comorbid illness.
Maximal exercise testing has provided important insights into the aerobic capacities and cardiorespiratory systems of patients (8,35,36). This type of protocol is important for determining cardiorespiratory responses that occur during high-intensity exercise and provides critical information concerning metabolic adjustments that occur at or above the ventilatory threshold. However, there are limitations inherent to using maximal exercise protocols such that steady-state submaximal exercise could provide a better option for determining cardiorespiratory responses in CFS populations. First, maximal efforts are rarely encountered under normal circumstances. Thus, maximal exercise tests have limited generalizability to daily life. Second, time to volitional exhaustion for maximal exercise tests can have substantial variability, making direct comparisons between individuals and groups difficult. Steady-state submaximal protocols can be designed to deliver relative exercise intensities for a standardized period. Third, ramped tests that are often used in maximal exercise protocols force the cardiorespiratory system to constantly adapt to a progressively increasing workload and may mask abnormal adaptations and/or responses that may be revealed during submaximal and steady-state exercise. Fourth, the vigorous nature of maximal exercise tests make it difficult to obtain additional physiological information beyond HR, blood pressure, oxygen consumption, and carbon dioxide production. Exercise tests conducted at lower intensities provide the opportunity to use methods such as noninvasive impedance cardiography to obtain potentially important hemodynamic information about the cardiac cycle.
The purpose of the present investigation was to contrast the cardiorespiratory and perceptual responses to submaximal exercise of CFS patients with and without comorbid FM to those of sedentary healthy controls. Our 2006 study (8) highlighted the importance of aerobic fitness and FM status in interpreting exercise testing results. In the current study, we accounted for FM status (CFS + FM) and exercised individuals at a relative (40% of peak aerobic capacity) intensity to account for varying fitness levels.
Data for the present investigation were collected as part of a larger study intended to determine the influence of exercise on cognitive function in CFS (8). Sixty-five participants were randomly assigned to either an exercise or no exercise/quiet rest condition. Data reported here are for those participants assigned to the exercise condition. Thirty-five participants completed the submaximal exercise protocol (n = 21 CFS [n = 8 CFS only, n = 13 CFS + FM]; n = 14 healthy control). Participants with CFS were recruited from a large patient pool available through the NJ CFS Cooperative Research Center. All CFS patients met the 1994 Centers for Disease Control and Prevention’s case definition of CFS and had no known medical or psychiatric causes for their symptoms (12). Patients with comorbid FM were evaluated based on the American College of Rheumatology 1990 criteria for FM (38). Sedentary healthy control subjects were also recruited from a control subject pool at the NJ CFS Cooperative Research Center. These individuals reported themselves to be in “good” or “excellent” health and taking no medications other than birth control pills. “Sedentary” was defined as working in an occupation that did not require moderate-to-intense physical labor and not participating in physical exercise (leisure time or sport conditioning) for more than one session per week.
Exclusion criteria for all CFS patients were based on the clinical criteria listed in the Centers for Disease Control and Prevention’s case definition (12). Sedentary controls were excluded if they had a history of cardiovascular, respiratory, neurological, or major psychiatric disorders or were taking any medications other than oral contraceptives. The study was approved by the institutional review boards of the Veterans Affairs Medical Center, East Orange, NJ, and the University of Medicine and Dentistry – New Jersey Medical School, Newark, NJ. Written informed consent was obtained for all participants in the study.
The study was performed under controlled environmental conditions (20°C–24°C and 40%–60% relative humidity) between 11 a.m. and 2 p.m. A maximal exercise test, performed as part of a separate study (8) approximately 2 wk earlier, was used to determine the submaximal exercise intensities for the present study. Maximal exercise testing entailed a ramped cycle–ergometry protocol performed to volitional exhaustion to determine individual peak oxygen consumption (V˙O2peak) values. A maximal effort was determined based on meeting at least two of the following criteria: 1) RER ≥ 1.1, 2) change in V˙O2 < 200 mL with an increase in work, 3) RPE ≥ 17, and 4) achieving 85% of age-predicted maximal HR. For the present protocol, subjects reported to the Human Performance Laboratory located at the East Orange Veterans Affairs Medical Center having abstained from smoking for 2 h, ingesting caffeine and alcohol for 4 h, and exercising for 24 h before testing. Participants were also instructed to fast for the 4 h preceding their exercise test. After signing the informed consent, subjects completed the POMS and the short-form McGill Pain Questionnaire (MPQ) to assess mood and resting pain, respectively, before exercise (27,28).
A modified lead(II) ECG was used to monitor cardiac activity throughout the test. Blood pressure was measured during the last 30 s of every 4-min interval during exercise using a Dinamap (Model 1846 SX; Critikon, Tampa, FL) automated blood pressure unit. Expired air was collected breath-by-breath (i.e., O2 consumption, CO2 production, and ventilation) using a two-way nonrebreathing valve (Hans-Rudolph, Kansas City, MO) and was analyzed with the Max-1 metabolic measurement system (Physio-Dyne Instruments, Quoge, NY). The system was calibrated before each test using standard gases with known concentrations and a standard 3-L syringe.
An impedance cardiograph (Model R03; University of Miami, Miami, FL) was used to obtain noninvasive measures of stroke volume, cardiac output (Q), preejection period (PEP), and left ventricular ejection time (LVET). A tetrapolar aluminum band electrode configuration was used as previously described (33). Stroke index (SI) was derived by dividing stroke volume by body surface area [weight (kg)0.425 × height (cm)0.725 / 139.2], and cardiac index (CI) was derived by dividing Q by body surface area. Total peripheral resistance (TPR) was calculated as mean arterial pressure divided by the ratio Q/16.67 (16). An indexed value of TPR (TPRI) was calculated as mean arterial pressure divided by the ratio CI/16.67. The Heather index (HI; Ω·s−2) was used as an estimate of myocardial contractility (17). Impedance cardiographic data were collected during the final 30 s of each 2-min interval during exercise. Data were ensemble averaged and scored as previously described (31).
Subjects were seated on an electronically braked cycle ergometer (SensorMedics, Loma Linda, CA), with the seat and handlebars adjusted for optimal performance, and allowed a few minutes to habituate to the cycle and various monitoring devices. The exercise test began with a 1-min warm-up at 20 W. Exercise intensity was then increased to a level designed to elicit a metabolic response equal to 40% of each participant’s V˙O2peak. Exercise intensity was maintained by adjusting the power output of the cycle ergometer. Adjustments were made when the oxygen consumption equivalent to the target percentage of V˙O2peak varied by ±3 milliliters per kilogram body weight of the desired value. Subjects were instructed to maintain a pedaling cadence between 60 and 70 rpm that was signaled by the digital readout mounted on the cycle ergometer. Subjects exercised for 20 min followed by a gradual 5-min active recovery.
RPE were obtained during the last 10 s of every minute during the submaximal exercise test and every 30 s during recovery using the Borg 6–20 category scale (3). Before exercise, subjects were given standard instructions as to the proper use of the Borg 6–20 category scale. Briefly, subjects were instructed that the Borg 6–20 scale would be used to determine the intensity of effort or stress felt only in the legs during exercise and recovery. Subjects were further instructed that each number represents a category of sensation, which is ordered according to its intensity and that the verbal anchors (e.g., “very light,” “light,” “somewhat hard,” “hard,” etc.) should be used to help determine the level of effort at the moment they are asked to rate. Subjects were also provided cognitive anchors at the high and low ends of the perceptual continuum. Specifically, subjects were instructed that a “6” on the scale refers to the amount of effort exerted in their legs while they were sitting in a chair (i.e., no effort), whereas a “20” refers to the most effort imaginable (e.g., carrying a child out of a burning building or finishing a marathon).
Leg muscle pain intensity ratings were obtained during the last 10 s of every minute during exercise and every 30 s during recovery. Pain intensity was measured by use of a validated category-ratio of pain intensity scale (9). The pain intensity scale ranges from 0 (“no pain at all”) to 10 (“extremely intense pain, almost unbearable”). Subjects were instructed that the 0–10 pain intensity scale would be used to determine the intensity of pain felt only in the leg muscles during exercise and recovery. Subjects were further instructed that 1) pain is defined as the intensity of hurt felt in the leg muscles, 2) each number represents a category of sensation that is ordered according to its intensity, and 3) the verbal anchors (e.g., “no pain,” “weak pain,” “moderate pain,” “strong pain,” “extremely intense pain,” etc.) should be used to help determine the level of pain intensity at the moment they are asked to rate.
For the purpose of this investigation, the cardiovascular and perceptual variables collected during exercise were of primary interest. Given the large number of potential variables that could be derived from the impedance cardiographic data and the fact that many of these variables are directly related to one another, we selected two relevant yet theoretically independent variables: HR and SI. To best capture the cardiovascular and perceptual response to the submaximal exercise, we also included systolic blood pressure (SBP) and RPE in our model. Although ratings of leg muscle pain were also collected during exercise, RPE was chosen to be in the model because of its established relationship to cardiovascular responses to exercise. We chose these variables deliberately to evaluate multiple aspects of the cardiovascular response to exercise in these patients, while at the same time limiting redundancy between variables. As a test of the primary hypothesis, the selected variables were analyzed using a group-by-time (3 × 6) doubly multivariate, repeated-measures MANOVA with an overall level of significance (α) equal to 0.05. The overall MANOVA compared the groups on a linear combination of all four dependent variables across the repeated measures collected during the exercise bout. A total sample of 33 participants provided a power (1 − β error probability) of 0.929 for the overall MANOVA, given an effect size [f 2(V)] of 0.36 and α = 0.05. For the purpose of more fully characterizing the response to exercise and exploring possible relationships to other variables, averages of the remaining participant characteristic, cardiorespiratory, impedance cardiographic, and perceptual variables were compared with a series of exploratory one-way ANOVA with group membership as the lone factor and α = 0.05. These comparisons were based on data collected during minutes 4–20 of the submaximal exercise protocol, to reflect steady state. Effect sizes for these comparisons were calculated using Cohen d (6).
Of the original 35 participants, two individuals, a CFS patient with comorbid FM and a healthy control, were excluded from analysis owing to incomplete impedance cardiography data. Characteristics, baseline mood, and symptoms for the final sample (n = 33) are detailed in Table 1. The participant groups (CFS only [n = 8], CFS + FM [n = 12], and controls [n = 13]) did not differ significantly regarding age, height, weight, resting HR, resting SBP and diastolic blood pressure (DBP), reported leisure time physical activity, or V˙O2peak. The groups were also similar regarding sex breakdown and level of education. Both CFS patient groups reported significantly greater fatigue, confusion, and overall mood disturbance and less vigor than controls (P < 0.05; POMS). Current pain intensity, documented immediately before exercise using the MPQ, was greater for the CFS + FM group compared to both the CFS-only group and controls (P < 0.05).
Baseline cardiac and submaximal exercise
There were no significant group differences in baseline measures of HR, SI, CI, PEP, LVET, TPRI, or HI (P > 0.05; Table 1). The doubly multivariate repeated-measures comparison of the physiological and perceptual variables collected during exercise resulted in a significant multivariate group-by-time interaction (Wilks Λ = 0.046, F 40,22 = 2.006, P < 0.05). This interaction effect shows that the combined changes in the dependent variables observed during exercise differed as a function of group. Inspection of these data (Fig. 1) indicates that the CFS + FM group exhibited an exercise response characterized by higher RPE and SI and lower SBP relative to the other groups. No differences in HR during exercise were apparent. The significant interaction was eliminated when a similar analysis of the same variables was conducted with the CFS-only and CFS + FM patients collapsed into one group, demonstrating that the CFS-only and CFS + FM groups had different cardiac and perceptual responses to submaximal exercise.
Average cardiovascular and perceptual responses collected during submaximal exercise (minutes 4–20) are listed in Table 2. The groups did not significantly differ on either percent oxygen consumption or average watts during exercise; however, the effect size difference for watts between the CFS + FM and CFS-only groups was large. CFS + FM patients had higher ventilatory equivalents for O2 and CO2 and reported greater leg muscle pain (Fig. 2) during exercise compared to both CFS-only patients and controls. In addition, individuals in the CFS + FM group had lower SBP and higher RPE compared to controls. Impedance cardiography data during exercise are listed in Table 3. CFS + FM patients had significantly higher SI compared to both CFS only and controls. The CFS + FM group had moderately, but nonsignificantly, lower TPRI and higher CI than both CFS-only and control groups (Fig. 3).
Our previous work using maximal exercise testing found no differences in the cardiorespiratory responses between CFS patients and healthy controls when matched on aerobic fitness (8). These results challenged earlier studies reporting slow acceleration of HR and low ventilatory responses in CFS suggestive of subtle cardiac abnormalities or autonomic dysfunction (20,29). In the present investigation, we sought to extend on our previous research by determining the cardiorespiratory and perceptual responses to moderate-intensity, steady-state exercise in CFS. Our results indicate that CFS patients with comorbid FM differ in their response to exercise compared to CFS patients without comorbid FM and healthy sedentary controls. These differences were characterized by an elevated perception of exertion, an exaggerated SI response, and a diminished SBP response. The CFS + FM patients also had moderately lower TPR and experienced greater musculoskeletal pain during submaximal exercise.
The elevated SI response in the CFS + FM patients was unexpected. In general, stroke volume is determined by five primary factors: 1) the volume of blood returned to the heart by the venous system, 2) the ventricular capacity or compliance of the heart (i.e., Frank Starling mechanism), 3) ventricular contractility, 4) arterial pressure placed against the ventricles, and 5) systemic vascular resistance. Examination of the data shows no differences in baseline variables including systemic vascular resistance, SI and CI. This suggests that differences in blood volume, which have been previously observed (19) and hypothesized to contribute to stroke volume abnormalities in this population (32), are an unlikely explanation for the observed results. However, when exposed to an exercise challenge several interesting findings emerged. The elevated SI response to submaximal exercise in the CFS + FM patients was accompanied by a significantly lower SBP response and a trend toward lower DBP, lower TPR, and higher cardiac contractility. When examined in aggregate, these results point toward a cardiovascular system that is relatively normal at rest (baseline) but that does not show the expected increase in SBP in response to a light exercise challenge.
For the CFS + FM patients, stroke volume may have increased to a greater extent to maintain blood pressure and oxygen delivery to active skeletal muscle during exercise. The mechanism for this is not apparent, but recent research in CFS suggests that muscle bioenergetic abnormalities, expressed as abnormal phosphocreatine-to-adenosine triphosphate ratios and reduced proton efflux rates, are present in a subset of CFS patients (18). These reported abnormalities were associated with greater cardiac contractility during standing and interpreted as enhanced cardiac work during a relative physical stressor. In addition, work by McCully and Natelson (25) and McCully et al. (26) have demonstrated abnormal muscle metabolism, reduced oxygen delivery, and slower recovery of oxygen saturation after exercise in CFS patients compared to controls. These results suggest impaired vascular control in CFS that could compromise muscle blood flow and metabolism during exercise. An enhanced SI response could be indicative of compensation to maintain muscle blood flow and oxidative metabolism during exercise. The elevated ventilatory equivalents for oxygen and carbon dioxide (indices of ventilatory efficiency) also indicate that the CFS + FM patients were less efficient, requiring greater ventilation to remove excess carbon dioxide accumulation during low-intensity exercise, perhaps to maintain oxygen delivery to working muscle. It is important to note that none of the studies cited above accounted for FM status of CFS patients. Our results suggest this explanation would only apply to CFS patients with comorbid FM.
Our results add to the growing literature suggesting autonomic nervous system (ANS) dysfunction in CFS (13,30) and FM (14,21,23). Previous investigations of the hemodynamic and metabolic responses to exercise suggested that patients with CFS might exhibit abnormalities indicative of dysfunction of the central cardiovascular control center. The present study suggests the cardiovascular responses of CFS patients without comorbid FM are similar to healthy control subjects. However, patients with concurrent diagnoses of CFS and FM exhibit abnormal responses. Further, FM patients have been shown to have low baroreflex sensitivity (BRS) that was not improved with resistance exercise training (11). Our observed trend of lower peripheral resistance as well as significantly lower SBP in patients with CFS + FM during mild exercise suggests that autonomic control of vasoconstriction during exercise may be compromised perhaps due in part to low BRS. This would be consistent with converging evidence of normal ANS or enhanced sympathetic activity at rest and impaired modulation of the ANS response to a variety of experimental stressors in FM (34). In general, FM patients have been shown to exhibit a hypoactive ANS, both in general (1) and in response to exercise. As pointed out by Adler and Geenen (1), a major limitation of previous research of ANS function in FM is the failure to control for physical activity and/or fitness, variables that have a profound influence on the ANS.
Under normal circumstances, during exercise and in response to the subsequent effect of vasodilation on blood pressure, peripheral baroreceptors are stimulated and activate brain regions responsible for cardiovascular control (central command). This resultant efferent signaling elevates sympathetic activity, causing reflexive vasoconstriction, increased HR, myocardial contractility, and/or stroke volume. The elevated SI exhibited by the CFS + FM group could be interpreted as evidence that autonomic regulation was at least partially intact. However, HR was not similarly affected, and this overall response did not reverse the abnormal blood pressure and peripheral resistance trends observed during exercise. The integrated result was an abnormal physiological response to a gentle exercise demand for the CFS + FM group. This finding encourages continued attention to the constitution of the patient group under study.
In addition to the cardiovascular differences, CFS + FM patients also experienced greater pain and exertion during submaximal exercise, despite exercising at a lower absolute workload. These data are consistent with our prior work using maximal exercise testing procedures and extend them to steady-state and longer-duration submaximal exercise (7,8). CFS patients without comorbid FM did not report greater pain or exertion during submaximal exercise, challenging the widespread assumption that CFS patients have altered effort sense or that CFS is an illness of altered effort sense (24,37). Our results suggest that chronic widespread pain can influence perceived exertion during exercise perhaps through enhanced sensory input from contracting skeletal muscle during exercise.
Our data indirectly contradict previous research showing reduced stroke volume in CFS. Peckerman et al. (32), using impedance cardiography, reported reduced stroke volume at rest in CFS patients categorized as severe compared to both a less severe CFS group and sedentary health controls. Similarly, Hurwitz et al. (19) reported moderately reduced stroke volume at rest in CFS that was almost entirely explained by low blood volume. A major strength of the study by Hurwitz et al. (19) was the categorization of controls as either sedentary or active and the assessment of fitness in the CFS and sedentary control groups. We did not observe differences in any of resting measures, including SI, between patients and controls (Table 1), although our small sample sizes may have precluded detection.
The primary limitation of the present study is the small sample size, particularly the size of the CFS-only group (n = 8). Despite the small sample, we did observe a significant interaction for the overall model, which speaks to the power of the finding. However, a larger sample would permit us the freedom to include additional variables in the model as well as the possibility of planned comparisons to explore the group differences between individual variables of interest. Related to that point, our decision to evaluate a single a priori defined model of cardiovascular and perceptual variables using the MANOVA has limited our ability to make conclusions about how CFS patients with and without comorbid FM, as well as healthy controls, may differ regarding the influence of submaximal exercise on individual variables.
Another limitation is related to intensity of the submaximal exercise used in the present investigation. As was pointed out in the introduction, the use of a submaximal exercise protocol enabled us to use noninvasive impedance cardiography to monitor the hemodynamics of the cardiac cycle during exercise. However, only a single relative intensity (40% V˙O2peak) of submaximal exercise was used in our study. We cannot rule out the possibility that the pattern of cardiovascular and perceptual variables for CFS patient groups and controls during exercise may be different from our results at greater or lower intensities. It is also worth noting that, despite a lack of significant difference between groups regarding level of fitness and the fact that all groups exercised at roughly the same relative intensity of exercise, the CFS + FM group, on average, exercised at a relatively low absolute intensity (25 W) compared to that in the CFS-only group (46 W). Given this fact, it may be that we have underestimated the magnitude of the differences in cardiovascular and perceptual responses between CFS patients with comorbid FM and pure CFS patients and healthy controls. Finally, the design of the current study is limited in that it does not permit us to draw conclusions as to whether the differential response of CFS + FM patients to submaximal exercise is due simply to the presence of FM or the combination of CFS and FM.
Using a submaximal exercise challenge and using a multivariate model to determine the cardiovascular and perceptual responses to steady-state exercise, we found that CFS patients with comorbid FM differ from CFS patients without widespread pain. These differences were characterized by exaggerated SI, low pressure, and elevated exertion and pain. When CFS and CFS + FM patients were combined in the model, the differences were eliminated, underscoring the necessity of controlling for FM in CFS research. The pattern of observed responses in the CFS + FM patients suggest ANS dysfunction that may lead to chronic blood flow abnormalities and that clearly could be implicated in the sequelae of illnesses associated with unexplained fatigue and pain.
FM is the most common comorbid illness in CFS. This has led some to speculate that these and other multisymptom illnesses represent a spectrum of functional somatic disorders (22), perhaps reflecting common pathophysiological mechanisms. However, beyond symptom profiles, CFS and FM have rarely been directly compared. Our results suggest that having both CFS and FM is different from having CFS without FM. This, in some ways, challenges the spectrum hypothesis that CFS and FM have the same underlying pathophysiology. Future research with larger samples of patients and the inclusion of an FM group without comorbid CFS would help to further clarify similarities and differences in these complex illnesses.
This research was supported by the National Institutes of Health grant AI-32247.
The authors wish to acknowledge Dr. Norman A. Cagin, M.D., for his insight and assistance with data interpretation.
The authors declare that they have no competing interests.
The results of the present study do not constitute endorsement by the American College of Sports Medicine.
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Keywords:©2012The American College of Sports Medicine
PAIN; FATIGUE; IMPEDANCE CARDIOGRAPHY; STROKE VOLUME; RPE