Psychosomatic Medicine Faster Service from Outside North America
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Peckerman, A.
Right arrow Articles by Natelson, B. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Peckerman, A.
Right arrow Articles by Natelson, B. H.
Related Collections
Right arrow Musculoskeletal
Right arrow Stress and Coping
Right arrow Other Cardiovascular Medicine
Psychosomatic Medicine 65:889-895 (2003)
© 2003 American Psychosomatic Society

ORIGINAL ARTICLES

Baroreceptor Reflex and Integrative Stress Responses in Chronic Fatigue Syndrome

Arnold Peckerman, PhD, John J. LaManca, PhD, Bushra Qureishi, MD, Kristina A. Dahl, MD, Roseli Golfetti, PhD, Yoshiharu Yamamoto, PhD and Benjamin H. Natelson, MD

From the VA Medical Center, East Orange, New Jersey (A.P, B.H.N.); the CFS Cooperative Research Center, Department of Neurosciences, University of Medicine and Dentistry of New Jersey, Newark, New Jersey (A.P., B.Q., K.A.D., B.H.N.); the Heart Failure Center, Division of Circulatory Physiology, New York Presbyterian Hospital, New York, New York (J.J.L.); the Exercise Physiology Laboratory, State University of Campinas, Sãn Paulo, Brazil (R.G.); and the Educational Physiology Laboratory, Graduate School of Education, University of Tokyo, Tokyo, Japan (Y.Y.).

Address reprint requests to: Arnold Peckerman, PhD, VA Medical Center, War-Related Illness and Injury Study Center (129), 385 Tremont Ave., East Orange, NJ 07018. Email: apeckerm{at}njneuromed.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
OBJECTIVE: Altered cardiovascular responses to mental and postural stressors have been reported in chronic fatigue syndrome (CFS). This study examined whether those findings may involve changes in baroreceptor reflex functioning.

METHODS: Chronotropic baroreceptor reflex (by sequential analysis) and cardiovascular stress responses were recorded during postural (5-minute of active standing) and cognitive (speech task) stress testing in patients with CFS grouped into cases with severe (N = 21) or less severe (N = 22) illness, and in 29 matched control subjects.

RESULTS: Patients with CFS had a greater decline in baroreceptor reflex sensitivity (BRS) during standing, although only those with severe CFS were significantly different from the controls. Systolic blood pressure declined during standing in the control group but was maintained in the CFS patients. In contrast, the patients with less severe CFS had blunted increases in blood pressure during the speech task, which could not, however, be explained by inadequate inhibition of the baroreceptor reflex, with all groups showing an appropriate reduction in BRS during the task.

CONCLUSIONS: These results indicate that in CFS, deficiencies in orthostatic regulation, but not in centrally mediated stress responses, may involve the baroreceptor reflex. This study also suggests that classifying patients with CFS on illness severity may discriminate between patients with abnormalities in peripheral vs. central mechanisms of cardiovascular stress responses.

Key Words: chronic fatigue syndrome, • baroreceptor reflex, • orthostasis, • cardiovascular reactivity.

Abbreviations: AD ACL = Activation-Deactivation Adjective Check List;; BRS = baroreceptor reflex sensitivity;; CFS = chronic fatigue syndrome;; DBP = diastolic blood pressure;; HR = heart rate;; MFI = Multidimensional Fatigue Inventory;; PI = pulse interval;; SBP = systolic blood pressure;; SF-36 = Medical Outcomes Study Short Form-36.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Chronic fatigue syndrome is a medically unexplained illness characterized by severe depletion of energy, mental slowing, and other nonspecific symptoms such as problems with sleep, diffuse pain, and signs of low-grade infection (1). Investigations into earlier outbreaks of the illness observed signs of circulatory impairment during its acute phase (2–4) and later when it became a chronic condition (5). More recently, the hypothesis of cardiovascular involvement in CFS re-emerged with reports of blunted blood pressure responses to cognitive stressors (6, 7) and apparent changes in blood pressure and heart rate postural homeostasis (8, 9). The pathophysiology of these effects of illness remains poorly understood, however. The present study examined whether abnormalities in baroreceptor reflex functioning may explain the observed changes in cardiovascular stress responses.

The baroreceptor reflex activity is an integral part of responses to challenges. The maintenance of blood pressure in the upright position depends on the baroreflex-mediated shift in autonomic balance toward increased sympathetic and decreased parasympathetic activities. Withdrawal of baroreceptor vagal excitation manifests as a reduction in the chronotropic BRS (10, 11). During stressful mental activities, part of the overall autonomic response is inhibition of the baroreflex by rostral brain structures (12), which allows blood pressure to increase to a level demanded by the task. Inhibition of tonic baroreceptor influences on vagal motor neurons during mental stress is manifested in reduced sensitivity of the baroreceptor heart rate reflex (13, 14). Failure of this mechanism thus could explain the blunted blood pressure responses to stressful cognitive activities in patients with CFS.

Chronic fatigue syndrome is a heterogeneous disorder, and different groups of patients are likely to have different physiological abnormalities underlying their symptoms (15). Our earlier preliminary investigation took an approach that classified patients with CFS into cases with severe and less severe forms of CFS (16). The results suggested that blood pressure hyporeactivity to mental stressors may mark patients with less severe CFS. Our goal for this study was to confirm this effect in a larger sample and to examine the usefulness of this approach for discriminating CFS patients with abnormalities in postural regulation.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Subjects
A total of 43 CFS patients and 29 control subjects participated in the study. All patients met the 1994 Centers for Disease Control and Prevention case definition for CFS (17), which requires a substantial reduction in activities and the presence of four or more symptoms from a specified eight-symptom list. As part of the diagnostic interview, the subject also rated severity of symptoms in the previous month on a 0 to 5 scale, with 0 signifying no problem, 3 a substantial problem, and 5 a very severe problem. This information was used to classify each patient as having either severe or less severe CFS using a system devised in our center (18). Patients with severe CFS fulfilled the more demanding 1988 case definition (19), which specifies a decrease in activities of at least 50% and seven or more symptoms from a 10-symptom list. Although the Holmes et al. (19) case definition specifies an 11-item symptom list, one of the items is sudden onset, which is not strictly speaking a symptom, and, therefore, its presence or absence was not counted. In addition, to fulfill criteria for severe CFS, the patient had to rate at least seven symptoms as substantial or as worse in severity in the month before intake. Patients with less severe CFS could have fulfilled either the 1988 or 1994 case definition but did not meet our severity requirement. The severe and less severe CFS groups had similar rates of comorbid fibromyalgia (20), 37% and 33%, respectively.

All subjects entering the study were given a history and physical examination by a licensed medical professional aimed at detecting any disease that could explain chronic fatigue and other presenting symptoms. Medical conditions that could explain CFS and the psychiatric conditions specified in the case definition (schizophrenia, mania, bulimia, and substance abuse disorders) were standard rule-outs. Assessment was also made to rule out any conditions known to affect cardiovascular autonomic regulation, such as hypertension or diabetes. We also excluded patients on drugs with sympathomimetic or blocking activity and on tricyclic antidepressants. Eight patients with CFS were on other medication at the time of the study; most common (taken by five patients) were selective serotonin reuptake inhibitors. Comparisons between medicated and unmedicated patient groups revealed no significant effects of the medication status on cardiovascular and BRS stress responses.

Control subjects were people in good health screened for sedentary lifestyle, which was operationally defined as nonparticipation in regular (>1/week) physical activities. The CFS and control groups has similar demographic characteristics (Table 1), including ethnic composition, which was 89% white, 9% Asian, and 2% African American.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Descriptive characteristics (mean ± SD) of the study samples
 
Study Design and Procedures
The postural and mental stress testing was performed on 2 separate days, in the morning and afternoon, respectively. Of the 29 controls and 43 patients with CFS recruited for the study, 27 controls, 18 patients with severe CFS, and 20 patients with less severe CFS participated in postural testing, and 29 controls, 15 patients with severe CFS, and 16 patients with less severe CFS completed mental stress testing. The postural testing protocol consisted of a 10-minute period of supine rest followed by 5 minutes of quiet standing. Mental stress testing was performed in a sitting position and consisted of a 3-minute speech task, as described in a previous report (6). The testing session also included a 2-minute forehead cold pressor test (21), a contrasting stressor condition not involving high-level cognitive functioning. A 20-minute baseline period preceded each task. Data were collected during the last 2 minutes of the baseline and throughout test periods. Ratings of perceived stress, challenge, and threat were obtained for the baseline and stressor periods using a 1 to 8 Likert scale. The mean of the computed change scores was used as a measure of task engagement. In addition, the subject completed the MFI, a validated 20-item questionnaire that provides measures of fatigue-related mental and physical impairments, including reduced motivation (22). The latter measure was used as a more global indicator of engagement during testing.

Physiological Measurements
Systolic blood pressure and DBP were recorded intermittently from the left arm with a Dinamap blood pressure monitor (model 1846 SX; Critikon, Tampa, FL) and beat-by-beat with a Finapres device (model 2300; Ohmeda, Louisville, CO). The Finapres cuff was placed on the subject’s right index finger and kept supported approximately at heart level. The Finapres device, which uses the vascular unloading technique to measure blood pressure on beat-by-beat basis, has been demonstrated to provide reliable measures of blood pressure (23) and to be suitable for studies of baroreceptor reflex functioning (24). In the present study, Finapres SBP and HR data were used for calculations of BRS, and Dinamap blood pressures and heart rate measurements were used in analyses of responses to the postural (supine vs. standing) and behavioral (baseline vs. cold pressor and speech) stressors. The means of two Dinamap measurements recorded during the last 2 minutes in the supine and standing positions, at the end of the 20-minute sitting baseline period, and during the last 90 seconds of the speech stressor and cold pressor periods were used in analyses.

Finapres blood pressure recordings were scored offline using a program implemented in S-Plus (Statistical Sciences, Seattle, WA). Beat-by-beat SBP and systolic-to-systolic PIs were analyzed for baroreceptor reflex activity using the method of sequential analysis (25). The beat-by-beat records of SBP and PI were computer scanned for sequences of consecutive increases or decreases in both SBP and PI, and coefficients of linear regression were calculated for each detected sequence as a measure of BRS. Spontaneous baroreflex sequences were defined as three or more beats in which SBP and PI of the same beat (ie, lag 0) changed in the same direction. No limits were set on the minimal amount of change in either SBP or PI. The detected sequences were retained only if correlations between SBP and PI were .85 or greater. A previous methodology study had shown that the chosen parameters provide optimum estimations of spontaneous BRS (26). The obtained BRS measurements were averaged over the last 2 minutes of the supine period and in 30-second intervals throughout the 5-minute standing period. Preliminary polynomial trend analyses found no significant minute-by-minute trends in BRS across the 5-minute standing period (p > .20). Analyses of postural effects on BRS, therefore, were performed on the means for the last 2-minute intervals in the supine and standing positions. The BRS means computed over the last 2 minutes of sitting baseline period and over the entire 2-minute cold pressor and 3-minute speech task periods were used in analyses of responses to behavioral stress tests.

Questionnaire Assessments of Clinical Status
As part of the intake, the subjects filled out a 15-item questionnaire, rating severity of their symptoms over the previous week period on a 0 to 5 Likert scale. Ratings for the 10 symptoms from the 1988 CFS case definition (19) were averaged to provide a measure of overall symptom severity. In addition, on the day of the study before the testing began, the subjects filled out the AD ACL (27), which yields scores for energy and tiredness. After appropriate scaling, energy and tiredness items were added to provide scores on a bipolar dimension of energetic arousal, which will be referred to as energy scores. The AD ACL energy scores on the day of testing and average 1-week symptom severity ratings were viewed as providing complimentary information on a day-to-day variability in symptoms and on more long-term trends in basal levels of illness. Effects of illness on functional status were measured with the Karnofsky Illness Severity Scale (28) and the SF-36 (29). A Karnofsky scale score is an aggregate measure of retained functionality, and the SF-36 subscales quantify effects of illness on different aspects of daily activities. Scores on four of the subscales—general health, physical functioning, social functioning, and vitality—were used in the study. The patients with severe CFS were expected to have greater symptom severity ratings because they were part of the case definition, but they were also expected to have worse scores on other measures of illness.

Statistical Analysis
All data in the text are reported as mean ± SD. The data were analyzed using a 3 (group: control, severe CFS, less severe CFS) by 2 (period: baseline, test) analysis of variance, followed where indicated by tests of simple effects and interactions. Multiple regression analyses were used to estimate independent (partial) relationships between variables of interest. BRS values were transformed using natural logarithm before analyses. Two subjects had incomplete Finapres data during standing and were not included in analyses of postural effects on the baroreceptor reflex. One subject failed to complete the cold pressor test, and one other subject declined the speech task. A p value <.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 
Clinical Characteristics of Patients With CFS
Table 2 displays symptoms and functional status data. CFS symptom severity ratings were greater in the severe than less severe CFS groups. On the day of the study, the patients with CFS had less energy and worse fatigue on the AD ACL than the controls, but there were no significant differences between the two CFS groups. On measures of functional status, the patients with severe CFS were more impaired than those with less severe CFS on the SF-36 physical and social functioning scales, but not on the scales measuring general health perceptions and vitality, and not on the Karnofsky global disability scale (Table 2). The MFI Reduced Motivation scores were elevated in patients with CFS (p < .0001) but were not significantly different between the severe and less severe CFS groups (11 ± 5 vs. 12 ± 4, respectively; 6 ± 3 in controls).


View this table:
[in this window]
[in a new window]
  		TABLE 2. Clinical status (means ± SD) of the study samples
 
Baroreceptor Reflex and Cardiovascular Responses to Upright Posture
Measurements taken in the supine and standing positions are shown in Table 3. Analyses of these data identified significant group difference in the effects of posture for SBP and BRS; interaction F(2,62) = 3.31 and 4.56, p < .05. Specifically, SBP declined during standing in the control group (p < .005) but did not change significantly in the CFS groups (Table 3). The effects of posture on SBP in the control group were significantly different from responses in the patients with severe CFS (simple interaction p < .01) but not in the patients with less severe CFS (p > .10). Analyses of postural effects on BRS revealed that the patients with severe CFS had a greater BRS in the supine position (p < .05) and had a greater decline in BRS during standing (p < .005) than the controls. A similar pattern of changes in the patients with less severe CFS was not significantly different from responses in the control subjects, although as a group, patients with CFS had a greater postural decline in BRS than the controls; F(1,61) = 4.58, p < .05. Responses to standing also included increases in DBP and HR (Table 3), but there were no other significant effects of groups.


View this table:
[in this window]
[in a new window]
  		TABLE 3. Postural measurements (mean ± SD) in the CFS and control groups
 
Baroreceptor Reflex and Cardiovascular Responses to Behavioral Stressors
Cardiovascular responses to the speech and cold stressors are depicted in Figure 1. The less severe CFS group had smaller SBP increases during the speech task than the control and severe CFS groups (p values <.05) and had smaller DBP increases than the control group (p < .006); interaction F(2,57) = 3.56 and 4.13, p < .05, for SBP and DBP, respectively. In contrast, there were no significant group effects on responses to the cold pressor test (Figure 1). Increases in blood pressure during speaking were accompanied by significant decreases in BRS (Figure 1), which, however, were of similar magnitude in all groups (interactions F < 1). Declines in BRS during speaking were significant predictors of increases in SBP and HR during the task (Figure 2), but there were no significant group differences in the regression slopes relating changes in BRS to changes in SBP and HR. The speech task produced increases in ratings of perceived stress, challenge, and threat (p < .0001), but there were no significant effects of groups; mean change scores 1.7 ± 1.6 vs. 2.1 ± 2.2 vs. 1.7 ± 1.8, group by period interaction p > .10.



View larger version (22K):
[in this window]
[in a new window]
  		Fig. 1. BRS, SBP, DBP, and HR responses to the cold pressor and speech stressors in the severe CFS (N = 15), less severe CFS (N = 16), and control (N = 29) groups. Both stressors elicited significant increases in SBP and DBP (p values <.0001). HR increased and BRS declined during the speech task (p values <.0001) but remained unchanged during the cold pressor test.

 


View larger version (15K):
[in this window]
[in a new window]
  		Fig. 2. Relationships between changes in BRS, SBP, and HR during the speech task for the combined sample of patients with CFS and controls.

 
Relation Between Cardiovascular Changes and Clinical Status
The important question posed by these results was whether low blood pressure responses to speaking in the less severe CFS group, and excessive declines in BRS during standing in the patients with severe CFS, were related to the patient’s clinical status, as measured in this study by the AD ACL energy levels and mean symptom severity ratings (Table 2). It was found that in the less severe CFS group, reduced SBP responses during the speech task were uniquely related to lower AD ACL energy scores, whereas reduced DBP responses were related specifically to increased mean symptom severity ratings (Figure 3). In contrast, there was no significant relationship between symptoms and blood pressure responses to speaking in the severe CFS group (Figure 3). A similar set of analyses found no significant relationship between postural BRS responses and symptoms in either patient group.



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 3. AD ACL energy scores, the mean symptom severity ratings, and blood pressure responses during the speech task. In the patients with less severe CFS, low SBP and DBP responses were predicted, respectively, by lower energy scores (R = .57, p < .03) and greater mean symptom severity ratings (R = -.76, p < .001). None of these relationships were significant in the severe CFS group (p > .13).

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
ACKNOWLEDGMENTS
 REFERENCES
 
This study indicates that CFS alters baroreceptor reflex functioning. This included increased baroreflex sensitivity in the supine position and a greater reduction in sensitivity on standing. The effect of illness was accentuated in the patients with severe CFS and was associated with a deviation from the normal pattern of SBP response to standing. There were no discernible effects of illness on the baroreflex modulation by stressors, however.

Spontaneous baroreceptor reflex activity mainly reflects vagal responses to transient changes in blood pressure. In the upright position, unloading of baroreceptors results in vagal withdrawal and a proportional increase in sympathetic activity (10). A greater decline in BRS and maintained SBP during standing in the severe CFS group was therefore suggestive of an abnormal orthostatic hemodynamic function compensated by increased sympathetic vasomotor activity. An increased supine BRS has been reported in subjects who became syncopal during tilt table testing (30), whereas resistance to syncope was associated with lower BRS (31). Sodium loading in patients with orthostatic syncope, while expanding their blood volume and increasing orthostatic tolerance, also reduced BRS (32). Presumably, the effect of treatment was to improve blood flow, suggesting that cardiovagal baroreflex augmentation may develop as an adaptation to low cardiac output, for which there is some evidence in patients with severe CFS (16, 33). This relationship between cardiac output and BRS may involve mediation by cardiopulmonary receptor activity. For example, unloading of cardiopulmonary receptors causes an increase in vasopressin release (34), which can increase sensitivity of neuronal networks processing baroreceptor afferent information (35). Altered cardiopulmonary receptor functioning may also cause some of the clinical signs seen in patients with severe CFS. Stimulation of juxtacapillary pulmonary receptors (the J-receptors) is believed to cause the feeling of muscle weakness, limiting capacity for physical activities (36). The involvement of cardiopulmonary reflexes in pathogenesis of symptoms in severe CFS is a hypothesis that merits a careful study.

BRS declines with aging (37). The greatest decline occurs between the fourth and fifth decade of life (38), which was the age of the study subjects. Although the causes of this decline are not well understood, stiffening of the arteries containing the baroreceptors appears to play a critical role (39, 40). Arterial compliance in women is greater than in men because of estrogen-mediated increase in nitric oxide activity (41). However, nitric oxide also acts centrally to inhibit baroreceptor reflex responses (42). As a result of the interplay of these and other competing influences, spontaneous BRS in women is similar to that in men (38, 43). One can hypothesize, however, that in women with severe CFS, the balance of those activities can become altered, perhaps as an adaptive response, resulting in an increase in BRS.

This study replicated our previous findings of blunted blood pressure responses to cognitive stressors in civilian patients with CFS (7) and in Gulf War veterans (6). An important new finding of this study is that this abnormality may be specific to a less severe form of illness. Although patients with CFS in our earlier report (7) were not classified on illness severity, the reported mean symptom severity rating ({approx}2.0) was similar to that obtained in the less severe CFS group in this study (1.9, Table 2). This finding indicated that the subjects in that study were mainly patients with less severe CFS. Similarly, review of the patients’ records from our study of Gulf War veterans (6) revealed that 85% of them had less severe CFS according to our case definition. This study also replicated in civilian patients with CFS the pattern of disturbed regulation of responses to cognitive but not sensory (the cold pressor test) challenges that we previously reported in Gulf War veterans (6), suggesting a similar underlying pathology. As in our previous studies (6, 7), hyporeactivity to mental stress was not explainable by the lack of engagement and low motivational state, and indeed, this would not be plausible in patients with less severe CFS.

Blood pressure responses to mental challenges depend on integrated activities in multiple central and peripheral control systems and target organ functioning (44). We hypothesized that hyporeactivity in patients with CFS might be a result of inadequate suppression of the baroreceptor reflex that is part of feed-forward responses evoked by mentally challenging stimuli (13, 14). However, there were no indications in the present data to support this hypothesis. It was also unlikely that the observed hyporeactivity was attributable to efferent sympathetic dysfunction, because the patients had normal responses to the cold pressor test. One other possible explanation for stress hyporeactivity that has not been ruled out by this or other studies and for which there is some indirect support is a dysfunctional cardiopulmonary receptor reflex. Engagement of cardiopulmonary receptors during mental stress results in vasodilation in the forearm (45) and perhaps in other major muscle beds, which, if excessive, could result in blunted blood pressure increases. A study of cardiopulmonary reflexes thus may be highly informative in clarifying the mechanisms of several core impairments in CFS. Hyporeactivity to mental stress may also be a symptom of a brain disease (46), for which there is some evidence in CFS (47, 48). This hypothesis can be tested using functional brain imaging (49).

We have previously shown that blood pressure hyporesponsiveness in CFS is symptom-related (6, 7). However, CFS symptoms vary considerably from day to day (50), and it cannot be assumed that the short-term and long-term patterns of illness have the same underlying pathology. Using energy scores on the day of testing and average 1-week symptom severity ratings as measures of short-term and long-term trends, we found each to be uniquely related to a different aspect of blood pressure hyporeactivity—SBP and DBP, respectively. Thus, it would appear that acute and chronic illness processes may selectively impair activity in cardiac and vasomotor regulatory pathways. This finding lends further support to a view that reduced responsiveness of the brain mechanisms mediating cardiovascular responses to mental challenges is an integral part of the pathophysiology of CFS in its less severe form. A broad literature review by Chrousos and Gold (51) suggested that reduced stress responsiveness may be the basis of symptoms in a number of unexplained illness conditions. This study provides a partial support for this view in CFS.

Decreased functionality in patients with CFS was only weakly related to symptom severity. This finding could indicate that the patients who reported severe symptoms overrated their illness, and that the difference between groups was perceptual rather than organic, or it may reflect a nonlinear relationship between symptoms and functioning, such that patients with more severe illness find ways to maintain some minimal level of activities through a greater effort or by other means. The coherent relationship between altered physiological functioning and symptoms in the present and earlier (6, 7) studies is in line with other evidence suggesting a biological basis of symptoms in CFS (52) and thus is not supportive of symptom amplification in CFS.

Overall, these results add to understanding of physiological bases of symptoms in CFS. They also show that classifying patients with CFS on illness severity may have a significant potential for unraveling the diversity of causes and pathogeneses of CFS, and in particular, for identifying patients with symptoms referable to peripheral cardiovascular abnormalities vs. those with abnormalities in central mechanisms of autonomic control.


   ACKNOWLEDGMENTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
REFERENCES
 
This study was supported by Grant U01-34427 from the National Institute for Allergy and Immune Disorders establishing the New Jersey CFS Cooperative Research Center.

Received for publication July 16, 2002.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGMENTS
 REFERENCES
 

  1. Komaroff AL, Fagioli LR, Doolittle TH, Gandek B, Gleit M, Guerriero RT, Kornish J, Ware NC, Ware JE Jr, Bates DW. Health status in patients with chronic fatigue syndrome and in general population and disease comparison groups. Am J Med 1996; 101: 281–90.[CrossRef][Medline]
  2. Wilson J, Walker P. Acute anterior poliomyelitis. Arch Intern Med 1936; 57: 477–92.[Abstract/Free Full Text]
  3. Ramsay AM. Myalgic encephalomyelitis and postviral fatigue states: the saga of Royal Free disease. 2nd ed. London: Gower Medical Publishing; 1988.
  4. Leon-Sotomayor L. Epidemic diencephalomyelitis: a possible cause of neuropsychiatric, cardiovascular and endocrine disorders. 1st ed. New York: Pagent Press; 1969.
  5. Dowsett EG, Ramsay AM, McCartney RA, Bell EJ. Myalgic encephalomyelitis—a persistent enteroviral infection. Postgrad Med J 1990; 66: 526–30.[Abstract/Free Full Text]
  6. Peckerman A, LaManca JJ, Smith SL, Taylor A, Tiersky L, Pollet C, Korn LR, Hurwitz BE, Ottenweller JE, Natelson BH. Cardiovascular stress responses and their relation to symptoms in Gulf War veterans with fatiguing illness. Psychosom Med 2000; 62: 509–16.[Abstract/Free Full Text]
  7. LaManca JJ, Peckerman A, Sisto SA, DeLuca J, Cook S, Natelson BH. Cardiovascular responses of patients with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise. Psychosom Med 2001; 63: 756–64.[Abstract/Free Full Text]
  8. Schondorf R, Benoit J, Wein T, Phaneuf D. Orthostatic intolerance in the chronic fatigue syndrome. J Auton Nerv Syst 1999; 75: 192–201.[CrossRef][Medline]
  9. Naschitz JE, Sabo E, Naschitz S, Shaviv N, Rosner I, Rozenbaum M, Gaitini L, Ahdoot A, Ahdoot M, Priselac RM, Eldar S, Zukerman E, Yeshurun D. Hemodynamic instability in chronic fatigue syndrome: indices and diagnostic significance. Semin Arthritis Rheum 2001; 31: 199–208.[CrossRef][Medline]
  10. Cooke WH, Hoag JB, Crossman AA, Kuusela TA, Tahvanainen KU, Eckberg DL. Human responses to upright tilt: a window on central autonomic integration. J Physiol 1999; 517: 617–28.[Abstract/Free Full Text]
  11. Iida R, Hirayanagi K, Iwasaki K, Ogawa S, Suzuki H, Yajima K. Non-invasive assessment of human baroreflex during different body positions. J Auton Nerv Syst 1999; 75: 164–70.[CrossRef][Medline]
  12. Dampney R, Coleman M, Fontes M, Hirooka Y, Horiuchi J, Li YW, Polson J, Potts P, Tagawa T. Central mechanisms underlying short- and long-term regulation of the cardiovascular system. Clin Exp Pharmacol Physiol 2002; 29: 261–8.[CrossRef][Medline]
  13. Conway J, Boon N, Jones JV, Sleight P. Involvement of the baroreceptor reflexes in the changes in blood pressure with sleep and mental arousal. Hypertension 1983; 5: 746–8.[Abstract/Free Full Text]
  14. Steptoe A, Sawada Y. Assessment of baroreceptor reflex function during mental stress and relaxation. Psychophysiology 1989; 26: 140–7.[Medline]
  15. Natelson BH. Chronic fatigue syndrome. JAMA 2001; 285: 2557–9.[Free Full Text]
  16. Peckerman A, LaManca J, Smith S, Latif S, Natelson B. Postural hemodynamics and cardiovascular stress responses in chronic fatigue syndrome [abstract]. Ann Behav Med 1998; 20: 98.
  17. Fukuda K, Straus SE, Hickie I, Sharpe MC, Komaroff A, Schluederberg A, Jones JF, Lloyd AR, Wessely S, Gantz NG, Holmes GP, Steele L, Reyes M, Abbey S, Rest J, Jolson H, Peterson DL, Vercoulen JHMM, Tirelli U, Evengard B, Natelson BH, Reeves WC. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994; 121: 953–9.[Abstract/Free Full Text]
  18. Pollet C, Natelson BH, Lange G, Tiersky L, DeLuca J, Policastro T, Desai P, Ottenweller JE, Korn L, Fiedler N, Kipen H. Medical evaluation of Persian Gulf veterans with fatigue and/or chemical sensitivity. J Med 1998; 29: 101–13.[CrossRef][Medline]
  19. Holmes GP, Kaplan JE, Gantz NM, Komaroff AL, Schonberger LB, Straus SE, Jones JF, Dubois RE, Cunningham-Rundles C, Pahwa S. Chronic fatigue syndrome: a working case definition. Ann Intern Med 1988; 108: 387–9.
  20. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee Arthritis Rheum 1995; 38: 19–28.[Medline]
  21. Peckerman A, Saab PG, McCabe PM, Skyler JS, Winters RW, Llabre MM, Schneiderman N. Blood pressure reactivity and perception of pain during the forehead cold pressor test. Psychophysiology 1991; 28: 485–95.[Medline]
  22. Smets EMA, Garssen B, Bonke B, De Haes JCJM. The multidimensional fatigue inventory (MFI): psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995; 39: 315–25.[CrossRef][Medline]
  23. Gerin W, Pieper C, Pickering TG. Measurement reliability of cardiovascular reactivity change scores: a comparison of intermittent and continuous methods of assessment. J Psychosom Res 1993; 37: 493–501.[CrossRef][Medline]
  24. Parati G, Casadei R, Groppelli A, Di Rienzo M, Mancia G. Comparison of finger and intra-arterial blood pressure monitoring at rest and during laboratory testing. Hypertension 1989; 13: 647–55.[Abstract/Free Full Text]
  25. Hughson RL, Quintin L, Annat G, Yamamoto Y, Gharib C. Spontaneous baroreflex by sequence and power spectral methods in humans. Clin Physiol 1993; 13: 663–76.[Medline]
  26. Blaber AP, Yamamoto Y, Hughson RL. Methodology of spontaneous baroreflex relationship assessed by surrogate data analysis. Am J Physiol 1995; 268: H1682–7.
  27. Thayer RE. The biopsychology of mood and arousal. New York: Oxford University Press; 1989.
  28. Karnofsky DA, Abelmann WH, Craver LF, Burchenal JH. The use of nitrogen mustards in the palliative treatment of carcinoma. Cancer 1948; 1: 634–52.[CrossRef]
  29. Ware JE, Snow KK, Kosinski M, Gandek B. SF-36 health survey: manual and interpretation guide. 1st ed. Boston (MA): The Health Institute, New England Medical Center; 1993.
  30. Mosqueda-Garcia R, Furlan R, Fernandez-Violante R, Desai T, Snell M, Jarai Z, Ananthram V, Robertson RM, Robertson D. Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt. J Clin Invest 1997; 99: 2736–44.[Medline]
  31. el Sayed H, Hainsworth R. Relationship between plasma volume, carotid baroreceptor sensitivity and orthostatic tolerance. Clin Sci (Lond) 1995; 88: 463–70.[Medline]
  32. Mtinangi BL, Hainsworth R. Early effects of oral salt on plasma volume, orthostatic tolerance, and baroreceptor sensitivity in patients with syncope. Clin Auton Res 1998; 8: 231–5.[CrossRef][Medline]
  33. Peckerman A, LaManca JJ, Dahl K, Qureishi B, Natelson BH. Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome. Am J Med Sci 2003; 326: 55–60.[CrossRef][Medline]
  34. Shepherd JT, Mancia G. Reflex control of the human cardiovascular system. Rev Physiol Biochem Pharmacol 1986; 105: 1–99.[Medline]
  35. Hasser EM, Bishop VS, Hay M. Interactions between vasopressin and baroreflex control of the sympathetic nervous system. Clin Exp Pharmacol Physiol 1997; 24: 102–8.[Medline]
  36. Paintal AS. The significance of dry cough, breathlessness and muscle weakness. Indian J Tuberculosis 1986; 33: 51–5.
  37. Gribbin B, Pickering TG, Sleight P, Peto R. Effect of age and high blood pressure on baroreflex sensitivity in man. Circ Res 1971; 29: 424–31.[Abstract/Free Full Text]
  38. Tank J, Baevski RM, Fender A, Baevski AR, Graves KF, Ploewka K, Weck M. Reference values of indices of spontaneous baroreceptor reflex sensitivity. Am J Hypertens 2000; 13: 268–75.[CrossRef][Medline]
  39. Avolio AP, Deng FQ, Li WQ, Luo YF, Huang ZD, Xing LF, O’Rourke MF. Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China. Circulation 1985; 71: 202–10.[Abstract/Free Full Text]
  40. Monahan KD, Tanaka H, Dinenno FA, Seals DR. Central arterial compliance is associated with age- and habitual exercise-related differences in cardiovagal baroreflex sensitivity. Circulation 2001; 104: 1627–32.[Abstract/Free Full Text]
  41. Virdis A, Ghiadoni L, Sudano I, Buralli S, Salvetti G, Taddei S, Salvetti A. Endothelial function in hypertension: role of gender. J Hypertens 2002; 20 (suppl 2): S11–6.
  42. Paton JF, Deuchars J, Ahmad Z, Wong LF, Murphy D, Kasparov S. Adenoviral vector demonstrates that angiotensin II-induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat. J Physiol 2001; 531: 445–58.[Abstract/Free Full Text]
  43. Steptoe A, Fieldman G, Evans O, Perry L. Cardiovascular risk and responsivity to mental stress: the influence of age, gender and risk factors. J Cardiovasc Risk 1996; 3: 83–93.[CrossRef][Medline]
  44. Schneiderman N, McCabe PM. Biobehavioral responses to stressors. In: Field TM, McCabe PM, Schneiderman N, editors. Stress and coping. Hillsdale (NJ): Lawrence Erlbaum; 1985. p. 13–61.
  45. Lindqvist M, Kahan T, Melcher A, Bie P, Hjemdahl P. Forearm vasodilator mechanisms during mental stress: possible roles of epinephrine and ANP. Am J Physiol Endocrinol Metab 1996; 270: E393–9.[Abstract/Free Full Text]
  46. Thomaides TN, Zoukos Y, Chaudhuri KR, Mathias CJ. Physiological assessment of aspects of autonomic function in patients with secondary progressive multiple sclerosis. J Neurol 1993; 240: 139–43.[CrossRef][Medline]
  47. Lange G, DeLuca J, Maldjian JA, Lee H, Tiersky LA, Natelson BH. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. J Neurol Sci 1999; 171: 3–7.[CrossRef][Medline]
  48. Lange G, Holodny AI, DeLuca J, Lee HJ, Yan XH, Steffener J, Natelson BH. Quantitative assessment of cerebral ventricular volumes in chronic fatigue syndrome. Appl Neuropsychol 2001; 8: 23–30.[CrossRef][Medline]
  49. Pozzilli C, Passafiume D, Bernardi S, Pantano P, Incoccia C, Bastianello S, Bozzao L, Lenzi GL, Fieschi C. SPECT, MRI and cognitive functions in multiple sclerosis. J Neurol Neurosurg Psychiatry 1991; 54: 110–5.[Abstract/Free Full Text]
  50. Fuentes K, Hunter MA, Strauss E, Hultsch DF. Intraindividual variability in cognitive performance in persons with chronic fatigue syndrome. Clin Neuropsychol 2001; 15: 210–27.[Medline]
  51. Chrousos GP, Gold PW. The concepts of stress and stress system disorders: Overview of physical and behavioral homeostasis. JAMA 1992; 267: 1244–52.[Abstract/Free Full Text]
  52. Komaroff AL. The biology of chronic fatigue syndrome. Am J Med 2000; 108: 169–71.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 GutHome page
D E J Jones, N Bhala, J Burt, J Goldblatt, M Prince, and J L Newton
Four year follow up of fatigue in a geographically defined primary biliary cirrhosis patient cohort
Gut, April 1, 2006; 55(4): 536 - 541.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Figures Only
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Peckerman, A.
Right arrow Articles by Natelson, B. H.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Peckerman, A.
Right arrow Articles by Natelson, B. H.
Related Collections
Right arrow Musculoskeletal
Right arrow Stress and Coping
Right arrow Other Cardiovascular Medicine

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS