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Catecholamines and heart rate in female fibromyalgia patients

Catecholamines and heart rate in female fibromyalgia patients
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  Catecholamines and heart rate in female  fi bromyalgia patients ☆ Roberto Riva  a, ⁎ , Paul Jarle Mork  b , Rolf Harald Westgaard  c , Tonje Okkenhaug Johansen  d , Ulf Lundberg  e,f  a Department of Psychology, Stockholm University, Sweden b Department of Human Movement Science, Norwegian University of Science and Technology, Trondheim, Norway c Department of Industrial Economics and Technology Management, Norwegian University of Science and Technology, Trondheim, Norway d Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway e Department of Psychology, Stockholm University, Stockholm, Sweden f  CHESS (Centre for Health Equity Studies), Stockholm University, Stockholm, Sweden a b s t r a c ta r t i c l e i n f o  Article history: Received 19 January 2011Received in revised form 12 September 2011Accepted 27 September 2011 Keywords: Chronic musculoskeletal painStressNoradrenalineAdrenalineDopamineAutonomic imbalance Background:  Fibromyalgia syndrome is a disease of unknown pathogenesis characterised by widespreadchronic musculoskeletal pain. Fibromyalgia has been associated with dysregulation of the stress systems,but results are inconsistent. Purpose:  To investigate autonomic nervous system activity (urinary noradrenaline, adrenaline, dopamine,and heart rate) of   fi bromyalgia patients and healthy controls. Methods:  Urinary catecholamines and heart rate were assessed for a 24-hour period in a controlled hospitalsetting (including relaxation, a test with prolonged mental stress, and sleep), and during daily activity in 29female  fi bromyalgia patients and 29 age-matched female healthy controls. Results:  With repeated measures ANOVAs, catecholamine levels were lower in patients than controls( P  =.035 for noradrenaline;  P  =.005 for adrenaline;  P  =.001 for dopamine). One-way ANOVAs for the singleperiods showed that patients compared to controls had signi fi cantly lower adrenaline levels during the night( P  =.010) and the second day ( P  =.010), signi fi cantly lower dopamine levels during the  fi rst day ( P  =.008),the night ( P  =.001), andthe second day( P  =.004). However, single timepoint noradrenaline levels were notsigni fi cantly different between the groups. Overall, heart rate was signi fi cantly higher in patients than con-trols ( P  =.014). Speci fi cally, signi fi cant differences emerged during relaxation ( P  =.016) and sleep( P  =.011), but not during stress provocation or daily activities. Conclusions:  The results indicate an altered regulation of the autonomic nervous system in  fi bromyalgia pa-tients, with attenuated activity of both the sympathetic (adrenal medulla component) and the parasympa-thetic branch.© 2011 Elsevier Inc. All rights reserved. Introduction Fibromyalgia syndrome is characterised by prolonged widespreadmusculoskeletal pain and multiple tender points [1]. Approximately3% of adults are affected, with a female-to-male ratio of about 5:1[2]. The incidence increases with age and peaks between 30 and50 years [3]. Comorbid symptoms commonly associated with  fi bro-myalgiainclude poorsleep quality, morningstiffness, fatigue,anxiety,depression, and psychosocial stress [1,4].According to the allostatic load model, the pathogenesis of psy-chosomatic diseases is associated with the physiological responsesto psychosocial stress [5]. Studies indicate that women with  fi bromy-algia are characterised by abnormalities in the major stress systems,the hypothalamic – pituitary – adrenal axis, with reduced levels of cor-tisol [6 – 9], and the sympathetic and the parasympathetic branchesof the autonomic nervous system [10 – 14]. However,  fi ndings are in-consistent [15].Assessment of catecholamines' release by the sympathetic ner-vous system is a commonlyused method to investigatethe regulationof sympathetic activity. Three primary catecholamines have beenidenti fi ed operating in the two main components of the sympatheticnervous system (the sympathoneural and the adrenomedullary),namely noradrenaline, adrenaline, and dopamine [13,16]. Previousresearch shows con fl icting  fi ndings as regards catecholamine levels inpatients with  fi bromyalgia during both basal and stressful conditions.Several studies show no differences in basal levels of noradrenalineand adrenalineinblood [17 – 21],orinurine[19,22], andinplasmanor- adrenaline and adrenaline levels after a reaction-time stress provoca-tion between  fi bromyalgia patients and healthy controls [17]. Onestudy found normal levels of plasma noradrenaline and adrenaline  Journal of Psychosomatic Research 72 (2012) 51 – 57 ☆  The study wasperformedat theDepartment of Human Movement Science,Norwe-gian University of Science and Technology, Trondheim, Norway. The analysis of urinarycatecholamines andthe statistical analyses forthe present paper were conducted attheDepartment of Psychology, Stockholm University. ⁎  Corresponding author at: Stockholm University, Department of Psychology; 106 91Stockholm, Sweden. Tel.: +46 8 163892; fax: +46 8 159342. E-mail address: (R. Riva).0022-3999/$  –  see front matter © 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.jpsychores.2011.09.010 Contents lists available at SciVerse ScienceDirect  Journal of Psychosomatic Research  aftera postural challenge test, role-playsimulatingasituationof verbalaggressionand ischemic pain stimulation [23], but low basalnoradren-aline levels in  fi bromyalgia patients [23]. However, another studyshowedhighnoradrenalinelevelsin fi bromyalgiapatientsbothatbase-line and after interleukin-6 injections, together with normal adrena-line levels [24]. Also, submaximal exercise, which mainly inducesa sympathoneural response, has been found to elicit attenuated nor-adrenaline and adrenaline secretion in blood in  fi bromyalgia patients[21]. Interestingly, other studies show normal noradrenaline levels,but attenuated adrenaline levels in the blood in  fi bromyalgia patientsduringstandardisedisometriccontraction[20,25],andafterhypoglyce-miainduction[18].Finally,dopaminelevelsinbloodorurinehavebeeninvestigated in a fewstudiesshowingnormal valuesduringdailyactiv-itiesin fi bromyalgia patients [19,24]. These inconsistencies may be dueto different types of stress provocation, i.e., mental or physical stress,which may have different physiological effects [17,18,23,24], or toparticipants being examined during or after a physical exercise ses-sion [21].In addition to catecholamines, heart rate and particularly restingheart rate are considered indicators of autonomic balance [11,26].Fewstudieshave investigated heartrate and catecholamines togetherin  fi bromyalgia patients, and the existing  fi ndings are inconsistent.One study showed increased sympathoneural activity, with high nor-adrenaline and heart rate, in  fi bromyalgia patients [24], while otherstudies reported an attenuated sympathoadrenal response, with lowadrenaline levelsandheartrate,in fi bromyalgiapatientsduringphys-ical exercise [21], muscular contraction [20,25], and stress provoca- tion [17,23].The aim of the present study was to compare autonomic nervoussystemactivityinlong-termfemale fi bromyalgia patientsandhealthycontrols. This study combines 24-hour measurements of urinarycatecholamines and heart rate, including two experimentalconditions(relaxationperiodandmentalstressprovocation),duringthenightandduring unconstrained daily activities. Moreover, participants providedsubjective ratings of pain in neck, shoulders and low back during thecorrespondingtimeperiods.Thepresentstudywasperformedinacare-fullycontrolledhospitalsetting,inwhichpatientsandcontrolshadsim-ilaractivities,thusallowingareliablecomparisonofautonomicactivity.Onthebasisofthemutualinteractionbetweenthemajorstresssystems[27] and on previous  fi ndings of attenuated hypothalamic – pituitary – adrenal axis activity in the same study sample [8], we hypothesisedthat  fi bromyalgia patients would show an altered activity of the auto-nomic nervous system compared with healthy controls. Methods Participants Twenty-nine female patients with  fi bromyalgia and 29 age-matched (±3 years) female healthy controls took part in the study(Table 1). The patients were mainly recruited through the local  fi bro-myalgia association in Trondheim, Norway. The controls wererecruited among donors to the hospital blood bank. Inclusion criteriawere age between 35 and 67 years. Upon inclusion in the study, eligi-ble  fi bromyalgia patients underwent a clinical examination to verifythe  fi bromyalgia syndrome diagnosis as de fi ned by the AmericanCollege of Rheumatology [1]. Number of years since the  fi rst symp-tom and number of years with con fi rmed diagnosis were retrievedfrom each participant's medical record (Table 1). Participantswere excluded if they had: a) cardiorespiratory, cerebrovascular,neurologic, neuromuscular, endocrine, infectious, metabolic, lung,or cancer disease, b) injury that affected function, c) connective tis-sue disorder, d) tendinitis or capsular affection of the shoulder joint,or e) highbloodpressure(i.e.,systolicpressure N 140 mmHgordiastol-ic pressure  N 90 mmHg) or were taking anti-hypertensive medication.Participants were also excluded if they were taking medicationthat may interact with neural, vascular, or muscular function or thephysiological measurements to be performed (e.g., antidepressants,antiepileptics,  β -blockers). After the clinical examination, 11 eligi-ble  fi bromyalgia patients were excluded because they did not ful fi lthe criteria. Fibromyalgia patients using analgesics and/or sleepmedicine on a regular basis were instructed to cease medication2 days prior to the experiment. All participants volunteered forthe study but they were compensated for travel costs and otherexpenses.The study protocol was approved by the Regional Ethics Commit-tees in Norway (project no. 4.2005.2728) and Sweden (Dnr 2006/87-31/1). The study was carried out according to the Declaration of Helsinki. Procedure Fig. 1 shows the order and time schedule of the data collection.Participants had dinner at the hospital-hotel next to the laboratorybefore meeting in the laboratory at around 4:45 p.m. After mountingthe electrophysiological recording equipment, a series of experimen-tal conditions was performed. First, participants were comfortablyseatedinanarmchairandwatchedacartoonmoviefor30 min(relax-ation period). A previous study found that watching cartoons is ac-companied by few changes in bodily sensation and only involvestemporary heart rate decrease [28]. Second, participants underwentstress provocation consisting of four six-minute periods alternatingbetweentheStrooptestandanarithmetictestwithbackwardcounting(mean duration 28 min, range 26 – 29 min), which provided high stressexposure [29]. Details of the experimental procedure have beenpublished elsewhere [8]. The experimenter performing the testswas blinded to the participants' diagnosis. After the laboratory ses-sion, all participants had an evening meal (bread, salad, fruit) ataround 8:30 p.m. and were then free to choose activities (e.g., read-ing, watching TV, playing cards), but were instructed to stay insidethe hospital-hotel. Before going to sleep in a comfortable room atthe hospital-hotel (mean time 11:33±0:29 p.m.) they completeda set of questionnaires including the Subjective Health Complaintsinventory, the Karolinska Scales of Personality, the Perceived StressScale, and the subscale Neuroticism of the Eysenck PersonalityQuestionnaire (for details see [8]). Upon awakening (mean time6:38±0:25 a.m.), the participants responded to a short question-naire on sleep quality and were then free to go home or to work. Urinary catecholamines Urine samples were collected over a 24-hour period to assesslevels of noradrenaline, adrenaline, and dopamine, and were divided  Table 1 Descriptive statistics for demographic and other background variables of   fi bromyalgiapatients (N=29) and healthy controls (N=29).Patients ControlsMean (SD) Mean (SD)Age (years) 52.1 (8.9) 52.7 (8.4)Body mass index (kg/m 2 ) 27.1 (5.9) 25.0 (3.5)No. of tender points 15.7 (2.2) Not addressedYears since diagnosis 5.5 (6.0) Not addressedYears since  fi rst symptoms 13.1 (8.6) Not addressed% (N) % (N)Employment fraction ≥ 50%* 24 (7) 90 (26)Smokers 24 (7) 21 (6)Exercise sessions per weekOnce 7 (2) 10 (3)1 – 3 times 69 (20) 59 (17) N 3 times 24 (7) 31 (9)*Patients signi fi cantly differ from controls ( P  b .001).52  R. Riva et al. / Journal of Psychosomatic Research 72 (2012) 51 – 57   into three periods for the statistical analysis (Fig. 1). The  fi rst peri-od comprises catecholamine levels from arriving at the hospital,when participants were asked to empty their bladders (meantimes 4:34±0:15 p.m. for controls and 4:43±0:12 p.m. for  fi bromy-algia patients; signi fi cantly different;  P  =.032), until the end of thestress provocation, when participants were asked to provide a urinesample (mean times 7:59±0:21 p.m. for controls and 8:01±0:17 p.m. for  fi bromyalgia patients; not signi fi cantly different; P  =.354); This measure is labelled  “ Day1 ”  in Fig. 1. The secondperi-odincludescatecholaminelevelsfromtheendofthestressprovocationuntilwaking up onthe secondday, when all participantswereasked toprovide a urine sample (mean times 6:39±0:36 a.m. for controls and6:41±0:27 a.m. for  fi bromyalgia patients; not signi fi cantly different; P  =.761); this measure is labelled  “ Night ”  in Fig. 1. The thirdperiod in-cludescatecholaminelevelsfromwakingupontheseconddayuntilthelast urine sample in the afternoon (mean times 2:09±1:51 p.m. forcontrols and 3:51±1:06p.m. for  fi bromyalgia patients; signi fi cantlydifferent;  P  b .001). This  fi nal measure is labelled  “ Day2 ”  in Fig. 1.To determine the excretion of urinary catecholamines, the volumeof urine was measured and its pH adjusted to 3.0 with 6 M HC1. Then,20 ml of each sample was frozen ( − 18 °C) until being analysed fornoradrenaline, adrenaline and dopamine by high-pressure liquidchromatography. Finally, catecholamine concentration was multi-plied by volume and divided by time, and expressed in terms of picomol/min. Heart rate To measure heart rate, a portable recording system (MyomonitorIV, Delsys Inc., Boston MA) was used to record a modi fi ed lead II elec-trocardiogram from the beginning of the laboratory session until 1 hafter the participants woke up the next morning. The QRS complexwas detected, and the intervals between the R peaks (R  – R intervals)were derived on a beat-by-beat basis. Data were corrected for arte-facts and heartbeats with inter-beat interval  ≤ 0.4 s were omittedfrom further analysis. Finally, a mean value of the heart rate was cal-culated for each participant during the relaxation period, the stressprovocation, and the sleep period.After the electrocardiographic recording equipment was removedupon awakening the second day, participants were equipped with aPolar heart rate monitor S610. The mean R  – R intervals of every  fi ve-second period were used to obtain a heart rate expressed as beatsper minute. Finally, a mean heart rate value during daily activitywas calculated for each participant. Additionally, a Silva step counterwas used to record the number of steps during the second day, as anindicator of physical activity. Self-ratings On arrival, after relaxation, after the mental stress provocationon the  fi rst day, and upon awakening on the second day, all partic-ipants were asked to rate their levels of general tension, pain(neck/shoulder, low back), and mental fatigue on a visual analoguescale (VAS, 0 – 100 mm) and physical fatigue on Borg's scale [30].Right before bedtime the participants were asked to  fi ll in a shortdiary to describe their activities during the evening (after the labo-ratory session) and the number of cigarettes smoked and cups of coffee consumed during the day. Statistical analysis A repeated measures mixed ANOVA, using Greenhouse – Geissercorrection of degrees of freedom if the sphericity assumption was vi-olated, was conducted to investigate differences between patientsand controls. Periods of measurements for the catecholamine levelsand for the heart rate served as within-subject factor. The between-subject factor was the group ( fi bromyalgia patients vs. healthy con-trols). Additionally, separate one-way ANOVAs were conducted foreach single time point for noradrenaline, adrenaline, and dopaminelevels, heart rate values, and self-reported pain and fatigue, withgroups ( fi bromyalgia patients vs. healthy controls) as between-subjects factor. The signi fi cance level (alpha) was set to  P  b 0.05.Pearson's r and Spearman's  ρ  values were used to explore possiblecorrelations between variables excluding cases list-wise. Correlationswere calculated separately for  fi bromyalgia patients and healthy con-trols when there was a signi fi cant difference between groups, whilein the other cases correlations were calculated including the wholesample (N=58). The two methods showed the same results andonly correlations based on the Pearson's r are reported. Variablesknown to in fl uence catecholamines secretion, including age, bodymass index, number of cigarettes smoked, coffee intake, total amountof sleep, sleep ef  fi ciency (i.e., total amount of sleep divided by totaltime in bed), sampling time, and physical activity (i.e., average num-ber of exercise sessions during a week, and number of steps duringthe secondday)[31,32], were introducedas covariatesinthe ANOVAsif these variables correlated with the dependent and the independentvariables. Fig. 1.  Order and time schedule of the data collection. Urine samples were collected throughout the experimental session. For the statistical analysis the urine samples were dividedinto three periods:  “ Day1 ” , “ Night ” , and  “ Day2 ” . Recording equipment was mounted immediately after participants' arrival at the hospital (4:45 p.m., range 4:30 – 5:00 p.m.) fol-lowed by an experimental session with laboratory recordings. After an evening meal, the participants were free to choose activities (e.g., reading, watching TV, playing cards)until bedtime. One hour after awakening, participants were equipped with a heart rate monitor and a step counter before going home or to work.53 R. Riva et al. / Journal of Psychosomatic Research 72 (2012) 51 – 57   Results Catecholamine levels Catecholamine levels were generally lower in  fi bromyalgia patients than inhealthy controls. For the noradrenaline levels, a repeated measures ANOVA showed asigni fi cant effect of group ( F  (1,49)=4.70;  P  =.035), of period ( F  (2,98)=135.02; P  b .001), but no interaction effect ( F  (2,98)=2.26;  P  =.118). For the adrenaline levels,there was a signi fi cant effect of group ( F  (1,47)=8.81;  P  =.005), of period ( F  (2,94)=83.84;  P  b .001), but no interaction effect ( F  (2,94)=2.11;  P  =.127). For the dopa-mine levels, there was a signi fi cant effect of group ( F  (1,49)=13.21;  P  =.001), of peri-od ( F  (2,98)=34.55;  P  b .001), but no interaction effect ( F  (2,98)=1.49;  P  =.231).Separate one-way ANOVAs on the single periods showed signi fi cant differences dur-ing the night and the second day for adrenaline, during all the time periods for do-pamine, whereas the differences for noradrenaline failed to reach signi fi cance(Fig. 2). Table 2 shows means, standard deviations, con fi dence intervals, and  F  values for the catecholamine levels during the three periods of measurements. Heart rate Mean heart rate was higher in  fi bromyalgia patients than in healthy controls. A re-peated measures ANOVA showed a main effect of group ( F  (1,35)=6.76;  P  =.014), of period ( F  (3,105)=64.43;  P  b .001), but no interaction effect ( F  (3,105)=1.25; P  =.295). Separate one-way ANOVAs on the single periods showed signi fi cant differ-ences during the relaxation period and during sleep, but not during stress provocationor during daily activities (Fig. 3). In addition, a mixed between-within subjects ANOVAshowed a signi fi cant difference between the relaxation period and the stress provoca-tion ( F  (1,56)=60.83;  P  b .001), no signi fi cant difference between patients and controls( F  (1,56)=2.77;  P  =.101), and a signi fi cant interaction effect ( F  (1,56)=7.81; P  =.007). Table 3 shows means, standard deviations, con fi dence intervals, and  F   valuesfor heart rate during the four periods of measurements. Self-ratings Patients with fi bromyalgia had signi fi cantly higher subjective ratings of pain in theneck/shoulders and low back, of general tension, and mental and physical fatigue thandid the healthy controls (Table 4). Among  fi bromyalgia patients signi fi cant negativecorrelations were found between noradrenaline-day2 and low back pain during thelast 6 months (r= − .49; N=24;  P  =.016), between adrenaline-day2 and physical fa-tigue (r= − .42; N=24;  P  =.041), between heart rate during sleep and low back painduring the last 6 months (r= − .49; N=21;  P  =.025), and a signi fi cant positive corre-lation between heart rate during relaxation and low back pain during the last 24 h(r=.50; N=21;  P  =.022). In addition, among healthy controls signi fi cant negativecorrelations were found between noradrenaline-day2 and low back pain during thelast 6 months (r= − .42; N=23;  P  =.044), between adrenaline-day1 and general ten-sion (r= − .45; N=23;  P  =.032), and between heart rate during stress provocationand physical fatigue (r= − .56; N=16; p=.024). Potential confounders With an independent-samples  t   test, there was no difference between patients andcontrols for the variables that may in fl uence the catecholamine secretion, such as age( t  (56)=.26;  P  =.796), body mass index ( t  (55)= − 1.554;  P  =.127), number of ciga-rettes smoked ( t  (56)=0;  P  =1), coffee intake ( t  (56)=.22;  P  =.830), average numberof exercise sessions during a week ( t  (56)=.23;  P  =.822), and number of steps duringthe second day ( t  (47)= − .118;  P  =.907). The only variables that showed a signi fi cantdifference between patients and controls were the total amount of sleep ( t  (46)=3.80; P  b .001), and the sleep ef  fi ciency ( t  (46)=3.16:  P  =.003), with lower values for the  fi -bromyalgia patients. The correlations for this variable were calculated separately forthe two groups. Among healthy controls, a signi fi cant positive correlation was foundfor total amount of sleep versus dopamine-night (r=.65; N=17;  P  =.005), but no sig-ni fi cant correlations were found with heart rate. After adjusting for the total amount of sleep, the difference between  fi bromyalgia patients and healthy controls remained sig-ni fi cant ( P  b .05). Discussion In the present study, we found lower urinary catecholamine levelsin  fi bromyalgia patients than in healthy controls with signi fi cant dif-ferences for adrenaline and dopamine levels, but not for noradrena-line levels. The present study showed elevated resting levels of heart rate in  fi bromyalgia patients compared with healthy controls.Signi fi cant differences were found during the relaxation period inthe laboratory and during sleep, but not during the stress provocationor daily activities on the second day. Finally, in line with expectations, fi bromyalgia patients had signi fi cantly higher self-reported pain andtension as well as mental and physical fatigue than did healthycontrols and, as reported previously, more psychological problems[4,8,18,23]. In the present study, self-ratings (particularly back painand physical fatigue) correlated with noradrenaline and adrenalinelevels, and with heart rate.The results of the current study indicate an altered regulation of the autonomic nervous system activity in  fi bromyalgia patients. Thepatients' high resting heart rate may suggest that  fi bromyalgia pa-tients have an attenuated parasympathetic activity with low heartrate variability [26]. The low heart rate variability has also beenreported in a forthcoming paper of our group for the  fi bromyalgia pa-tients from the same study sample [33]. However, the heart rate in  fi -bromyalgia patients was similar to that of controls during mental Fig. 2.  Bar plot showing the mean values in  fi bromyalgia patients (N=29) and healthycontrols (N=29) during the three periods of urinary measurements ( “ Day1 ” ,  “ Night ” ,and  “ Day2 ” ) for the levels of noradrenaline (A), adrenaline (B), and dopamine (C).Error bars represent 95% CI. * P  b .05, ** P  b .01.54  R. Riva et al. / Journal of Psychosomatic Research 72 (2012) 51 – 57   stress provocation and during daily activities. Additionally, partici-pants' higher heart rate on the second day compared with heartrate on the  fi rst day may be explained by differences in participants'physical activity between the 2 days. On the  fi rst day, participantsunderwent the stress provocation in a seated position, while duringdaily activities on the second day they were more physically active.Interestingly and in line with previous reviews [13], patients' lowlevels of adrenaline and dopamine during sleep and on the secondday suggest an attenuated activity of the adrenal medullary compo-nent of the sympathetic nervous system in fi bromyalgia patients. Pre-vious research has shown that the synthesis and release of noradrenaline are constantly stimulated under chronic stress condi-tions [34]. Thus, a lack of suf  fi cient synthesis of the neurotransmitterleads to a depletion of noradrenaline storage vesicles and preventstheir re fi lling [34]. Furthermore, an altered sensitivity of the cardiac β -adrenoceptors or a reduction in the parasympathetic tone to theheart may occur in  fi bromyalgia patients in response to stimulationof the stress system [24]. Among the  fi bromyalgia patients studiedhere, noradrenaline levels did not differ signi fi cantly from those of healthy controls, but the lower adrenaline levels and the elevatedheart rate during rest may follow the pattern of altered cardiac sensi-tivity of the  β -adrenoceptors previously described in fi bromyalgiapa-tients [24], and in other diseases, such as diabetes and uraemia [35]. Previous  fi ndings on the catecholamine levels show inconsistent re-sults. Among the studies that have examined urinary catecholaminesin  fi bromyalgia patients and healthy controls, one has shown normal24-hour adrenaline, noradrenaline and dopamine levels during dailyactivities, but responses to stress provocation were not measured[19]. Additionally, normal catecholamine values have been found,but only when collecting 12-hour overnight urine samples [22].The differences in the catecholamine levels between the twogroups found in the present study might also be explained by differ-ences in work-related stress exposure (i.e., employment fractionwashigherinhealthycontrolsthanin fi bromyalgiapatients).However,work-related stress exposure could have in fl uenced the catecholamineexcretion only during the second day, because during the  fi rst day andnight  fi bromyalgia patients and healthy controls were tested in thesame well-controlled hospital environment. In addition, on the secondday  fi bromyalgia patients provided their last urine sample later thanthe healthy controls. Because of the diurnal variation in catecholaminelevels, this difference might have contributed to the lower catechol-amine levels among fi bromyalgia patients compared with healthy con-trols on the second day, but no differences in time of urine samplingoccurred after the stress provocation and upon awakening. Moreover,the autonomic nervous system is also in fl uenced by genetic and envi-ronmental factors, and the interplay between such factors [36]. Differ-ences in catecholamine levels between groups might be explained byageneticvulnerabilityin fi bromyalgiapatientslinkedtotheexpressionof catechol- O -methyltransferase (COMT) [36], an enzyme responsiblefor the degradation of the catecholamine neurotransmitters [37]. Fi-nally, it is still unclear whether the altered activity of the stress sys-tems in  fi bromyalgia patients results from decreased sympatheticactivity, decreased parasympathetic activity, or a combination of both, as pointed out by other authors in their neurovisceral integrationmodel [38]. Additional studies investigating heart rate variability in  fi -bromyalgia patients may provide more detailed explanations.The present study included an analysis of relevant confounders.Release of catecholamines, especially noradrenaline, and heart ratecan be in fl uenced by physical demands and body posture [39,40].Thus, the higher heart rate in  fi bromyalgia patients compared to con-trols might also be explained by differences in nocturnal activities, asshowed in another study [41]. Furthermore, catecholamine secretion  Table 2 Mean (M), Standard Deviation (SD), 95% Con fi dence Interval (CI),  F   value, and signi fi cance level for the ANOVAs on the urinary catecholamines (noradrenaline, adrenaline, dopa-mine) at the three different points of the experimental session. Comparisons between  fi bromyalgia patients (N=29) and healthy controls (N=29). Values are expressed inpmol/min.Catecholamines Patients Controls  F   valueM SD CI M SD CINoradrenaline: Day1 103.3 47.0 84.7 – 121.9 113.7 46.8 95.2 – 132.2 .66Night 28.4 14.5 22.8 – 34.0 36.6 23.7 27.5 – 45.6 2.45Day2 109.2 44.5 92.0 – 126.5 133.2 45.6 114.8 – 151.6 3.81Adrenaline: Day1 17.2 11.0 12.9 – 21.6 22.1 9.4 18.4 – 25.8 3.04Night 3.1 1.9 2.3 – 3.8 5.1 3.4 3.8 – 6.4 7.16  ⁎ Day2 14.5 7.0 10.9 – 18.0 21.2 9.3 17.4 – 25.0 7.09  ⁎ Dopamine: Day1 660.3 409.0 498.5 – 822.1 1028 565.6 804.2 – 1251.7 7.49  ⁎⁎ Night 328.1 193.7 253.0 – 403.2 584.2 319.5 460.3 – 708.1 13.16  ⁎⁎ Day2 749.5 404.9 595.5 – 903.5 1183.2 635.2 926.6 – 1439.7 9.31  ⁎⁎⁎  P  b .05. ⁎⁎  P  b .01. Fig. 3.  Bar plot showing the mean heart rate values in  fi bromyalgia patients (N=29)and healthy controls (N=29) during the different periods of measurements (relaxa-tion, stress provocation, sleep, and day 2). Error bars represent 95% CI. * P  b .05.  Table 3 Mean (M), Standard Deviation (SD), 95% Con fi dence Interval (CI),  F   value, and signi fi -cance level for the ANOVAs on the heart rate during different periods on two days of measurement. Comparisons between  fi bromyalgia patients (N=29) and healthy con-trols (N=29). Values are expressed in beats per minute.Heart Rate Patients Controls  F   valueM SD CI M SD CIRelaxation (TV) 71.9 8.1 68.9 – 75.1 66.7 8.2 63.6 – 69.8 6.13  ⁎ Stress provocation 75.8 8.0 72.8 – 78.8 74.6 6.9 72.1 – 77.4 .29Sleep 67.8 6.4 65.2 – 70.5 62.4 7.8 59.2 – 65.6 7.09  ⁎ Day2 88.2 9.8 84.1 – 92.4 82.8 10.6 77.7 – 87.9 3.03 ⁎  P  b .05.55 R. Riva et al. / Journal of Psychosomatic Research 72 (2012) 51 – 57 
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We need your sign to support Project to invent "SMART AND CONTROLLABLE REFLECTIVE BALLOONS" to cover the Sun and Save Our Earth.

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