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The muscle metaboreflex during exercise in chronic obstructive pulmonary disease Sherman, Megan F. B. 2010

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 THE MUSCLE METABOREFLEX DURING EXERCISE IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE   by  MEGAN F.B SHERMAN  B.Kin., McMaster University, 2007    A THESIS SUBMITED IN PARTIAL FULLFIMENT OF THE REQUIREMENTS FOR THE DEGREE OF  MASTER OF SCIENC  in  THE FACULTY OF GRADUATE STUDIES (HUMAN KINETICS)   THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  February 2010 © Megan F.B. Sherman, 2010  ii ABSTRACT  Chronic obstructive pulmonary disea (COPD) is charaterisd by deteriorating lung and irway function.  Altered peripheral skeleta musle propertis, favouring glycolytic metbolis, re also wl-documnted in this popultion.  Skelta muscle properties uch as thos found in COPD patients may have significant efcts on the gnitude ofthe muscle metaboreflex.  Hypothss: Itws hypothesizd tha the muscle taboreflex would be gnifid in people with COPD compared to althy controls, and tha dis sverity and exercise capaity ould be orrelated with he mgnitude of the muscle taboreflex.  Mthods: Eleven people with mild-tosvere COPD (FEV1.0 = 56.3 ± 7.4% preditd) nd 11 age- nd gender- matched ontrols performed isometric handgrip exercise (IHG) for 2.5 minutes, t 35% VC, followed by 2 minuts of post-xercis circulatory occlusion (PECO).  Hemodynaic hanges wre easured throughout the protocol to se the magnitude ofthe taboreflex.  Particpants lo performed a progresive cycle ts to volitonal exhaustion. Results: Hrt rate, man rterial presure (MAP), leg blood flow and leg vascular resitance responss were silr betwn the COPD group and controls throughout IHG nd PECO (%! from basline) (p > 0.05).  Heart rate was highest minute 2.5 of IH (COPD 18 ± 4%, control 18 ± 3%) and returned to basline during PECO, whil MAP peaked t minute 2.5 of IHG (COPD 29 ± 5%, control 30 ± 3%) and remained elvatd throughout PECO (COPD 25 ± 3%, control 21  2%).  Total peripheral resitnc ros more in the D group throughout the protocol and pproached significance tminute 2 of PECO (COP 39 ± 9, control 18 ± 4%, p = 0.09).  Cardi output remined significantly higher throughout IHG and PECO in the control group (IHG 2.5 in: COPD 0.08 ± 7, ontrol 17 ± 4%, p = 0.01).  There was no asociton betwen disea sverity (r = -0.22, p = 0.32) or exercise capaity (r = -0.02, p=0.92) nd the magnitude ofthe muscle taboreflex. Conclusion: The musle taboreflex is preerved in  iii people with COPD.  The mechanis responsible remain unclear, however, unchanged upper limb skelta muscle propertis and desensitzaion of peripheral frents to metabolites are plausible explnations.   iv TABLE OF CONTENTS  ABSTRCT..................................................................................................................................ii TABLE OF CONTENTS............................................................................................................iv LIST O TABLES........................................................................................................................v F FIGURES.....................................................................................................................vi LIST O ABBREVIATIONS....................................................................................................vii ACKNOWLEDGMENTS.........................................................................................................vii ITRDUTIN........................................................................................................................1 OBJECVES & HYPOTHES..............................................................................................8 METHDS....................................................................................................................................9 RESULTS....................................................................................................................................16 DISCUSSION..............................................................................................................................27 REFERENCES...........................................................................................................................38 APDIX A: REVIEW OF LITERATURE.........................................................................46 ENI B. INDIVUAL RW DTA............................................................................65   v LIST OF TABLES  Table 1:  Canadian Thoraci Society COPD clasifcation...........................................................2 l 2: The Medicl Research Council dyspne sle..............................................................11 Table 3:  T modifid Borg scle..............................................................................................14 l 4: Descriptive charatristi and resting pulmonary function..........................................16 Table 5:sripti cracteristic and resti ry ftion for men and women........17 l 6: Heart rate variability parametrs...................................................................................18 Table 7: Rest and pek exercis values.......................................................................................19   vi LIST OF FIGURES  Figure 1: Changes in HR during IHG and PECO........................................................................20 i 2:s in MAP duri a....................................................................21 Figure 3: Changes in LBF during IHG and PECO......................................................................22 i 4:s in LVR duri a.....................................................................23 Figure 5: Changes in Q during IHG and PECO..........................................................................24 i 6:s in TPR duri a......................................................................25 Figure 7: Relationship betwen disea sverity and the muscle mtaboreflex..........................26 i 8:ltihitn exercis cpacity and tltfl........................    vii LIST OF ABBREVIATIONS  BMI = body mas index COPD = chronic obstructive pulmonary disease  EFL = expiratory flow litaion Fb = breathing frequency EV1.0 = forced expiratory volume in 1 second HF = high frequency band HR = heart rate  HRV = hert rat variability IHG = isometric handgrip exercise LBF = lg blood flow LF = low frequency band LVR = leg vasculr resitnce MAP = man arterial presure MVCximl voluntry contraction PECO = post-exercise circulatory oclusi etC2 = partial presure of end-tidal carbon dioxide Q = cardic output SaO2 = arterial blood oxygen saturation TPR = totl peripheral resitnce VO2peak = peak oxygen uptake VE = minute ventilton T = tidal volum  vii ACKNOWLEDGMENTS  I would like to expres my gratiude to everyone who provided me with support and encouragement throughout y acdeic arer.  I am grteful to y supervisor Dr. Wilm Shel for his guidance tl stge of y Mster’s degre and for providing e with opportunities to further my larning and love ofscinc.  ny thanks go to Dr. Jremy Road for helping with  inception of this project and throughout data colletion.  r. on McKenzi I want to hank not only for providing m with valuable advie nd input on this theis, but for giving me an opportunity o work outside the laboratory sting with omen who continualy inspire m.   A special thanks to my lab tes in the Health nd Integrative Physiology Laboratory for providing valuable insght nd knowldge and creting  wlcoming learning environment.  I am extremely gratful to Emily Mitchel Simone Tomzak for their moral support and sntil help during data collection.   Finaly, I m specialy grateful to Micha Ben-Zvi for his patienc and constant encourageent and to y fily nd frinds, whose support has been critial to my suces. I will never truly be able to articulate just how important you al are to m.  1 INTRODUCTION  Chronic obstructive pulmonary disea (COPD) is aprogresive condition charaterisd by impaired lung and irway function.  Eighty milon people worldwide urrently ive with oderate-tosevere COPD, nd the World Health Organization anticpates aths from the disa wil rise by almost 30% over t next 10 yers (89).  In 2005, 52,296 Canadins were dignosed ith COPD, cting the alth cre system approxiately $5,178 per cas (52).  Pulmonary ipairments aount for 35% of deaths in this popultion, while rdiovasular disea nd cancrs c for another 48% (56).  These taistc emphasiz the need for fctive smoking esation nd rehabilitaon programs tha work to iprove quality of lif and reduce the number of deaths cused by COPD and related co-morbidities. A more comprensive understanding of the pathophysiology underlying this diase ight contribute to improving the efectivenes of tse rehabilitaon programs.  Approximatly 85% of COPD cse re caused by exposure to obaco smoke, while 14% are cused by workplace irritants uch as dust nd fums (89).  Asmal number of cas, 1-2%, re d a geneti ondition, lpha1-ntitrypsin deficency, in which  defiency in elaste inhibitor cuses latic fbres ofthe lung to be broken down (41).  Regardls ofthe cus, the symptoms xperinced by people with COPD remain the same nd include: fatigue, exertional dyspnea (breathlsne), xcsive sputum production nd chronic oughing (89).  As COPD progrese, n individual’s ability o perform low intensity exercise alo delines, a isevidenced by lowr maxil oxygen uptke values, and  stronger sation of dyspne tlower xercis intnsites.  This exercise intoleranc often becomes the most pervasive ymptom making activis of daily living (e.g. walking up stairs) chalnging to perform (4).    Chroni obstructive pulmonary dise primrily afects he lungs and irways, thus, diagnosis and clasifcation of disea sverity is ade basd on pulmonary function; forced  2 expiratory volume in 1 second (FEV1.0) relative to forced vital cpaity (FVC) of les than 70% post-bronchodilator is usd to diagnose COPD, whil dis severity is clasifd acording to the percent predicted FEV1.0 an individual achieves (55) (Tabl 1).   Tabl 1: Canadian Thoraci Society COPD lasifction.  FEV1.0 = forced xpiratory volume in 1second;% preted = percnt ofpredicted FEV1.0 ahieved acording to age, nder and z adjustd norml vaues (9).  Clasifcation  Criteria Mild FEV1.0 " 80 % predicted Moderate 1.0 = 50-80 % predit Severe FEV1.0 = 30-50 % predicted Vry sre 1.0 " 30 % predit  Pulmonary Pathophysiology There a two major subtypes ofCOPD, the first, chronic bronchitis, afects airwys, while t second, ephyse, fects he lungs.  Most people with COPD have ombination of the to (53).  In the lungs, mphysa cuses parenchymal damage leading to reductions in lung elastic reoil and increased lveolr dead sce.  In the irwys, chronic bronchitis generats inflamtion which uss airwy remodeling and wal thikening (53).  These altered airwy properties, primarily in the peripheral irwys, cn ontribute to xaggeratd lumn dimetr narrowing nd consequently ead to expiratory flow limtaion during dynamic exercis and ven at rest in peopl with svere COPD (53; 58).  Expiratory flow litaion, combined with reduced lung elastic reoil, imt he aximl expiratory fl rate an individual with COPD isabl to achive.  During dynaic exercis, a ventilaton incres to met metabolic demnds, ventiltory flow rates must also increse, mking it dificult for peopl with COPD who ha saler maxil f rates to pty their lungs suffiently before commencing their next breth.  Brething at higher lung volumes, wre there isl resitance  3 to flow, people with COPD are ble to reduce their expiratory flow limtaion (57; 59).  Termd dynamic hyperinflation, this ft in the flow volum loop to higher lung volumes placs the diaphragm in  positon where t length-tension relationship is ub-optimal nd the elsti workload on the respiratory muscls increas, ultimtely ading to ltered ventilatory mechanis and increased total work of brething (12; 53).   Periphal Skeltal Muscle Pathophysiology Whil COPD isaocitd primarily with deteriorating lung and irway function, it shypothesized tha peripheral uscle hanges alo company the dise nd contribute to exertional dyspnea nd exercis ntolranc (24; 25; 44-46; 87).  Muscl biopsies taken from the vastus lateralis n peopl with COPD suggest oxidative enzyme ativiy nd mitochondrial density s reduced and tha fibre type distribution difrs from tha ofhealthy older dults.  Specifaly, the ctiviy of 3-hydroxy-CoA dehydrogenase, citrae synthase nd cytochrome oxidase, key enzymes beta-oxidation, the citri acid ycl and the lctron transport hain, respectively, are lowr in people with COPD.  Reduced concentrations ofthese nzymes iindiati of reduced capaity of oxidative metabolis.  An increased proportion of type-II glycolytic fbres and red proportion of type-I oxidative fibres re lso wel documentd in the lower limbs ofpeople with COPD.  These changes are particularly notorthy as they are opposit o the changes acompanying althy geing, where greter proportion of type-I oxidative fibres ioften present (25).  Gosker et al. (24) measured hybrid type-I/IIA and t-IIA/IIB transiton fibres in the vastus latralis ofpeopl with COPD and healthy ge-mtched controls in aefort to explain t divergent fibre type distributions mesured in tse two populations.  Alrger proportion of transiton fis were present in the COPD group compared to controls uggesting COPD efcts peripheral skelta muscl properties and leds to fibre type onversion (type-I to ype-I/IIA to ype-IIA to ype-IIA/IIB to ype-IIB).  Thes findings support  4 several other studies which have observed the presenc ofa greter proportion of glycolytic type-II fibres in peopl with COPD (24; 25; 71).    The phosphogen system relies on the breakdown of phosphocreatine to provide energy quickly at  onset ofxercis and gain during transitons to higher exercise intnsits.  Reltive to helthy controls, people with COPD, rely more on the phosphogen systm for energy provision and re slower to resynthesiz phosphocreatine following a bout ofsustained xercis (90).  The consequenc isan exaggerated acumultion of inorganic phosphates nd lower intracelular pH in the working muscl of person with COPD following high intnsity xercis (90).   In contrast o the oxidative and phosphogen systems which might becompromised in people with COPD, t glycolytic system ppears to be presrved.  Concentrations ofa number of key rat-limting glolyti enzyms uch s phosphofructokinas, pyruvat dehydrogenase and lctae dehydrogenase are simlar in people with COPD and healthy controls (24; 27; 46).  Despit simlr concntrations ofthese glycolytic nzymes, lcte production during exercise xaggerated in people with COPD (46).  Musle biopsis wre taken from the vastus latralis ofpeopl with COPD and healthy controls during a stpwise xercise t on a cycle rgometr.  Despit imlar evels oflcte dehydrogenase nd phosphofructokinas, the COPD group had a larger nd “xcsi” ris in blood lact lvels for a given exercise ntnsity compared to controls (46).   The efct reduced oxidative capaity, reduced phosphocreatine potential, nd greater lacte production has on xercise tolrance in peopl with COPD isnot wl understood.  Howver, significant sociatons betwn thes keleta muscle haracteristic and reduced exercise tolrance have been mde (25) including a positve orrelation betwn itrae synthas concntrations and peak oxygen uptake (VO2peak) (r = 0.33, p = 0.006) (45).  5 A number of mechanis have been proposed to xplain the changes in keleta muscle properties highlightd above: 1) disus, occurring as people with COPD avoid activis whih elict dyspnea, 2) mlnutrition, the underlyiuse remains unknown, but its ommon in peopl with COPD and efcts protein balance (17); 3) xposure to cortiosteroid therapies, usd to miniize pulmonary litaions (4) nd; 4) chronic e to hypoxia nd hypercapne, resulting from the ventilton-perfusion misath nd asocited with impaired ventiltory mechanis (4).  Tse mchanis are not wel understood, howver, combined they contribute to nges in kelta usle properties hich are hypothesized to ontribute to  developmnt of exercise intoleranc in peopl with COPD.  The Muscletaboreflx Three systms are thought to regulate he cardiovascular responses to voluntary exercise: central comand, the rteril baroreflx nd t presor reflex (68; 81).  The presor reflx is prised of two components: the mechanoreflex and the mtaboreflex (or cmoreflex).  While the mchanoreflex is lited by nialy snsitve group III frents located peripheraly in skeleta usl, the muscl taboreflex relies onchemialy sensitve group IV ferents alo loctd in skeleta le (67).  Anumber of tbolits re invold in the inition nd control ofthe muscl taboreflex during exercise ncluding: lacte, hydrogen ions, potasium ions, analogues of ATP nd intrstial phosphats (35; 51).  Conceptualy, the muscle metboreflex aims to corret amistch betwen oxygen supply and demand prevent xcs tabolite cumultion in working tisue (42).  There isome bate sto he efctines ofthe metboreflex in restoring blood flow to working tisue (34).  Howver, it sthought tha to achive homostasi betwen blsupply and demand during exercise, initaion of the muscle metboreflex, incres ympatheic nerve ctiviy, nd consquently, rais rt rate (HR), ventricular contractily, blood presure and redistributes blood to active tisue awy from  6 inactive tisue through vasoconstricion (68; 90). This reponse istermd “the presor response”.    To sparate he efct he muscle taboreflex has on the magnitude ofthe presor response, indepent from t efts inducd by cntral comnd, t rterial baroreflex and the mchanoreflex, one can perform ischemi exercise (e.g. isetric handgrip xercis (IHG)), followed idiatly by post-exercis irculatory occlusion (PECO) and cesation of handgripping.  In this model, the by-products cumulted during IHG remin trapped in the rm during PECO (47). The build-up of metabolites from the  isensd by group IV aferents prompting arise HR, blood presure nd lg vascular resitanc (LVR), while blood flow (LBF) to inactive tisue (in this cae the legs) derese.  Incresed crdia output (Q) and ventricular ontratily also occur as part of t presor respons in healthy individuals (11).    The onset and magnitude ofpresor rese can be ltered by the ype and magnitude ofmetabolit acumultion.  Using microdialysis ofthe vastus latralis during quadriceps xercise in young helthy men, MacLen t l. (42) demonstraed tha interstial phosphats help inita the presor respons, whil muscle acte concntrations stblish the magnitude of the cardiovascular djustents requid. Fibre type distribution is akey determinant skeleta musle lte concntrations and thus is relevant to the discusion of the muscl metaboreflx.  Wilson t al. (88) applied chronic low-frequency stimulation to a rabbit’s primrily glycolytic gastrocnemius cl nd lited an increase in the proportiof type-I fibres and up-regulated oxidative enzyme ativiy.  When t muscl taboreflex was generated by the newly oxidative muscl, the mgnitude oft presor response s lowr than the response licted in the glycolyti control leg.  Reliance on anaerobic mtabolis, and specifaly glycolyti type-II fibres for energy provision during xercis, i therefore jor determinant ofthe magnitude ofthe presor response (as measured by changes in HR, blood presure, blood flow nd vascular resitance).  In COPD, where production of lacte during exercise “xcesive” aoxidative  7 capaity is reduced (17), the metaboreflex may be agnified and exaggerating the rdiovascular respon to exercis through redistribution of blood flow.  Insight into cardiovascular control in people COPD can be obtained from research examining the presor response in hert failure patints.  Altered skelet muscle propertis acompany t central hemodynaic hanges tha crateriz heart filure.  Not unlike COPD, people with heart filure exhibit alrger proportion of type-II fibres, le mitochondrial enzyme activiy, rapid depltion of phosphocreatine during exercise and n overal reducd oxidative paity (63).  An exaggerated muscle tboreflx respons during handgrip exercise ha been measured in heart filure (54).  The silarities betwen the skelet muscl propertis ofpeopl with COPD nd people with art filure suggest an xaggeratd presor response, caused by skeleta muscle abnormalits, my lso occur in COPD.  In both populations thes kelta uscl derents re negatively correlated with overal exercise capaity (26).  To date, one study has examined the musle tboreflx respons in peopl with COPD.  Using IHG, Roseguini tal. (66) found HR and blood presure reses re simlar beten people with COPD nd helthy age-mtched ontrols.  They also found reduced clf blood flow during E in controls while t COPD group showed no change. Thes findings sem unexpected considering lat acumulation is known to be greater in people with COPD and tha lat oncentrations re partly responsible for determining the magnitude ofthe muscle tboreflex (42; 83).  The authors ofthis tudy did not xamine t reltionship betwen disa sverity and exercise cpaity on the magnitude ofthe presor response.  Howver, these re levant relationships to consider, s reduced lung function is aocitd with he percntage ofglycolytic type-II fibres and equently relianc on anaerobic metabolis (25).  Furthermore, exercise capaity, s msure ofxercise tolra, if orreltd with he magnitude ofthe muscl metboreflex, ay provide insght into the efct he presor response has on people with COPD during whol body exercise.  8 OBJECTIVES & HYPOTHESES  Objectives There were to objectivs ofthis tudy: 1) To compare the muscle taboreflex response in peopl ith mild-tosevere COPD to hat ofhealthy age- nd gender- mtched controls through easureent ofheart rate, man rterial presure (MAP), cardi output, total peripheral resistnc (TPR), lg blood flow, nd lg vasculr resitance (LVR) during isometric handgrip exercise and post-exercise circulatory occlusion.  2) To s the relationship betwn exercis capacity and disa sverity and the mgnitude of the muscle mtboreflex response.   Hypothes From this, two specif hypothese wre proposed and tesd: 1) It was hypothesied tha following isometric handgrip exercis, individuals with COPD, hen compared ith althy age-matched ontrols, would demonstrae agreter magnitude musle taboreflex response, as indited by a lrger increase in hert rat, n rtril presure, lg vasculr resitanc nd decreas in leg blood flow during post-exercise circulatory occlusion.  2) It was hypothesized tha reducd xercise apacity and greatr disa sverity would be correlted ith a lrger muscle mtaboreflx response.   9 METHODS  This tudy received ethical pproval from the University of British Columbia clinial research ethics board and writn informed consent was obtained from al partints.  Al tsing ws performed t he Vancouver Gneral Hospitl Pulmonary Function Laboratory and progresive exercis tts were supervised by a respirologist.  Participants  Eleven individuals diagnosed with mild-tosever COPD (7 women) and 11 healthy ge- and gender- matched ontrols partictd in this tudy.  Clasifcation of the individuals with COPD ws et ording to he Canadian Thoraci Society rite for % predicted FEV1.0 (56) (Table 1).  Individuals with COPD were linialy stabl nd had resting oxygen saturation (SO2) greater han 90% hile breathing room ir.  Exclusion critea for the COPD group included mjor underlying mdicl onditions such as hert failure, peripheral vascular disea, neuromuscular onditions, ancer nd autonomic onditions.  Prticpants took their mdictions as preribed prior to esting (typicl meditions included bronchodilators, cortiosteroids, !2-sympathomimetics, theophylline and other respiratory medications). The lthy ontrol group consisted of 11 age- nd gender- mtcd particnts (±5 yers) who demonstraed normal ge-preditd respiratory function and were fe ofneurologic, imune and lowr lib orthopaedic conditions as wel as those conditions listd as exclusion for the COPD group.    Experimental Protocol  Upon arrival to he laboratory anthropometric measure and pulmonary function tes were performed.  After se initl semnts, partints ly supine in a dark room for 10 minuts hil heart rat variability (HRV) was esd.  Particpants then resumed a setd  10 positon before resting blood presure was measured.  Two maxil voluntary handgrip manoeuvres were performed by the right rm nd held for 5 seconds to determine mxium grip strength (MVC).  To particnts were lft handed, howver, grip strength was ilar betwen hands and thus these rtints re tsed on the right side.  Four minutes ofresting HR, MAP, QTR, LBF and LVR were colltd and veraged to establish reting basline values.  These masure were tken continuously throughout the reminder of the protocol.  Following this baline period, partints performed IHG for 2.5 inutes at35% MVC.  During the IHG particnts were instructed to avoid valsa manoeuvres nd breth holds and were provided with visual fdback on their gripping intensity s wel asverbal encouragement.  At2.5 minutes the PECO cuff was inflated (DE Hokaon Inc, Belvue, WA, US).  Particpants continued IHG for another 10 sconds to ensure full occlusion had been atined before relaxing.  The occlusion cuff remained inflatd for 2 minutes aftr which it s deflted and the modynaic measure continued to be monitored at rest for another 4 minutes.  The variables ofinterest, HR, MAP, QTPR, LBF, VR were masured continuously throughout t protocol and averaged over 1 minute intrvals and compared to he baseline average obtained for each particpant.   Following mesureent ofthe muscle taboreflex, xercise capaity was esd using a symptom litd progresive cycl exercis tt to volitonal exhaustion.  Measurments and Procedurs Anthropometric Measrs:  Age, height, weight and body mas index (BMI) were colletd for al particnts.  The COPD particnts compltd he Medicl Research Council dyspnea scle (5) to rate heir subjective feling ofbreathlesne during daily tivis as an indictor of their level of disability (Tabl 2).     11 Table 2:The Medical Research Council dyspnea scle usd to ase functional capaity of peopl with COPD.  Prtipant with COPD self-reportd where ty fl on the se. Grade escription 1 (mild)Not troubled by breathlesne except with srenuous exercise  2 (mild)Troubled by shortnes ofbreath when hurrying on the level or walking up a slight hil  3 (moderate) Walks slower than contemporaries on the level because of brethlene, or s to op for breath wn aking atown paon the lvel 4 (moderate) Sops for breath after about 100 m or after a f minutes on the level 5 (sever) Too breathles to leave the house, or breathles when dresing or undresing     Pulmonary Function Testing: Pulmonary function was esd using standard spirometry guidelines et by the Arican Thoraci Society (50).  Particpants performed 3 FVC manoeuvres on t spirometr (Vmx eris 2130 Spirometr, SensorMedics Corporation, California, USA) which intrfaced with a computer running Vmax software.  Measured parametrs included FVC, FEV1.0 nd the ratio of FEV1.0 to FC (FEV1.0/FVC).  The highest recorded values were taken for each measure (9).  These values were used to ase disea severity in the COPD group, and estblished normal respiratory function in the control group.  Heart Rate Variability: Heart rate variability was measured in order to provide insght into difrencs betwen the groups in tonic baseline utonomic function (61). Particpants lay supine for 10 minuts in a dark room and wre asked to math their breathing duty ycle to  metronome to aintn 12 breths per minute to control for t efcts ofrespiratory sinus arrhythmias (91). Hert rate variability was pld and recorded at rat 1 kHz using 1-lead  12 elctrocardiogram and n analog to digital converter (Powerlab/165P model ML795, ADIinstrument Colorado springs, CO). Five minutes oftabl continuous data ws used in the asemnt ofHRV.  Calculations were performd on norml R-R intervls.  The square root ofthe an  the square diferencs beten N intervals (rMSD) was nalyzed in the time domin.  This measure reflcts instantneous HR and vagal tone.  RMSD isoftn usd in clinial popultions sit more stble than other time domain ndices.  In the frequency domain nalysis, low frequency (LF) (0.04 – 0.15 Hz) and high frequency (HF) (0.15-0.4 Hz) were calulted using Fast ourier Transformation reported in standardized units (nu).  Thes varibls decribe osciltions ofthe HR signal based on difrences in frequency and mplitude.  The LF band is mediatd by parasympatheic-sympatheic nflues, while the HF band is thought to be ditd solely rasti omponents.  LF/H ist global measure ofsympatho-vagal baanc (1).  Muscle Metaboreflx: Heart rate and MAP were measured beat-bybeat using finger photoplthysmography on the non-xercisng arm (lft) (Finomter, FMS, inapres Medical Systes BV, Arnhe, T Netrlands).  The photoplethysmograph cuff was plced on middl digit on the middle phalynx.  he blood presure values atined ere libratd to he inital blood presure asurement taken t rest (BPM-100, VS Medtch Ltd., Vancouver, Canada).  Cardiac output nd TPR wre derived from the photoplethysmograph based on  three-lment Windkesel model of arterial input impedance.  Lg blood flow nd LVR were asd using a Doppler ultrasound (Sonos 5500, Philips Electronis, Andover MA) athe fmoral rtery.  Al mesure wre performed and nalysed by the sam investigaor.  Using n 11-3L linear transducr placed 2-3 cm distl o the inguinal ligaent the time-averaged velocity men was recorded.  This lndmark ws used because it is asily csible nd is ite awhich turbulnt flow isminiized (64).  Blood velocits (cm/s)  13 were calulted online approximately 6-9 times very minute and veraged over 1 minute intrvals during offli nalysis from the VHS recording.  On-scren calipers were usd to determine the two-dimensional femoral artery ross-etional diametr following recovery to calult feoral artry are (#r2).  Blood flow (L/min) was derived from the product ofblood velocity and fml rtery rea ((cm/s x c2 x 60)/1000). Leg vascular resitance was calulted as the quotint of LBF and MAP (M/LBF).  Exercise to Exhaustion: Particpants performed cycle xercise on an elctrialy braked cycle ergomtr (Ergoselct 100P, Ergoline, Lindenstras 5, Grmany) to detrmine VO2peak.  Prior to commencing the xerise t, particnts were quipped with  12-lead lctrocardiogram (Mac 5000 RestiECG Analysis Stem, GE Systms Information Tchnologies, Wisconsin, USA).  Particpants then sat on the bike for 5 inutes while resting data ws colltd on ventilatory rametrs.  Ech particnt began their xercis t ateiher 5, 10, 15 or 20 wats nd the workload increased by the same starting interval very minute until volitonal exhaustion.  Workld ws chosn t investigaor to ry to achie ats lating betwn 7 and 12 minutes.  Al but one COPD particnt ben at eiher 5 or 10 wts.  Metbolic and ventiltory responss were colletd breath-bybreath using open circuit spiromtry (Vmx Seris V6200 Autobox, SnsorMdis Corporation, California, USA).  the end of each inut-long stage, particnts were asked to rate heir senstion of breathlsne lg ftigue using the modified Borg scale (Tbl 3).  Artrial blood oxygen sturation was determined ipulse oxitry (OXIMA N-595 Pulse Oximetr, Nelcor Puritan Bennet Inc, California, USA).  Peak HR, minute ventilaton (VE), breathing frequency (Fb), tidal volume (VT) nd partial presure of nd-tidal crbon dioxide (PetCO2) were ased breath-bybreath hroughout exercise.  Pak values were based on 30 scond verages corresponding to VO2peak. Upon  14 completion of the exercise t particnts were asked whether they stopped exercise due to breathlsne, lg fatigue, or both their legs and brething. Table 3: The modified Borg scale usd to ase breathlesne and leg fatigue each minute ofthe progresive exercs tt to volitonal exhaustion. Scale Severity 0 Nothing at al 0.5Vry, very sight (just noticeabl) 1 ery sli 2Slight 3 Moderate 4omwha svere 5 Severe 6 7 Vry sre 8 9 ery, very severe (almost maxil) 10Maximl  Data Analysis and Statistic  Staistcl software (SPS 17, SP Inc, Chicago, Illinois, USA) was used to measure diferencs ross groups by time. Independent smples t-st ere performd to identify difres in group charateristic.  The variables ofthe presor respons, HR, MAP, QTR, LBF, VR were asd using a 2x7 mixed odel ANOV procedure to examine the relationship betn group (control nd COPD) and time (Baseline: BL; Handgrip: H1, 2, H2.5; Oclusion: O1, 2; Recovery: R2) on these varibls.  Al variables wre examined using the percentage change from baseline values (%!) for ach individual.  Tukey’s HSD post-hoc analysis w used when a signficant F-l ws obtined to determine which means were significantly difrent from eh other.  In addition, a Person product-moment orreltion as performed to ase the relationship betwen xercis cpaity (VO2peak) and disa severity (% predictd FEV1.0) nd t presor respons using the value atined t he second minute of 15 PECO (O2) for percent change in MAP from baseline (%!MAP).  Staistcl significance was satifed at p < 0.05.  Dat are presentd as man ± standard error.  16 RESULTS  Participant Characteristic  articpant charateristi are presentd as means ±SE for each group (COPD and control) nd provided in tabl 4.  Age, height, wight nd BMI wre not significantly diferent betwen groups (p> 0.05).  The COPD group had moderate airflow obstruction with a mean % predictd FEV1.0 of56.3 ± 7.4%.  wo particnts wre dignosd by their physican s having COPD, however, spirometry indicated they only had mild obstruction (% predited FEV1.0 = 94% and 95% post-bronchodiltor).  Wn reoved from the ean data, dictd 1.0 was 47.8 ± 5.8%, charaterizing the remainder of the group s vere.  The Medial Research Council dyspnea sore which provide prognostic nformation bout  COPD group ranged from 1-4 on the 5-point sale ith a men sore of2.5.  Characteristic for male nd femal particnts are provided in tbl 5.  Table 4:Descriptive charateristic and resting pulmonary function. BMI = body mas index; MRC = dial Research Councldyspne cale; FEV1.0 = orced xpired volume in 1 econd; FVC = forcd vit cpaity.  * Signifintly diferent atp < 0.05.   COPD Controls (n=11)(n=11)Age (years) 66 ± 3 64 ± 4 Height (cm164.7 ± 3.3 167.5 ± 3.0 W (kg) 64.6 ± 4.668.2 ± 3.9BMI (kg/m2) 23.9 ± 1.7 24.2 ± 0.9 MRC dyspnea scale (1-5) 2.5 (1-4)NA FEV1.0 (L) 1.4 ± 0.2 2.7 ± 0.2* (% predicted) 56.3 ± 7.497.3 ± 3.0FVC (L) 2.9 ± 0.3 3.8 ± 0.3 C (% predit) 84.5 ± 4.7107.1 ± 3.1*FEV1.0/FVC (%)50.4 ± 5.1 70.9 ± 2.0      17 Table 5:Descriptive charateristic and resting pulmonary function of men and women. BMI = body ma index;MRC = dilReerch Council dyspnea scale; FEV1.0 = forcd xpired volum in 1 sond; FVC = forcd vit cpacity.     Heart Rate Variablity  Table 6provides the group means for the variables masured to reflect HRV.  One particnt from the COPD group ws linated due toxcsive nois in the signal.  The removed particnt’s age matched ontrol as lo limnated as hehad dificulty breathing to the etronome and had to bret athis own rate.  This particnt’s data ws excluded in the analysis avaritions in athing paterns can modify the LF/H reltionship (22).  In t ime domin nalysis, rMSD ws imlar betwn groups (p= 0.23).  In the frequency domain, LF, HF and LF/H approached, but did not reach stitcal significance (p= 0.08, 0.08 nd 0.09 respectively), however, t COPD group demonstraed lower values for the LF ba(COPD 35.1 ± 4.5, control 50.7 ± 6.9 nu), and lrger values for the HF band (COPD 64.9 ± 4.6, control 49.3  6.9 nu), reflecting a lrger sympatheic ontribution to he parasympatheic–sympathei balance in peopl with COPD (1).  Finaly, a lower LF/H ratio was mesured in t COPD group (COPD 0.6 ± 0.1, control 1.8 ± 0.6), reflcting reduced RV nd lvated sympatheic activiy which is aocited in the literaure with smoking, and increased morbidity and mortality (28).  COPD MaleCOPD FemaleControl MaleControl Female (n=4) (n=7) (n=4) (n=7) Age (years) 61 ± 669 ± 159 ± 666 ± 2Height (cm177.6  2.7 157.3  1.3 177.4  3.2 161.8  2.6 W (kg) 70.7  10.561.0  4.481.8  4.860.4  2.2BMI (kg/m2) 22.4 ± 3.4 24.8 ± 2.0 26.0 ± 1.4 23.2 ± 1.1 MRC dyspnea scale (1-5) 2.8 2.3   FEV1.0 (L) 1.6  0.4 1.3  0.2 3.59  0.2 2.2  0.1 (% predicted) 44.0 ± 11.963.3 ± 8.997.0 ± 4.297.4 ± 4.4FVC () 3.7  0.2 2.4  0.2 4.9  0.3 3.2  0.1 C (% predit) 78.5  0.687.9  7.2103.5  3.9109.1  4.3FEV1.0/FVC (%)44.0 ± 12.0 54.0 ± 4.5 73.5 ± 1.3 69.4 ± 3.1  18 Table 6:Heart rate variability parametrs.  rMSD = square root ofthe mean of the squares ofdifrencs betwn adjcent NN intrvals, LF= low frequency band, HF= high frequency band.   COP Controls p-value (n=11)(n=11) rMSD (ms) 49.6 ± 19.6 24.2 ± 4.6 0.23LF (nu) 35.1 ± 4.650.7 ± 6.90.08 H64.9 ± 49.3 ± 6.9 LF/HF 0.6 ± 0.11.8 ±0.60.09  Exercis to Exhaustion  Resting and peak exercise data re displayed in table 7. At rest, he COPD group had significantly higher VE (COPD 13.0 ± 1.1, control 9.8 ± 0.7 L/min, p = 0.03) and Fb (CO 18 ± 1, ontrol 14 ± 1 breaths/min, p = 0.04).  The COPD group reached a significntly ower peak work rate (COPD 64.5 ± 9.6, control 166.6 ± 21.2 W, p < 0.001) nd VO2peak (COPD 18.1 ± 1.6, control 32.4 ± 2.9 ml/kg/in, p < 0.001) than the control group.  Exercise duration betwen the two groups was ilar (COPD 8.2 ± 0.8, control 9.3 ± 0.9 min, p = 0.15) asch particnt’s orkload increments ere chosen prior to exercise to nsure an exercise duration betwen 7-12 minutes (i.e. 5, 10, 15, 20 wats).  Pak HR was lor in the COPD group (COPD 126 ± 7, control 155 ± 4 bpm, p = 0.42).  ek VE nd T ere also ignificantly ower in the COP group (VE: COPD 46.0 ± 5.9, control 78.5 ± 28.7 L/min, p =0.006; VT: COPD 1.37 ± 0.12, control 2.26 ± 0.20 L, p < 0.001). The particpants were asked at he end of the exercise t why they stopped exercise (breathlesne, leg ftigue, or lgs nd brething).  In t COPD group, 7 answered breathlsne, 2 lg ftigue, and 2 both le aathing, while in the control group the responses wre 5, 3 and 3 respectively.      19 Table 7:Rest and peak exercise values during the progresive cycle rgometry st o volitonal xhaustion. HR = hert rat;SBP= ystolic blood preure;DBP= diasolic blood presure;MAP = mn rterilpresure aO2 arteriloxygen saturation; PtCO2 = partal  ofend-tidalcarbon dioxide; VE= minutventiton; VT = idal volume;Fbbrething frequency;VO2peak = pek oxygen uptke; W= workload;RER respiratory xchange raio; Dyspnea = dyspnesore on odified Borg scale tpeak exercie; Lg faigue = scoreon modified Borg scale for lg fatigue at peak exerci  COPD Controls (n=11)(n=11)Resting Values   HR (bpm) 66 ± 3 63 ± 3SBP (mmg) 129.6 ± 4.4 121.2 ± 4.2 D (mH73.0 ± 2.372.1 ± 3.6MAPg) 91.9 ± 2.5 88.5 ± SaO2 (%) 97.5 ± 0.398.8 ± 0.2etCO2 (mmg) 32.3 ± 1.3 35.8 ± 0.7* VE (L/in) 13.0 ± 1.19.8 ±T (L 0.69 ± 0.04 0.78 ± 0.07 Fb (breaths/in) 18 ± 1 14 ± 1*  Peak Values   VO2peak (ml/kgmin) 18.1 ± 1.6 32.4 ± 2.9* Wpeak (wats) 64.5 ± 9.6166.6 ± 21.2Exercie duraion (mi 8.2 ± 0.8 9.3 ± 0.9 RER 1.09 ± 0.031.18 ± 0.02* HR (bpm) 126 ± 7 155 ± 4* SaO2 (%)94.0 ± 1.395.4 ± 0.9VE (L/min) 46.0 ± 5.9 78.5 ± 8.7 T 1.37 ± 0.122.26 ± 0.19*Fb (breaths/i) 33 ± 2 36 ± 3 PetCO2 (mHg)35.1 ± 1.9 37.6 ± 1.5 Dyspne 8.9 ± 0.37.8 ± 0.7Lg fatigue7.7 ± 0.5 7.7 ± 0.6   Effect of IHG and PECO on the Prsor Respone  eart Rate:  Figures 1-6 depict he group mean dat for the percentage ech particnt changed from basline for the variables asured during t IHG and PECO protocol.  The ANOV result for HR indicted  significnt min efct oftime [F(3.01*, 20) = 34.89, p < 0.001, partial et-squared = 0.64].  Post-hoc analysis ti indicatd %!HR was elvatd relative to basline tH1 (p < 0.001), H2 (p < 0.001), H2.5 (p < 0.001) nd O1 (p = 0.04).  Hert rate  20 returned to baseline atO2 (p =1.0).  The %!HR peaked t H2.5 in both groups (COPD 17 ± 4, control 18 ± 2%).  No significant diferenc ws found for the main efct ofgroup [F (1,20) = 0.002, p = 0.96, partial et-squared < 0.001].  There as no intraction ft for by time [F (3.01*, 20) = 0.25, p = 0.86, partial et-squared = 0.01].  Figure 1:Changes in HR during IHG and PECO. Values represent the percent change from baslne. Mean Arterial Presur:  Like HR, there was n efct oftime on the agnitude of%!MAP in both groups [F(2.42*, 20) = 62.44, p < 0.001, partial t-squared = 0.76].  Al time points, with the excption of recovery, were significantly greter han baseline (p < 0.001).  Unlike HR, %!MAP remained elvatd above resting values atO2 (COPD 25 ± 3, control 18 ± 2%, p < 0.001).  There ws no min efct ofgroup [F (1, 20) = .35, p = 0.56, partial et-squared = * * * *  21 0.017].  Also, there was no interaction for group by time on the agnitude ofthe MAP response [F (2.42*, 20) = 1.07, p = 0.36, partial et-squared = 0.05].    Figure 2:Changes in MAP during IHG and PECO.  Values represent the percent change from baslne.     Leg Blood Flow and Leg Vascular Resitance:  There was ignificant min efct oftime for %!BF [F(2.47*, 20) = 8.58, p < 0.001, partial et-squared = 0.3), which increasd bove baseline n both groups throughout IHG and PECO peking at O1 (COPD 37 ± 16, control 51 ± 17, p = 0.001).  There was no min efct ofgroup for %!LBF [F(1, 20) = 0.52, p = 0.5, partial et-squared = 0.03].  Unlike LBF, there was no ignificant efct oftime for %!LVR [F (3.02*, 20) = 0.54, p =0.77], nor was tre n efct ofgroup [F (1, 20) = 1.20, p = 0.30].  There  22 was no interaction efct for either %!LBF [F(2.47*, 20) = 1.13, p = 0.34, partial et-squared = 0.05] or %!LVR [F (3.03*, 20) = 1.96, p = 0.66, partial et-squared = 0.09].  Figure 3:Changes in LBF during IHG and PECO.  Values represent the percent change from baslne.           23 Figure 4:Changes in LVR during IHG and PECO.  Values represent the percent change from baslne.   Cardiac Outpu and Total Periphral Resitance:  The main efct oftime was tistcaly significant for %!Q [F(2.71*, 20) = 3.87, p = 0.02, partil t-squared = 0.16].  The hange from baseline was ignificant tH1 (p = 0.005), H2.5 (p = 0.04), O1 (p = 0.01) but not atH2 (p = 0.06) or O2 (p = 0.69). There was ignificant min efct ofgroup for %!Q [F(1, 20) = 4.79, p = 0.04, partial et-squared = 0.19] with he lrgest difrence betwen groups occurring at H2.5 (COPD 0.08 ± 6.9, control 16.6 ± 3.6 %) and O1 (COPD 1.1 ± 5.6, control 15.4 ± 2.4%). There was main eft oftime for %!TPR [F (1.83*, 20) = 9.5, p = 0.001, partial et-squared = 0.32] here %!TPR was ignificantly diferent from baseline atH2 (p = 0.004), H2.5 (p = 0.01), O1 (p = 0.007), O2 (p < 0.001) before returning to sli tR2 (p = 0.25). The main efct ofgroup approached, but did not reach stitcal significance for %!TPR [F (1, 20) = 3.13, p =  24 0.09, partial et-squared = 0.14].  There was nointeraction efct for %!Q [F(2.71*, 20) = 1.66, p = 0.19, rtil ta-sred = 0.077], or %!TPR [F (1.83*, 20) = 2.07, p = 0.09, partial et-squared = 0.14].  Figure 5:Changes in Q during IHG and PECO.  Values represent the percent change from baslne.           25 Figure 6:Changes in TPR during IHG and PECO.  Values represent the percent change from baslne.  Effect of Exercis Capacity and Diseas Severity on the Magnitude of the Muscle Metaborflx  Figures 6 and 7 show the relationship betwen VO2peak and % predicted FEV1.0 and the %!MAP at O2, s n indicator of the magnitude ofthe metboreflex respons.  APerson product-moment correltion reveled no sificant relationship betwn !M atO2 and VO2peak (r = -0.02, p =0.92).  There was no stitcly significant relationship betwen % predicted FEV1.0 and %!MAP at O2 (r = -0.22, p = 0.32).     26 Figure 7:Relationship betwen disea sverity and the muscle taboreflex. Prcent predicted FEV1.0and %!MAP a minut 2 of PECO.   Figure 8: Relationship betwen exercise capcity and the muscle mtaboreflex. Pak oxygen uptake and %!MAP a minut 2 of PECO.   r = -0.22 p = 32r = -0.02 p = 92 27 DISCUSSION   Main Fidgs  The current study examined the cardiovascular responses to IHG and isolated the muscle taboreflex during PECO in people with mild-tosevere COPD helthy controls.  The two in findings are: 1) e ith COPD had silar HR, MA, LBF and LVR responses throughout IHG nd PECO compared to age- nd gender- mtched lthy individuals.  2) There was no sociaton betwen xercise cpaity (VO2peak) or disea sverity (% predicted FEV1.0) nd the mgnitude ofthe MAP respons during PECO.  Thes findings suggest he xercise presor reflex is unaltered in people with COD. This tudy was deigned with nteion of tsing the hypothesi tha the muscl taboreflex is xaggerated in people ith COPD.  The non-significant findings lit he bility o addres the mchanis responsible for t preserved musle taboreflex and thus only indirect explanations an be offered lating to: 1) the chanis involved in the preserved musl tboreflex nd; 2) the fctors which ontributed to he disparity betwen our findings and previous work xamining t musle mtaboreflx in people with COPD.  Mechanisms for Presved Muscletaboreflx in COPD  Three mchanis may xplain why people with CO demonstraed a preserved muscle taboreflex response during exercise: 1)upper limb skeleta uscl propertis wre intat in peopl with COPD 2) desnsitzaion of peripheral frents to exs metabolite cumultion 3) elvatd resting sympatheic tone reduced sympatheic responsivenes in the COPD group, whil a scondary compensatory mehanism helped preserve the presor response.   28 1) Presvd Upper Limb Skeletal Muscle Characteristc:  The muscle taboreflex is reliant on an cumulation of etabolic by-products during xercise to iulat group IV frents nd inite the presor respons.  The metabolites involved in this proces include: inorganic phosphats, potasium, lacte, and hydrogen ions (21; 32; 35; 42).  Itwas hypothesized tha altered skelet musle propertis in the COPD group, which include impaired phosphogen kinetics, reducd oxidative capaity, and  shift in fibre type distribution towards glycolytic type-II fibres, would generate lrger concentrations ofthese by-products during IHG nd PECO, and consequently, produc alr musl taboreflx response.  Contrary to he hypothesi, hanges in HR, MAP, LBF nd LVR were silr in the COPD group and controls throughout IHG and PECO.  reserved upper limb skeleta muscle haracteristi may explain these findings.    There a number of studies indicating oxidative capaity s reduced, phosphocreatine potential sdecresed, and lcta production is n excs in people with COPD (4; 6;7; 13; 17; 24; 25; 27).  Howver, the mjority of thes tudis bae their conclusions on biopsies taken from the vastus lateralis uscle.  Fw studies have examined t skeleta mcle haractristic in t upper limbs ofpeopl ith COPD, likey becaus its ore chalnging to obtain biopsies.  Also, it has been thought tha the major ehanism inducing nges in skelet muscl properties, uch as hypoxeia, cortiostroid us, detraining, and malnutrition (4) would generat simlr changes in the upper and lower limbs.  However,  study performed by Gea et al. (23), whih easured fibre type nzym activiy in biopsy samples from the deltoid muscles ofpeopl ith mild-tosevere COPD (FEV1.0 = 51 ± 15% predictd) suggest otrwise.  The COPD group, despite having significantly ower O2peak values to he ontrol group (COPD 57 ± 20, control 85 ± 12% predicted, p =0.01), maintned simlar handgrip strength (CO 77  19rols 87  29% ditd), silar fibre type distribution, nd comparable muscle fibre cross-sectional are (p >0.05).  These findings suggest upper lib skelta l  29 charateristic are comparable betwen people with COPD and healthy ge- matched ontrols.  The presrvation of upper limb skelta muscl ay reflect smler degree ofdetrining than sen ithe lower libs.  Upper body tivies utils ls usl as nd generate asmler ventilatory load than lower limb activis.  Therefore, activies requiring the upper libs generate ls dyspnea nd are not voided as often by peopl with COPD compared to lower limb activis which use moreuscle ms and elict more dyspnea.    The demographi and disa harateristi (age, BMI, FEV1.0, FEV1.0/C) of the COPD group studied by Ge tl. were simlar to hose ofthe COPD group tesd in the present study, and thus, itwould be reasonabl to sum som lvel ofpreserved upper limb strength and fibre type distribution lso charaterizs thi COPD group.  Fibre type isa n important determinant ofthe magnitude ofthe presor response asglycolytic fs, which rely ore heavily on aerobic metabolis than oxidative fibres, produce larger oncentrations ofthe metbolites involved in the uscle mtaboreflex (88).  Dscribed previously, chronic low-frequency stimulation applied to apririly glycolytic musle in the hindlimb of arabbit induces tbolic hanges fvouring oxidative metabolis and generates areduced presor respons, measured as the change in MAP from baseline n the control and xperimntal ib (p = 0.008).  Ifthe COPD group in our study had no decrements in upper lib skelet uscle properties, tn fibre type and metabolite acumulation would be silar betwen the COPD and control groups and would explin the presrved presor response licted by upper limb IHG PECO in the COPD group.    2)  Desnitzation to Metabolite Accumlation: Returning to he study by Gea tl. (23), despit presrved upper limb strength and fibre type distribution, t particnts with severe COPD (FEV1.0 "50% predicted) had significantly greater concentrations of lact dehydrogenase (p= 0.001) and itra syntse (p < 0.01) t rest ompared to controls.  Up- 30 regulation of lacte dehydrogenase, in the presenc of preserved upper limb fibre type distribution, suggest lactate and hydrogen ion concntrations lictd by IHG would be larger in individuals with more severe COPD, producing a mgnified presor response.  However, no correlation beten disa srity and the tude ofthe sor res was found.  Interestingly, simlar findings have been sn ipeople with art filure (HF) compared to healthy ge- tched ontrols.  Fi minuts ofrhythmic handgrip exercise produced larger concentrations ofvenous hydrogen ions (control 49.6 ± 1.0, HF 57.4 ± 1.3 nmol) nd lcte (ontrol 1.02 ± 0.2, HF 1.9 ± 0.2 mol) in people with heart filure.  Despit greatr acumulation of these important etabolites, aftr 5 minuts ofhandgrip exercis (Post) he rise in HR (Rest: control 63 ± 3, HF 69 ± 4 bpm; Post: control 68 ± 2, HF: 75 ± 4bpm) and MAP (st: control 100  5,  80  4mg; t: rol 107  5,: 90  5 mHg) ws imlar in people with heart filure and controls.  A the changes in HR and MAP ere saler for  given ll ofmetbolite cumultion, the authors propose tha the metboreflx respons was atenuatd.  Dsnsitzaion of peripheral ferents to he mtabolits reponsible for determining the magnitude ofthe muscle taboreflx, ay explin why the presor respons was not fied in t presenc of lrger concentration of lacte.  T rise in HR and MAP the end of 5 minuts ofhandgrip exercis n the art filure nd control groups in Shoemaker’s study parale those atined by the COPD and control groups athe end of 2.5 inutes ofIHG.  Desnsitzaion of peripheral aferents my lso be aplusibl xplanation for the presrved muscl etboreflex respons sured in the COPD group, who like the art filure group, was likely exposd to a greater acumulation of lacte than the controls.  3) Elevatd Sympathetic Tone and Reduced Sympathetic Reactivy:  Studies xamining sympatho-vagal balanc in peopl with COPD indicat overativiy of the sympatheic nervous system atrest (30) nd reduced responsivenes ofthe utonomic nervous system to siuli such  31 as a pasive head up til manoeuvre (85).  The mechanis contributing to he chronic overstimulation nd reduced rectiviy of the sympati nervous system in people with COPD are not wel defined.  Ithas ben speulated hat se autonomic nervous syst changes are the result of chronic exposure to hypoxemi, nd consquently, modulation of peripheral chemoreeptor ativaon (30).  Measureent ofMSNA using icroneurography t he roneal nerve supports thi hypothesi, howing peopl with COPD have higher resting MSNA ctiviy than healthy ge matcd ontrols.  When supplemntal oxygen is provided, resting S decrese in people with COPD but remains unchanged in controls.  Other mechanis which might becontributing to elvatd resting sympatheic tone and reduced sympathei reativiy include, sympatho-excitaory mdications used by people with COPD such as tophylline nd diuretics, and changes within rteril nd cardiopulmonary baroreflexes.  These mchanis, in addition to others, are explained in detil by Heindl et al. (30).    Consistent with his literaure showing impaired sympatho-vagal regulation, the COPD group tested had reduced resting HRV, elvatd resting HF values, and lower LF values, which combined, is ndicative ofincreased ympatheic tone (1).  These findings may help explain the preserved presor response in the COPD group.  Speifcaly, t uscle tboreflx relis on activaon of the sympatheic nervous system to inite the ferent arm ofthe presor response.  A study performed in people with COPD and healthy controls msured HRV atrest and gain after  pasive orthostaic halnge (pasive d up til-est) (85).  The COPD group, which ws younger than te usd in this tudy (55 ± 11 years) but had a simlar evel ofdisea severity (FEV1.0 = 52 ± 8.3% predicted) and were normoxic, showed  reducd sympatheic response to he til est compared to he ontrol group.  The onclusion drawn from this tudy was tha n peopl with COPD were faced with a chalenge to he autonomic system, they had  smler range ithin hich to mke sympathei nd parasympatic djustnts because oftheir alredy levatd resting sympatheic tone. T preserved presor response whih ocurred  32 in spite ofreduced HRV and elvatd sympatheic tone in the COPD group, supports the idea tha amchanis condary to a rise in MSNA lped t  group maintn a simlr presor response to the healthy controls.  Disociaton betwen MSNA and vascular resitance during PECO has been suggested in young helthy individuals and my explin the preserved presor response which ocurred ven in t presenc ofelvatd resting sympatic tone in the COPD group.  Dspite a continued rise in MSNA during IHG and PECO, Shoemaker et al. (77) observed a lowering of MAP during PECO.  This reduction in MA the onset ofPECO ws aocitd with  decrease in fmoral artery vascular resitance, which quently, as hypothesized to be sensitve to changes in MAP sparate from SNA (whih ontinued to rise throughout PECO).  Asimlar drop in MAP at he end of IHG xercise was mesured in both the COD and control groups.  Ifchanges in MAP wre, in part, responsibl for odulating t vasculr resitnce response during PECO, then t simlarity betwen the COPD nd control groups in the MAP ress would be echoed in the LBF nd LVR and may ount for the preserved presor response in the COPD group occurring despite elvated resting sympatic tone.  Comparison to Curent Literatue  A previous study masuring the muscle taboreflex in people with COPD and healthy controls concluded tha the uscle taboreflx is tnuatd (66).  Thre factors my explin the disparity betwen tse findings nd those in the present work showing  presrved uscle metaboreflex: 1) intrpretaion of result 2) masurent tchniques 3) hetrogeneity of the popultion.   1) Interprtation of Result: Asimlar rise in HR and MAP was mesured throughout IHG and PECO in people with COPD compared to controls in both the presnt tudy and the study by  33 Roseguini etal. (66).  The blunted ris in calf vascular resitance masured in Roseguini’s study was intrpretd by t authors’ as being inditive ofn tnuatd uscle mtaboreflx in the COPD group.  However, this interpretaion fails to explain the aintned HR nd MAP responses which  intrpret as msure of presrved muscle tboreflex.  Simlar discrepancis are present in the litera exaining the l taflx in people with heart filure.  Areviw oft litraure consistently show simlr rise in HR and MAP betwen heart filure patients and healthy ontrols when t uscl taboreflex is being xamined (10; 31; 37; 54; 63; 78; 82). Despit simlar HR and MAP responss, thes papers difer in their conclusions regarding the staus ofthe uscle mtaboreflex response.  For xampl one study suggest is preerved (78), two studis uggest is ugmntd (54; 63), two studies uggest is reducd (37; 81), and one suggest he blood presure response ispresrved with an ltered hemodynaic response (10).  Each of tse tudies masured the sor response using difrent variables in addition to HR nd MAP, such s MSNA, calf blood flow and fmoral artery blood flow.  Therefore, inconsistencis across findings my be consequence ofusing varying masure to represent ferent activiy nd my depend on which masurent authors take to reflect he muscl taboreflx (i.e. MAP or SNA or blood flow).  Regardles, the discrepancy betwen findings, both in the art filure and now in the COPD litraure, highlights the ned for more comprensive semnt of the muscle metaboreflex with measure not only of HR and MAP, but ofMSNA concurrently with blood flow.  2) Measurment Tchnique: Vnous occlusion plethysmography was employed by Roseguini etal. (66) to asure alf blood flow and determine calf vascular during IHG and PECO.  Using this technique, clf blfl isclultd by inflting n oclusion cuff round the upper thigh for ycls of15 seonds.  This ocludes venous blood flow, while alowing arteril fow to  34 continue to entr the limb.  Asecond uff isnflated continuously around the ankle to prevent blood flow to  foot.  strain gauge plethysmograph is placed t clf tis largest circumferenc and detecs hanges in blood flow to he limb by asuring the hange in clf ircfre, whih increase arteril blcontinues to entr the limb and venous blood remains trapped (8).  In this tudy Dopplr ultrasound was usd to asure blood locity n the feoral rtery and consequently derived, based on femoral rtery dimetr, foral artery blood flow.  Both venous oclusion plethysmography and Dopplr ultrasound have ben validatd as techniques capable ofmeasuring changes in blood flow and vascular resitance (8), but sthey both quantify blood flow nd vasular resitance in diferent parts ofthe lg nd use difrent physiologic asumptions in making these msure, som ofthe disrity betwen findings may be explined.    3) Effect of particpant characteristc: The discrepancy betwen blood flow and vascular resitance responses in this study ompared to hat ofRoseguini tal. (66) my be tributed to difres in particnt charateristic.  The COPD particnts ted by Roseguini tal. included 11 men haraterizd with svere airflow obstruction (FEV1.0 = 35 ± 16% predicted), with ild desaturation at rest (SaO2 = 94 ± 2%), and  low O2peak (15.8  4.3 ml/kg/in).  Thes particnts therefore had more severe COPD than the particnts in our study, who had mild-tosevere COPD (FEV1.0 = 56.3 ± 7.4% predicted) and had normal resting SaO2 (97.5 ± 0.3%) and slightly higher xercise capaity (18.1 ± 1.6 ml/kg/in).  This diferenc in disea severity betwen studis may be relvant s% predicted FEV1.0 isnegatively correlatd with he proportion of type-IIA fibres in keleta muscle ofpeopl with COPD (r = -0.21, p <0.001) (25).  As dicussed arlier, type-IIA fibres re priarily glycolytic and produce greater mounts ofmetaboli by-products uch as lctae nd hydrogen ions whih re critil in detrmining the gnitude ofthe presor respons (42).  Therefore, the terogeneity of the COPD population in  35 our study (mild-tosevere) may have masked diferencs in the presor response tha were exaggerated in the study by Roseguini etl. who xamined a ore homogenous COPD population (svere) with a potntialy greatr proportion of type-IIA glycolytic fbres.  These tidiferencs my not count entirely for the disparity betwen our findings asw found no asociaton betwen disea sverity and t magnitude of the mtaboreflex response.  Limitations  The present tudy has hown tha the muscle taboreflex response to handgrip exercise is preerved in peopl with COPD.  Tse findings difr rom previous work  suggesting the muscl taboreflex is atenuatd in peopl with COPD (66).  Measurement tchniques and partint charatristic my acount for some of thes difrencs, however, more importantly, measureent ofMSNA in ddition to LBF, would provide amore comprehensive understnding of the modynaic response to xercise in people with COPD and would provide more information regarding the mchanis responsibl for the preserved metboreflex.  Previous work by Seals (74) measured a orrelation coefient ofr = 0.67 (p < 0.001) at 35% MVC for the relationship betwn MSNA nd lf vasular resitance IHG in young helthy men.  Acording to his correlation the use ofHR, MAP, LBF nd LVR as amethod y which to as the presor response isvalid. asurement ofblood lacte, blood pH and hydrogen ions would also provide more informtion bout the ehanism underlying the preserved muscle mtboreflex in COPD.  This tudy’s findings are not generalizable to whole-body exercise aisometric handgrip exercise may only reflect tivaon of the muscl taboreflx by the upper xtremites. As ntioned, upper lib strength and fibre type distribution might bepreserved in the upper lib of people with COPD and thus the metaboreflex response ay difr if masured in t lower limbs where morerked changes in skelt muscl propertis have been msd.  36  Future rsarch An interesting finding in this tudy tha isworth pursuing in future research relates o the Q and TPR responses masured during IHG and PECO in the COPD group.  A significant diferenc inthe Qrese to IHG and PECO exercise occurred betwen the COPD group nd healthy controls.  T respons in the control group showd a ris in Q throughout IHG which remined elvatd until recovery, wre t COPD sed no change in Q throughout exercis reaining at or below baseline levels.  This trend coincides with literaure in heart failure patients howithey have reducd Q despite simlar rise in blood pres to lthy controls during IHG (10).  Wre the althy control group tained their ncreased blood presure by increasing Q, the art filure group increased ystemic vasulr resitnc to achieve this me ris in blood pres. The rise in TPR w s throughout exercise was not stitaly significantly diferent betwen groups; however the COPD group did tnd to have larger values but did not reach significanc due to a lrge degree ofbetwen subject variability.  Though direct omparisons nnot bemde betwen peopl with heart filure and COPD sthe hemodynai haracteristic ofheart filure are difrent than those ofCOPD, these findings are worth pursuing further as ty my contribute to our understanding of t modynaic responses to exercise in people with COPD.    Direct masurent ofMSNA using microneurography at rest and during IHG and PECO would lso be valuable addition to he literaure pertining to he muscle tboreflex in COD.  Concurrent masure ofAP, LBF and LVR with MSNA ay lso help carify the mechanis involved in the preservation of the muscle taboreflex w mesured in people with COPD.    Finaly, charaterizing the muscle taboreflex response licted by lower limb exercise, distinc from the respons generated by upper limb xercis, may be valuabl in understanding  37 the relationship betwen the presor response and xercise ntoleranc, which is often brought on by whole body xercis ratr than upper limb recruitnt hich is atply during handgrip exercis.  Conclusion The result from this tudy indicate hat he muscle taboreflex is preerved in people with COPD and tha exercise capaity nd disae sverity re not correlatd with he magnitude of the muscle taboreflx. While the mechanis for this preerved presor response rein unclear, retntion of upper limb skelta usl racteristic and desnsitzaion of peripheral frents may be contributing fctors. Also, increasd resting sympatheic tone nd reduced reactiviy to sympatheic and parasympatheic stimuli asocited with COPD suggest aompensatory mechanis lped the COPD group generat he presrved presor response during IHG and PECO.  38 REFERENCES   1.   Heart rate variability: standards of measurement, physiological interpretaion and clinil us. Tsk Force of the Europen Socity of Cardiogy and the North American Socty of Pcing and Elctrophysiology. Circulation 93: 1043-1065, 1996.  2.  Dorland's Medial Ditonary. Toronto: W.B. Saunders Company: A Divison of Harcourt Brace & Company, 1994.  3.  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Diferential control of heart rate and sympatheic nerve actviy during dynamic exercis. Journal of Clinical Investigation 79: 508-516, 1987. 84.  itor R, Sechr N, Lyson T and Mitchel J. Central command increase muscle sympathei nerve activiy during intns intrmiten isetric exerci in humans. Circulaton Rsar 76: 127-131, 1995.  85.  Volteani M, Scalvini S, Mazzuero G, Lanfranchi P, Colombo R, Clark AL and Levi G. Dereased heart rate variability in patients wth chronic obstructive pulmonary disea. Chet 106: 1432-1437, 1994.  86.  Wagnr PD. Skeleta muscles in chronic obstructive pulmonary disea: deconditioning, or myopathy? Rspirology 11: 681-686, 2006.  87.  hittom F, Jobin J, Simard PM, Leblanc P, Simard C, Bernard S, Beleau R and Maltais F. Hstochemcal and morphologial characteristic of the vastus latralis musclein patient wih chroni obstructive pulmonary disa. Mediine and Scinc in Sport and Exrcs 30: 1467-1474, 1998.  88.  Wilson L, Dyke C, Parson D, Wall P, Pawelczyk J, Sanders Wilams R and Mtchel J. Efct of skeleta musce fiber type on the preor reponse evoked by staic contraction in rabbis. Journal of Appld Physiology 79: 1744-1752, 1995.  45  89.  World Health Organization. chronic respiratory disea [Online].  2007.  90.  uyam B, Payen JF, Levy P, Benaidane H, Rutenaur H, Le Bas JF and Benabid AL. Metabolism and aerobic capacity of skelta muscle in chronic respiratory failurereltd to chronic obstructive pulmonary dis. European Respiratory Journal 5: 157-162, 1992.  91.  Yasuma F and Hayano J. Respiratory sinus arrhythmia - Why does the heartbet synchronize with respiratory rhythm? Chest 125: 683690, 2004.   46 APPENDIX A: REVIEW OF LITERATURE Introduction  Chronic obstructive pulmonary disea (COPD) is aprogresive, irreversible condition afecting the respiratory syste.  The priry cuse ofthis dies imoking (85% of COPD popultion), while orkplac irritants uch as dust and fums, and  genetic ondition (alpha-1anti-trypson deficncy) ount for the reminder of COPD cse (14% and 1-2% respectively) (4; 55).  Chroni obstructive pulonary disea ischaratrizd by impaired lung and irway function and present as excs putum production, chronic oughing,  senstion of breathlesne (dyspne) upon xertion and repeated respiratory tra infections (55).  Diagnoses nd clsifcation of this dieas ibased on pulmonary function.  Aratio of forced xpiratory volume in 1 seond (FEV1.0) reltive to forcd vital cpaity (FVC) (FE1.0/FVC) of ls than 0.7 post-bronchodilator determines the degree ofobstruction.  The percent ofage nd gender predicted FEV1.0 chived tis dias verity (55).  Dyspna isthe primry complaint of COPD patients alow intensity exercise nd activies requiring minial exertion (such s activies ofdaily iving) lict his nsation (39; 58). The chanis thought to generate he dyspnea sociated with COPD is reductiin t pulmonary system’s ability o rat mxil expiratory flow rates due to pathology in the lungs, such as parenchymal damage, combined with nflamtion and fibrosis n the airwys (53).  Dyspne istherefore brought on by ativies hich increse ventilatory demnds and consequently increase flow rates.  Pharmcologial interventions are used to iniize the ft flow limtion has on xercis capaity nd daily iving. Howver, videnc from biopsy studies uggest peripheral factors my lso be contributing to he dyspnea experied by peopl with COPD during low intensity activiy (39; 56). Altered structural nd functional charateristic, such as ler phosphogen kinetis, reduced mitochondrial enzyme activiy and n increasd proportion of type-II glycolytic  47 fibres, are present in the skeleta muscles ofpeople with COPD (24; 25; 45; 46; 87).  The reltionship betwn ts lt l charatristic and exercise intoleranc may be related to activaon of the muscle taboreflex during exercis. The muscl taboreflex is reflx oop relint stiulation of group IVafrents locatd peripheraly in skelet muscl (3;35).  These afrents are sensitve to metbolites uch s phosphates, potasium ions, and lctate and init rise in muscl sympatheic nerve activiy (MSNA).  This levatd MSNA elicts arise in heart rat, blood presure and redistribution of blood flow awy from inactive tisue towards working muscle.  Conceptualy, the muscle taboreflex correts amisath betwen blood supply and deand (21; 67).  However, tre isdebat asto he reflex’s fectivenes atrestoring blood flow to working tisue (34).  The cardiovasculr hanges aocitd with he muscle taboreflex are termd the “presor response”.  Skeleta muscle properties hich favour glycolytic mtbolis, uch as those masured in peopl with COPD, produc larger concentrations ofthe by-products reponsibl for initing and determining the magnitude ofthe musl taboreflex, and thus for a given exercise ntnsity produc larger increse in art rate, blood presure concurrently with reductions in blood flow in nactive tisue for  given xercis ntensity (42; 88).  Interestingly, heart filure, a dise tha parales COPD in tha diminished capaity of acntral organ (hert vs. lungs), is the primary charatristic ofthe disea.  Like COPD, people with heart filure have altered skelet usle properties whih company reduced muscl strength nd exercise cpaity (79).  Itis uggestd tha xercise intoleranc in peopl with heart filure iscausd both by the limted capaity of the art to respond to he demands ofexercise (cntraly), nd also peripheral ftors such as t ltered skeleta uscle haractristic which are hypothesized to magnify the cardiovasculr respons to xercis through ativaon of the musle mtaboreflx (63).  It isreaonable to draw parals betwen COPD and heart filure with regards to exercise ntoleranc nd the contributing mchanis.  The muscle tboreflex during exercise  48 must herefore also be explored in people with COPD asit may provide insght into the factors contributing to dyspnea nd exercis ntolrance hich re so liting for patients nd often leads to reduced quality of lif.  The purpos ofthis review isto describe the structural and functional changes occurring within t pulmonary systm and skeleta musles ofindividuals with COPD.  The eft hese central and peripheral changes have on the ventilatory nd hemodynaic responss to xercis wil be explored.    Pulmonary Physiology of COPD Definig COPD:  eclining pulmonary function is the charateristic feature ofCOPD.  Appropriately, spiromtry is the priary dignostic ool used to identify this dise and to determine dis severity.  Tre  number of underlying structural changes occurring within the lungs and airwys which are companied by functional changes.  Emphysea, present in most people ith COPD, is haratrizd parenchymal daage nd consquently increase lung compliance nd alveolr dead sce ausing  ventilton-perfusion misatch (19; 53). In the airwys, chronic bronchitis socitd with a chronicaly elvatd inflatory response leding to fibrosis and cusing lumen diametr narrowing during xpiration to n extnt not sn in healthy individuals (53).  The ost problatic outome ofthese tructural and functional changes ithe development ofexpiratory flow limtion and consquently ltered breathing menics.    Pulmonary Function at Rest: Expiratory flow limtaion slow the rate oflung and irway emptying during expiration.  At rest, when l fl rates re quired, most individuals with COPD are bl tobreathe  49 without flow limtaion.  However, in moderate-tosvere COPD the consequences ofxpiratory fl litaion re presnt, as ny patints ha reduced resting SaO2 and ireasd PetCO2 (55).  Pulmonary function t rest may lso be indicative ofoveral exercise cpaity.  Diz tal. (16) found tha COPD patients who ere flow limted t rest had greatr nd-expiratory lung volumes and poorer performanc on a progresive xrcis te (12 ± 0.5 ml/kg/in) than COPD patints with no expiratory flow limtion atrest (17 ± 0.9 l/kg/in) (p < 0.001).  Resting pulmonary function, specifaly expiratory flow limtaion, is an important predictor of the ry response to exercis (16).  Pulmonary Function During Exercise:  As exercise ntnsity ncreas, o to do the demands placed on the pulmonary system.  In an fort to match ventilaton to he increasing etboli dends asocited with xercis, inspiratory nd expiratory flow rates must lso increas.  Reduced lung elstic reoil, increased alveolr dead spac and reducd lumn diaetr limt he bility of aperson with COPD to mt these incresed flow rates (57; 59).  To compensat, people with COPD il shorten the duration of tir xpiration, thus commencing their next ipiration before reaching their “normal” end-expiratory lung volume (57).  This phenomenon is termd dynami hyperinflation nd result in air remaining trapped in the lungs athe nd of xpiration (19; 59).  Brething paterns and the degree ofxpiratory flow limtion determine the extnt to which dynamic hyperinfltion occurs and nd-ratory lung volume increas (39).  In alth, physial tiviy initaes derease in e-xpiratory l s and n increase intidal volume (VT) through recruitmnt ofrespiratory muscles. While respiratory muscl recruitmnt does occur in ndividuals with COPD, the increasd breathing frequency aompanying exercise, ombined with expiratory flow limtaion, exaggerates dynamic hyperinfltion and increas nd-xpiratory lung volume insted of VT  (58-60; 62).  O’Donnel etal. (59) mesured VT the end of an incremental cycl  50 exercise t and found tha individuals with moderate COPD atpek exercise only reached a VT of 1.10 ± 0.44 L compared to healthy subjects ho reched 2.41 ± 1.04 L (p< 0.0005). his study demonstraes tha individuals with COPD have ablunted ability o increase their VT in response to he respiratory drive ofexercise.  Failure to rais VT during exercis mns tse individuals must rely on changes in breathing frequency to met ventilatory deands, nd as consequence, dynai hyperinflation worsens (15; 39).  In this e study, the correltion betwn peak VT and peak oxygen uptke (r = 0.682, p < 0.0005) demonstraes tha pulmonary function, as mesured by the increase in VT, is associated with exercise capacity.   The pulmonary pathophysiology of COPD isalo sociatd with n increased work of breathing (12; 49; 62; 72).  First, as  patients operate thigher lung volums their inspiratory muscles ust generate greter forc to overcom the inward recoil ofthe lungs and chest wal. This prompts the recruitmnt ofacesory inspiratory musles to lp overcome the incresed resitance (19; 58).  Seond, elevtd breathing frequency and dynamic hyperinflation during xercis res the velocity a which muscle shortening must occur and lead to further muscle waknes and ftigue (58).  Finaly, at higher lung volums, the diphragm isplced at disadvantge in to wys: the diaphragm becomes l dome-shaped and sit lower within the body which means ith downwrd displamnt ofthe diaphragm during inspiration, smaler than norml hanges in ntrathoraci presure occur and inspiratory muscles ust berecruitd o compensate (12; 62).  As wel, the diaphragm experiencs progresive shortning at higher lung volums nd thus, producs l than optimal forc acording to he length-tension reltionship (49).  Areview by Dempsy et al. (14) suggest n incresed work of breathing in healthy people exercisng at very high intnsits leds to competion for blood flow betwen respiratory and locomotor muscles.  This may lso ocur in ople with COPD astheir ncreased work of breathing ay reduc blood flow to peripheral skelta muscles during exercise nd contribute to exercise intoleranc and early ftigue.  51  Levison and Cherniak (40) examined the work of breathing asocited with pulmonary dysfunctiby comparing the oxygen cost ofbreathing betwen COPD patints and healthy controls.  During light exercise athe same ventilton (30 L/min), the  group’s oxygen onsumption (315 ml/in) ws ore than doubl tha ofthe althy group (140 ml/in).  The oxygen consption directed towards respiratory muscles w 10-15% of total VO2 in alth and upwards of35-40% of totl VO2 in COPD (40). Clarly, COPD isocited with n incresed oxygen cost of breathing.  Eves tal. (18) mnipulted he work of breathing in COPD patients to ase the impact this variable had on exercis capaity.  Ten patients with moderate  cycld t 60% of peak work until ftigue whil inspiring one offour gas ixtures: air (21% oxygen, 79% nitrogen), hyperoxia (40% oxygen, 60% nitrogen), helium-oxide (21% oxygen, 70% helium), and helium-roxi n, helium). Exercise tim while breathing t gas mixtures wa longer than exercise performed in room air nd as ignificntly onger when t helium-hyperoxia mixture was provided (air: 9.4 ± 5.2 min, hyperoxia: 17.8 ± 5.8 min, lium 16.7 ± 9.1 min, helium-hyperoxi 26.3 ± 10.6 in; p = 0.0002).  Helium-hyperoxia reduced the work of breathing, and specifaly inspiratory muscle work, and in doing so extnded the amount time particnts ould exercise before experincing dyspne dynamic hyperinfltion.  Hlium-oxide gas mixture asn shown to decrease irway resitance nd lower xpiratory flow limitation, while helium-hyperoxia helps not only to reduc irway resitance nd fl limtaion, but to decrease ventiltory demands (18).  Interestingly, 7 of the 10 particnts stopped exercisng beus oflg discomfort in the lium-hyperoxia tril, while in the room air trial 8 of 10 trminated exercise beause of breathing discomfort.  There isa strong cs implictng pulmonary ipairments, pecifaly dynamic hyperinflation nd elvatd end-xpiratory lung volumes with ncreasd work of brething and exercise ntolranc inCOPD (15; 39; 59).  Strengthening this rgument isevidence from  52 study in which 61 of 104 COPD patients reported trminatng a symptom limted incremental cycle ts beause breathing discomfort, where only 18 reported lg discfort astheir reson for trminatng the tst (59).    Pulmonary Function: Not the Only Detrminant of Exercise Capacity:  Ferrer t al. (20) demonstrad tha, asn index of disa severity, spirometry alone (% predictd FEV1.0) correlated poorly with helth-related quality of lif.  As wl, vidence from lung transplant nd mdiction studies how tha improveents in pulmonary function do not alwys correlte with iprovents in exercise capacity (29; 38; 73).    Schwablmir et al. (73) examined xercise intoleranc in COPD patients using a progresive ycl ts pre- nd post- ither a singl or doubl lung transplant.  spite he transplants bility o improve lung mechanis, ga exchange and cpaity o met he ventilatory demnds iposed by exercise, patints ontinued to demonstrae VO2peak values nd pek workloads lowr than predictd following the ransplant.  Thes findings support those ofLands et al. (38) who found tha 18 months after receiving  lung transplant, work capaity nd quadriceps strength continued to be litd.  Both studies uggest bnorml peripheral skeleta musl function is ributing to he exercise intolranc charateristic ofCOPD.  It is iportant to recognize the limtaions ofts tudis.  Immunosuppresive mediations such as cyclosporine Amay be contributing to he limted work capaity following transplnt through their efects on mitochondrial function and oxidative city (70).    In an fort to improve pulmonary function and decrease the impact ofCOPD on the ability o perform activies of daily iving, medictions including short and long acting bronchodilators nd ortiostroids are used regularly. Followithe administraion of these medictions COPD patients often s mrked iprovements in pulmonary function, specifaly as result ofreducd xpiratory flow litaion.  Howver, some ofthese patints ontinue to  53 exprienc diminished exercise capaity and reduced ability o perform activies ofdaily iving. Grove tal. (29) found tha following dministraion of salmetrol,  long acting ß2-agonist, pulmonary function improved, yet he COPD patients deonstrad no iprovement in exercise toleranc. Silarly, Saey t al. (69) used magnetic stimulation of the feoral nerve to as quadricps ftigue following xercis. Two constnt work rate cycl xercis ts to exhaustion were performed by individuals ith moderate-tosvere COPD. rior to he exercis bout ither the bronchodilator ipratropium bromide (IB) or a plcebo was dministred. Twitch force was measured before beginning exercise and then gain t 10 nd 30 minutes following ompltion.  Intrestingly, while performithe plcbo trial, half the COPD patints xperiencd a drop in quadriceps tich forc ofmore than 15%, indicting fatigue.  uring the bronchodiltor ril, a COPD patints deonstraed iprovements in FEV1.0 (ftirs: 11 ± 18%, non-fatiguers: 13 ± 18%).  However, thos who fatigued in the placebo trial showed no increase in ndurance tim in the bronchodilator rial (plcebo: 394 ± 220 sec, IB: 400 ± 119 sc), whil the COPD patints who did not ftigue in the plabo trial did improve endurance tim (plaebo: 249 ± 124 sec, IB: 479 ± 298 sec; p < 0.05).  These findings strongly suggest hat intrinsic skelta musl abnormalits are plguing a significant number of COPD patients with diret iplictons on exercise performnce.    Evidenc for Skeltal Muscle Impairment  In COPD, skeleta musl appers to exhibit metabolic and morphologic adapttions uncharacteristic ofhelthy ge-tched individuals (4; 7;24; 65).  These findings support the hypothesi tha skeleta musle dysfunction is contributing to exercis intoleranc, where dysfunction refrs to a “disturbanc, impairment, or abnormality of the functioning of an organ” (Dorland's Medical Dictonary2).  This reviw, il not try nd et debate surrounding the underlying us ofskeleta muscle dysfunction and hetr it spathological in nature ratr  54 than the outcome ofdisuse, but wil nstead provide an overview ofthe changes which have been noted in t lowr limbs ofpeople ith COPD, nd wil brifly disus t potential menis lading to these changes.    Structral Changes:  ignificant declines in peripheral skeleta muscle as company COPD.  Magnetic resonance imging ws used to determine the volum ofthe quadrieps, adductor and hamstring muscls in 20 individuals ith COPD and 20 althy older adults (48).  uscle volume was found to be staitcly significantly ower in the COPD patients compared to he lthy controls for al three musles imged.  Other studis deonstra tha ipaired muscle strength and endurance acompany this decline n muscle as (43; 87).  When comring basline quadricps strength, ftr ounting for diferencs in quadriceps activaon, COPD patients produced 72.9% of the force output achived by healthy ontrols (43).  In addition, xercisng at n bsolute workload for a fixed duration, COPD patients demonstraed significantly more contractil fatigue, mesured s quadriceps twich forc, at10, 30 and 60 inutes post-exercise than ge-tched althy controls (p < 0.005).     Among the ost significant structural adapttions observed in the skeleta muscles ofCOPD patients ia shift in fbre-type distribution.  Multipl studis have notd COPD patints exhibit gretr proportion of t-II, glycolytic, more quickly fatigued fibres and  reduced proportion of type-I, oxidative, fatigue resitant fibres ompared to ge-matched ontrols (24-26; 71; 87) These changes are typicl ofhelthy ging, which is often socited with a shift towards a greatr proportion of type-I ratr than type-II fibres (24; 71).   Gosker et l. (24) examined these cnges in f type distribution in the vastus lateralis of 15 COPD patints and 15 althy ontrols using muscle biopsies.  Not only wre the  55 proportion of type-I, type-IIA and type-IIB fibres aesd, but also the intermdiate st ofthese fibres, labeled as t-I/ t-IIA/IIB.  A higher percentag ofthe hybrid fibres wre found in COPD patients uggesting the shift in fbre type distribution is agradual proces starting from more oxidative fibres and transitoning to more glycolytic fbres (type-I to ype-I/IIA to ype-IIA to ype-IIA/IIB to ype-IIB).  Chronic obstructive pulmonary disea patients also had a reduced proportion of type-I fibres (COPD: 16%, age-atched: 42%), which is consistent with previous literaure and suggest he positve reltionship beten type-I fibres and typical helthy ageing is opposite in individuals with COPD.  A systematic review and mta-nalysis of19 studies wa recently published by this ame research group to xaine the reltionship betwen dis sverity and fibre type distribution (25).  The analysis demonstraed tha individuals in the later stge ofCOPD exhibited a greater decrese in t proportion of type-I fibres and n elvatd proportion  type-II fibres compared to thos with les vere COPD.  As wel, there was n asocitbetwen both FEV1.0 and FEV1.0/FVC and the proportion of type I fibres (r = 0.56, p <0.001; r = 0.57; p< 0.001 respectively) demonstraing a relationship betwen skeleta muscle function and disea sverity.  Metabolic Changes:  Enzymatic hanges acompany the increased proportion of type-II fibres and reduced proportion of type-I fibres found in ndividuals with COPD.  The study mentioned previously by Gosker et al. (24) which measured fibre type distribution in t vastus latralis ofindividuals with COPD nd healthy ontrols lo examined their enzyme profiles.  The COPD group had a simlar proportion of type-IIA uscl fibres to  control group, but demonstraed reduced oxidative enzyme activiy in these mle fis (cytochrome coxidase (COX) (p < 0.01) and succinat dehydrogenase (SDH) (p <0.05)). Recntly, Gren t al. (27) published  omprehensive study xamining the metabolic pathways in ndividuals with moderate-tosvere  56 COPD and healthy controls.  After masuring the maxil activiy of 11 enzymes representative of oxidative nd glycolytic pathwys, t paterns oftiviy both within and betwn the metabolic pathways were omred. The group concluded tha oxidative phosphorylation nd bet-oxidation re suppresed relative to glycolysis n the COPD group.  These findings are consistent with a number of studies (24; 33) noting reduced maxil activiy of oxidative enzyms.  Specifly, citrae synthas (COPD: 22.3 ± 7.3 $ol/in/g usle, ontrol: 29.5 ± 7.3 $mol/in/g musle; p <0.0001) and 3-hydroxy-CoA dehydrogenas (COPD: 5.1  2.0 ol/in/g cl,  ontrol: 6.7 ± 1.9 $mol/in/g muscle; p < 0.005) (45).  Interestingly, compiled, these nzyme studies fail to deonstrae onsistnt up-regulation of anarobic enzyms uch as xokinas, phosphofructokinas and lcta dehydrogenase.  However, rterial lacti id mesure taken during a step-wise cycle ts howed a stper increas throughout exercise than controls while no difrenc in glolytic nzyms wre noted (46).  Consistent with his finding, is atudy by Calvert etal. (6) whih measured amonia nd lact concentrations in people with COPD during both n increntl nd  constnt-work rate ycl xercis t.  Amonia is urrogate masure ofoxidative stre, as it produced only at high intensity exercise in helthy individuals when ATP resynthesi cnnot mt ATP demnd.  Excs ADP and AMP are broken down to increase phosphorylation potential nd keep the adenylate kinase rections occurring.  While ts procs ustins the working tisue, it sonly for  short period, as deminaton of AMP isrreversible and reduces t ATP pool, increase muscle IMP nd increse aonia in the blood strem.  The authors noted two disti aonia paterns in the COPD group.  Hlf t group showed  rise in plsma onia levels simlr to he controls but atlower work rates, while aportion of the COPD showed no incres in plas monia concentrations atl.  Both COPD subgroups had simlar VO2peak values and simlr ctae incres during exercise tha was lower tn the lthy controls.  No cler deographi difrees ditinguished ts to groups and t authors offer no strong  57 hypothese to xplain this ditinc diferenc in the COPD subgroups, only mentioning type-II fibres tnd to produce greater monia lvels and perhaps fatigue in the non-aa group was relted o somthing other than skelet muscle ftigue.  This inot t first ime subgroups have ppeared within t COPD population (desribed low) and these findings ay speak to the individuality of this dieas on skelet muscle responses to exercis.     The phosphocretine (PCr) systm provides an narobic energy source and may not befunctioning optimaly in people with COPD (76; 86; 90).  Wuyam tal. (90) compared PCr utilsation nd resynthesi n the calf muscles during contractions performed t 20, 35 and 50% MVC betwen individuals with COPD nd healthy rols. Depit simlar resting intracelular pH and Pi/Cr profiles (Pi/Cr as n index of PCr utilsation) at 50% MVC COPD patints demonstraed a greatr Pi/ratio nd a lower intracelulr pH (COPD: 6.65 ± 0.11, control: 7.06 ± 0.02; p <0.01).  As wel, PCr resynthesi during reovery was lower in COPD patients.   These findings, however, are not alays consistent across studies (6).  Dspite inconsistncies cross the litraure, there istil cear vidence pointing to altered lowr limb skelta musl etabolic function in peopl with COPD.  First, a greter proportion of glycolytic type-IIB fibres have been consistently documentd, as ha reducd oxidative enzyme ativiy indicating reducd oxidative potntial.  Scond, the phosphogen system appers to be les fient in ts provision of energy during high intensity exercise.  Third, lcte production s greatr during exercise n COPD compared to controls in the absnc of hanges in the activiy of itsrate limtinzym late dehydrogenase.  Finaly, monia production is lo in excs in a portion of people with COPD indicating oxidative stre isoccurring at he lvel ofthe muscle during xercis.  The variability n these tudy findings highlights t dirsity  t COPD population while draing tention to  potential ofskeleta muscle changes to contribute to exercise intolranc.       58 Potential Cause of Skeltal Muscle Dysfunction Deconditing:  A number of mechanis have been proposed to xplain the morphologic and metabolic adapttions to skelta usle descrid above. In a critil review xaining the potntil mechanis which led to skelta musle dysfunction Wgner (86) hypothesize tha cnges in skelta usl propertis re ltd to long-term disuse asCOPD patints avoid ativies which generate dyspnea.  Support for this hypothesi coms from astudy by Serres tl. (75) hih provided COPD patients with a physical tiviy questionnaire daptd for older adults.  They found tha this population not only had lower lvels ofphysical tiviy than age-mtched individuals (p< 0.05), but their activiy score wre positly orrelted with skelet usle endurance (r = 0.60, p <0.05).  However, deconditioning may not acount ntirely for the skelta muscl hanges aocitd with COPD (4; 90) Some of the otr mechanis hypothesized to explain this keleta muscle dysfunction are described below.  Poor Blood Gases:  Amplifcation of physiologic dead space is acommon outcome of dynamic hyperinflation nd n generate aventilton-perfusion isth.  The ismatch result in impaired gas exchange indictd by elvatd arteril carbon dioxide content nd dereased arteril oxygen saturation.  Even during slp xpiratory flow limtaion auss ome patints to xperince pisode ofdesaturation lastion averge 100 inutes (71).  Thes periods ofsustained hypoxia nd hypercpne have been hypothesized to reduc phosphocreatine nd glycogen concentrations, to decrease oxidati nzyme concntrations, and to contribute to fibre type redistribution (4; 76; 87).  St tal. (71) masured pulmonary function and took biopsies from the vastus lateralis of22 COPD patients nd 10 healthy controls.  Reducd difusion  59 capaity across the lung, and  negative correlation betwen difusion capaity and type-IIB fibre ontent ws measured.  Malnutrion and Corticosteroids:  alnutrition may lso contribute to impaired skeleta muscle function by interfring with protein synthesi.  The cuse ofmalnutrition is not clr, howver, it san ongoing concrn for many COPD patients.  Corticosteroid therapies whih are commonly used to addres the pulonary limtaions in COPD, an cuse mcl yopathy (7; 13; 76).  Combined, these two factors ay help to explain the signifint aount ofweight loss and muscle wasting prevalnt in individuals with this dise.  Exercis Intoleranc and Skeltal Muscle Dysfunction  It isapparent from the above disusion tha skeleta muscle dysfunction isprevalent in COPD nd my result f combinatiof disus, poor gas xchange, malnutrition and cortiosteroids.  The ipact hat his keleta mcle dysfunction s on exercise cpaity was explored by Kilan et l. (36) who exained dyspnea nd lg efort using the Borg sal during a maxil exercis tt in 97 COPD patients.  Contrary to O’Donnel (59), 26% of individuals with chronic airflow limtaion reportd dyspnea sbeing greater han leg discomfort, 43% reported lg efort ws greter han  nd 31% reportd thes to be qual.  Skeleta muscl ipairmnts are likely contributing to exercise intoleranc.  Sion et al. (80) measured leg blood flow, lg VO2 (V2LEGS) and whole body VO2 (VO2TOT) during xercis n 14 n with severe COPD during a symptom-limtd incremental cycle ts.  Despit further increase in the workload nd VO2TOT during the irentl xercis, 6 subjcts demonstrad  pltau in VO2LEGS, leg blood flow and oxygen extraction.  At submaxil exercise (30 W) the COPD patints who plteued lso demonstraed  60 significantly greater VT (p =0.037), minute ventilaton (p =0.048) and dyspnea (p= 0.037) and peked t lowr work rates han thos who did not plteu (40 ± 13W vs. 51 ± 10W, p = 0.043).  Not only as peripheral muscl blood flow impaired, but reduced oxygen extraction in the legs contributed to the reduced xercise apacity.  Central Pulmonary Versu Periphal Skeltal Muscle  Debat surrounding cntral versus peripheral mechanis in generating exercise intolranc in COPD patients iongoing.  Evidenc for ntral pulmonary factors limting exercise capaity coms from studies xamining lung mechanis, ga exchange nd work of breathing.  Peripheral skeleta muscl asthe litifator relats to cs in fibre type proportions and nzym concntrations tha decrese the muscle’s bility o sustain erobic activiy, potentily triggering the muscle taboreflx and liting exercise cpaity. The ontribution of both central and peripheral fctors in cusifatigue must herefore be considered.    The Muscletaboreflx and Isometric Handgrip Exercis  It ishypothesizd tha skeleta musle dysfunction ontributes to impaired exercise capaity n COPD through its pact on rdiovascular ontrol.  In health, n increas in MSNA omnies the ransiton from rest o exercise,  does n increse in rt rate, blood presure and peripheral vasoconstricion.  Thre mchanis work together to regulat hese changes.  The first, “central command” initaes rdiovasular changes at onset ofvoluntary xercise and is t priary ehanis responsible for the initl increse in heart rate (35; 84).  The second mechanis, artril baroreflx, aims to corret amistch betwn vascular onductanc nd crdi output by controlling rterial vasoconstriion in skeleta musles to regulte blood presure.  The baroreflex is ctid early in exercis nd continuously  61 throughout (68).  The final mechanis, the presor reflex, is comprised of the mechanoreflex and metaboreflex (or coreflx).  T mechanoreflx is ativad by chanial deformation cusd by uscl ontration or streh. he uscle mtboreflex responds to  mistch betwen oxygen supply and demand does not play n active role in controlling cardiovascular ctiviy until sufficent etabolite acumultion has occurred.  Group IV ferents locted in skeleta musl at o init the frent arm ofthe musle taboreflex, a ris in MSNA which producs the presor response (21).  The presor respons ncompas the rise inheart rate, blood presure and vasoconstricion in nactive skeleta muscles n during xercis (35).  The sor response tmpts to elite he mistch betwn oxygen supply and demand by increasing oxygenatd blood flow to working skeleta usles.  However, not alstudies uggest i succesful in doing so (34).  The muscl tboreflx relis onmtbolite acumulation to not only initae the presor response, but also tcontrol itsagnitude.  The type nd intensity of exercis,  wl askeleta muscl harateristi, such s muscle fibre t and mtabolism, can alter the onset and mgnitude of the presor response (21).    The specif tbolits initaing the efrent arm oft muscl taboreflex are stil unknown.  However, lacti id, bradykinins, phosphates nd potasium ions re lspeculted as being important tbolites in this reflex  (81).  MacLn et l. (42) used mirodialysis probes insertd into the vastus latralis muscl of7 helthy mn to as the reltionship betwn intrstial cti aid, phosphate and potasium and the presor response during static quadriceps xercise performed t 25% MVC intermitntly for 5 minutes (20 sconds contracting followd by 5 sconds ofrelaxation).  This tudy exained the ti ourse ofby-product acumulation nd orresponding rise in SNA during xercise.  Tir result indicat: 1) lacte influences the magnitude ofthe presor response, but does not directly inite the musl metaboreflx  2) potsium concentrations, which increase rapidly at he onst ofxercise and rein levatd following ompltion of exercise, ontribut only to he initaion  the muscl  62 metaboreflex  3)interstial phosphate, which rise and fls in conjunction with he presor respons during xercis nd recovery, is the primry etbolite responsible for initaing nd sustainng the presor response.  These findings have significant implicatons for understndiexercise ntoleranc in peopl with COPD as greater proportion of type-II fibres, in mpaired phosphogen kinetics ombination ith decresd oxidative enzyme activiy, ay ke the more susceptibl to greater lvels of inorganic phosphats, lt nd hydrogen ion acumulation and intraclulr acidosis during exercise (76).    The onset and magnitude ofthe presor respons isalo fectd by the type, duration and intensity of xercise.  Isometric xercise followed by post-xercis irculatory occlusiis oftn the model chosn to as the muscl taboreflex.  In this model, etabolites acumulated during ishemic work reain the rm during occlusion at he s tim the working muscl isalowed to relx.  T contribution of entral comand t echanoreflex to he presor response istherefore removed, and the mtabolites hat remain trapped in the arm during occlusion are sponsible for the presor response occurring during the occlusion period.  The intensity t which thes iomtric ontractions are performed is alo relevant, as iometric handgrip xercise performed at 25 nd 35% MVC elicts greatr increse in hert rat, blood presure, MSNA and clf vasculr resitance, than t lited by 15% MVC (74).  Fibre type also influences the magnitude ofthe presor response. Wilson et al. (88) applied 21 days ofchronic stiulation to he tibial nerve ofa rabbit’s hindlimb, cusing the primrily glycolyti gastrocnemius, to become primrily oxidative.  Followithis transformation, the converted gastrocneius ml initaed  saler presor response during sustined contration (rest: 83 ± 3 mHg, contraction: 91 ± 5 mHg) than t achived by the unchanged glycolytic muscle (rest: 84 ± 2 mg, ontraction: 97.5 ± 5 mHg), (p= 0.008).  Intrestingly, the unchanged glycolytic usle was orking at lower percent ofaximum than  63 the oxidative muscle, yet ielictd a greter magnitude presor respone than the oxidative muscle.    Basd on our knowledge ofCOPD and the changes in keleta muscle asocited with this dieas, it sreaonabl to hypothesize tha t musle tboreflx is ltred.  First, as mntioned previously, the metabolites which initae nd control the magnitude ofthe presor response are more abundant in the skelta muscls ofCOPD patients compared to althy controls uch s inorganic phosphates nd lte ions.  Second, with reduced muscle s nd strength, COPD patients wil be orking at higher percntage oftheir axium while performing any isomtric ontraction (including those involved in ctivies ofdaily iving); hence, greter presor response isxpected.  Third, a greter proportion  glycolytic fbres may also contribut to a magnifid musl mtaboreflex respons during exercise.    Litle work has been done examining the relationship betwn rcis ntolrance and the presor response in COPD.  To dat, only one study has examined this relationship the findings from this tudy difer rom those hypothesized to occur.  Roseguini etl. (66) compared changes in heart rate, blood presure and clf vascular resitanc in COPD patints and healthy ontrols following isomtric handgrip exercise performed t 30% MVC for 3 minutes followed by circulatory occlusion.  Surprisingly, the COPD group demonstraed a silar presor respons ompared to healthy ontrols, with simlar changes from basline in hert rate and blood presure in both groups.  Calf vascular resitnce, asured using strain gauge plthysmography, did fer betwen  asit ncresd from baseline in the althy group by 38% and increasd by only 20% in the COPD group.  Thes findings re unexpected onsidering the evidee pointing to he role skelta muscle haracteristic play in controlling the magnitude ofthe muscl taboreflx.  Furthermore,  silar study msuring the muscle tboreflex was performed in hert filure patients who as mentioned previously, deonstra silar vels ofskelta muscle dysfunction to COPD patints (26).  After masuring heart rate, blood presure  64 and MSNA throughout isometric handgrip exercise (30% MVC) and during post-exercise circultory occlusion and reovery, Notarius tal. (54) found tha despite simlar basline and exercise blood presure values, hert rate in hert filure patients reained elvatd during circulatory occlusion where in controls itreturned to baseline (p < 0.05).  MSNA followed this trend s wel (p < 0.05).  Obvious discrepancies xit betwen these 2 studies and further exploration of the relationship betwen COPD and th muscl mtaboreflx is neded.  Summary  COPD ismost comonly described as disea ofthe lungs and irways.  Though this emphasi on central pulonary pathophysiology is wrranted, vidence from studies xamining skelta usl hanges in the legs suggest peripheral factors are lso at ply in this dieas.   The efct entral impairmnts have on exercise capaity s obvious, s itgenerates xpiratory flow limtaion nd a ventilaton-perfusimisth which, in turn, alter lung and diaphragm mechanics the work of brething during exercise and even t rest in people with severe COPD.    etraining, altered blood gase, and malnutrition have been xplored as potential mechanis generating changes in the skelt uscle properties ofpeopl with COPD.  Thes nges include, reduced oxidative capaity, impaired phosphogen kinetics and  larger proportion of glycolytic fbres.  Through tivaon of the uscle mtaboreflex these changes in skeleta muscle properties may lso be contributing, along with pulonary impairmnts to he xercis intolranc asocitd with COPD.  65 APPENDIX B. INDIVIDUAL RAW DATA  Dat presentd in the appendix represent absolute values for each particnt in the variables ofintere. Partcpant ID’s incase with incresing age in both the COPD and control groups. Tabl 8: Individual subjects’ anthropometric and pulmonary function characteristic   ID Age Sex Weight Height BMI FEV1.0 FEV1.0 FVC FVC FEV1/FVC   (years)1=M2=F (k)(cm)(kg/m2)(L)(%predicted) (L)(%predictd) (%) COPD 1 45 1 53.9 181.5 16.4 1.3 32 4.1 78 32  26186.5183.025.86423.877433 64  91.1 173.2 30. 2.7 78 4 79 78  4247.160.618.31.3582.81565 66  65.9 156.0 27.1 0 49 1.7 66 58  6 47.158.59.0.8382.591337 68 2 65. 163. 24.8 2.1 95 3.4 117 62  87171.0155.329.51.942.101719   53. 154.0 22.3 3 68 6 95 50  1074151.4172.717.20.8243.3802311 75 2 76. 153.8 32. 7 41 1.5 64 48 Controls 1 42 1 81.8 178.0 25.8 3.8 91 5.4 105 70  260269.0160.27.02.51073.3110773 61  72.1 169. 25.2 3.3 101 4.5 109 73  462194.9178.329.9 8992765 63 2 69.0 162.0 26.3 2.6 111 3.4 112 78  66456.4163.21.2399097797 65  56.6 160. 22.1 1.7 77 2.8 96 63  868257.1174.318.82.4893.6104659 69  58. 162.5 22.2 1 96 4 117   10178.5184.23.14.01075.31087511 75 2 56.4 151.1 24.7 1.7 103 2.8 128 61    66 Table 11: Resting heart rate variability charateristic. The ID with a * indicates data was removed from average. rMSD= square root ofhe man oftsquaresofdifrencbewen adjcnt NN intervals, LF= low frequency band, HF= high frequency band   ID LF HF) LF/HF rMSSD (nu)(n) (ms)COPD 1 23.7 76.3 0.311134.9  2  3 43.7 56.3 0.77611.1  441.858.20.718 17.15 26.1 73.9 0.35412.9  648.151.90.926 13.87 51.5 48.5 1.0629.6  851.148.91.044 16.39 14.5 85.5 0.17029.0  1035.464.60.549 65.711 14.7 85.3 0.173185.9 Controls 145.954.10.847 39.5 2 27.6 72.4 0.38233.1 3*47.652.40.908 19.0 4 46.5 53.5 0.86718.4 526.773.30.365 17.4 6 74.3 25.7 2.89613.7 750.849.21.033 15.2 8 34.4 65.6 0.52352.6 935.065.00.538 32.3 10 79.1 20.9 3.79513.9 1186.513.56.393 6.6  67 Table 12: Individual subject haracteristic atrest. HR = heart rate; VE = minute ventilaton; VT = tidavolume; Fb= breahing frequency;PeCO2 partil presureofnd-tdalcrbon dioxide;SaO2 = artrial oxygen sturation   ID HR VE T Fb PetCO2 SaO2 (bpm)(L/min)(L)(bpm)(mmHg)(%)COPD 1 63 13.2 0.70 9 37.5 98  24815.60.931731.2973 73 16.2 0.87 22 28.2 96  46312.50.5527.5985 69 11.3 0.76 15 35.7   6740.661727.8977 71 12.0 0.93 13 31.5 99  8678.30.531630.89 59 12.2 0.59 21 31.7 98  108321.50.502031.59711 53 9.0 0.54 18 41.6 96 Controls 16111.61.071133.998 2 60 9.3 0.92  34.4 100 35513.60.761836.1 4 57 13.7 0.75 19 37.2 98 5568.80.511738.299 6 79 7.8 0.92    7669.90.651532.8 8 54 7.3 0.49  37.1  95810.70.821333.299 10 73 8.4 1.24 7 38.5 98 11707.00.491634.0  

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