the physiology of exercise

8/9/2019 The Physiology of Exercise

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are important for rectifying pulmonary functionsduring treatment with antimalarial drugs.

See also: Arterial Blood Gases. Colony Stimulating

Factors. Hemoglobin. High Altitude, Physiology and

Diseases. Peripheral Gas Exchange. Systemic Dis-

ease: Sickle Cell Disease.

Further Reading

Fredriksson K, Lundahl J, Palmberg L, et al. (2003) Red bloodcells stimulate human lung fibroblasts to secrete interleukin-8.

Inflammation 27: 7178.Harris JW and Kellermeyer RW (eds.) (1970) The Red Cell Pro-

duction, Metabolism, Destruction: Normal and Abnormal.Cambridge: Harvard University Press.

Hillman RS and Finch CA (eds.) (1974) Red Cell Manual, 4th edn.Philadelphia: F A Davis Company.

Ingley E, Tilbrook PA, and Klinken SP (2004) New insights

into the regulation of erythroid cells. IUBMB Life 56:

177184.

James MF (1985) Pulmonary damage associated with falciparum

malaria: a report of ten cases. Annals of Tropical Medicine andParasitology 79: 123138.

Klinken SP (2002) Red blood cells. International Journal of Bio-chemistry and Cell Biology 34: 15131518.

Knight J, Murphy TM, and Browning I (1999) The lung in sickle

cell disease. Pediatric Pulmonology 28: 205216.Lane DJ (ed.) (1976) Respiratory Disease. London: William

Heinemann Medical Books Ltd.

Pawloski JR, Hess DT, and Stamler JS (2001) Export by red blood

cells of nitric oxide bioactivity. Nature 409: 622626.Pouvelle B, Buffet PA, Lepolard C, Scherf A, and Gysin J (2000)

Cytoadhesion of plasmodium falciparum ring-stage-infectederythrocytes. Nature Medicine 6: 12641268.

Sprague RS, Ellsworth ML, Stephenson AH, Kleinhenz ME, and

Lonigro AJ (1998) Deformation-induced ATP release from red

blood cells requires cystic fibrosis transmembrane conductance

regulator activity. American Journal of Physiology 275: H1726H1732.

Sprague RS, Stephenson AH, Ellsworth ML, Keller C, and Lonigro

AJ (2001) Impaired release of ATP from red blood cells of

humans with primary pulmonary hypertension. Experimental

Biology and Medicine 226: 434439.

EXERCISE PHYSIOLOGY

B J Whipp, University of Leeds, Leeds, UK

& 2006 Elsevier Ltd. All rights reserved.

Abstract

Exercise intolerance is a consequence of the inability to meet the

energy requirements of the chosen, or imposed, task. The goal

of clinical exercise testing is to stress the organ systems con-

tributing to the intolerance to a level at which the abnormality

becomes discernible from the magnitude or profile of appropri-

ately selected response variables. Assessing the normalcy, or

otherwise, of these responses to exercise requires the investiga-

tor to select and appropriately display the cluster of response

variables that are themselves reflective of the particular sys-

tem(s) behavior. Interpretation is then based on two interrelated

perspectives: discriminating a magnitude or pattern of deviation

from the normal response (age, gender, and activity matched

standard subject); and matching the magnitude or pattern of

abnormality with that characteristic of particular impairments

of physiological system function.

Exercise is not a mere variant of rest: it is the essence of the

machine Joseph Barcroft

Introduction

Purposeful increases in muscular activity are essentialcomponents of human cultural expression. However,the limits to plausible physical aspiration are setby the adequacy of functioning of the physiological

systems that link and support oxygen transfer fromthe atmosphere to the energy transduction siteswithin contracting muscles. When the ability to meetthe energy requirements of the chosen or imposed

tasks becomes limited, exercise intolerance ensues.Physiological, as other, systems tend to fail under

stress; an optimized stress profile can therefore beutilized to allow abnormalities in the magnitude orcontour of change of selected variables of interest tobe discerned providing clues to the source of theintolerance. This naturally requires a context of nor-mal response.

Determinants of Normal Responses

Metabolic Considerations

Exercise is fueled by the chemical energy of ingestedfood, which is transformed into the mechanical en-ergy of muscular force generation. Skeletal muscle,however, is composed of different fiber types withdifferent mechanical and metabolic characteristics.For tasks requiring relatively low force generation,the more efficient and more aerobic Type I fibers arepredominantly recruited; with higher demands forforce generation (or for rapid contractions), the lessefficient and more glycolytic (anaerobic) Type IIfibers are also recruited. The contraction profile of

146 EXERCISE PHYSIOLOGY


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the muscles must be effectively orchestrated for skill-ful performance.

While adenosine triphosphate (ATP) is the obliga-tory energy resource for muscle contraction, its lowconcentration (B5mMkg1) is maintained by in-creased aerobic and anaerobic production (Table 1).The immediate reaction for ATP resynthesis is split-ting of locally stored phosphocreatine (PCr) to crea-tine (Cr) and inorganic phosphate (Pi):

PCr-Cr Pi DG 1

where DG is the free energy of ATP hydrolysis. PCrconsequently decreases in proportion to work rate(WR), the magnitude of decrease depending on therate at which O2 utilization increases towards itssteady-state value. Consequently, less fit subjectshave a greater PCr decrease for a given WR thanfitter subjects. The major route of ATP resynthesis,however, is oxidative phosphorylation, deriving fromatmospheric O2 transported to the muscle during theexercise and O2 already stored in the body. The pul-

monary O2 uptake

VO2 therefore conflates the im-mediate influence of the increased cardiac output Qand the delayed influence of the increased musclearteriovenous O2 content difference.

In the steady state, all the energy transformationsderive from aerobic exchange from the transportedO2 with no further contribution from O2 stores oranaerobic mechanisms. VO2 subsequently remainssteady, as long as WR remains constant. The steady-state level of CO2 output VCO2 will, in addition,depend on the substrate mixture being metabolized.

Prior to the steady state, energy must be providedfrom other sources. The O2-equivalent of these re-actions is termed the O2 deficit (O2def). While ittakes B3 min for VO2 to attain steady state VO2 ssin healthy young subjects, it takes considerablylonger in older and/or sedentary subjects, whoseO2def will consequently be greater. As a result of thegreater tissue capacitance for CO2, the VCO2 timecourse will be appreciably longer; consequently, therespiratory exchange ratio R VCO2= VO2 under-shoots during the transient.

Below the lactate threshold (yL), the VO2 ss incre-ment is a relatively constant function of increasing

WR for moderate intensity cycle ergometry atconstant pedaling frequency; not varying apprecia-bly with fitness, training, gender, or age. The typicalslope (or gain) of this VO2 WR relationship(i.e., D VO2=DWR) averages an easy-to-rememberB10 ml min

1W.For a 100-W WR, the VO2 ss of the standard

70-kg slim adult cycling at 6070 rpm is composedof:

1. resting VO2 (B250 mlmin1);

2. the unmeasured additional VO2 to movelegs with no load on the flywheel (0 W)(B250 mlmin1); and

3. an increase D VO2 ss ofB1000 ml min1, reflect-

ing the 100 W applied WR, to an absolute VO2 ssofB1500 ml min1.

Although obesity increases VO2 ss at 0 W, the D VO2 ssassociated with a measured WR increment is not. Andwhile the task performance is inefficient, in the sense

that the total energy and O2 costs are high, the effi-ciency of transducing substrate energy into effectivemuscular work is not (B2530% in both cases).

The treadmill is less suitable for interpreting theVO2 response to the apparent WR. That is, inefficient

gait patterns, the subject being partially supported bythe handrails or by an investigator (e.g., during ablood-sampling procedure) modify metabolic cost ofthe task. The substrate mixture being oxidized influ-ences the O2 cost of the task. Carbohydrate is themore efficient fuel (by B6%) in terms of O2 uti-lization (thereby minimizing the cardiovasculardemands for O2 delivery). However, fats produceappreciably less CO2 (byB40%) per unit ATP yield(thereby reducing the ventilatory demands for acidbase regulation).

The rate at which VO2 increases towards its steadystate (faster in trained subjects) is a major determi-nant of the O2def. A large O2def for a given WRrequires greater utilization of stored energy resourcesand predisposes to early-onset lactic acidosis (lowyL). When O2 is not utilized at appropriate rates(either inadequate delivery or impediment to utiliza-tion), ATP can only be formed through the low-yield

Table 1 Sources of ATP resynthesis during exercise

Aerobic O2 transport

O2 stores

Anaerobic PCr stores

Lactate and H production

O2 defmusc

O2

def (lung)

EXERCISE PHYSIOLOGY 147


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anaerobicglycolytic pathway:

C6H12O6 glucose-2lactate H 2ATP 2

This increase in cellular proton load generatesgreater stress, influencing muscle contractile proper-

ties and ventilatory control mechanisms. The benefit,however, is that the ATP supply can be maintained: 1ATP per lactate molecule formed from glucose, or1.5 ATP from glycogen.

The bicarbonate (HCO3 ) system is the most im-

portant nonrespiratory contributor to acidbase regu-lation during exercise, being functionally open withrespect to the atmosphere:

CH3 CHOH COOH NaHCO3

lactate proton sodiumbicarbonate

-CH3 CHOH COONa H2CO3sodium lactate carbonic

acid3

and

H2CO3-H2O CO2

While each proton that combines with an HCO3 ionproduces one additional CO2 molecule to be ventedVCO2 , the rate at which this CO2 is produced VCO2 depends on the rate at which HCO

3 falls.

Ventilatory Considerations

The major ventilatory demands of exercise are arte-rial blood-gas and acidbase regulation, whileoptimizing the cost in terms of the respiratory mus-cle work.

Alveolar (A), and hence arterial (a), PCO2 andPO2 can only be maintained constant during exerciseif VA changes in precise proportion to VCO2 and VO2 ,respectively:

863 VCO2

PACO2 VA

863 VO2

PIO2 PAO2

4

(The small effect of the difference in inspiratory andexpiratory ventilation that occurs when R does notequal 1 is neglected.) As VA is common to both re-lationships, it cannot meet the regulatory demands ofboth O2 and CO2 exchange when they differ duringexercise. VE changes in close proportion to VCO2with PaCO2 being the more closely regulated varia-ble, although the control mechanisms remain poorlyunderstood. Any consequent changes in PaO2 nor-mally only traverse the relatively flat region of the

oxyhemoglobin dissociation curve, with little effecton O2 saturation.

As there is no sustained lactic acidosis duringmoderate exercise, arterial pH (pHa) will be regu-lated at its set-point level only if PaCO2 is main-tained at the appropriate level. This depends on

matching

VA to the CO2 exchange rate at the lung not its production rate in muscle.As a consequence of the physiologic dead space

(VD), a proportion of the total ventilation VE doesnot contribute to VA:

VE 863 VCO2=PaCO21 VD=VT 5

where VD/VT is the physiologic dead space fractionof the breath. The relationship between VE and VCO2during exercise is highly linear (but with a smallpositive intercept on the VE axis, normally ofB36lmin1) up to the onset of compensatory hyperven-

tilation. Consequently, the magnitude and profile ofthe ventilatory equivalent for CO2 VE= VCO2 isclosely linked to that of VD/VT:

VE= VCO2 863=PaCO21 VD=VT 6

High VE= VCO2 reflects a low PaCO2, high VD/VT,or both. Consequently, VE= VCO2 will be increasedunder conditions which impair pulmonary gas ex-change (high VD/VT) or induce excessive VE withrespect to CO2 exchange (low PaCO2) caused, forexample, by hypoxemia, metabolic acidosis, or anx-

iety. High VD/VT, however, does not necessarily reflectabnormal pulmonary function, as rapid, shallowbreathing yields a high VD/VT even in normal subjects.

The alveolar-to-arterial partial pressure diffe-rence (A a) for the gas of interest provides anindex of its exchange efficiency. Thus, while alveolarhypoventilation leads to arterial hypoxemia andhypercapnia, it does not widen (A a); diffusionimpairment, right-to-left shunt, and maldistributionof VA with respect to Q VA= Q all do, particularlyfor O2.

PaO2 and PaCO2 are maintained at, or close to,resting levels during moderate exercise in normalsubjects at sea level. Arterial hypocapnia, however, isa common feature of supra-yL exercise. Why, there-fore, does PaO2 not systematically increase? It tendsto be maintained close to resting levels at all WRsdespite both VE= VO2 and end-tidal PO2 (PETO2) in-creasing progressively4yL. That is (A a) PO2 eitherbegins to widen at yL, or begins to widen more rap-idly, normally without significant hypoxemia (al-though this is seen in some highly fit normal subjects).

In lung disease patients, pulmonary gas exchangeinefficiencies leads to often-marked differences



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between alveolar (either ideal or real) and arterialpartial pressures. And while this increases the VEdemand during the exercise, the ability to respondappropriately is constrained and, in the extreme,limited by the impaired pulmonary mechanics.

Normal Response ProfilesVirgils dictum hoc opus hic labor est (there is thetask and there is the toil) recognizes the distinctionbetween work rate, an absolute physical construct,which we measure in units of power, and work in-tensity, a relative construct reflecting its impact onthe degree and perception of the consequent stress.

Moderate Exercise

Sub-yL WRs are considered to be of moderate inten-sity as they are (1) generally not stressful; (2) sustain-able for prolonged periods of time; and (3) typified

by steady states of cardiopulmonary and metabolicresponse (e.g., Figure 1(b)). The response time coursesare different, however; VO2 normally increases witha time constant (t) ofB3040 s while t VCO2 isB5060 s, reflecting the influence of the fraction of meta-bolically produced CO2 taken up into muscle storesduring the on-transient. VE changes marginally moreslowly (t VE is B5565 s). Consequently, as t VE isappreciably longer than t VO2 , PAO2 and PaO2 falltransiently. But, owing to the relatively small kineticdissociation between VE and VCO2 , the transientPaCO2 increase is hardly discernible.

The values of PaCO2 and PaO2 are typicallyaverages of blood sampled over several respiratorycycles, providing a mean of the intrabreath oscilla-tions. For example, end-inspiratory PACO2 is re-duced because of the greater dilution of alveolar gas,while end-expiratory, or end-tidal, PCO2 (PETCO2)is increased because of increased CO2 flux across thealveolarcapillary membrane during exhalation (theincreased mixed-venous PCO2 P%vCO2 causing theslope of the alveolar phase to increase). The intra-breath PaO2 profile will, naturally, closely mirrorthat of PaCO2. In normal exercising subjects there-fore, PETCO2 is typically higher than PaCO2 (by as

much as 6 mmHg), depending on P%vCO2 and theexpiratory duration. PETCO2 should not therefore beused to represent PaCO2 in computing VD/VT. Al-gorithms for estimating PaCO2 from PETCO2 arepoor in normal subjects and do not work in subjectswith lung disease.

Heavy and Very Heavy Exercise

For the more stressful range of WRs above yL, atwhich the increase in arterial lactate (La) and Hacan stabilize (or even decrease) with time (heavy

intensity), VO2 can also attain a delayed steadystate but with a higher-than-expected VO2 that is aresult of a slow component of the VO2 kinetics whichsupplements the early response. This additionalincrement can result in D VO2 ss=DWR values as highas 14 mlmin1W (rather than the sub-yL value

ofB

10mlmin1

W).At even higher WRs, beyond what is termed crit-ical power (CP), VO2 steady states are not attainable(very heavy intensity). All very heavy WRs are asso-ciated with inexorable increases in VO2 , VE, andHa to the limit of tolerance (Figure 1(a)). In con-trast, the VCO2 profile appears more exponential-like(Figure 1(a)). This can be easily misinterpreted, how-ever; its profile conflates the influence of the aerobiccomponent with that from HCO3

-buffering (whichpeaks early in the transient and then declines as therate of HCO3

decrease progressively slows) and thatfrom hyperventilation (which develops slowly).

Above CP, VO2 increases towards its maximalvalue VO2max at a rate that is greater the higher theWR, progressively reducing tolerance time.

On average yL occurs atB50% VO2max and CP atB75% (Figure 2) in groups of normal subjects. Butboth yL and CP occur at highly variable fractions ofVO2max in individual subjects. Consequently, two sub-

jects exercising at the same % VO2max, as in Figure 1,could manifest markedly different patterns of re-sponse. The use of the % VO2max as an index of workintensity among subjects is therefore not justifiable;a common temporal profile of VE, pulmonary gas

exchange, and arterial acidbase response should becharacterized as a common intensity.

When the subjects limit of tolerance is set bythe ability to increase VE, as in chronic obstructivepulmonary disease (COPD) patients, for example,CP (and yL) occurs at a higher % VO2max than normal(e.g., Figure 2). This provides the potential for usinga higher fraction of the VO2max in a training regimen.Above CP, each progressive increase in WR results inthe same VO2max. In contrast to normal subjects,however, this is also associated with effectively thesame (limiting?) VE (Figure 2).

Endurance training increases CP in normal subjects(Figure 3) and COPD patients. And even if the train-ing only leads to a relatively small increase in themaximum WR (WRmax) achieved on an incrementalexercise test, small changes in CP can translate intoconsiderable improvements in the tolerable durationof some high fraction (e.g., 80%) of that maximum.

Unfortunately, while CP is an important parametercharacterizing the upper limit of sustainable powergeneration for this kind of exercise, it can at presentonly be determined as the power asymptote of aseries of exhausting WRs.



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Response Limitations

When a subject has ostensibly exercised to the limitof tolerance, it is important to determine whether

particular systems that contribute to the energy ex-change have reached their limit. For example, if themaximum voluntary ventilation (MVV) determinedat rest is considered the maximum attainable VE,

Time (s) Time (s)

0.0

0.2

0.4

0.6

0.8

1.0

0 120 240 360 0 120 240 360

VO2max(%)

0

1

2

3

4

VCO2(lmin1

)

0

20

40

60

80

100

VE(l

min1)

100

80

60

40

20

0

(a) (b)Figure 1 Oxygen uptake VO2 , CO2 output

VCO2 , and ventilatory VE responses to constant-load exercise on a cycle ergometer in

two subjects (a, b) exercising at the same % VO2 max; this work rate was below the lactate threshold for subject b, but above for subject a.

Note the marked VO2 slow component in subject a, and its absence in subject b. Reproduced from Whipp BJ, Ward SA, and Rossiter HB

(2005) Pulmonary O2 uptake during exercise: conflating muscular and cardiovascular responses. Medicine and Science in Sports and

Exercise 37: 15741585, with permission from Lippincott Williams & Wilkins.



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then the difference between this and the value actu-ally attained at the end of exercise (Figure 4) can beconsidered to represent the subjects breathing re-serve (BR). This can be zero (or even negative in asubject who bronchodilates during exercise) either asa result of MVV being low (lung disease patients) orachievable WRs and VE being high (highly fit normalsubjects). Also, if the maximum effort expiratoryairflow is considered to reflect the greatest possibleflow at a particular lung volume (not necessarilythe case in COPD patients), then achieving theseflows during exercise indicates an absence of flowreserve (Figure 5). Similarly, a tidal volume (VT) thatencroaches upon the inspiratory capacity (IC) is re-flective of lack of volume reserve. Significant heartrate (HR) reserve at maximum exercise is usuallyjudged relative to the subjects age-predicted maxi-mum; unfortunately, this has high variability. Theseexpected maxima therefore provide useful frames ofreference for discriminating among potential causesof the exercise limitation.

Unlike normal (especially young) subjects, the tol-erable WR range in patients with lung disease is con-strained by a combination of pulmonary factors,chief of which are:

1. impaired pulmonary-mechanical and gas-ex-change functions, which increase the VE demands;

2. limitations of airflow generation or lung distention;3. increased physiological costs of meeting the VE

demands, in terms of respiratory muscle work,perfusion, and O2 consumption;

4. predisposition to shortness-of-breath or dyspnea,consequent to the high fraction of the achiev-able flow or lung distention demanded by theWR, commonly exacerbated by arterial hypo-xemia and early-onset metabolic acidosis; alongwith

5. other factors, such as coexistent heart disease,pulmonary hypertension, nutritional deficiencies,and detraining as a result of low-activity patternsof daily living the latter helping explain the high

250

500

7501000

1250

1500

1750

2000

2250

250

500

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1250

1500

1750

2000

2250

0 200 400 600 800 10001200 0 200 400 600 800 10001200

0 200 400 600 800 10001200

0

20

40

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MVV

Time (sec)

Peak VO2

Peak VO2

VO2(mlmin1)

0 200 400

Time (sec)

600 800 10001200

0

20

40

60

80

100

120 MVV

VE(lmin1)

WR4WR3

WR1

WR2

Critical power

Figure 2 The responses of VO2 andVE to five progressively greater work rates performed on a cycle ergometer, to the limit of

tolerance or for 20 min (whichever came first) in a healthy control (left panels) and a COPD patient (right panels), matched for age.

Note that, both in the control and the patient, the lowest WR (closed circles) corresponded to critical power, with consequent stability

of VO2 ; at the higher four WRs,VO2 at end exercise attained

VO2max. In the control subject,VE at end exercise was progressively

higher with increasing work rate, but in no instance was the maximum voluntary ventilation (MVV) approached; in the COPD patient,

however, all WRs above critical power resulted in VE attaining MVV (i.e., with zero breathing reserve). Reproduced from Neder JA,

Jones PW, Nery LE, and Whipp BJ (2000) Determinants of the exercise endurance capacity in patients with chronic obstructive

pulmonary disease: the powerduration relationship. American Journal of Respiratory and Critical Care Medicine162: 497504, OfficialJournal of the American Thoracic Society, & American Thoracic Society, with permission.



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incidence of fatigue rather than dyspnea as thedominant reported cause of exercise limitation.

The increased airways resistance and/or decrea-sed pulmonary recoil pressure reduces maximumexpiratory airflow in COPD patients. This reduces

the effective operating range of the subjects

VEduring exercise. The VE demands, however, are com-monly greater than normal, reflecting the high VD/VT(a component of which is also seen, as a result of lossof lung recoil, in the otherwise healthy elderly). Thisleads to high VE= VO2 and

VE= VCO2 which may befurther increased from arterial hypoxemia. However,some COPD patients can have higher-than-normalPaCO2, especially those with poor peripheral chemo-sensitivity.

The combination of increased VE demands anddecreased maximum-attainable VE leads to little orno BR at maximum exercise (Figures 25). COPD

patients, especially, also generate spontaneous expi-ratory airflows during exercise which equal, or evenexceed, those achieved at a given lung volume duringa maximal flow-volume maneuver (Figure 5). Theseeming paradox of expiratory airflow during exer-cise exceeding that generated during a maximalexpiratory effort at rest can be explained by:

1. bronchodilatation from exercise-induced increasesin circulating catecholamines;

VE

BR

BR

VO2

MVV

BR

Figure 4 Schematic of the VE response to incremental exer-

cise, as a function of VO2 . In healthy subjects (black), note thatVE at the lactate threshold (filled symbols) and at VO2 max (open

symbols) becomes progressively greater as fitness increases:

sedentary (circles), normal fitness (squares), high fitness (dia-

monds). As maximum voluntary ventilation (MVV) is unaffected

by training status, breathing reserve (BR) therefore decreases. In

a COPD patient (blue), VE at any particular VO2 is increased

(reflecting the characteristically increased ventilatory require-

ment) and MVV (dashed-dotted line) is reduced. Modified from

Whipp BJ, and Pardy R (1986) Breathing during exercise. In:

Macklem P and Mead J (eds.) Handbook of Physiology, Respi-

ration (Pulmonary Mechanics), pp. 605629. Washington, DC:

American Physiological Society, used with permission from the

American Physiological Society.

500

400

300

200

100

0 10 20

Time (min)

WR(W)

L

(WR CP) t= W

Figure 3 Relationship between work rate (WR) and its tolerable

duration (t) for exercise performed above critical power (CP),before (open circles, solid line) and after (closed circles, dashed

line) a period of exercise training. Note that both relationships are

well described by a hyperbolic relationship (see equation box),

where W0 is the curvature constant. Also note that, as training

increases CP, a given supra-CP work rate can be sustained

longer post-training. QL is the lactate threshold.

10

8

6

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Flowrate(ls1)

1 2 3 4 5

Normal Airways disease

Exercise rest

1 2 3 4 5

Figure 5 Spontaneous flow-volume curves from a normal

subject (left) and a COPD patient at rest (inner black loop), at

submaximal exercise (blue loop), and at maximal exercise (outer

black loop) (right); inspiration downwards; expiration upwards.

Note that for the COPD patient, the maximal exercise curve im-

pacts on the volitionally generated maximal flow-volume curve,

with dynamic hyperinflation; this is not the case for the normal

subject. Modified from Leaver DJ and Pride NB (1971) Flow

Volume curves and expiratory pressures during exercise in pa-

tients with chronic airway obstruction. Scandinavian Journal of

Respiratory Diseases Supplement 77: 2327, with permission.



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2. the forced-expiratory maneuver from total lungcapacity allows lung units with fast mechanical ts(the product of airways resistance and thoraciccompliance) to empty at high lung volumes, leav-ing the longer t units to empty at lower volumes.When these less-than-maximum lung volumes are

attained during spontaneous breathing, the fastt

units are now recruited at these lower lung vol-umes, resulting in greater airflow at that lungvolume; and

3. maximum expiratory airflow not being achievedwith maximum expiratory effort (especially at lowlung volumes) because of dynamic airway comp-ression, and even closure in some cases, during theforced maneuver.

The increase in end-expiratory lung volume duringexercise (dynamic hyperinflation) in COPD patients(Figure 5) is a result of the mechanical t values

being long with respect to the time available forexpiration. This results in the VT encroaching uponthe compliance limits, adding a restriction-likecomponent to the obstruction. Factors that reducebreathing frequency ( fB), such as hyperoxic inspi-rates and/or physical training, prove effective atreducing the hyperinflation and improving exercisetolerance.

When the upper limit for exercise tolerance is setby pulmonary determinants, other components of thebodys energy supply systems may not be stressed totheir limits. Consequently, maximum HR, O2 pulse,

and L

a are often markedly less than predicted inCOPD patients. Although the pattern of blood-gasresponse to exercise is highly variable in such pa-tients, in many cases the resting levels of PaO2 can bemaintained without further hypoxemia; diffusionlimitation across the alveolarcapillary bed doesnot seem to be significantly contributory and the in-creased VA= Q dispersion does not appear to worsen.Also, those patients who are capable of generating ametabolic acidosis during exercise usually evidencelittle or no respiratory compensation owing to theobstructive constraint.

In patients with restrictive lung diseases, such asdiffuse interstitial fibrosis, reduced airflow genera-tion (at a particular lung volume) is not of concern.Rather, the increased pulmonary elastance demandsgreater inspiratory muscle force and increased workof breathing. This predisposes to their typical tachy-pnea (fB450 min

1 being common at maximumexercise), with VT often reaching their (reduced) IC.Unlike COPD, however, the hypoxemia in these pa-tients typically worsens as WR increases not, itseems, because of further impaired VA= Q matchingbut because of increasing diffusion limitation, often

leading to (A a)O2 in excess of 60mmHg at thelimit of tolerance.

While exercise does not usually worsen the degreeof airway obstruction in the emphysematous and/orbronchitic forms of COPD, it typically does so inpatients with asthma. Although the exercise-induced

bronchoconstriction which can also occur in sub-jects with no history (or even a recognition) ofairway hyperreactivity is sometimes manifest dur-ing exercise, it is most typically a postexercise pheno-menon, with high-intensity exercise the more potenttrigger. A prior moderate-intensity warm-up canameliorate the degree of bronchoconstriction duringa subsequent high-intensity exercise bout, as does for a short period a prior exercise-inducedbronchospastic episode itself.

Patterns of Response Indicative of

DiseaseWhile the constant-load exercise test provides acloser simulation of the demands for sustained oc-cupational or daily living tasks, the appropriatenessof the integrated system responses to exercise is beststudied (at least, for the initial exercise evaluation)by means of an incremental test which spans the en-tire tolerance range. This allows both cause(s) andseverity of exercise intolerance to be identified fromconsiderations of the normalcy of response of vari-ables of interest, compared with those for an appro-priate reference population. It can also establish both

the limits and effective operating range of systemfunction, allowing disability and impairment to beassessed and training protocols to be optimized, andproviding a frame of reference for discriminatingthe need for, or benefits of, therapeutic interventions(including those related to major surgery).

A test duration of 20 min or less is usually suffi-cient, comprising:

1. a resting phase,2. a control phase of at least 3 min of unloaded

exercise (or another suitably low WR) to ensurethat the responses have stabilized,

3. a linearly incremental exercise phase to the limitof tolerance, and

4. a recovery phase.

The results are not appreciably different when WR isincreased continuously (ramp test) or by uniformlysmall amounts over short intervals (e.g., 1-minincremental test). An incremental phase durationofB10 min provides optimum discrimination, with1020 W min 1 being an appropriate incrementalrate for healthy nonathletic subjects but as low as



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5Wmin1 in a patient. A subsequent constant-loadtest (at a now-known intensity) may, on occasion, beneeded to gain additional information about parti-cular system response kinetics.

Useful Noninvasive Relationships

The response profiles and maximum values of certainnoninvasive variables, in addition to the standardlyassessed electrocardiogram (ECG) and arterial bloodpressure, have proven especially informative withrespect to inferring system pathophysiology, in thecontext of the available normal predicted values.

VO2 WR relationship In response to a constantWR, VO2 attains a constant steady-state value (overthe WR range for which steady states are attainable).For a ramp test (e.g., Figure 6), a constant rateof change of WR yields a constant rate of change

of VO2 , after a small lag-phase (reflecting the sys-tem response kinetics). The gain of this responseD VO2=DWR has been shown not to differ fromthat of the steady-state response (normally 911mlmin1W). The incremental gain is thereforeoften used as an index of the work (in)efficiency. Butwhile the rate of change, in the linear region of theramp, is normally the same as that for the steady-state test, the actual value of VO2 at any WR is lower.However, in many patients with cardiopulmonarydiseases, this incremental gain can be very low (e.g.,8mlmin1W1 or less), suggestive of impaired aero-

bic exchange.The highest value achieved with good subject ef-

fort is termed the peak VO2 VO2peak orVO2max

when VO2 does not continue to increase with furtherincrease in WR. While the good effort VO2peak is notdifferent with different ramp slopes, the WRmax isprogressively greater the faster the ramp; this must beaccounted for when choosing a %WRmax for a sub-sequent constant-WR strategy. Abnormalities of theVO2 response predominantly reflect inadequacies of

cardiovascular function. Consequently, poorly fit(but otherwise normal) subjects typically evidencelow V

O2peakand y

Lbut with a normal D V

O2=DWR.

Patients with lung disease, other than those with sig-nificant pulmonary vascular dysfunction, present aVO2 response pattern similar to the sedentary normal

subject but with a VO2peak that is even more signi-ficantly reduced, that is, when impaired lung me-chanics limit the tolerable WR range. Patients withcardiac, peripheral, and/or pulmonary vasculardisorders, on the other hand, often also manifest ab-normally low VO2 WR slope throughout the incre-mental test. Those with coronary heart diseasecommonly present with a relatively normal response

slope over the lower reaches of their WR range,which then becomes reduced in concert with ECGevidence of developing ischemia.

VCO2 VO2 relationship The profile of VCO2 as afunction of VO2 (V slope) is one in which the VCO2

response initially lags behind that of

VO2 early in thetransient (as some of the metabolically producedCO2 is diverted into the body stores) and then in-creases often as a linear function of VO2 (Figure 6).The slope of the relationship D VCO2=D

VO2 in thisregion has been termed S1, with a value typicallyclose to unity in subjects on a typical Western diet.

When the aerobically produced CO2 is supple-mented by additional CO2 released from HCO3

buffering, the slope increases (Figure 6) termed S2in this higher WR region. As the amount of CO2released in the proton-buffering process is a functionnot of the magnitude of HCO3

decrease but its rate

of decrease, S2 is highly dependent on the WRincrementation rate. At slow incrementation rates,additional CO2 from compensatory hyperventilationsupplements VCO2 in the S2 range. The presence of anisocapnic buffering region with more rapid WRincrementation rates obviates the concern for hyper-ventilation being the cause of the slope increase.Having ruled out both aerobic metabolism andhyperventilation as the source of the increased S2,one is left with the remaining source HCO3

de-crease reflecting yL. Why VE retains the same rela-tionship to VCO2 in this supra-yL region as below yL,

that is,

VE increases as a function of

VO2 but notVCO2 (Figure 6) is not fully understood. But when the

V-slope plot may not be partitioned into two defen-sibly linear segments, the unit tangent to the curvemay be used as a second-order estimate of yL. At ahigher VCO2, however, the beginning of an increase inVE= VCO2 and decrease in PETCO2 provides evidence

of compensatory hyperventilation. This is termed therespiratory compensation point (RCP).

VE VCO2 relationship and ventilatory equi-valents The VE VCO2 relationship is linear up toRCP (Figure 6), with a slope ofB25 in healthyyoung subjects but increasing with age. VE= VCO2however declines hyperbolically with respect to VCO2(toward the value of the VE VCO2 slope itself), re-flecting the influence of the small positive VE inter-cept. As discussed previously, VE= VCO2 is closelylinked to VD/VT in the regulation ofPaCO2 and pHa(eqn [6]). Thus, high values of VE= VCO2 reflect eithera low PaCO2, high VD/VT, or both. But, without ar-terial blood sampling, how can a low PaCO2 beruled out as the cause of the high VE= VCO2? It cant at least not conclusively! This is especially so when



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PETCO2 is low simultaneously, less so if it is nor-mal, but it is an unlikely cause if PETCO2 is high.

Patients with lung disease consequently manifesthigh values for both the VE2 VCO2 slope and

VE= VCO2 measured at its minimum or at yL. Patientswith heart disease also evidence high values ofthese variables during exercise, predominantly (it ap-pears) to an increased VD/VT resulting from uneven

VT(ml)

VE/VO2,VE/VCO2

HR,VO2/HR(min1,mlbt1)

VCO

2(mlmin1)

VO2(mlmin1)

VE(lmin1)

A

B

1000

1000

500

00

S1= f()

WR (W)

1000

500

B

00 80

B

A50

40

30

7060

60

50

40

200 1000

S2=C

30

10

20

40

50

00 1000

B

A

PETCO2,PETO2

60

50

40

30

200 1000

100

150

180 10

5

60WR (W)

E

D

VO2

VO2

0 1000

1.6

0.9

0.6

1.4

1.1RER

F

1500

1000

500

00 60

G

A = L

D = HR max

E = O2-P max

F = R pattern

0 80

VCO2

VE

140

130

120

110

C

VO2

VO2

B = VO2peak (max ?)

C = VE (in)efficiency

G = Breathing pattern

VE limitation ?

Figure 6 Left and middle panels show a multipanel display of the system responses of a series of physiological variables to an

incremental cycleergometer exercise test performed to the limit of tolerance. The selected clusters of variables are those that have been

shown to be particularly useful both for establishing parameters of system function (e.g., the estimated lactate threshold ( yL), the gain(D VO2=DWR) and peak of the

VO2 response, and the ventilatory efficiency (DVE=D VCO2 ) and for assessing the normalcy, or otherwise,

of the magnitude and profile of system responses. The values commonly derived from such a display are designated A, B, C, D, E, F and

G in the data display; their physiological equivalents are given in the right panel. Left panel, top to bottom: the steady-state level of CO2output VCO2 , ventilatory equivalents for O2 and CO2 (

VE= VO2 ,VE= VCO2 ), end-tidal PCO2 and PO2 (PETCO2, PETO2), and the respiratory

exchange ratio (RER) as a function of VO2 . Middle panel, top to bottom:VO2 vs. WR;

VE vs. VCO2 ; heart rate (HR) and O2-pulse (VO2/

HR) vs. WR; and tidal volume (VT) vs. VE.



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distribution of pulmonary perfusion. The magnitudeof the increase is correlative of poor prognosis, espe-cially when yL and VO2peak are also low.

The increase in VE= VO2 following its initialVD/VT-linked decline is used as an index of the ad-ditional VE drive above yL.

End-tidal gas tensions These are easy to measureand extremely difficult to interpret. As describedabove, PETCO2 normally increases progressivelywith increasing WR up to yL (Figure 6); it then sta-bilizes with increasing WR in the region of isocapnicbuffering (as the effect of the increasing P%vCO2 isoffset by the decreasing TE), and subsequently de-creases as frank compensatory hyperventilation ismanifest. PETO2, in contrast, decreases progressivelyup to yL, at which point it begins to increase sys-tematically as the rate of VE increase exceeds that ofVO2 (Figure 6), that is, there is no iso-oxic equi-

valent of the isocapnic period.Mean PaCO2, however, differs from mean PACO2

as a result of VA= Q inhomogeneities and/or right-to-left shunt, leading to PETCO2 being commonly lessthan PaCO2 in patients with COPD or pulmonaryvascular disease, for example. Consequently, a PETCO2which is less than mean PaCO2 during exercise (oreven equal to it) is reflective of abnormal gas exchange.

Breathing pattern While some individuals entrain fBto some unit multiple of their cycling or stride fre-quency, VE during exercise normally increases pre-

dominantly through changes in VT over the relativelylinear thoracic compliance range, thereby minimizingairflow-related work of breathing. At higher WRs,further increases in VE are usually mediated largelythrough increases in fB, obviating large increases inelastic work of breathing over the shallow thoraciccompliance region. The VT VE is commonly used todiscern both the breathing pattern response and theextent to which VE and/or VT reach limiting values.

Patients with COPD have, in addition to an aug-mented VE response, a disproportionately large fBincrease during the exercise and little or no BR at thelimit of tolerance. This is also true of the patientswith restrictive disorders, but in this case VT in-creases to the level of the IC early in exercise with fBoften in excess of 50 min1.

VO2 HR relationship and O2 pulse HR during ex-ercise is normally a linear function of VO2 to an age-dependent maximum (averagingB220age, but witha large standard deviation ofB10min1) and a slopethat is an inverse function of a physical fitness. Asthis linear relationship has a positive intercept on theHR axis, the O2 pulse O2-P VO2=HR increases

hyperbolically as WR increases. But the O2-P isof further interest, as it is numerically equivalent tothe product of stroke volume and the arteriovenousO2 content difference. And so, if O2-P fails to in-crease with increasing WR, then either both varia-bles are constant or one is increasing while the other

decreases either way a reflection of poor cardiovas-cular functioning. The rate at which O2-P increases isnot only abnormally low but actually becomes flat inpatients with impaired cardiovascular function, in-cluding heart failure, hypertrophic cardiomyopathy,and coronary artery disease, and also patients withsignificant pulmonary circulatory pathology.

Conclusion

A clinical exercise tests is a device for educing flaws orabnormalities of physiological system function thatcontribute to exercise intolerance. The results of an

appropriately designed test can also provide a frameof reference for the need for, and any benefits of, in-terventions designed to improve performance. Appro-priately interpreting deviations from an expectedresponse profile (i.e., characteristic of a reference pop-ulation) needs a clear justification of their underlyingphysiological determinants. Commercially availablecarts now readily provide a wealth of relevant evi-dence. But this is information; appropriate inter-pretation remains the investigators challenge.

See also: Asthma: Exercise-Induced. Carbon Dioxide.

Energy Metabolism. Hypoxia and Hypoxemia. Neuro-

physiology: Neuroanatomy. Space, Respiratory Sys-tem. Ventilation: Overview; Control.

Further Reading

American College of Sports Medicine (1995) Guidelines forExercise Testing and Prescription. Baltimore: Williams &Wilkins.

American Thoracic Society/American College of Chest Physicians

(2003) Statement on cardiopulmonary exercise testing. AmericanJournal of Respiratory and Critical Care Medicine 167: 211277.

Casaburi R and Petty TL (eds.) (1993) Principles and Practice ofPulmonary Rehabilitation. Philadelphia: Saunders.

Gallagher C (1990) Exercise and chronic obstructive pulmonarydisease. Medical Clinics of North America 74: 619641. Johnson BD, Badr MS, and Dempsey JA (1994) Impact of the

aging pulmonary system on the response to exercise. Clinics inChest Medicine 15: 229246.

La nnergren J and Westerblad H (2003) Limits to human perform-

ance caused by muscle fatigue. Physiology News 53: 710.Leaver DJ and Pride NB (1971) Flowvolume curves and expi-

ratory pressures during exercise in patients with chronic airway

obstruction. Scandinavian Journal of Respiratory Diseases Sup-plement77: 2327.

Neder JA, Jones PW, Nery LE, and Whipp BJ (2000) Determinants

of the exercise endurance capacity in patients with chronic ob-

structive pulmonary disease: the powerduration relationship.



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American Journal of Respiratory and Critical and CareMedicine 162: 497504.

Roca J and Whipp BJ (eds.) (1997) Clinical Exercise Testing,

European Respiratory Monograph, vol. 2, no. 6. Sheffield:European Respiratory Journals.

Rowell LB (1993) Human Cardiovascular Control. New York:Oxford University Press.

Wagner PD (1996) Determinants of maximal oxygen transport and

utilization. Annual Review of Physiology 58: 2150.Wasserman K, Hansen JE, Sue DY, Stringer WW, and Whipp BJ

(2004) Principles of Exercise Testing and Interpretation. Phila-delphia: Lippincott Williams & Wilkins.

Weisman IM and Zeballos RJ (eds.) (1994) Clinical exercise

testing. Clinics in Chest Medicine 15.Whipp BJ and Pardy R (1986) Breathing during exercise. In:

Macklem P and Mead J (eds.) Handbook of Physiology,Respiration (Pulmonary Mechanics), pp. 605629. Washington,DC: American Physiological Society.

Whipp BJ and Sargeant AJ (eds.) (1999) Physiological Determi-nants of Exercise Tolerance in Humans. London: Portland Press.

Whipp BJ, Ward SA, and Rossiter HB (2005) Pulmonary O2uptake during exercise: conflating muscular and cardiovascular

responses. Medicine and Science in Sports and Exercise 37:15741585.

EXTRACELLULAR MATRIX

Contents

Basement MembranesElastin and Microfibrils

Collagens

Matricellular Proteins

Matrix Proteoglycans

Surface Proteoglycans

Degradation by Proteases

Basement MembranesJ H Miner and N M Nguyen, Washington University

School of Medicine, St Louis, MO, USA

& 2006 Elsevier Ltd. All rights reserved.

Abstract

Basement membranes (BMs) are thin sheets of specialized extra-

cellular matrix that underlie endothelial and epithelial cells and

surround all muscle cells, fat cells, and peripheral nerves. They

play important roles in filtration, in compartmentalization

within tissues, and in maintenance of epithelial integrity, and

they influence cell proliferation, differentiation, migration, and

survival. In the lung, BMs are associated with bronchial

and vascular smooth muscle cells, bronchial epithelium, nerve,

and pleura, and they are part of the airblood barrier betweenmicrovascular endothelial cells and alveolar epithelial cells.

Collagen IV and laminin are the major components of all BMs

which also contain entactin/nidogen and various heparan sulfate

proteoglycans, including perlecan. Two collagen IV hetero-

trimeric protomers, (a1)2a2 and a3a4a5, are found in alveolar

basement membranes, but the latter does not appear to have an

important function in the lung. However, the a3 chain contains

the epitope that is attacked in Goodpastures syndrome, an au-

toimmune disease characterized by pulmonary hemorrhage and

glomerulonephritis. Laminins containing the a5 chain are wide-

spread in both developing and adult lung. Preventing expression

of laminin a5 via targeted mutagenesis interferes with lung lobe

septation and maturation of the lung parenchyma.

Introduction

Basement membranes (BMs) are thin sheets of spe-

cialized extracellular matrix that were first identifiedby transmission electron microscopy as continuousribbon-like structures adjacent to a subset of cells.

They are evolutionarily ancient structures, beingpresent even in primitive organisms such as sponges

and Hydra. In mammals, BMs underlie endothelialand epithelial cells and surround all muscle cells, fat

cells, and peripheral nerves. They play importantroles in filtration, in compartmentalization withintissues, and in maintenance of epithelial integrity,

and they influence cell proliferation, differentiation,migration, and survival. In the lung, BMs are asso-

ciated with bronchial and vascular smooth musclecells, bronchial epithelium, nerve, and pleura, and

they are part of the airblood barrier between micro-vascular endothelial cells and alveolar epithelial cells

(Figure 1).The biochemical characterization of BM proteins

was facilitated by the EngelbrethHolmSwarm(EHS) tumor, a transplantable tumor of mouse ori-gin that produces large amounts of BM components

that can be easily isolated. Studies of EHS tumormatrix proteins led to the identification of the four

EXTRACELLULAR MATRIX/Basement Membranes 157
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the physiology of exercise

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