ventilatory responses to exercise and co2 after menopause in healthy women: effects of age and...

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Respiratory Physiology & Neurobiology 184 (2012) 1–8 Contents lists available at SciVerse ScienceDirect Respiratory Physiology & Neurobiology j our nal ho me p age: www.elsevier.com/locate/resphysiol Ventilatory responses to exercise and CO 2 after menopause in healthy women: Effects of age and fitness Margie H. Davenport a,e,d , Andrew E. Beaudin a,e,d , Allison D. Brown a,e,d , Richard Leigh a,c,e,d , Marc J. Poulin a,b,c,e,f,g,d,a Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 b Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 c Department of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 d Libin Cardiovascular Institute of Alberta, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 e Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 f Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 g Faculty of Kinesiology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1 a r t i c l e i n f o Article history: Accepted 19 June 2012 Keywords: Hypercapnic ventilatory response Ventilatory equivalent for carbon dioxide Aging a b s t r a c t The extent to which aging affects respiratory control in postmenopausal women remains relatively unknown. In a cross-sectional study of 39 postmenopausal women (50–79 years), we examined the influence of age and fitness on the ventilatory responses to hypercapnia (HCVR; +8 mmHg) and exercise ( ˙ V E / ˙ V CO 2 ) above and below the anaerobic threshold (AT). Data were analyzed using the full cohort, by age (younger postmenopausal: YPM, 50–64 years; and older postmenopausal: OPM, 65–79 years) and fitness as per our previous work (Active: ˙ V O 2 max 90% age-predicted values; and Sedentary: ˙ V O 2 max < 90% age-predicted values). Although age did not affect the sensitivity of HCVR, Active women had significantly lower HCVR gain compared to sedentary women (Sedentary: 2.12 ± 0.80; Active: 1.57 ± 0.73, p = 0.02). In contrast, age, but not fitness, was inversely related to ˙ V E / ˙ V CO 2 above AT (YPM: 46.8 ± 11.5; OPM: 34.8 ± 6.9, p < 0.01) which may be explained, at least in part, by age-related declines in lung function. HCVR and ˙ V E / ˙ V CO 2 were not correlated. © 2012 Elsevier B.V. All rights reserved. 1. Introduction In 2050, the proportion of adults over the age of 65 years world- wide is projected to double to 15.9% of the population with more than half of this elderly population being women (United Nations, 2004). Normal aging is associated with a decreased sensitivity of the respiratory system to respond to stressors which may suggest a loss of protective mechanisms. The ventilatory response to increased CO 2 (i.e., hypercapnia; HCVR) is primarily mediated by the central chemoreceptors and typically (but not always (Patrick and Howard, 1972; Rubin et al., 1982)) decreases with age (Kronenberg and Corresponding author at: Department of Physiology & Pharmacology, Faculty of Medicine, Heritage Medical Research Building Room 210, University of Calgary, 3330 Hospital Drive NW, Calgary Alberta, Canada T2N 4N1. Tel.: +1 403 220 8372; fax: +1 403 210 8420. E-mail addresses: [email protected] (M.H. Davenport), [email protected] (A.E. Beaudin), [email protected] (A.D. Brown), [email protected] (R. Leigh), [email protected] (M.J. Poulin). Drage, 1973; Altose et al., 1977; Peterson et al., 1981; McConnell et al., 1993; Poulin et al., 1993; Kara et al., 2003). This decline in the HCVR has been attributed to reductions in neuromuscu- lar inspiratory output, central drive sensitivity and/or alterations in the central chemoreceptors (Peterson et al., 1981; Brischetto et al., 1984). In contrast to HCVR, the exercise ventilatory response ( ˙ V E / ˙ V CO 2 ) is increased in older men and women (Brischetto et al., 1984; McConnell and Davies, 1992; McConnell et al., 1993; Poulin et al., 1994) due to a small but significant increase in dead space ventilation (Brischetto et al., 1984; McConnell and Davies, 1992; Poulin et al., 1994). A previous study examining the ventilatory response to exercise below the anaerobic threshold, between the sixth and ninth decade, reported that ˙ V E / ˙ V CO 2 below the anaerobic threshold (AT) does not change with age in postmenopausal women (Poulin et al., 1994). Above the AT, ˙ V E / ˙ V CO 2 typically increases to maximal exercise and is depen- dent on the degree of the lactic acidosis. If ˙ V E / ˙ V CO 2 fails to increase above AT, this can be reflective of decreased chemorecep- tor sensitivity and/or a higher work of breathing (Wasserman et al., 2005). 1569-9048/$ see front matter © 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resp.2012.06.020

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Page 1: Ventilatory responses to exercise and CO2 after menopause in healthy women: Effects of age and fitness

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Respiratory Physiology & Neurobiology 184 (2012) 1– 8

Contents lists available at SciVerse ScienceDirect

Respiratory Physiology & Neurobiology

j our nal ho me p age: www.elsev ier .com/ locate / resphys io l

entilatory responses to exercise and CO2 after menopause in healthy women:ffects of age and fitness

argie H. Davenporta,e,d, Andrew E. Beaudina,e,d, Allison D. Browna,e,d, Richard Leigha,c,e,d,arc J. Poulina,b,c,e,f,g,d,∗

Department of Physiology & Pharmacology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1Department of Clinical Neurosciences, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1Department of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1Libin Cardiovascular Institute of Alberta, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1Hotchkiss Brain Institute, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1Faculty of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1Faculty of Kinesiology, University of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1

r t i c l e i n f o

rticle history:ccepted 19 June 2012

eywords:ypercapnic ventilatory responseentilatory equivalent for carbon dioxideging

a b s t r a c t

The extent to which aging affects respiratory control in postmenopausal women remains relativelyunknown. In a cross-sectional study of 39 postmenopausal women (50–79 years), we examined theinfluence of age and fitness on the ventilatory responses to hypercapnia (HCVR; +8 mmHg) and exercise(�V̇E/�V̇CO2) above and below the anaerobic threshold (AT). Data were analyzed using the full cohort,by age (younger postmenopausal: YPM, 50–64 years; and older postmenopausal: OPM, 65–79 years) andfitness as per our previous work (Active: V̇O2 max ≥ 90% age-predicted values; and Sedentary: V̇O2 max < 90%

age-predicted values).

Although age did not affect the sensitivity of HCVR, Active women had significantly lower HCVR gaincompared to sedentary women (Sedentary: 2.12 ± 0.80; Active: 1.57 ± 0.73, p = 0.02). In contrast, age, butnot fitness, was inversely related to �V̇E/�V̇CO2 above AT (YPM: 46.8 ± 11.5; OPM: 34.8 ± 6.9, p < 0.01)which may be explained, at least in part, by age-related declines in lung function. HCVR and �V̇E/�V̇CO2

were not correlated.© 2012 Elsevier B.V. All rights reserved.

. Introduction

In 2050, the proportion of adults over the age of 65 years world-ide is projected to double to 15.9% of the population with more

han half of this elderly population being women (United Nations,004). Normal aging is associated with a decreased sensitivity of theespiratory system to respond to stressors which may suggest a lossf protective mechanisms. The ventilatory response to increased

O2 (i.e., hypercapnia; HCVR) is primarily mediated by the centralhemoreceptors and typically (but not always (Patrick and Howard,972; Rubin et al., 1982)) decreases with age (Kronenberg and

∗ Corresponding author at: Department of Physiology & Pharmacology, Facultyf Medicine, Heritage Medical Research Building Room 210, University of Calgary,330 Hospital Drive NW, Calgary Alberta, Canada T2N 4N1. Tel.: +1 403 220 8372;ax: +1 403 210 8420.

E-mail addresses: [email protected] (M.H. Davenport),[email protected] (A.E. Beaudin), [email protected] (A.D. Brown),[email protected] (R. Leigh), [email protected] (M.J. Poulin).

569-9048/$ – see front matter © 2012 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.resp.2012.06.020

Drage, 1973; Altose et al., 1977; Peterson et al., 1981; McConnellet al., 1993; Poulin et al., 1993; Kara et al., 2003). This declinein the HCVR has been attributed to reductions in neuromuscu-lar inspiratory output, central drive sensitivity and/or alterationsin the central chemoreceptors (Peterson et al., 1981; Brischettoet al., 1984). In contrast to HCVR, the exercise ventilatory response(�V̇E/�V̇CO2) is increased in older men and women (Brischettoet al., 1984; McConnell and Davies, 1992; McConnell et al., 1993;Poulin et al., 1994) due to a small but significant increase indead space ventilation (Brischetto et al., 1984; McConnell andDavies, 1992; Poulin et al., 1994). A previous study examining theventilatory response to exercise below the anaerobic threshold,between the sixth and ninth decade, reported that �V̇E/�V̇CO2below the anaerobic threshold (AT) does not change with agein postmenopausal women (Poulin et al., 1994). Above the AT,�V̇E/�V̇CO2 typically increases to maximal exercise and is depen-

dent on the degree of the lactic acidosis. If �V̇E/�V̇CO2 fails toincrease above AT, this can be reflective of decreased chemorecep-tor sensitivity and/or a higher work of breathing (Wasserman et al.,2005).
Page 2: Ventilatory responses to exercise and CO2 after menopause in healthy women: Effects of age and fitness

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There is increasing evidence to demonstrate higher levels ofhysical fitness may slow age-related declines in respiratory func-ion. Aerobic training in previously sedentary older men (Yergt al., 1985) and postmenopausal women (Anaya et al., 2009)ttenuates the age-related increase in �V̇E/�V̇CO2. In contrast,he influence of fitness on HCVR remains controversial. Althoughross-sectional studies indicate that HCVR is lower in athletesompared to sedentary individuals (Byrne-Quinn et al., 1971;iyamura et al., 1976), exercise interventions have resulted in

ncreases (Kelley et al., 1984), maintenance (Bradley et al., 1980)r decreases (Miyamura et al., 1988) in HCVR. However, thesetudies were conducted in younger populations with the effect oftness on HCVR in a postmenopausal population not yet exam-

ned.As the majority of data from previous studies are specific

o men, the extent to which aging affects respiratory controln postmenopausal women remains relatively unknown. Centralhemoreflex drive to breathe is attenuated in postmenopausalomen in direct association with a decline in estrogen and pro-

esterone (Preston et al., 2009). With the progressive decline inhese hormones after menopause, it may be assumed that the agingrocess of females is dynamic. Thus, the aim of this study was toxamine the effects of age and fitness on HCVR and �V̇E/�V̇CO2n postmenopausal women. We hypothesized that increased lev-ls of physical fitness would augment the age-related decline inCVR and counteract age-related increase in �V̇E/�V̇CO2 duringxercise.

. Materials and methods

.1. Study subjects

Thirty-nine healthy postmenopausal women (50–79 years),articipating in a concurrent study investigating the relationshipetween cardiorespiratory fitness and cognition (Brown et al.,010), were included in the present study. Participants were non-mokers and capable of performing moderate-intensity exercise.olunteers were excluded if they had a history of myocar-ial infarction, venous thromboembolic disease, angina or chestain upon physical exertion, asthma or sleep apnea, uncon-rolled hypertension, had undergone recent surgery or trauma,r were using hormone replacement therapy, beta-blockers, anti-epressants, oral anticoagulants, or anti-arrhythmia medication.ll participants gave written, informed consent. The Conjointealth Research Ethics Board at the University of Calgary approved

his study.

.2. Methods

Participants visited the laboratory on three separate occa-ions. Prior to all visits, participants were instructed to refrainrom consuming any caffeinated food or beverages for a min-mum of 4 h. Visit one consisted of collection of demographicata, anthropometric measurements of height, weight, and skinolds (bicep, triceps, suprailiac, and subscapular), as well as pul-

onary function testing for determination of functional vitalapacity (FVC) and forced expiratory volume in one second (FEV1).he ratio of FEV1/FVC was calculated to determine the pres-nce of a respiratory limitation. During the second experimentalay, each participant’s cardiopulmonary fitness was determined

sing a maximal oxygen consumption (V̇O2 max) test on a recum-ent cycle ergometer consisting of a step protocol from rest toxhaustion conducted under the supervision of the study physi-ian (R.L). The step protocol began with 1 min of seated rest,

logy & Neurobiology 184 (2012) 1– 8

followed by a 1 min warm-up at 25 Watts (W). Following thewarm-up, participants were instructed to maintain a cadence of50–70 rpm while the work rate was increased by 15 W min−1 forparticipants under the age of 65 years and by 10 W min−1 forparticipants who were 65 years or older. The work rate incre-ments were utilized such that V̇O2 max was reached in 8–12 min.Variables measured included ventilation and its components,oxygen uptake and carbon dioxide production assessed using amass spectrometer (AMIS 2000, Innovision, Odense, Denmark),heart rate (HR) from a 12-lead ECG, continuous blood pres-sure (Finometer, Finapres Medical Systems BV, Amsterdam, NL),oxyhemoglobin saturation using a pulse oximeter (3900p, Datex-Ohmeda, Madison, WI, USA), and ratings of perceived exertionusing the Borg scale (Borg, 1982). Achievement of maximal exer-cise was based on the criteria of the Canadian Society for ExercisePhysiology (Canadian Society for Exercise Physiology, 1996). Atest was considered to be maximal if one of the following crite-ria was met: (1) oxygen consumption plateau in the last minuteof graded exercise (less than 2 ml/kg/min between final teststages); (2) RER > 1.15; or 3) HR within 10 beats of age-predictedmax.

During the final experimental day, each participant provideda venous blood sample for determination of ovarian hormoneconcentrations (albumin, estradiol, progesterone, sex hormonebinding globulin (SHBG), testosterone, and free testosterone as pre-viously described (Brown et al., 2010) followed by a euoxic HCVRtest. The euoxic HCVR test started with 10 min of air-breathingrest for collection of end-tidal partial pressures of carbon dioxide(PETCO2) and oxygen (PETO2) values. Respiratory parameters weredetermined for each participant breathing through a mouthpiecewith their nose occluded. The mouthpiece was connected to a salivatrap, which was connected to a turbine device and volume trans-ducer (VMM-400, Interface Associates, Laguna Niguel, CA, USA)to measure respiratory volumes. This was followed by a pneu-motachograph and differential pressure transducer to measurerespiratory flow direction and timing (RSS-100 HR, Hans RudolphInc., Kansas City, MO, USA). Total apparatus dead space was approx-imately 110 mL. Respiratory gases were sampled continuously at20 mL min−1 via a fine capillary at the mouth and analyzed forfractional concentrations of CO2 and O2 by a mass spectrometer(AMIS 2000, Innovision, Odense, Denmark). Resting end-tidal val-ues were used to determine the target PETCO2 and PETO2 valuesfor the euoxic hypercapnia protocol. For the ventilatory responsetest to euoxic hypercapnia, the above assembly was connected toa dynamic end-tidal forcing (DEF) system. The DEF system usesdedicated software (BreatheM v2.38, University of Oxford, Oxford,UK) and a negative feedback loop to control PETCO2 and PETO2 attarget levels on a breath-by-breath basis independent of ventila-tory rate and depth (Brown et al., 2010). Transitions between targetlevels of euoxic hypercapnia occurred rapidly over 2 to 3 breaths.HR was measured via a 3-lead ECG (Micromon 7142 B, KontronMedical, Milton Keynes, UK). The first stage of euoxic hypercapniaentailed PETCO2 being maintained at +1 mmHg above the partic-ipant’s resting value for 5 min. This was followed by an increasein PETCO2 to +5 mmHg and +8 mmHg in 4 min increments and adecrease back to +1 mmHg for a final 5 min. At all levels of hyper-capnia (i.e., +1, +5, +8, and +1 mmHg), PETO2 was maintained euoxicat 88 mmHg to take into account that Calgary is 1103 m above sealevel.

The sub-maximal exercise test consisted of two 6 min exer-cise periods interspersed by three 6 min rest periods. Therefore,following instrumentation the entire submaximal exercise test

lasted 30 min and followed the format Rest1-Exercise1-Recovery1-Exercise2-Recovery2. For each exercise period, work rate (W) wasset to 40% of the maximal work rate achieved during the V̇O2 maxtest.
Page 3: Ventilatory responses to exercise and CO2 after menopause in healthy women: Effects of age and fitness

M.H. Davenport et al. / Respiratory Physiology & Neurobiology 184 (2012) 1– 8 3

Table 1Descriptive, spirometry, fitness and sex hormone concentration measures of participants separated into age and fitness groups.

Age groups Fitness groups

YPM OPM p-value Active Sedentary p-value

N 20 19 26 13Age (y) 58.0 ± 4.1 70.9 ± 3.4 <0.001 65.3 ± 7.4 62.3 ± 7.8 0.25Height (cm) 161.8 ± 6.5 160.7 ± 5.32 0.54 161.1 ± 5.9 161.5 ± 6.1 0.84Weight (kg) 69.6 ± 11.2 65.0 ± 7.5 0.14 63.6 ± 6.5 74.9 ± 11.0 <0.001BMI (m kg−2) 26.6 ± 3.8 25.3 ± 3.3 0.26 24.6 ± 2.9 28.7 ± 3.4 0.00FVC (L) 3.30 ± 0.51 2.83 ± 0.39 0.01 3.13 ± 0.54 3.05 ± 0.47 0.68FVC (% age predicted) 100± 13 98± 8 0.75 101± 12 95± 9 0.13FEV1 (L) 2.54 ± 0.41 2.07 ± 0.32 <0.001 2.33 ± 0.44 2.36 ± 0.43 0.84FEV1 (% age predicted) 98± 14 95± 7 0.36 98± 13 95± 12 0.55FEV1/FVC (%) 77± 5 73± 5 0.02 74± 5 77± 5 0.13VD/Vt (L min−1) 0.19 ± 0.07 0.21 ± 0.06 0.34 0.21 ± 0.04 0.21 ± 0.07 0.95V̇O2 max (L min−1) 1.74 ± 0.29 1.58 ± 0.34 0.13 1.78 ± 0.27 1.42 ± 0.30 <0.001V̇O2 max (mL kg−1 min−1) 25.6 ± 6.0 24.7 ± 6.1 0.64 28.2 ± 4.3 19.2 ± 4.1 <0.001V̇O2 max (% age predicted) 90 ± 21 107 ± 25 0.02 112 ± 16 71 ± 14 <0.001Albumin (g L−1) 43.4 ± 2.78 42.3 ± 2.8 0.36 43.6 ± 2.7 41.33 ± 2.39 0.01Estradiol (pmol L−1) 38.9 ± 46.05 13.9 ± 24.3 0.06 21.1 ± 42.2 35.6 ± 28.0 0.33Progesterone (nmol L−1) 1.67 ± 0.41 1.06 ± 0.49 <0.001 1.31 ± 0.52 1.43 ± 0.61 0.64Testosterone (nmol L−1) 0.81 ± 0.73 0.82 ± 0.43 0.81 0.76 ± 0.45 0.92 ± 0.79 0.32SHBG (nmol L−1) 42.4 ± 17.76 61.6 ± 28.0 0.03 58.4 ± 26.2 40.3 ± 14.8 0.05Free Testosterone (pmol L−1) 13.3 ± 12.8 10.8 ± 6.1 0.41 10.4 ± 6.9 15.2 ± 13.8 0.16FT/SHBG index 0.37 ± 0.40 0.26 ± 0.27 0.41 0.26 ± 0.30 0.44 ± 0.40 0.16

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ll data are mean ± SD. YPM: younger postmenopausal (50–64 years); OPM: older

apacity; FEV1: forced expiratory volume in one second; VD/Vt: dead space to tidal vlobulin; FT/SHBG Index: ratio of free testosterone to sex hormone binding globin.

.3. Analysis

The sensitivity of HCVR (HCVR gain) was calculated as thehange in pulmonary ventilation (V̇E) over the change in PETCO2etween the last 2 min of isocapnic rest (PETCO2 = +1 mmHg) and0 s when PETCO2 was +5 and +8 mmHg. The slope of the linearegression was taken as HCVR gain (L min−1 mmHg−1).

Resting cardiorespiratory variables from the V̇O2 max test werealculated as 30 s averages immediately preceding the onset ofxercise (Rest) and peak values from the last 15 s preceding voli-ional fatigue. The anaerobic threshold (AT) was determined usinghe v-slope method of the V̇CO2/V̇O2 graph (Beaver et al., 1986).he ventilatory response to exercise was assessed by calculat-ng the ratio between the change in V̇E and CO2 production (i.e.,

V̇E/�V̇CO2) both above and below the AT from the maximalxercise test.

Initially the full cohort was combined to determine correla-ions between age, BMI, V̇O2 max, FEV1, HCVR, progesterone and

V̇E/�V̇CO2 above and below AT. The participants were thenivided into two age groups – younger postmenopausal (YPM,0–64 years) and older postmenopausal (OPM 65–79 years) foromparison. Finally, participants were separated by fitness levels per our previous work (Brown et al., 2010) into Active (defineds V̇O2 max ≥ 90% of age-predicted values) and Sedentary (defineds V̇O2 max < 90% of age-predicted values).

.4. Statistical analyses

Age and fitness group differences in participant characteristics,CVR gain and �V̇E/�V̇CO2 were analyzed using independent

-tests. An analysis of co-variance (ANCOVA) was used whenomparing the age groups to control for V̇O2 max, FEV1 and proges-erone. An ANCOVA was also performed in the fitness analysis usingge a covariate. Pearson product–moment correlation coefficients

ere calculated to determine the association between HCVR gain,V̇E/�V̇CO2, age, BMI, V̇O2 max, and sex-hormone concentrations

f the full cohort. For all analyses, p values <0.05 were consideredo be statistically significant.

enopausal (65–79 years); N: sample size; BMI: body mass index; FVC: forced vital ratio; V̇O2 max: rate of maximal oxygen consumption; SHBG: sex hormone bindinges are for between group comparisons by independent t-tests.

3. Results

Table 1 illustrates participant baseline characteristics, spirom-etry, aerobic capacity and sex-hormone concentration for the Ageand Fitness groups. Progesterone levels, absolute FVC, and absoluteFEV1 were higher (p ≤ 0.01) and SHBG levels were lower (p = 0.03)in YPM compared to the OPM. However, when expressed as a per-cent of age-predicted values, FVC and FEV1 were within normalranges and not different between groups. Age-predicted V̇O2 maxwas higher for OPM compared to YPM; however, both groups werewithin normal limits. When classified by fitness, the Active grouphad a lower body weight and BMI (p ≤ 0.01) and higher relativeV̇O2 max, absolute V̇O2 max, percent age-predicted V̇O2 max, albumin,and SHBG levels than the Sedentary group.

3.1. Correlations

There was no correlation between HCVR gain and �V̇E/�V̇CO2above or below the AT. Progesterone (r = −0.368, p = 0.02), FEV1(r = −0.599, p < 0.01) and �V̇E/�V̇CO2 above AT (r = −0.524,p = 0.003) were each negatively correlated with age. When sepa-rated by age groups, progesterone was correlated with age in YPM(r = −0.654, p ≤ 0.01) but not OPM participants (r = −0.002, p = 0.97).Relative V̇O2 max was negatively correlated to HCVR (r = −0.348,p = 0.03).

3.2. The influence of age and fitness on HCVR gain

By design, hypercapnia (+8 mmHg above baseline) increasedPETCO2 from 37.7 mmHg ± 2.7 at rest (+1 mmHg above baseline) to44.5 mmHg ± 2.9 (p < 0.01). This produced an increase in V̇E (rest:9.16 L min−1 ± 3.53 vs. hypercapnia: 21.86 L min−1 mmHg−1 ± 8.71,p < 0.01), VT (rest: 0.70 L ± 0.26 vs. hypercapnia: 1.29 L ± 0.43,p < 0.01), and fR (Rest: 13.46 breaths per minute (bpm) ± 4.02 vs.

hypercapnia: 17.08 bpm ± 4.22, p < 0.01; see Fig. 2) in all partici-pants, with no change in PETO2.

While HCVR was not affected by age, the gain was lower in theActive versus the Sedentary group (p = 0.02; Fig. 1A and B).

Page 4: Ventilatory responses to exercise and CO2 after menopause in healthy women: Effects of age and fitness

4 M.H. Davenport et al. / Respiratory Physiology & Neurobiology 184 (2012) 1– 8

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.3. The influence of age and fitness on the ventilatory responseo exercise

Age had no effect on V̇E at rest (YPM: 9.21 L min−1 ± 1.59; OPM:.93 L min−1 ± 2.07; p = 0.65), the AT (YPM: 25.16 L min−1 ± 6.75;PM: 26.39 L min−1 ± 7.11; p = 0.61), or 40% V̇O2 max (YPM:1.76 L min−1 ± 5.21; OPM: 31.87 L min−1 ± 6.87; p = 0.96). How-ver, V̇E was higher in the YPM group (64.14 L min−1 ± 11.78)ompared to OPM group (51.61 L min−1 ± 12.70; p < 0.01) at max-mal exercise (Fig. 3), despite similar maximal O2 consumptionsTable 1).

Mean and individual values of �V̇E/�V̇CO2 are illustrated inig. 1C–F. Although age did not affect �V̇E/�V̇CO2 below the

T, the YPM group had a higher �V̇E/�V̇CO2 above the AT. Thisreater hyperventilation was associated with a lower PETCO2in thePM group at V̇O2 max (p < 0.05). After controlling for FEV1 androgesterone, �V̇E/�V̇CO2 above the AT was no longer different

E/�VCO2: ratio between the change in pulmonary ventilation and CO2 productionan 65–79 years, p < 0.05.

between YPM and OPM (F = 0.891, p = 0.35) Fitness did not affect�V̇E/�V̇CO2 below or above the AT.

4. Discussion

4.1. Major findings

In this cohort of postmenopausal women, there was an inverserelationship between the HCVR gain and fitness. As fitness declineswith age, these data suggest that the age-related loss in protectivemechanisms of HCVR may be counteracted by increased levels offitness. Further, age, but not fitness, inversely affects �V̇E/�V̇CO2above the AT. However, this relationship was due in part to age-

related decrease in progesterone and FEV1 which may suggestan age-related decline in lung function and an increased work ofbreathing. Finally, HCVR gain and �V̇E/�V̇CO2 during exercisewere not related to one another.
Page 5: Ventilatory responses to exercise and CO2 after menopause in healthy women: Effects of age and fitness

M.H. Davenport et al. / Respiratory Physiology & Neurobiology 184 (2012) 1– 8 5

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ig. 2. Mean ventilation and breathing pattern during euoxic hypercapnia by ageolume and fR: breathing frequency; Error bars = SD. *Significantly different than 65

.2. The influence of age and fitness on HCVR gain

Previous studies have found a lower HCVR in older (>50 years)ompared to younger men and women (<37 years) (4–8). However,t is reasonable to suggest that comparisons of young versus olderarticipants do not fully explain the progressive nature of the agingrocess. Further, previous studies have largely relied on data fromale participants, with little emphasis on sex differences. Recent

ata suggest that age-related changes in ventilatory responsivenesso HCVR may differ between genders (Wenninger et al., 2009). Asuch, the present study addresses the current lack of understand-

ng of the physiological effects of aging in females as well as thenfluence of physical fitness on these age-related changes.

An important finding of the present study is that there is nopparent effect of advancing age (55–79) on HCVR in our cohort of

hand panels) and fitness (right-hand panels). V̇E: pulmonary ventilation, VT: tidalears, p < 0.05.

postmenopausal women. This is similar to the findings of Garcia-Rio et al. (2007) who found no age-related differences in HCVRin a cohort of men and women aged 65–84 years (although theauthors did not distinguish between men and women). In the cur-rent study, although all of the women were postmenopausal andnot taking hormone replacement therapy, there remained a neg-ative relationship between progesterone and age in the youngerwomen. Female sex hormones play an important role in respira-tory control, with increases in estrogen and progesterone that occurover the menstrual cycle and with pregnancy resulting in signifi-cant increases in ventilation (Jensen et al., 2005; Slatkovska et al.,

2006). In the post-menopausal state, central chemoreflex drive tobreathe is attenuated in direct association with a decline in estro-gen and progesterone (Preston et al., 2009). The lack of relationshipbetween progesterone and HCVR in the present study could be due
Page 6: Ventilatory responses to exercise and CO2 after menopause in healthy women: Effects of age and fitness

6 M.H. Davenport et al. / Respiratory Physiology & Neurobiology 184 (2012) 1– 8

REST AT 40 % Max

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ig. 3. Mean ventilation and breathing pattern during exercise stages equivalent to

right-hand panels). V̇E: ventilation, VT: tidal volume and fR: breathing frequency, A

o our recruitment of postmenopasual women who have relativelyow levels of circulating progesterone.

Although cross-sectional studies demonstrate HCVR is lowern male athletes compared to sedentary individuals (Byrne-Quinnt al., 1971; Miyamura et al., 1988), exercise interventions causencreases (Kelley et al., 1984), maintenance (Bradley et al., 1980) orecreases (Miyamura et al., 1988) in HCVR in young men. The pro-osed mechanism for decreased HCVR gain with increasing fitness

s decreased neural drive to respiratory muscles and/or diminishedhemoreceptor sensitivity (Byrne-Quinn et al., 1971; Peterson et al.,981; Miyamura et al., 1988). The present study demonstrated

lower HCVR in active compared to sedentary postmenopausal

omen. This suggests that differences between fitness groups may

e due to differences in mechanical ventilatory capacity and/orhemoreceptor sensitivity. Without a measure of neuromuscularrive we cannot determine if neural drive is similarly altered.

naerobic threshold, 40% of V̇O2 max and V̇O2 max by age (left-hand panels) and fitnesserobic threshold; Error bars: SD. *Significantly different than 65–79 years, p < 0.05.

4.3. The influence of age and fitness on the ventilatory responseto exercise

Comparisons of young versus older populations consistentlydemonstrate an age-related increase in �V̇E/�V̇CO2 during exer-cise, in part due to an increase in dead space ventilation (Brischettoet al., 1984; McConnell and Davies, 1992; Poulin et al., 1994). Inaccordance with Poulin et al. (1994), we found no effect of increas-ing age on �V̇E/�V̇CO2 below AT in postmenopausal women.Further, calculated resting dead space ventilation (V̇d; 50–64 y:1.77 ± 0.43 L min−1; 65–79 y: 1.92 ± 0.43 L min−1, p = 0.26) and theratio of Vd/VT (50–64 y: 0.19 ± 0.07; 65–79 y: 0.21 ± 0.06, p = 0.34)

were not different between age groups. However, there remaineda positive correlation between V̇d and �V̇E/�V̇CO2 below the AT.Above the AT, �V̇E/�V̇CO2 normally increases until maximal exer-cise. Although there is much debate, this is believed to be the result
Page 7: Ventilatory responses to exercise and CO2 after menopause in healthy women: Effects of age and fitness

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M.H. Davenport et al. / Respiratory

f hyperventilation in response H+ accumulation that stimulateshemoreceptors, central command and/or neural feedback fromontracting limb muscles (Wasserman et al., 2005; Gariepy et al.,010). In the present study, �V̇E/�V̇CO2 above the AT was signifi-antly lower in OPM compared to YPM. However, as the differencesetween age groups were abolished after controlling for FEV1, theecreased ventilatory response above AT in OPM may be explainedy an age-related decline in lung function and an increased workf breathing.

Increasing fitness decreases �V̇E/�V̇CO2 in young populationsMiyamura et al., 1976), however, the results in older populationsre equivocal. Yerg et al. (1985) examined the effect of aerobic exer-ise training in previously sedentary older men (63 years). Despite aignificant increase in V̇O2 max, �V̇E/�V̇CO2 remained unchangedYerg et al., 1985). In contrast, Anaya et al. (2009) found a small butignificant decrease in �V̇E/�V̇CO2 in previously sedentary, mildlyypertensive postmenopausal women following 6 months of aer-bic exercise training. In the present study, in the absence of anyifferences in lung function (as measured by FEV1), �V̇E/�V̇CO2oth above and below the AT was unaffected by fitness of nor-otensive postmenopausal women.

.4. HCVR and �V̇E/�V̇CO2

A strong correlation between HCVR and �V̇E/�V̇CO2 has beenemonstrated in young (McConnell et al., 1993) but not older pop-lations (Brischetto et al., 1984; Yerg et al., 1985). In the presenttudy, there was no correlation between these two variables forhe entire cohort, or when the cohort was split by age or fit-ess. This finding suggests the ventilatory response to inspired CO2nd the ventilatory response to CO2 production during exercisere mediated by different mechanisms. This is not surprising asCVR is primarily mediated by central chemoreceptors with someontribution by the peripheral chemoreceptors. In contrast, theechanism behind the ventilatory response to exercise is under

ebate but has been proposed to be a combination of detectionf metabolic changes by peripheral and central chemoreceptors,entral command and/or neural feedback by exercising limbsGariepy et al., 2010). Further research into the differing mecha-isms responsible for the increased respiratory drive with inspiredO2 and CO2 production is required.

There are two important considerations regarding the presenttudy. First, the study population was relatively healthy and freef major cardiovascular or respiratory disease and, thus, may note representative of those populations. Second, the cross-sectionaltudy design only allows us to explore correlative but not causalelationships between age, fitness, HCVR and �V̇E/�V̇CO2; how-ver, these novel findings provide insight into the influence ofging and fitness on the respiratory physiology of postmenopausalomen.

In conclusion, the present study provides novel data indicatingn inverse relationship between the HCVR and fitness, regardlessf age, in postmenopausal women. In contrast, age, but not fitness,nversely affects the �V̇E/�V̇CO2 relationship above the anaerobichreshold which may be explained, at least in part, by age-relatedeclines in lung function. Intervention studies in postmenopausalomen are required to determine if the relationship between fit-ess and HCVR is indeed causal. If the relationship is causal, exerciseay be a simple cost-efficient method to counteract the age-related

oss in HCVR protective mechanisms.

rants

This study was supported by an Establishment Grant from thelberta Heritage Foundation for Medical Research (AHFMR, MJP);

logy & Neurobiology 184 (2012) 1– 8 7

a Grant-in-Aid from the Heart and Stroke Foundation of Alberta,NWT & Nunavut (MJP); Canadian Foundation for Innovation (MJP);a Fellowship from the Heart and Stroke Foundation of Canada(HSFC) and Canadian Institute for Health Research (CIHR) (MHD);a Doctoral Research Award from the HSFC and AHFMR (AEB); anAHFMR Clinical Investigator Award and a Glaxo-Smith-Kline-CIHRProfessorship in Inflammatory Lung Disease (RL) and a CIHR NewInvestigator Award, an AHFMR Senior Medical Scholar Award andthe Brenda Strafford Foundation (MJP).

Acknowledgment

We thank Dr. Craig Steinback for his critical review of themanuscript.

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