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Original Article

Habitual Exercise and Blood Pressure: Age Dependency and


Underlying Mechanisms
Barry J. McDonnell1, Kaisa M. Maki-Petaja2, Margaret Munnery3, Yasmin2, Ian B. Wilkinson2,
John R. Cockcroft3, and Carmel M. McEniery2

Background systolic and pulse pressure were lower in older active individuals, com-
Regular exercise is associated with a reduction in cardiovascular risk, pared with their sedentary counterparts. Moreover, regular exercise
but the precise mechanisms responsible are unknown. The aim of the was associated with lower wave reflections and peripheral vascular

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current study was to examine the relationship between regular exer- resistance in younger individuals, but lower large artery stiffness in
cise, aortic stiffness, and wave reflections, and to determine whether older individuals.
this relationship differs by age.
Conclusions
METHODS These data suggest that regular exercise is associated with a benefi-
Younger (<30 years) and older (>50 years) individuals, who were either sed- cial vascular profile. However, this differs between younger and older
entary or undertook regular aerobic exercise, were drawn from the Anglo- individuals such that the smaller preresistance and resistance vessels
Cardiff Collaborative Trial population. This yielded 1,036 individuals, all are involved in younger individuals whereas the large elastic arteries
of whom were nonsmokers, and were free of cardiovascular disease and are involved in older individuals. Despite these differential findings, the
medication. All individuals undertook a detailed lifestyle and medical his- current data provide support for strategies that increase habitual physi-
tory questionnaire including details of physical activity. Brachial and central cal activity levels in the general population.
blood pressure, together with aortic stiffness, wave reflections, cardiac
output, and peripheral vascular resistance were assessed in all individuals. Keywords: age; blood pressure; hypertension; large artery stiffness;
exercise.
RESULTS
In younger individuals, regular exercise was associated with lower
diastolic blood pressure but elevated pulse pressure. In contrast, both doi:10.1093/ajh/hps055

Lack of physical activity is an independent risk factor for have been investigated previously,12–21 the results have been
cardiovascular disease (CVD)1 and increased physical conflicting, owing to differences between populations, type
activity and physical fitness are associated with a decreased of exercise, and variations in methods used to assess arterial
incidence of coronary artery disease (CAD) events.2–3 The stiffness. Moreover, chronic exercise tends to decrease blood
mechanisms whereby exercise reduces cardiovascular (CV) pressure,22 making it difficult to assess whether any observed
risk are unclear but may involve an improvement in tra- changes in arterial stiffness are independent of reductions in
ditional cardiovascular risk factors such as hypertension, blood pressure. Furthermore, indices such as AIx and aor-
hyperglycemia, and hypercholesterolemia.4 However, recent tic PWV (aPWV) are differentially affected by aging,23 and
evidence suggests that the cardiovascular protective effect is whether aging influences the relationship between regular
still evident after adjusting for such factors.5 exercise and arterial properties is unclear.
Although the importance of blood pressure in CV risk The aim of the current study was to examine the relation-
prediction is firmly established,6 recently, aortic stiffness ship between regular exercise, aortic stiffness, and wave
and wave reflections have emerged as important, independ- reflections, in a large group of healthy individuals across a
ent risk factors for CV events.7–10 Moreover, increased aortic wide age range. Specifically, we wished to determine whether
stiffness may underlie the development of hypertension.11 the relationship between regular exercise and cardiovas-
While the relationship between exercise and indices such as cular hemodynamics differs between younger and older
pulse wave velocity (PWV) and augmentation index (AIx) individuals.

1Cardiff School of Health Sciences, Cardiff Metropolitan University,


Correspondence: Barry J. McDonnell (bmcdonnell@cardiffmet.ac.uk).
Cardiff, UK; 2Clinical Pharmacology Unit, University of Cambridge,
Initially submitted June 19, 2012; date of first revision September 25, Addenbrooke’s Hospital, Cambridge, UK; 3Department of Cardiology,
2012; accepted for publication October 14, 2012. Wales Heart Research Institute, Cardiff University, Cardiff, UK.
© American Journal of Hypertension, Ltd 2013. All rights reserved.
For Permissions, please email: journals.permissions@oup.com

334  American Journal of Hypertension  26(3)  March 2013


Exercise, Aging, and Arterial Function

METHODS SphygmoCor system (SphygmoCor, Atcor Medical, Sydney,


Australia) as previously described.25 This method allows non-
Study population
invasive generation of a central (ascending aortic) waveform
Participants were drawn from the ACCT study popu- from that recorded at the radial artery, using a validated gen-
lation, which consists of more than 12,000 individuals, eralized transfer function.26 Using the integral software, aug-
selected at random from local General Practice lists and mentation pressure was calculated as the difference between
open-access Cardiovascular Risk Assessment Clinics, across the second and first systolic peaks, and AIx (a measure of
East Anglia and Wales. To examine the influence of age, we wave reflection) as the augmentation pressure expressed as
elected to study two groups of individuals: those <30 years a percentage of the pulse pressure. Nonaugmented systolic
(younger) and those >50 years (older). Within each group, pressure was identified as the first systolic peak. Heart rate
comparisons were made between sedentary and active indi- was determined from the aortic waveform and mean arterial
viduals, who were matched for age using frequency match- pressure (MAP) was obtained by integration of the waveform.
ing. This approach yielded 1,036 healthy nonsmokers, who Aortic PWV was measured using the same device by sequen-
were free from cardiovascular disease and medication, and tially recording electrocardiography-gated carotid and femo-
who had undertaken a detailed lifestyle and medical history ral artery waveforms, as previously described in detail.27 Path

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questionnaire that included questions concerning physical length for the determination of aPWV was measured as the
activity (see below). Ethical approval was obtained from the surface distance between the suprasternal notch and femoral
local research ethics committees and written informed con- site minus the distance between the suprasternal notch and
sent provided by all participants. carotid site, using a tape measure.
Cardiac output and stroke volume were assessed with the
subject resting supine, using a validated,28 noninvasive, inert gas
Protocol
rebreathing technique. In brief, while resting, subjects continu-
Height and weight were assessed and a medical history ously rebreathed a gas mixture (1% SF6, 5% N20, and 94% O2)
questionnaire, including details of medication and physi- over 20 seconds, with a breathing rate of 15 breaths per minute.
cal activity completed. Following 15 minutes of supine rest, Expired gases were sampled continuously and analyzed by an
brachial blood pressure (BP) and radial artery waveforms infrared photoacoustic gas analyzer (InnoCor, Innovision A/S,
were recorded, and aPWV was determined. Ten milliliters Denmark), for the determination of cardiac output and stroke
of blood were then drawn from the antecubital fossa into volume. Peripheral vascular resistance (PVR) was calculated
plain tubes. The samples were centrifuged at 4°C, and the using the equation [PVR = (80 * MAP)/CO].
serum separated and stored at –80°C for subsequent analy-
sis. Cholesterol, triglycerides, and glucose were determined Statistical analysis
using standard methodology in an accredited laboratory.
All data were analyzed using SPSS (version 17.0) software
for windows. Unpaired 2 tailed t tests were used to deter-
Assessment of physical activity
mine differences between groups. Unless otherwise stated,
The International Physical Activity Questionnaire results are expressed as mean (SD). A P value of <0.05 was
(October 2002)  was used to assess each individual’s physi- used to determine significance.
cal activity levels over the previous 12  months. Based on
the questionnaire data, those individuals who did not par- RESULTS
ticipate in any structured physical activity throughout their
average week were deemed sedentary. The active group Younger and older participants were stratified according
consisted of subjects who reported that they participated in to their level of habitual physical activity. This yielded a total
moderate to high-intensity aerobic exercise (e.g., running, of 487 young (194 sedentary and 293 active) and 549 older
cycling, swimming), ≥3 times per week and for at least 1 (320 sedentary and 229 active) participants in whom com-
hour duration (American College of Sports Medicine guide- plete data were available for the current analyses. The data
lines, 1998). To ensure a clear separation of the groups in presented here are for males and females, since separate anal-
terms of the amount of physical activity undertaken, indi- yses based on gender showed the same trends throughout.
viduals who undertook regular resistance training and/or
low-intensity physical activity were excluded from the analy- Anthropometric characteristics
ses. Individuals who took part in a mixture of resistance and
aerobic physical activity were also excluded. Anthropometric characteristics for the two groups are
presented in Table 1. The sedentary vs. active subjects within
Hemodynamic measurements each group were matched for age. In younger individuals,
there were no differences in weight, body mass index (BMI),
Brachial blood pressure was measured with the subject or waist circumference between active and sedentary indi-
resting supine, using a validated semiautomated oscillomet- viduals. However, in older individuals, regular exercise was
ric device24 (HEM-705CP, Omron Corporation), according associated with significantly lower body weight, BMI, and
to British Hypertension Society guidelines. All measurements waist circumference. A  comparison of younger and older
were taken in duplicate and mean values used in the subse- subjects within the sedentary and active groups revealed that
quent analyses. Pulse wave analysis was performed using the although body weight, BMI, and waist circumference were

American Journal of Hypertension  26(3)  March 2013  335


McDonnell et al.

Table 1.  Anthropometric characteristics in sedentary and active younger and older individuals

<30 years >50 years

Parameter Sedentary (n = 194) Active (n = 293) P value Sedentary (n = 320) Active (n = 229) P value

Age (years) 21 ± 5 21 ± 3 NS 63 ± 7 63 ± 6 NS


Gender (% male) 46 53 0.01 39 49 0.02
Height (m) 1.71 ± 0.1 1.74 ± 0.1 <0.001 1.66 ± 0.1 1.68 ± 0.1 0.03
Weight (kg) 69 ± 16 70 ± 12 NS 80 ± 15 72 ± 14 <0.001
BMI (kg/m2) 23.5 ± 4.5 23.0 ± 2.9 NS 28.8 ± 4.7 25.4 ± 4.0 <0.001
Waist circumference (cm) 78 ± 11 78 ± 8 NS 93 ± 16 88 ± 11   0.002

Data are mean ± SD.


Abbreviations: BMI, body mass index; NS, not significant.

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Table 2.  Hemodynamic indices in sedentary and active younger and older individuals

<30 years >50 years

Parameter Sedentary (n = 194) Active (n = 293) P value Sedentary (n = 320) Active (n = 229) P value

Brachial SBP (mm Hg) 121 ± 17 120 ± 15 NS 142 ± 21 133 ± 18 <0.001


Brachial DBP (mm Hg) 77 ± 11 72 ± 9 <0.001 85 ± 10 83 ± 10  0.008
Central SBP (mm Hg) 105 ± 14 102 ± 12 0.02 132 ± 20 123 ± 18 <0.001
Non-augmented central SBP 103 ± 14 101 ± 11 0.05 118 ± 16 112 ± 14 <0.001
  (mm Hg)
Heart rate (bpm) 71 ± 11 64 ± 11 <0.001 67 ± 10 63 ± 10   0.003
Ejection duration (ms) 319 ± 18 329 ± 22 <0.001 328 ± 23 331 ± 21 NS
Cardiac output (L/min) 7.5 ± 1.9 7.9 ± 2.3 NS 4.6 ± 1.1 5.2 ± 1.4 0.02
Cardiac index (L/min/m2) 4.2 ± 0.9 4.3 ± 1.0 NS 2.5 ± 0.6 3.0 ± 0.9 0.002
Augmentation pressure (mm Hg) 0.9 ± 4.6 –0.3 ± 4.1 0.004 14.1 ± 6.9 13.3 ± 6.6 NS

Data are mean ± SD.


Abbreviations: DBP, diastolic blood pressure; NS, not significant; SPB, systolic blood pressure.

all higher in older individuals, the magnitude of the diffe- persisted after adjustment for age and MAP (Figure 2). All
rence between age groups was reduced in active individuals trends persisted following adjustment for differences in BMI
(Supplementary Table 1). between the older groups (data not shown).
As expected, all indices of blood pressure were higher
in older individuals, regardless of physical activity level.
Hemodynamic indices
However, the magnitude of the differences in brachial and
Haemodynamic indices are presented in Table  2 and aortic pulse pressures between age groups was consider-
Figures 1 and 2. Regular exercise was associated with lower ably lower in active individuals (Supplementary Table 2).
diastolic pressure and lower central, but not brachial systolic Similarly, AIx and aPWV were higher in older subjects.
pressure in younger individuals. In contrast, in older individ- However, whereas the age-related difference in AIx was simi-
uals, regular exercise was associated with lower brachial and lar between sedentary and active subjects, the difference in
central systolic pressures. Interestingly, regular exercise was aPWV in the active individuals was of a smaller magnitude.
associated with lower brachial and aortic pulse pressures in
older individuals, but higher brachial and aortic pulse pres- Biochemical indices
sures in younger individuals (Figure 1). Regular exercise was
also associated with significantly higher stroke volume in Overall, regular exercise was associated with a favorable
both age groups; however, cardiac output and cardiac index biochemical profile in both younger and older individuals,
were significantly higher only in older active vs. sedentary although the magnitude of the differences between seden-
individuals. AIx was significantly lower in younger active vs. tary and active younger individuals was small (Table  3).
sedentary individuals, even after adjustment for confound- After performing multiple regression analyses on younger
ers (Figure 2), and this was accompanied by a significantly and older groups, these data illustrated that no biochemi-
lower PVR in active subjects. In contrast, aPWV was signifi- cal parameter had any impact on vascular hemodynamic
cantly lower in older active vs. sedentary individuals, which parameters studied.

336  American Journal of Hypertension  26(3)  March 2013


Exercise, Aging, and Arterial Function

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Figure 1.  Brachial (a) and central (b) pulse pressure in younger and older sedentary (solid bars) and active (clear bars) individuals. **P < 0.01, ***P < 0.001
vs. sedentary. Abbreviation: PP, pulse pressure.

Figure 2.  Relationship between regular exercise and augmentation index (AIx; a), aortic pulse wave velocity (PWV; b), stroke volume (c), and peripheral
vascular resistance (PVR; d). Solid bars represent sedentary, clear bars represent active. *P < 0.05, **P < 0.01, ***P < 0.001 vs. sedentary. AIx was adjusted
for heart rate and height. Aortic PWV was adjusted for age and mean arterial pressure.

Discussion pressure, and provides a comprehensive insight into the


underlying hemodynamic mechanisms. Our major, novel
This is the largest study describing the influence of age finding was that the relationship between regular exercise
on the relationship between regular exercise and blood and blood pressure, wave reflections, and arterial stiffness

American Journal of Hypertension  26(3)  March 2013  337


McDonnell et al.

Table 3.  Biochemical profile of sedentary and active younger and older individuals

<30 years >50 years

Parameter Sedentary (n = 194) Active (n = 293) P value Sedentary (n = 320) Active (n = 229) P value

Total cholesterol (mmol/l) 4.1 ± 0.9 4.0 ± 0.7 NS 5.7 ± 1.1 5.5 ± 1.0 NS


LDL (mmol/l) 2.3 ± 0.8 2.2 ± 0.6 NS 3.5 ± 1.0 3.4 ± 0.9 NS
HDL (mmol/l) 1.4 ± 0.4 1.5 ± 0.4 0.01 1.4 ± 0.4 1.6 ± 0.5 <0.001
Triglycerides (mmol/l) 1.1 ± 0.7 0.9 ± 0.5  0.002 1.9 ± 1.0 1.4 ± 0.8 <0.001
Glucose (mmol/l) 4.9 ± 0.9 4.7 ± 0.7 0.01 5.5 ± 2.1 5.0 ± 1.1 NS

Data are mean ± SD.


Abbreviations: HDL, high-density lipoprotein; LDL, low-density lipoprotein; NS, not significant.

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differed significantly between younger and older individuals. higher stroke volume in both younger and older individuals, an
In younger individuals, regular exercise was associated with adaptation which has been described previously.22, 31 However,
lower diastolic blood pressure, but elevated pulse pressure. In despite the higher stroke volume, there were no differences in
contrast, both systolic and pulse pressure were lower in older brachial or nonaugmented central systolic pressures between
active individuals. Moreover, regular exercise was associated active and sedentary younger individuals. Instead, the widened
with lower wave reflections and PVR in younger individu- pulse pressure in younger active individuals was associated
als, but lower large artery stiffness in older individuals. These with a significantly lower diastolic pressure.
data suggest that regular exercise is associated with a benefi- The lower diastolic blood pressure is likely to involve
cial vascular profile, involving the smaller preresistance and exercise-related adaptations of the smaller, preresistance and
resistance vessels in younger individuals, whereas the large resistance vessels, which have a greater influence on diastolic,
elastic arteries are involved in older individuals. Despite rather than systolic, pressure. Indeed, in younger individuals,
these differential age-related findings, the current data pro- regular exercise was associated with a lower PVR, and a lower
vide further support for strategies which increase habitual AIx, indicating diminished wave reflections, which is also
physical activity levels in the general population. likely to explain the lower central systolic pressure observed
A recent meta-analysis22 emphasised the well-accepted in younger active individuals. These data are in agreement
view that regular exercise confers beneficial effects on brachial with other studies showing that increased habitual physi-
systolic and diastolic blood pressure, although the authors did cal activity is associated with a lower AIx in young female
not distinguish between younger and older individuals. To twins,32 in competitive, endurance trained athletes vs. recrea-
our knowledge, the current study is the first to demonstrate tionally active controls,20 and in patients with systemic lupus
that the relationship between regular exercise and blood pres- erythematosus.33 Although the mechanisms underlying the
sure may be dependent on age, where exercise is associated lower PVR and AIx cannot be confirmed in the current study,
with lower brachial diastolic pressure in younger individu- likely candidates include altered insulin sensitivity,34 shear
als, but systolic pressure in older individuals. Interestingly, stress,35 nitric oxide bioavailability35 and decreased sympa-
diastolic blood pressure is more predictive of cardiovascular thetic activity,36 as a result of regular exercise.
risk in younger subjects.29 Whereas in older individuals it is In older individuals, the lower brachial and central pulse
systolic and pulse pressure which have superior predictive pressures observed in active subjects were due predomi-
value.30 Therefore, the relationships between regular exercise nantly to lower systolic pressures in these individuals, with
and blood pressure observed in the current study appear to be a much more modest influence of diastolic pressure. Since
consistent with a longer-term reduction in cardiovascular risk. stroke volume was significantly increased in active individu-
Pulse pressure, the difference between systolic and diastolic als, the lower systolic pressures observed in this age group
pressure, is often considered a surrogate of large artery stiff- are likely to be due, at least in part, to a lower level of large
ness, and has even greater predictive value for cardiovascular artery stiffness. Indeed, aPWV was significantly lower in
events than either systolic or diastolic pressure alone, in older active than sedentary individuals. Previous data describing
individuals.30 Interestingly, regular exercise was associated the influence of exercise on arterial stiffness remain difficult
with opposite patterns of pulse pressure in younger and older to interpret, in part due to the wide variety of methods used
individuals. Both brachial and central pulse pressures were ele- to measure arterial properties, and differences in age ranges
vated in younger individuals who undertook regular exercise. and exercise modalities. Nevertheless, cross-sectional17,37–40
However, in older active individuals, both brachial and central and interventional41 studies have previously demonstrated
pulse pressures were significantly lower relative to sedentary that regular exercise is associated with beneficial effects on
controls. Physiologically, the major determinants of pulse pres- large artery stiffness in older individuals, although others
sure, and, in particular, nonaugmented pulse pressure, are the have shown only modest42 or no effects15 of regular exercise.
stroke volume and aortic stiffness, representing the volume In contrast to the situation in older individuals, there were
of blood flowing into the aorta, and the ability of the aorta to no differences in aPWV between younger active and seden-
buffer this volume and thus minimize any rise in intra-arterial tary individuals in the current study, despite the higher pulse
pressure. As expected, regular exercise was associated with a pressures observed in active individuals. This illustrates that

338  American Journal of Hypertension  26(3)  March 2013


Exercise, Aging, and Arterial Function

pulse pressure may not be a reliable surrogate of large artery focussed on differences between active and sedentary indi-
stiffness in younger individuals. Previous cross-sectional stud- viduals within each age group, although it is apparent from
ies in younger subjects show an inverse association between our data that age-related differences in hemodynamic vari-
cardiorespiratory fitness and aPWV16 and between regular ables also varied according to the level of physical activity
physical activity and measures of carotid artery stiffness.43–44 undertaken. In addition, we did not record the number of
However, intervention studies have failed to detect an effect of years over which an individual has exercised at their cur-
aerobic exercise training on aPWV in young rats14 or carotid rent level and therefore we cannot quantify life-course expo-
stiffness in young humans.45 In addition, and in keeping with sure to physical activity, which is bound to differ between
previous cross-sectional data,19 we did not observe any differ- younger and older individuals. Finally, because of the cross-
ences in AIx between older sedentary and active individuals, sectional nature of these analyses, we cannot examine causal
although previous intervention studies have demonstrated relationships. For example, as alluded to above, it may be the
significant reductions in AIx during acute dynamic exercise46 case that exercise induces beneficial age-related changes in
and following exercise training in older healthy subjects21 and cardiovascular hemodynamics, or simply that healthier indi-
those with coronary artery disease.47 Aging exerts one of the viduals are more likely to undertake regular exercise, espe-
most potent effects on the cardiovascular system. Indeed, pre- cially later in life.

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vious data from the ACCT study suggest that aging exerts a Blood pressure is a major risk factor for cardiovascular
differential effect on arterial stiffness and wave reflections,23 events. However, it is now widely recognised that aging influ-
and that associations between traditional cardiovascular risk ences the association between blood pressure and cardiovas-
factors and AIx are stronger in younger individuals, whereas cular risk, such that elevated diastolic pressure is associated
risk factors are more strongly related to aPWV in older indi- with increased risk in younger individuals, whereas systolic
viduals.48 The findings of the current study are in keeping with and pulse pressures hold greater predictive value in older
these previous observations, particularly with regard to the individuals. Interestingly, in the current study, the relation-
lower AIx observed in younger active individuals, but lower ship between regular exercise and blood pressure was also
aPWV observed in older active individuals, compared with age-dependent, where diastolic pressure and wave reflec-
sedentary subjects. Unfortunately we cannot clarify the mech- tions were lower in the young but systolic and pulse pres-
anisms underlying the apparent beneficial effects of regular sures, together with large artery stiffness, were lower in older
exercise on aPWV in older individuals. However, it is possible individuals. Therefore, the current data support the concept
that life-course exposure to regular exercise may retard the that strategies designed to increase habitual physical activity
process of large artery stiffening, which is prevalent in this age levels in the general population may have considerable ben-
group, whereas the smaller, more muscular vessels appear to efits in reducing cardiovascular risk, regardless of age.
be less affected by the longer-term benefits of regular exercise
in older individuals.
The current findings also support the concept that lifestyle
factors such as physical activity levels may affect the relation- Supplementary material
ship between age and markers of cardiovascular health, such
as blood pressure. Indeed, age-related differences in blood Supplementary materials are available at the American
pressure and large artery stiffness were blunted in individu- Journal of Hypertension online (http://www.oxfordjournals.
als who undertook regular exercise. Irrespective of whether org/our_journals/ajh/). Supplementary materials consist of
age affects the relationship between regular exercise and data provided by the author that are published to benefit the
the cardiovascular system or whether undertaking regular reader. The posted materials are not copyedited. The con-
exercise influences “cardiovascular aging” per se, the current tents of all supplementary data are the sole responsibility of
data suggest that the beneficial effects of regular exercise on the authors. Questions or messages regarding errors should
the cardiovascular system are consistent with longer-term be addressed to the author.
age-specific reductions in cardiovascular risk. Finally, body
weight, BMI, and waist circumference were all significantly
reduced in older active individuals compared with their sed- Acknowledgments
entary counterparts, demonstrating that those undertaking The ACCT Study Investigators: Samantha Benedict, John
regular exercise had a more favorable anthropometric profile Cockcroft, Lisa Day, Stacey Hickson, Julia Howard, Kaisa
and therefore, lower cardiovascular risk. Maki-Petaja, Barry McDonnell, Carmel McEniery, Karen
The current study has a number of limitations. The clas- Miles, Maggie Munnery, Pawan Pusalkar, Christopher
sification of “physically active” vs. “sedentary” was based on Retallick, Chloe Rowe, James Sharman, Jane Smith, Rachel
self-report, using a questionnaire administered at the time Stainsby, Edna Thomas, Ian Wilkinson, Susannah Williams,
hemodynamic measurements were undertaken. Moreover, Jean Woodcock-Smith, Yasmin.
although the same criteria were applied to define levels of
regular exercise in each age group, the average level of exer-
cise undertaken by each of the “active” groups may have Disclosure
differed. Nevertheless, every effort was made to include
only those individuals undertaking regular moderate-to- Ian B.  Wilkinson is a BHF Senior Fellow and Carmel
high intensity exercise, in order to minimise heterogene- M. McEniery is a BHF Intermediate Fellow. This work was
ity between the groups. Moreover, the major comparisons supported, in part, by the National Institute for Health

American Journal of Hypertension  26(3)  March 2013  339


McDonnell et al.

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