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Trial of Exercise to Prevent HypeRtension in young Adults (TEPHRA) a randomized controlled trial: study protocol

Authors:
  • US Air Force Academy & The University of Oxford

Abstract and Figures

Background Hypertension prevalence in young adults has increased and is associated with increased incidence of cerebrovascular and cardiovascular events in middle age. However, there is significant debate regards how to effectively manage young adult hypertension with recommendation to target lifestyle intervention. Surprisingly, no trials have investigated whether lifestyle advice developed for blood pressure control in older adults is effective in these younger populations. Methods/Design TEPHRA is an open label, parallel arm, randomised controlled trial in young adults with high normal and elevated blood pressure. The study will compare a supervised physical activity intervention consisting of 16 weeks structured exercise, physical activity self-monitoring and motivational coaching with a control group receiving usual care/minimal intervention. Two hundred young adults aged 18–35 years, including a subgroup of preterm born participants will be recruited through open recruitment and direct invitation. Participants will be randomised in a ratio of 1:1 to either the exercise intervention group or control group. Primary outcome will be ambulatory blood pressure monitoring at 16 weeks with measure of sustained effect at 12 months. Study measures include multimodal cardiovascular assessments; peripheral vascular measures, blood sampling, microvascular assessment, echocardiography, objective physical activity monitoring and a subgroup will complete multi-organ magnetic resonance imaging. Discussion The results of this trial will deliver a novel, randomised control trial that reports the effect of physical activity intervention on blood pressure integrated with detailed cardiovascular phenotyping in young adults. The results will support the development of future research and expand the evidence-based management of blood pressure in young adult populations. Trial Registration Clinicaltrials.gov registration number NCT02723552, registered on 30 March, 2016.
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S T U D Y P R O T O C O L Open Access
Trial of Exercise to Prevent HypeRtension in
young Adults (TEPHRA) a randomized
controlled trial: study protocol
Wilby Williamson
1*
, Odaro J. Huckstep
1
, Eleni Frangou
2
, Afifah Mohamed
1
, Cheryl Tan
1
, Maryam Alsharqi
1
,
Mariane Bertagnolli
1,3
, Winok Lapidaire
1
, Julia Newton
4
, Henner Hanssen
5
, Richard McManus
6
, Helen Dawes
7
,
Charlie Foster
8
, Adam J. Lewandowski
1,9
and Paul Leeson
1
Abstract
Background: Hypertension prevalence in young adults has increased and is associated with increased incidence of
cerebrovascular and cardiovascular events in middle age. However, there is significant debate regards how to effectively
manage young adult hypertension with recommendation to target lifestyle intervention. Surprisingly, no trials
have investigated whether lifestyle advice developed for blood pressure control in older adults is effective in
these younger populations.
Methods/Design: TEPHRA is an open label, parallel arm, randomised controlled trial in young adults with
high normal and elevated blood pressure. The study will compare a supervised physical activity intervention
consisting of 16 weeks structured exercise, physical activity self-monitoring and motivational coaching with a
control group receiving usual care/minimal intervention. Two hundred young adults aged 1835 years,
including a subgroup of preterm born participants will be recruited through open recruitment and direct
invitation. Participants will be randomised in a ratio of 1:1 to either the exercise intervention group or control
group. Primary outcome will be ambulatory blood pressure monitoring at 16 weeks with measure of
sustained effect at 12 months. Study measures include multimodal cardiovascular assessments; peripheral
vascular measures, blood sampling, microvascular assessment, echocardiography, objective physical activity
monitoring and a subgroup will complete multi-organ magnetic resonance imaging.
Discussion: The results of this trial will deliver a novel, randomised control trial that reports the effect of
physical activity intervention on blood pressure integrated with detailed cardiovascular phenotyping in young
adults. The results will support the development of future research and expand the evidence-based
management of blood pressure in young adult populations.
Trial Registration: Clinicaltrials.gov registration number NCT02723552, registered on 30 March, 2016.
Keywords: Young adult, Blood pressure, Hypertension, Prehypertension, Preterm birth, Randomised trial,
Exercise, Cardiac imaging, Cardiac Remodelling, Cerebrovascular health
* Correspondence: wilby.williamson@cardiov.ox.ac.uk
1
Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular
Medicine, Radcliffe Department of Medicine, University of Oxford, John
Radcliffe Hospital, Oxford OX3 9DU, UK
Full list of author information is available at the end of the article
© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Williamson et al. BMC Cardiovascular Disorders (2018) 18:208
https://doi.org/10.1186/s12872-018-0944-8
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Background
Hypertension contributes to 9 million annual global deaths
[1] and more disability-adjusted life years (DALYs) lost than
any other single cause [2]. Lifetime risk of cardiovascular
events is associated with modest increases in systolic blood
pressure above 115 mmHg [2]. Acknowledgement of these
risks have prompted a recent review of international criteria
for hypertension diagnosis, with several proposing stage 1
diagnosis be lowered from the threshold of 140 mmHg sys-
tolic or 90 mmHg diastolic down to 130 mmHg systolic or
80 mmHg diastolic [3]. Across the life course this diagnos-
ticchangehasgreatestsignificanceforadultsaged18to39,
in whom an estimated 3040% will now reach diagnostic
criteria for hypertension leading to a 3 fold increase in
prevalence [4][5]. Such a change could help tackle a global
trend of increased incidence of stroke and cardiovascular
events in young adults [6,7]. However, there is significant
debate regards how to achieve lower target blood pressures
in young adults [8,9]. Some trials in middle age adults at
intermediate risk have identified no benefit associated with
antihypertensive therapy and potential harm in pharmaco-
logical reduction of high normal blood pressure [10].
Globally, modifiable risk factors have the largest attrib-
utable risk to cardiovascular events and stroke [11] and
current guidelines recommend targeted lifestyle inter-
vention, and in particular physical activity promotion,
for young adults with hypertension [12]. However, our
recent systematic review of exercise intervention trials
for blood pressure identified bias in recruitment towards
older adults, lack of investigation of determinates of
physiological and behavioural exercise remodelling and
limited understanding of the cardiovascular adaptations
associated with change in modifiable risk profiles [13].
Therefore, there is limited trial evidence to support
physical activity intervention as a primary treatment op-
tion at present [14]. In addition, at younger ages, a range
of factors including birth history, familial predisposition
and young adult socio-economic exposures have influ-
ences on cardiac and cerebrovascular remodelling that
may make cardiovascular response to lifestyle interven-
tions more complex [5,15,16]. This means there is lack
of understanding regards effectiveness of intervention
across subgroups of the population and potential hetero-
geneity in response to exercise training [1522]. There-
fore, this study will trial an exercise intervention in a
young adult population with high and high normal blood
pressure to identify effectiveness for management of
blood pressure and also understand determinates of
behavioural and physiological remodelling as well as dif-
ferential effects across phenotypes.
Study aims and objectives
The primary aim of this study is to compare the effect of
a structured aerobic exercise and physical activity
intervention versus usual care/minimal intervention on
ambulatory blood pressure levels in young adults with
high normal or elevated blood pressure. Secondary aims
include investigation of the broader effects of exercise
on peripheral and central cardiovascular remodelling,
metabolic function, physical activity behaviours, and
physical function. Tertiary aims target an exploratory
analysis of remodelling across the liver, heart and brain
using MRI indices of structure and function and will
explore the potential that baseline phenotypes predict
exercise response (Table 1).
Hypotheses
The primary hypothesis is that structured aerobic exer-
cise training and physical activity self-monitoring will
improve ambulatory blood pressure measures for young
adults with elevated blood pressure. The secondary
hypotheses are that: structured aerobic exercise training
and physical activity self-monitoring will also improve
other cardiovascular, metabolic and cerebrovascular risk
profiles in young adults; that the degree of improvement
will associate with changes in vascular biology and
behaviour, as potential mediators of the changes; and
thirdly that response to exercise will vary depending on
baseline phenotypic differences between individuals.
Methods
TEPHRA is an open label, prospective single-blinded,
two-arm, parallel, randomized controlled trial in young
adults with elevated blood pressure. In total, 200 partici-
pants will be randomized (ratio 1:1) following baseline
measures to either exercise intervention or to a compari-
son control group with minimal intervention. There are
two follow-up visits post-randomisation: at 16 weeks
and 52 weeks (Fig. 1). The primary endpoint will be at
16 weeks post-randomisation, immediately after the end
of the intervention. The protocol is prepared in accord-
ance with the SPIRIT statement.
Participants who enter the trial will nominally
complete 4 study visits over the course of the trial:
I. Screening assessment (Visit 0)
II. Baseline Study Visit (Visit 1)
III. 16-week follow-up Study Visit (Visit 2) at 16 weeks
(post completion of structured exercise intervention
for those in the intervention arm)
IV. 52-week follow-up Study Visit (Visit 3) - (52 weeks
post randomisation)
Study measure collection is reduced for Visit 3 to
reduce redundant data collection of selected non-
primary outcome data and minimise excess burden
on study participants.
Williamson et al. BMC Cardiovascular Disorders (2018) 18:208 Page 2 of 16
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Table 1 TEPHRA trial objectives, outcome measures and measurement time-points
Objectives Measures Time-points
Benefits of Exercise
Short term Blood Pressure Response:
The primary objective is to compare the effect of
aerobic exercise intervention and physical activity
self-monitoring versus usual care/minimal intervention
on ambulatory blood pressure levels in young adults
with high normal and elevated blood pressure.
Systolic and diastolic blood pressure measured
during ambulatory blood pressure monitoring
Measured at baseline and at 16 week
follow-up
Sustained blood pressure response:
To compare the sustained effect of aerobic
exercise intervention with continued physical
activity self-monitoring and motivational coaching
versus usual care/minimal intervention on awake
blood pressure levels in young adults with high
normal and elevated blood pressure.
Systolic and diastolic blood pressure measured
during ambulatory blood pressure monitoring
baseline
16 weeks follow-up
52 weeks follow-up
Cardiovascular Fitness:
To compare the effect of aerobic exercise
intervention and physical activity self-monitoring
versus usual care/minimal intervention on
cardiovascular performance and stress response
in young adults with high normal and elevated
blood pressure.
Cardiopulmonary exercise testing - Oxygen
uptake and carbon dioxide exchange kinetics
across submaximal and peak exercise
Dynamic central and peripheral cardiovascular
response to exercise stress
Circulating plasma stress biomarkers collected
pre and post exercise.
Haemodynamic response to exercise: blood
pressure, heart rate, measures of cardiac
performance during cardiopulmonary exercise
testing.
Exercise stress echocardiography (subgroup)
baseline
16 weeks follow-up
52 weeks follow-up
Physical Function:
Compare the 16-week and sustained effect of
intervention on objectively measured walking
gait, walking cadence and global physical
function.
Objective measure of physical activity (7 day
wear of activity monitor)
Objective gait analysis
Questionnaire
baseline
16 weeks follow-up
52 weeks follow-up
Cardiac Remodelling:
Investigate cardiac adaptation and remodelling
following intervention, with reference to
gestational age and baseline cardiovascular
phenotypes.
Cardiac echocardiography measures
Cardiac MRI measures (subgroup)
Cardiac mass
Left and right ventricular structure and function
3D-shape and functional analysis
baseline
16 weeks follow-up
52 weeks follow-up (echocardiog-
raphy only)
Cerebrovascular Remodelling:
Investigate cerebrovascular adaptation and
remodelling following intervention, with
reference to gestational age and baseline
cerebrovascular phenotypes.
Brain MRI (subgroup)
White and grey matter volumes
Subcortical nuclei volumes
Cortical thickness
White matter integrity
White matter hyperintensities
White matter connectivity
Brain vessel morphology
Brain vascular resistance
Brain blood flow and arrival time
baseline
16 week follow-up
Hepatic Remodelling:
To investigate hepatic remodelling and mean
change in hepatic adiposity pre and post
exercise intervention compared to control.
Liver MRI (subgroup)
Structure and volume
Intra-hepatic lipid content
Steatohepatitis
Hepatic fibrosis
Hepatic Iron Load
baseline
16 weeks follow-up
Metabolic Function:
Compare the effects of intervention on the
fasting metabolic profile.
Fasting glucose profile
Fasting insulin profile
Fasting lipid profile
baseline
16 weeks follow-up
52 weeks follow-up
Retinal and Dermal microvascular structure:
Compare the effect of intervention on retinal and
dermal vascular structures.
Retinal imaging arteriolar and venular indices
Dermal capillary density
baseline
16 weeks follow-up
52 weeks follow-up
Mediators of Exercise Adaptation and Blood Pressure Response
Physical activity behaviours:
Compare the 16-week and sustained effect of
intervention on objectively measured ambulatory
Objective measure of physical activity (7 day
wear of activity monitor)
baseline
16 weeks follow-up
52 weeks follow-up
Williamson et al. BMC Cardiovascular Disorders (2018) 18:208 Page 3 of 16
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Table 1 TEPHRA trial objectives, outcome measures and measurement time-points (Continued)
Objectives Measures Time-points
physical activity and sedentary behaviour in
young adults with high normal and elevated
blood pressure.
Molecular endothelial and angiogenic function:
Compare the effect of aerobic exercise
intervention versus usual care/minimal intervention
on circulatory markers of angiogenesis and
endothelial colony-forming cells (ECFC) function
and association with change in blood pressure and
cardiovascular fitness.
Circulatory markers of angiogenic function.
ECFC colony growth (before or after 15 days in
culture)
ECFC function: ECFC proliferation rate and
number of branches and closed tubes formed
on matrigel
Systolic and diastolic blood pressure measured
during ambulatory blood pressure monitoring
Cardiopulmonary exercise testing
baseline
16 weeks follow-up
Vascular remodelling:
Compare the effect of aerobic exercise intervention
and physical activity self-monitoring versus usual
care/minimal intervention on central blood pressures,
vascular stiffness and vascular structures.
Pulse wave velocity
Augmentation index
Central blood pressure
Retinal imaging arteriolar and venular indices
Dermal capillary density
baseline
16 weeks follow-up
52 weeks follow-up
Predictors of Response to Exercise and Blood Pressure Change
Perceptions of the study and intervention
compliance:
Track compliance with the intervention and
characterize participantssubjective and
qualitative experience of intervention and
correlate with intervention effects on blood
pressure and cardiovascular fitness to assess
efficacy of the intervention.
Exercise log and Fitbit step counts via Fitabase
Structured interview of participants
016 weeks training log
1652 weeks step count
End of trial period
Physical activity beliefs:
Investigate the correlation between physical
activity behaviour change and participants
cognitive and psycho-social determinants of
exercise including self-efficacy to exercise,
motivations to exercise.
Objective measure of physical activity (7 day
wear of activity monitor)
Self-reported questionnaire responses, including
self-reported physical activity questionnaires,
cognitive and psycho-social questionnaire items
and self-efficacy measures.
baseline
16 weeks follow-up
52 weeks follow-up
Baseline cardiovascular phenotypes:
Investigate the associations between baseline
cardiovascular phenotypes including the preterm
born phenotype and response to exercise
intervention across outcomes.
Systolic and diastolic blood pressure measured
during ambulatory blood pressure monitoring
Cardiopulmonary exercise testing - Oxygen
uptake and carbon dioxide exchange kinetics
across submaximal and peak exercise
Cardiac remodelling: echocardiography and
cardiac MRI
baseline
16 weeks follow-up
52 weeks follow-up
Baseline cerebrovascular phenotypes:
Investigate the associations between baseline
cerebrovascular structures; white matter
connectome, subcortical volumes (caudate,
thalamus and hippocampus) and cortical
thickness (across insular, precuneus and posterior
cingualate) and responsiveness to exercise
intervention across outcomes.
Systolic and diastolic blood pressure measured
during ambulatory blood pressure monitoring
Cardiopulmonary exercise testing - Oxygen
uptake and carbon dioxide exchange kinetics
across submaximal and peak exercise
Cardiac remodelling echocardiography and
cardiac MRI
baseline
16 weeks follow-up
52 weeks follow-up
Tertiles of blood pressure and cardiovascular risk:
Investigate differences in response to exercise
intervention across outcomes in associations with
baseline tertiles of the study population blood
pressure and cardiovascular risk scores.
Systolic and diastolic blood pressure measured
during ambulatory blood pressure monitoring
Cardiopulmonary exercise testing - Oxygen
uptake and carbon dioxide exchange kinetics
across submaximal and peak exercise
Cardiac remodelling echocardiography and
cardiac MRI
baseline
16 weeks follow-up
52 weeks follow-up
ECFC function:
Investigate if baseline molecular and cellular
mechanisms in ECFC predict response to exercise
intervention across outcomes.
ECFC proteomics
ECFC molecular and cellular responses to in
vitro shear and metabolic stresses.
Systolic and diastolic blood pressure measured
during ambulatory blood pressure
Oxygen uptake and carbon dioxide exchange
kinetics across submaximal and peak exercise
Whole, plasma, and serum blood samples at rest.
Retinal imaging arteriolar
baseline
16 weeks follow-up
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Eligibility and recruitment
Recruitment strategies will include invitation from
general practice (GP) records, invitation from hospital
birth registers, open recruitment, targeted online
recruitment, and invitation following participation in
previous studies. Participants will be verified as pre-
term (born before 37 weeks gestation) or full-term
(born after 37 weeks gestation).
Eligibility criteria
The trial inclusion criteria are listed below.
Eligible participants will:
be willing and able to give informed consent for
participation in the study
be willing and able to complete intervention and
attend all baseline and follow-up study visits at the
John Radcliffe Hospital, Oxford, United Kingdom
be able (in the investigators opinion) and willing to
comply with all study requirements
be male or female, from 18 to 35 years old
have verified birth history: preterm birth (<
37 weeks) or full-term birth (> 37 weeks)
have the ability to access and use a computer and
the internet
have 24-h awake ambulatory systolic and/or diastolic
blood pressure > 115/75 mmHg
The participant may not enter the study if any of the
following apply:
clinic blood pressure > 159 mmHg systolic and/or
99 mmHg diastolic at initial screening
pregnancy
evidence of end organ damage secondary to
established diagnosis of hypertension
simultaneous participation in another human or
clinical randomized trial (if there is any possibility of
compromising health, safety, or well-being, or any
possible compromise of study data)
Fig. 1 TEPHRA Trial Overview and Visit Schedule. Provides an overview of the study, describing the study inclusion and exclusion criteria, study
visits, and summary of intervention arms
Williamson et al. BMC Cardiovascular Disorders (2018) 18:208 Page 5 of 16
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unable to walk briskly on the flat for 15 min
those currently maintaining levels of cardiovascular
fitness and aerobic activity at or above the levels
required for the intervention arm
unable to attend regular supervised exercise sessions
use of beta-blockers such as atenolol or equivalent
BMI > 35 kg/m
2
major contra-indications to exercise participation
evidence of cardiomyopathy
evidence of inherited cardiac conduction
abnormalities
evidence of congenital heart disease
other significant chronic disease relevant to
cardiovascular status
a permanent pacemaker
The following are exclusion criteria for the MRI
sub-study only:
shrapnel injuries
metal clips in blood vessels of the brain
other metal or electronic implants adversely affected
by the magnetic field
an injury to the eye involving fragments of metal
unsuitable for MRI based on responses on the MRI
safety screening form.
Setting and participants
Participants will complete a secure, online questionnaire
requesting the following information:
Sex, age at entry to the study, birth history
Reported pregnancy status
Medical history to identify exclusionary medical
conditions or pharmaceutical usage
Self-reported current physical activity levels
Willingness to change physical activity and ability to
access and attend supervised exercise sessions for 16
continuous weeks
A trained clinical research investigator will review
questionnaire responses and eligibility for study partici-
pation. The study investigator will clarify if there are sig-
nificant contraindications, diseases or disorders, which
in the opinion of the investigator might influence the
individuals ability to participate in the study. Potentially
eligible participants will then be invited to attend a
screening visit completed at the Oxford Cardiovascular
Clinical Research Facility, University of Oxford.
Informed consent
Individuals willing to participate in the study will be pro-
vided with the full participant information leaflets detail-
ing the study information in advance of the informed
consent process. Only after participants have had a mini-
mum of 24 h to review the study information will they
be invited to schedule a time for their screening visit.
The informed consent process will be completed on the
day of the screening study visit. The participant must
personally sign and date the latest approved version of
the informed consent form before any study specific
procedures are performed. Written and verbal versions
of the participant information leaflet and informed con-
sent form will be presented to the participants detailing
no less than: the exact nature of the study; what it will
involve for the participant; the implications and con-
straints of the protocol; the known side effects and any
risks involved in taking part. It will be clearly stated that
the participant is free to withdraw from the study at any
time for any reason without prejudice to future care, and
with no obligation to give the reason for withdrawal.
Written informed consent will be obtained by study
team members who are suitably qualified and experi-
enced, and have been authorized to do so by the princi-
pal investigator. A copy of the Informed Consent form
will be given to the participant. The original signed form
will be retained at the study site.
Candidates will be asked for their consent to access
their medical records including birth and neonatal
records. In absence of obstetric records, self-reported
birth history will be used. As appropriate, participants
will be asked to confirm their birth and pregnancy
details with appropriate family member(s).
Screening assessments
Anthropometric measurements including body compos-
ition measures, height, weight, body mass index (BMI),
waist and hip circumference, and resting blood pressure
shall be collected. Participants will have their blood pres-
sure checked after 5 min rest using the automated mode
of a validated sphygmomanometer (Dinamap V100, GE
Healthcare, Chalfont St. Giles, United Kingdom). Three
blood pressure readings will be taken at intervals of
1 min. For the outcome measure of clinic blood pressure
at screening, the mean of the second and third readings
will be used. Screening blood pressure will be assessed
based on National Institute for Health and Care Excel-
lence (NICE) guidelines [23] and are presented in
Table 2.
Electrocardiogram (ECG) - A 12 lead ECG will be con-
ducted and reviewed by a trained clinical research inves-
tigator. If the investigator determines that ECG results
potentially shows evidence of exclusionary cardiac dis-
ease, the ECG (and candidate if appropriate) will be re-
ferred for further clinical review.
24 h Ambulatory Blood Pressure (ABP) - 24-h ambula-
tory blood pressure monitoring will be initiated at the
end of the screening assessment session using validated,
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automated oscillometric, ambulatory devices (TM-2430,
A&D Instruments or equivalent). Correct cuff size will
be chosen based on arm circumference. Subjects will be
instructed to remain still during measurements. Mea-
surements will be automatically taken every 30 min dur-
ing daytime and then hourly from 11:00 PM to 7:00 AM.
Subjects will complete a diary documenting hours asleep
and awake. ABP data will be verified by a trained study
investigator prior to randomisation.
Study visits assessments and study measures for visits 1
3
Participant preparation (all visits)
Participants will be asked to attend the Oxford Cardio-
vascular Clinical Research Facility, having consumed
only water for 4 h beforehand.
Lifestyle and physical activity questionnaire (visits 1 & 2)
Study visit participants will be asked to complete the
study questionnaire. The questionnaire combines vali-
dated questions piloted or used in previous studies,
including question on smoking frequency,
alcohol consumption, physical activity (Recreational
Physical Activity Questionnaire (RPAQ)), and
self-reported determinants of physical activity including
environmental perceptions, physical activity beliefs, and
health related quality of life.
Physical examination (visits 13)
Assessments including body composition measures,
height, weight, BMI, waist to hip ratio, gait analysis, and
resting blood pressure will be taken. Participants will
undergo a brief gait analysis by completing a monitored
10 m walk while wearing an accelerometer fastened to
their lower back. Participants will have their clinic blood
pressure measured in the same manner performed and
recorded during screening.
Vascular measures (visits 13)
Resting measures of brachial-femoral pulse wave velocity
will be measured using sphygmomanometer-derived
indices (Vicorder, Skidmore Medical, Taunton, UK) with
cuffs placed around brachial and femoral arteries to
identify pulse arrival times [24]. In addition,
sphygmomanometer-derived indices of aortic blood
pressure will be derived from brachial blood pressure
measurements (Vicorder, Skidmore Medical, Taunton,
UK) [25].
Microvascular assessments (visits 12)
Dermal capillary density
Microvascular imaging of dermal capillary beds will be
done using intravital video capillaroscopy with a Leica
Stereo Microscope at × 200 magnification and Schott
light-emitting diode light (wavelength 450 to 610 nm,
consistent with haemoglobin absorption spectrum).
Imaging will be done on the dorsal surface of the middle
phalanx of the left hand in 6 adjacent image fields at
baseline for 1 min each. After completion of the baseline
images, a small blood pressure cuff around the proximal
phalanx will be inflated to 50 mmHg for 5 min, causing
venous occlusion, and then the same 6 images as for the
baseline will be recorded. Images will be captured using
a Moticam 580 digital camera (Motic, Wetzlar,
Germany), which will then stored for offline
post-processing using commercially available Image Pro-
Plus software as previously described [16].
Table 2 Responses to clinic blood pressure at screening
CLINIC BLOOD PRESSURE AT SCREENING RESPONSE
NORMAL
SBP < 110 & DBP < 70 Complete screening & exclude from trial
POSSIBLE PRE-HYPERTENSION
110 SBP 139 &/or 70 DBP 89 Complete screening & conduct 24-h ABP monitoring as appropriate
POSSIBLE STAGE I HYPERTENSION
140 SBP 159 &/or 90 DBP 99 In all cases: check for signs of end organ damage (resting 12 lead ECG, urinary spot
analysis, retinal imaging) if signs of end organ damage exist, exclude from trial and
refer for further assessment
As appropriate:
-complete screening & exclude from trial
-complete screening & refer for further assessment
-complete screening & conduct 24-h blood pressure monitoring
Note: If subsequent 24-h awake ABP > 135/85, review case and consider referral for
further assessment
POSSIBLE STAGE II HYPERTENSION
SBP > 159 Exclude from trial & refer for further assessment
DBP > 99 Exclude from trial & refer for further assessment
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Retinal vessel imaging
Static retinal vessel analysis will be performed using the
Static Retinal Vessel Analyzer (SVA-T, Imedos Systems
UG, Jena, Germany). For static analysis, three valid im-
ages will be taken from the retina of the left and right
eye, with the optic disk in the centre [26]. Retinal arteri-
oles and venules, coursing through an area of 0.51 disc
diameter from the margin of the optic disc, will be iden-
tified using special analysing software identifying retinal
vessels in ring-zones (Vesselmap 2, Visualis, Imedos
Systems UG). Diameters will be calculated to central ret-
inal arteriolar and venular equivalents (CRAE, CRVE),
using the Parr-Hubbard formula described elsewhere.
The CRAE and CRVE will be used to calculate the
arteriolar-to-venular-ratio (AVR), taking the mean of the
right and left eye results [26].
Echocardiogram (visits 12, optional on visit 3)
Cardiac ultrasound imaging will be used to evaluate car-
diac structure and function. Cardiac ultrasound will be
completed by an operator trained in echocardiography.
Resting transthoracic echocardiography will be per-
formed in the left lateral decubitus position using a com-
mercially available Philips iE33, Philips EPIQ 7C, or
equivalent cardiology ultrasound machine. British
Society of Echocardiography guidelines will be followed
for collection of a standard clinical imaging dataset [27].
Blood sampling (visits 13)
A fasting, venous blood sample (approximately 50 ml)
will be taken at rest. For visits 1 and 2, a further venous
blood sample (approximately 100 ml total) will be taken
after exercise testing. Blood samples will be centrifuged,
separated within 30 min, and stored at 80 °C. Fasting
lipid and metabolic profiles, including C-reactive pro-
tein, will be measured at the Oxford Hospital Biochem-
istry using routine clinical quality validated assays.
Additional circulating biomarkers will be quantified
using standard commercially available assays [16]. Circu-
lating endothelial colony forming cells (ECFCs) and per-
ipheral blood mononuclear cells (PMBCs) will be
isolated and cultured from peripheral blood as previ-
ously described [28]. Cells in culture will be followed
from days 730 to assess ECFC colony formation.
ECFCs will then be expanded to allow cell phenotype,
clonogenic and functional assessments including cell
proliferation (EdU incorporation) using the Click-iTTM
EdU Alexa FluorTM 488 Imaging kit (Thermo Fisher
Scientific), cell migration and vascular cord formation
capacity assessed by the numbers of closed tubes and
branching formed on Matrigel (Corning Matrigel
Matrix). Remaining PBMCs and ECFCs will be frozen in
10% dimethyl sulfoxide (Sigma Aldrich) fetal bovine
serum (Gibco, Thermo Fisher Scientific) and stored in
liquid nitrogen.
Cardiopulmonary exercise testing (CPET) (visits 13)
Participants will perform resting spirometry testing prior
to performing a peak CPET on a seated stationary cycle
ergometer (Ergoline GmbH, Germany) using a validated
incremental protocol with respiratory gases collected
and measured (Metalyzer 3B, Cortex Biophysik,
Germany). Heart rate will be recorded using continuous
electrocardiogram monitoring, rate of perceived exertion
will be recorded every two minutes and blood pressure
will be recorded every four minutes using a manual mer-
cury sphygmomanometer, with dynamic echocardiog-
raphy imaging collected in a subgroup. After one
quiescent minute of resting measurements, participants
will be instructed to maintain a rate of 60 rpm during
the active portion of test, which begins with a
two-minute warm-up with a 20-watt workload. After the
warm-up period, workload is increased to 35 watts. To
normalise test duration to approximately 812 min, par-
ticipants who report higher activity or fitness levels will
have their workload increased to 75 watts after the
warm-up period. Workload will automatically increment
by 15 watts each minute and participants will cycle con-
tinuously until safety termination criteria are met or
exhaustion prevents them from maintaining at least
50 rpm. Participants will then complete a two-minute
cool down period at 35 watts and the revolutions per
minute of their preference. Following the cool down
period, participants will be transferred to a reclined
treatment bed for post-exercise venous blood sampling.
24-h ambulatory blood pressure (visits 13)
Performed as described in screening measures.
7 day accelerometer (visits 13)
This will be attached to the participant at the end of the
study visit. It consists of a wrist worn accelerometer
(Axivity AX3) similar in design to a wrist worn watch.
Wrist worn accelerometers have high compliance and
reliability and are validated measures of physical activity.
Participants will be asked to wear the accelerometer for
7 days. Stamped addressed envelopes will be provided
for the return of monitoring devices.
MRI substudy (visits 12) (image acquisition and post-
processing)
Multi-organ MRI of the brain, liver and heart will be
completed on a subgroup of study participants with
images analysed for structure, function, and tissue prop-
erty. Participants will be invited to join the MRI sub-
study from the start of recruitment until 100
participants are recruited. Thereafter, all preterm
Williamson et al. BMC Cardiovascular Disorders (2018) 18:208 Page 8 of 16
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participants will be invited to complete the optional
MRI protocol. Participants will undergo multimodality
MRI scanning on the same Siemens 3.0 T scanner
(Siemens, Munich, Germany) at the Oxford Centre of
Clinical Magnetic Resonance Research, John Radcliffe
Hospital, University of Oxford, United Kingdom. Partici-
pant will have fasted for at least 4 h prior to attending
for the MRI measures, having only consumed water
beforehand. MRI imaging will be completed prior to the
exercise and other cardiovascular measures. All study
measures were completed within 48 h.
Brain MRI
The Brain MRI protocol will include T1-weighted struc-
tural imaging (TR/TE = 2040/4.7 ms, flip angle 8°, FOV
200 mm, voxel size 1.0 mm isotropic), T2-weighted
FLAIR (TR/TE = 9000/90 ms, flip angle 150°, FOV
220 mm voxel size 1.1 × 0.9 × 3.0 mm), Diffusion
Weighted Imaging (DWI) (TR/TE = 8900/95 ms,
2.0 mm isotropic resolution, multiband echo-planar
imaging (EPI), 64 slices, 64 diffusion weighted directions,
FOV 192 mm, b-value 1500s/mm
2
, five non-diffusion
weighted images, b-value 0 s/mm
2,
with one b0 volume
acquired in the reverse phase encoded direction),
Time-of-Flight (TOF) MRA (TR/TE = 23/8 ms, flip
angle 10°, FOV 300 mm voxel size 1.6 × 1.2 × 5.0 mm)
and multi-delay vessel-encoded pseudocontinuous Arter-
ial Spin Labelling (ASL), identical to a previously pub-
lished protocol [29].
Global Cerebral Volumes and Cortical Thickness -
T1-weighted structural images will be processed using
the suite of FSL anat pipeline [30]. Cortical parcellation,
cortical surface reconstruction, and cortical thickness
estimation will be completed with Freesurfer (http://sur-
fer.nmr.mgh.harvard.edu/).
White Matter Integrity - DWI will be pre-processed
with FSLs topup and eddy. A tensor model will be
applied with DTIFit [3033]. MRTrix single-shell con-
strained spherical deconvolution (CSD) [34] will be used
for whole-brain tractography with 10 million stream-
lines, followed by SIFT streamline filtering. The resulting
SIFT streamlines will be used to create binary and
SIFT-weighted connectomes [34].
Subcortical Volumes - Subcortical nuclei segmentation
will be completed using FSL MIST (Multimodal Image
Segmentation Tool (MIST)) a fully automated segmenta-
tion tool. MIST takes advantage of unique MRI contrast
properties of the subcortical nuclei to optimise shape
and boundary recognition across T1, T2 FLAIR and DTI
FA images [35].
Brain vessel morphology - Brain vessel segmentation
will be completed on TOF MRA imaging using previ-
ously described automated segmentation tools [36,37].
The binary segmentations will be used to determine
global and regional brain vessel morphology (vessel
density, caliber and tortuosity). All vessel segmentation
will be visually checked to ensure proper quality. Vessel
tortuosity will be defined by the deviation from the
shortest path between two points. This analysis will be
implemented by identifying the vessel endpoints and
bifurcations, calculating the shortest path and the length
of the actual centerline between each two connected
points. The final tortuosity will then be calculated by the
ratio and it will be averaged over all vessel segments.
Cerebral perfusion - Brain blood flow and blood arrival
time will be estimated from ASL images using a previously
described analysis pipeline and FSL BASIL [29,38].
White matter hyperintensity (WMH) lesions WHM
will be automatically segmented on FLAIR images with
BIANCA (Brain Intensity AbNormality Classification
Algorithm) a fully-automated, supervised method for
WMH detection [39,40]. BIANCA classifies the images
voxels based on their intensity and spatial features,
where the intensity features were extracted from
T2-weighted FLAIR, T1-weighted and DTI fractional
anisotropy (FA) images. WMH masks will be manually
segmented from 10 images to use as the training set for
BIANCA, these will be independently verified. BIANCA
probability output maps will be visually checked for
quality. Lesion count and volume will be calculated,
lesion count has previously been described as a measure
of burden of white matter hyperintensities, however glo-
bal and regional volume of white matter hypertensities
has been reported as sensitive measure to track in trial
settings. The minimum lesion size used in analysis will
be 1 mm
3
. T1-weighted structural images will be proc-
essed using the suite of FSL analysis tools [30].
Cardiac MRI
Steady-state free-precession cine sequences will be used
to acquire localization images, followed by optimized left
ventricular horizontal and vertical long-axis cines. From
these, a left ventricular short-axis cine stack will be
obtained with standardized basal slice alignment with a
8-mm slice thickness and 2-mm interslice gap. All car-
diovascular magnetic resonance imaging will be pro-
spectively ECG gated with a precordial 3-lead ECG and
will be acquired during end-expiration breath holding.
Image acquisition parameters for the steady-state
free-precession images are as follows: echo time, 1.5 mil-
liseconds; repetition time, 3.0 milliseconds; and flip
angle, 60°. The short- and long-axis steady-state
free-precession images will be stored on a digital archive
for post processing and analysis.
Quantification of Left and Right Ventricular Mass
and Volumes on Cardiac MRI - Image analysis for
left and right ventricular volumes and mass will be
performed offline on the short-axis cine stack with
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commercially available software (cvi/cmr42, Circle
Cardiovascular Imaging Inc., Calgary, Canada) as pre-
viously described [21,41]. Left and right ventricular
short-axis epicardial and endocardial borders will be
manually contoured at end diastole and end systole to
allow automated calculation of left and right ventricu-
lar mass and volumes. Mass represents the following:
(end-diastolic epicardialendocardial volume) × 1.05.
Stroke volume is end-diastolic volume minus
end-systolic volume, and ejection fraction is given by
the following: (stroke volume/end-diastolic volume) ×
100%. Left ventricular wall thickness will be measured
on the midventricular short-axis slice at end diastole,
and internal and external left ventricular cavity diam-
eters will be measured on the midventricular
short-axis slice at end diastole between the septum
and inferolateral wall. Left ventricular length will be
measured at end diastole on the horizontal long-axis
cine between the left ventricular apex and middle of
the mitral annulus. Left ventricular relative wall thick-
ness will be calculated as follows: (2 × inferior wall
thickness)/end-diastolic diameter. Right ventricular
length will be measured at end diastole on the hori-
zontal long axis cine by drawing a line along the tri-
cuspid valve annulus and measuring the length from
the right ventricular apex to the middle of the tricus-
pid valve annulus. Right ventricular diameter mea-
surementswillbemadeonthehorizontallongaxis
cine at end diastole within the basal third of the right
ventriclebelowthetricuspidvalveandatthelevelof
the right ventricular papillary muscles.
Assessment of Ventricular Myocardial Deformation on
Cardiac MRI - In addition to gross volumetric measures
of systolic left and right ventricular function (ejection
fraction and stroke volume), systolic and diastolic func-
tion and cardiac rotational movement will be measured
on the basis of myocardial deformation parameters
assessed with commercially available software (cvi/
cmr42, Circle Cardiovascular Imaging Inc., Calgary,
Canada). The left ventricular endocardial borders of the
steady-state free-precession horizontal long-axis, vertical
long-axis and left ventricular outflow tract cines and
basal, mid, and apical left ventricular short-axis cines
will be manually contoured on the end-diastolic frame.
Right ventricular myocardial deformation will be assessed
on the horizontal long axis cine only. The software tracks
the motion of related features adjacent to the endocardial
line such as the cavity-tissue boundary or individual tissue
patterns over the cardiac cycle to produce endocardial
strain parameters [42].
Cardiac Computational Atlas Formation Creation of
a cardiac statistical atlas of all cardiovascular magnetic
resonance images will be undertaken. The end-diastolic
frame from the DICOM file for each slice of the right
and left ventricular short axis cine stack that includes
the manually contoured endocardial and epicardial con-
tours drawn using cvi42/cmr42 will be retrieved and re-
built into a single DICOM file in Matlab. The file will
then be converted into a binary segmentation image
representing the right and left ventricles, and a mesh fit-
ted to this myocardial anatomy, achieving subvoxel
accuracy. The right and left ventricles for each subject
will then be described with a mesh definied by a set of
nodal variables. Principal and linear component analysis
will be undertaken to identify the key modes of variation
of the shape [21].
Aortic MRI
Aortic distensibility will be assessed to gain insight into
aortic stiffness. A transverse image obtained at the level
of the right pulmonary artery planned off an oblique
sagittal view of the aorta allows for the cross-sectional
assessment of the ascending aorta, proximal descending
aorta and pulmonary artery with its branches [43,44].
Maximum and minimum aortic cross-sectional areas
over the cardiac cycle will be determined using
semi-automated edge detection algorithms developed
using Matlab software (Mathworks Inc.) and distensibil-
ity will be calculated as the relative change in area
divided by the pulse pressure: (aortic distensibility
= {[(maximum area of the aorta minimum area of the
aorta)/(minimum area of the aorta)]/aortic pulse pres-
sure} × 10
3
). A surrogate measure of aortic blood pres-
sure using sphygmomanometer-derived indices will be
acquired with a blood pressure cuff around the right
arm (Vicorder, Skidmore Medical, Taunton, UK) during
the MRI scan for the calculation of aortic distensibility.
Hepatic and abdominal MRI
Transverse abdominal liver T
1
and T
2
* MR maps and
DIXON liver images are acquired for the estimation of
extracellular fluid, liver iron, and liver steatosis respect-
ively. T
1
relaxation time increases with increases in
extracellular fluid, such as in fibrosis and inflammation.
However, the presence of iron, which can be accurately
measured from T
2
* maps, has an opposing effect on the
T
1
. An algorithm has been created that allows for the
bias introduced by elevated iron to be removed from the
T
1
measurements, yielding the cT
1
. LiverMultiScan (Per-
spectum Diagnostics, Oxford, United Kingdom) is a soft-
ware product specifically developed to measure cT
1
from T
1
and T
2
* maps. For TEPHRA, the LiverMultiS-
can will be used to analyse cT
1
in at least a single,
operator-defined region of the liver away from vascular
and biliary structures. DIXON images will be used to
quantify proton-density fat fraction to assess liver steato-
sis. Transverse abdominal multi-slice T1-weighted TSE
images at the level of the 5th lumbar vertebra will be
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acquired to measure visceral and subcutaneous adipose
tissue.
Sample size
The rationale for the number of participants required to
address the primary outcome is as follows. Our system-
atic review and meta-analysis of randomised control tri-
als [14] identified an average decrease of 5.4 mmHg in
systolic blood pressure (SBP) post-intervention in adults
with prehypertension (mean systolic blood pressure at
baseline 126 mmHg) [14]. The post intervention stand-
ard deviation of change was 8.7 mmHg. Our available
cross-sectional pilot data suggests that change will be
higher in the preterm born participants and participants
exposed to maternal hypertension during pregnancy. To
calculate the sample size we have been conservative and
used an estimated change of 5 mmHg following 16 weeks
of intervention. We have used a standard deviation (SD)
of 11.3 from the pooled SD for ambulatory systolic blood
pressure from our cross-sectional pilot data. To observe
a treatment effect on systolic blood pressure of 5 mmHg,
powered to 80% (p= 0.05) requires a total sample size of
164 participants. The SD deviation for the pooled ambu-
latory diastolic blood pressure is 8.3 mmHg. To observe
a treatment effect on diastolic blood pressure of
5 mmHg, powered to 80% (p = 0.05) requires a total
sample size of 114 participants. The power calculations
for systolic blood pressure are used to determine the
final sample size, with adjustment to 200 participants to
allow for 18% attrition. To ensure primary objectives for
the study are answered, the study team may recruit add-
itional participants to replace those who drop out and
withdraw from the study.
This sample size will provide 80% power and 5% sig-
nificance to analyse the proposed secondary outcomes.
Randomisation
Participants meeting the study inclusion criteria will be
randomly allocated 1:1 to the two intervention arms.
This will be undertaken using Sealed Envelope(https://
www.sealedenvelope.com/), a computerised randomisa-
tion program. A minimisation algorithm (with a random
element of 80%) is used to ensure balanced allocation
across the two groups for key prognostic factors: gender,
age and gestational age of participants. The strata for
each prognostic factor are as follows:
Gender: male/female;
Age: < 24 years old, 2429 years old, 3035 years
old;
Gestational age: 32 weeks, 3237 weeks, >
37 weeks.
Allocation is concealed following the completion of
baseline study measures and only designated trial team
members monitoring potential exercise injuries and
adverse events and the trial statistician will be made
aware of each participants allocation. Outcome assessors
will be blinded to reduce potential bias. Due to the na-
ture of the intervention, participants will not be blinded.
An emergency randomisation schedule has been
prepared in advance and stored for use when the
online system in unavailable. The randomisation list
was created using simple block randomisation using
variable block size.
Study intervention
Participants in the intervention arm will complete
16 weeks of structured aerobic exercise training, with a
target of 3 training sessions per week, duration 60 min,
at exercise intensity of 6080% aerobic exercise capacity.
Exercise intensity of 6080% maximal aerobic capacity
defined using heart rate response during peak cardiopul-
monary exercise testing at baseline. Heart rate monitors
will be used to maintain training intensity. The interven-
tion replicates similar strategies identified during sys-
tematic review of randomised control trials delivering
exercise intervention for blood pressure reduction [14].
The minimum dose to start effecting positive changes in
cardiovascular fitness is estimated to be 40 min of mod-
erate intensity sessions three times per week. The study
team will monitor participantscompliance and progress
during the structured aerobic exercise training. The
study team will use motivational coaching strategies to
encourage participants to maintain compliance with the
training program. In addition to structured aerobic exer-
cise training, participants will be provided with a wrist
worn heart rate and accelerometer based activity moni-
tor (Fitbit Charge HR) to facilitate physical activity
self-monitoring and maintenance of heart rate targets.
Participants will be consented to allow investigators access
to the data collected from wear of the Fitbit. In addition,
participants will be sign-posted to educational materials
produced by the British Heart Foundation explaining
blood pressure, blood pressure prevention and recom-
mended lifestyle behaviours to maintain heart health.
On completion of the structure aerobic exercise train-
ing participants will be encouraged to continue to use
their activity monitor and maintain physical activity
goals until the final study visit at 52 weeks. The use of
the activity monitors will support the three most effect-
ive behaviour change strategies to promote increased
physical activity, including self-monitoring, goal setting
and regular feedback [45,46]. To encourage continued
regular, self-directed physical activity, participants will
be provided a motivational coaching session on comple-
tion of the structured 16 week training program. A study
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team member trained in motivational interview tech-
niques will provide the motivational coaching. Partici-
pants will be asked to reflect on their experience of
physical activity, their experience of participating in the
structured aerobic exercise training, will be encouraged
to set goals and rate their confidence and motivations to
achieve physical activity goals, participants will be
encouraged to discuss strategies to maintaining physical
activity participation.
Comparison group
Participants in the control group will be sign-posted
to educational materials produced by the British
Heart Foundation explaining blood pressure, blood
pressure prevention and recommended lifestyle behav-
iours to maintain heart health. Participants will be
asked to continue with their regular physical activity
routine with no change.
Withdrawals
Each participant has the right to withdraw from the trial
at any time. In addition, the Chief Investigator may dis-
continue a participant from the study at any time if he
considers it necessary for any reason including:
Pregnancy;
Ineligibility (either arising during the study or
retrospectively having been overlooked at screening);
Significant deviation from the study protocol;
Withdrawal of consent;
Loss to follow up;
Contraindication to exercise participation.
If participants withdraw from the study, the study
investigators will ask the participants if they can make
use of the information that has been collected up to the
time of withdrawal to facilitate intention to treat ana-
lysis. Participants may withdraw consent for any use of
their samples or data at any time. If this is the case, the
trial team will destroy any identifiable samples or infor-
mation held about the participant. Participants do not
need to provide any reason for withdrawal; should they
freely offer a reason it will be recorded in the case report
form (CRF). The research team may recruit additional
participants to replace participants who have withdrawn.
Participant confidentiality
Thestudystaffwillensurethattheparticipantsano-
nymity is maintained. Only the participantsIDnum-
berontheCRFandintheelectronicdatabasewill
identify the participants. All documents will be
stored securely and only accessible by study staff
and authorised personnel. The study will comply
with the General Data Protection Regulation and the
United Kingdom Data Protection Act, which requires
data to be anonymised as soon as it is practical to
do so.
Data management
Direct access to the data will be granted to authorised
representatives from the Sponsor or host institution for
monitoring and/or audit of the study to ensure compli-
ance with regulations. Data management will commence
with formation of a study database. Only a unique par-
ticipant number on any electronic database will identify
the participants. All documents will be stored securely
and only accessible by study staff and authorised
personnel. Electronic data will be encrypted and pass-
word protected, and stored on departmental computers.
Access will be granted only to members of the study
team and authorised personnel. The study will comply
with the United Kingdom Data Protection Act, which
requires data to be anonymised as soon as it is practical
to do so. Only one electronic study document will con-
tain identifiable information; this is the enrolment log
combined with the code breakwhich links the unique
participant number with participant name and contact
details. This will be encrypted, stored on a high security
server and only accessible by study staff and authorised
personnel. Study duration of 3 years is anticipated and
study data will be kept for 7 years following completion
of the study.
Safety considerations
Overall this is a low risk study. Exercise training is safe
and the established global benefits to health and
well-being outweigh negative complications and risks.
However, risk of injury, medical complications and ser-
ious adverse events are reported in association with ex-
ercise participation. Muscle and joint soreness and
minor musculoskeletal complaints are common adverse
effects of exercise training, however the risk of a serious
adverse event including sudden cardiac death or
non-fatal cardiac event is reported as below 0.01 per
10,000 h of participation. The detailed screening and
cardiovascular assessment prior to randomization will
identify any participants at potential cardiovascular risk
associated with exercise participation, if there is any con-
cerns regards an individuals participation they will be
referred for appropriate clinical review and excluded
from the trial. Should an participant experience or re-
port any adverse events or symptoms at any time during
the study period they will be advised on how to manage
these symptoms and will be advised to seek further med-
ical evaluation if required via their primary health care
practitioner or local emergency medicine department.
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Adverse events
All adverse events occurring during the trial or until
completion of the final study visit that are observed by
the Chief Investigator or reported by the participant will
be recorded on the study case report form (CRF),
whether or not attributed to the exercise intervention.
The following information will be recorded: descrip-
tion, date of onset and end date, severity, and assessment
of relatedness to exercise intervention, other suspect
drug or device and action taken. Follow-up information
should be provided as necessary.
Adverse events considered related to the trial as
judged by a medically qualified investigator or the Spon-
sor will be followed either until resolution, or the event
is considered stable.
It will be left to the Investigators clinical judgment to
decide whether or not an AE is of sufficient severity to
require the participants removal from the study. A par-
ticipant may also voluntarily withdraw from intervention
due to what he or she perceives as an intolerable adverse
event. If either of these occurs, the participant must
undergo an end of trial assessment and be given appro-
priate care under medical supervision until symptoms
cease, or the condition becomes stable.
Safety reporting will be from baseline to the 12-month
follow up visit. The participant using the trial telephone
number or email may also report adverse events. Partici-
pants will be directly asked about adverse events at each
study visit.
Serious adverse events (SAE) occurring to a partici-
pant will be reported to the research ethics that gave a
favourable opinion of the study where in the opinion of
the Chief Investigator the event was related(resulted
from administration of any of the research procedures)
and unexpectedin relation to those procedures. Reports
of related and unexpected serious adverse events will be
submitted within 15 working days of the Chief Investiga-
tor becoming aware of the event, using a human
research authority serious adverse event form.
Data analysis
The analysis will be carried out on the basis of
intention-to-treat. This is, after randomisation, partici-
pants will be analysed according to their allocated inter-
vention group irrespective of what they actually receive
during the specified period.
Patient demographic characteristics and other baseline
information will be summarised by intervention group.
Numbers (with percentages) for binary and categorical
variables and mean (standard deviation), or median
(interquartile or full range) for continuous variables will
be presented. Normality of variables will be assessed by
visual assessment of the normality curves and the
Shapiro-Wilk test. Methods such as the Student T-test
will assess for differences between the groups. The ana-
lysis of the primary outcome will be assessed using ana-
lysis of covariance (ANCOVA) adjusting for baseline
values and minimisation factors used in the randomisa-
tion process. Results will be presented as adjusted mean
difference in change in ambulatory blood pressure
between randomised groups at 16 weeks with 95% confi-
dence intervals and associated two-sided pvalue. No im-
putation will be carried out and analysis will be
performed on all available data. Sensitivity analyses will
be performed on the per-protocol populations. The defi-
nitions of these will be detailed in the statistical analysis
plan.
The analysis of secondary outcomes will also be done
using analysis of covariance (ANCOVA) to establish a
statistical model to examine the effect of cardiac struc-
ture, vascular function and lifestyle behaviours on exer-
cise capacity. Outcomes measured on more than one
occasion will be analysed using a mixed effects model. If
the model assumptions are not met and evidence of de-
parture from Normality is observed, transformations of
the data will be employed or non-parametric tests will
be carried out. Statistical analysis will be carried out
using STATA, SPSS or R statistical software. A detailed
statistical analysis plan will be written with our statistical
team and will be completed before receipt of the data.
Trial oversight
A Trial Steering Committee (TSC) has been formed to
oversee the conduct of the trial. The TSC consists of the
Chief Investigator, independent clinical experts who spe-
cialise in areas relevant to the trial (primary care hyper-
tension, sports medicine and rheumatology, and
physiotherapy), the trial statistician and an independent
statistician. The TSC meets approximately every six
months, either in person or via teleconference. A data
and safety monitoring committee (DSMC) has also been
formed with the appropriate specialties to provide
insight and oversight to the trial progression and man-
agement. Rates of recruitment, trial compliance, meas-
urement of the primary outcome and study attrition are
reviewed biannually by the independent members, in-
cluding an independent statistician, of this committee.
The data monitoring committee meets approximately
every six months, and shortly prior to TSC meetings
when possible.
Dissemination policy
An authorship plan has been drafted reflecting the de-
scribed primary and secondary objectives for the study.
A full manuscript detailing the primary outcomes will be
submitted within 12 months of completing the trial with
secondary outcomes reported within 24 months of com-
pleting the trial. Completion of study defined as full
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participant enrolment and data collection at 52 weeks
follow-up being completed.
Discussion
The TEPHRA trial is the first study with the primary
aim of determining the effects of structured aerobic
exercise and physical activity self-monitoring interven-
tion on ambulatory blood pressure in young adults [14].
Furthermore, it is the first study to explore the effects of
exercise intervention with reference to novel cardiovas-
cular risk factors such as preterm birth [14,18]. The
association between maintaining high cardiovascular fit-
ness and physical activity and the benefit for cardiovas-
cular and cerebrovascular health are well documented
[4750]. However, there is a paucity of trial evidence
supporting exercise and physical activity intervention as
an effective treatment option with sustained benefits in
young adult populations [14]. Despite this lack of evi-
dence lifestyle intervention is recommended as the pri-
mary intervention in young adults with hypertension
[23]. In addition, there is limited understanding, with
minimal prospective evidence in a trial setting, demon-
strating the multisystem physiological adaptations to ex-
ercise which may mediate the benefits on future
cardiovascular and cerebrovascular risk.
The results from the TEPHRA trial will provide pre-
liminary evidence to support whether or not exercise
and physical activity intervention should be primary
treatment options for management of blood pressure. It
will also provide evidence exploring potential heterogen-
eity in response to exercise intervention with reference
to novel cardiovascular risk factors and baseline pheno-
types such as those associated with preterm birth. The
detailed cardiovascular and cerebrovascular phenotyp-
ing, using multimodal imaging, resting and stress mea-
sures of cardiovascular function will facilitate insights
into disease mechanisms and phenotypic traits, which
may demonstrate plasticity and remodelling, and may
identify target mechanisms and interim outcomes for
future intervention. The results will expand the available
evidence-base for the management of blood pressure in
young adult populations and inform the future direction
of research targeting early cardiovascular risk reduction.
Trial status
Recruitment is on-going.
Abbreviations
ABP: Ambulatory Blood Pressure; AE: Adverse Event; ANCOVA: Analysis of
Covariance; ASL: Arterial Spin Labelling; AVR: Arteriolar-to-Venular-Ratio;
BHF: British Heart Foundation; BIANCA: Brain Intensity AbNormality
Classification Algorithm; BMI: Body Mass Index; CI: Chief Investigator;
CPET: Cardiopulmonary Exercise Testing; CRAE: Central Retinal Arteriolar
Equivalents; CRF: Case Report Form; CRVE: Central Retinal Venular
Equivalents; CSD: Constrained Spherical Deconvolution; DALYs: Disability-
Adjusted Life Years; DBP: Diastolic Blood Pressure; DSMC: Data and Safety
Monitoring Committee; DTI: Diffusion Tensor Imaging; DWI: Diffusion
Weighted Imaging; ECFC: Endothelial Colony-Forming Cells;
ECG: Electrocardiogram; EPI: Echo-Planar-Imaging; FA: Fractional Anisotropy;
FLAIR: Fluid Attenuated Inversion Recovery; FOV: Field-of-View; FSL: FMRIB
Software Library; GP: General Practice; ID: Identity; MIST: Multimodal Image
Segmentation Tool; MRA: Magnetic Resonance Arterogram; MRI: Magnetic
Resonance Imaging; NHS HRA: National Health Service Health Research
Authority; NICE: National Institute for Health and Care Excellence;
NIHR: National Institute for Health Research; PMBCs: Peripheral Blood
Mononuclear Cells; REC: Research Ethics Committee; RPAQ: Recreational
Physical Activity Questionnaire; SAE: Serious Adverse Event; SBP: Systolic
Blood Pressure; SD: Standard Deviation; TE: Echo Time; TEPHRA: Trial of
Exercise to Prevent HypeRtension in young Adults; TOF: Time of Flight;
TR: Repetition Time; TSC: Trial Steering Committee; TSE: Turbo Spin Echo;
UK: United Kingdom; WMH: White matter hyperintensity
Acknowledgments
Not applicable.
Funding
The study is supported by funding from the Wellcome Trust, British Heart
Foundation (BHF) (Ref PG/17/13/32860), the Oxford BHF Centre for Research
Excellence, and National Institute for Health Research (NIHR) Oxford
Biomedical Research Centre. Dr. Wilby Williamson is funded by a Wellcome
Trust Clinical Research Training Fellowship (Ref 105741/Z/14/Z).
Availability of data and materials
Not applicable.
Authorscontributions
WW, AJL, OH, CF, HD, PL contributed to the design of the study; WW, AJL
and PL secured funding; WW, AJL, OH, JN, RM, CF, HD, PL refined the overall
study protocol and will lead the project delivery. WW, CF and HD oversee
the delivery of the exercise intervention. EF provides statistical support to the
study. AJL and WW contributed to the development of the brain, cardiac
and hepatic MRI protocols; AJL, WW, AM and WL will contribute to MRI
image acquisition and quality control; WW and WL will contribute to brain
MRI image processing and analysis; AJL will lead the cardiac and hepatic MRI
analysis with support from AM, and MA. Echocardiography acquisition and
analysis will be overseen by AM, MA, AJL, WW and PL. Cardiopulmonary
exercise testing and peripheral cardiovascular risk assessment will be
overseen by AJL, WW and PL. HH will oversee retinal image acquisition and
analysis. CT, OH, AJL, MB and PL will oversee analysis of circulating
biomarkers. CT, AJL, PL and MB will oversee molecular and proteomic
analysis. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The protocol, informed consent form, participant information sheets, digital
platforms and proposed advertising materials were approved by the
University of Oxford as host institution and study Sponsor and the South
Central Research Ethics Committee (REC) for the National Health Service
Health Research Authority (NHS HRA) (Reference 16/SC/0016). The
investigators will submit and, where necessary, obtain approval from the
above parties for all substantial amendments to the original approved
documents. It is the requirement of the trial that written informed consent is
obtained prior to the enrolment of the participants. The investigators will
ensure that the study is conducted in accordance with the principles of the
Declaration of Helsinki. The investigators will ensure that the study is
conducted in accordance with relevant regulations and Good Clinical
Practice.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
PublishersNote
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
Williamson et al. BMC Cardiovascular Disorders (2018) 18:208 Page 14 of 16
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Author details
1
Oxford Cardiovascular Clinical Research Facility, Division of Cardiovascular
Medicine, Radcliffe Department of Medicine, University of Oxford, John
Radcliffe Hospital, Oxford OX3 9DU, UK.
2
Centre for Statistics in Medicine,
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal
Sciences, University of Oxford, Oxford, UK.
3
Centre Integré Universitaire de
Santé et de Services Sociaux du Nord-de-lÎle-de-Montréal, Hôpital du
Sacré-Cœur de Montréal Research Center, Montréal, Canada.
4
Nuffield
Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences,
University of Oxford, Oxford, UK.
5
Department of Sport, Exercise and Health,
University of Basel, Basel, Switzerland.
6
Nuffield Department of Primary Health
Care Sciences, University of Oxford, Oxford, UK.
7
Faculty of Health and Life
Sciences, Oxford Brookes University, Oxford, UK.
8
School of Policy Studies,
University of Bristol, Bristol, UK.
9
Oxford Centre for Clinical Magnetic
Resonance Research, Division of Cardiovascular Medicine, Radcliffe
Department of Medicine, University of Oxford, Oxford, UK.
Received: 22 September 2018 Accepted: 22 October 2018
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... Full details of the study objectives, outcomes and measurement procedures are detailed in the published study protocol. 22 There were no changes to the study outcomes after publication of the study protocol. Participants were asked to report adverse events. ...
... The study took place in the Cardiovascular Clinical Research Facility, John Radcliffe Hospital, Oxford, UK. The trial protocol 22 and any subsequent amendments were approved by the University of Oxford as host institution and study Sponsor and the South Central Research Ethics Committee (REC) for the National Health Service Health Research Authority (NHS HRA) (Reference 16/SC/0016).22 ...
Article
Full-text available
Background Exercise is advised for young adults with elevated blood pressure, but no trials have investigated efficacy at this age. We aimed to determine whether aerobic exercise, self-monitoring and motivational coaching lowers blood pressure in this group. Methods The study was a single-centre, open, two-arm, parallel superiority randomized clinical trial with open community-based recruitment of physically-inactive 18–35 year old adults with awake 24 h blood pressure 115/75mmHg-159/99 mmHg and BMI<35 kg/m². The study took place in the Cardiovascular Clinical Research Facility, John Radcliffe Hospital, Oxford, UK. Participants were randomized (1:1) with minimisation factors sex, age (<24, 24–29, 30–35 years) and gestational age at birth (<32, 32–37, >37 weeks) to the intervention group, who received 16-weeks aerobic exercise training (three aerobic training sessions per week of 60 min per session at 60–80% peak heart rate, physical activity self-monitoring with encouragement to do 10,000 steps per day and motivational coaching to maintain physical activity upon completion of the intervention. The control group were sign-posted to educational materials on hypertension and recommended lifestyle behaviours. Investigators performing statistical analyses were blinded to group allocation. The primary outcome was 24 h awake ambulatory blood pressure (systolic and diastolic) change from baseline to 16-weeks on an intention-to-treat basis. Clinicaltrials.gov registered on March 30, 2016 (NCT02723552). Findings Enrolment occurred between 30/06/2016-26/10/2018. Amongst the 203 randomized young adults (n = 102 in the intervention group; n = 101 in the control group), 178 (88%; n = 76 intervention group, n = 84 control group) completed 16-week follow-up and 160 (79%; n = 68 intervention group, n = 69 control group) completed 52-weeks follow-up. There were no group differences in awake systolic (0·0 mmHg [95%CI, -2·9 to 2·8]; P = 0·98) or awake diastolic ambulatory blood pressure (0·6 mmHg [95%CI, -1·4. to 2·6]; P = 0·58). Aerobic training increased peak oxygen uptake (2·8 ml/kg/min [95%CI, 1·6 to 4·0]) and peak wattage (14·2watts [95%CI, 7·6 to 20·9]) at 16-weeks. There were no intervention effects at 52-weeks follow-up. Intepretation These results do not support the exclusive use of moderate to high intensity aerobic exercise training for blood pressure control in young adults. Funding Wellcome Trust, British Heart Foundation, National Institute for Health Research, Oxford Biomedical Research Centre.
... Hypertensive patient's ongoing treatment, mode, pattern and timing of exercise can be personalized as compared to less efficient exercises to reduce the risk of CVD events [25]. To consider long-term changes in preventing hypertension related complications, lifestyle modification must be recommended particularly among young adults [26]. ...
... Anthropometry, Blood Samples, and Blood Pressure Measurements All participants fasted for a minimum of 6 hours before their study visit. As previously described, 7,10,11,13 trained clinical research investigators completed all height and weight measurements as well as blood sample collection. Participants were seated for 5 minutes before 3 resting brachial blood pressure readings (Dinamap V100; GE Healthcare) were taken on the left arm with a 1-minute interval in between. ...
Article
Full-text available
Importance Preterm-born individuals have higher blood pressure with an increased risk of hypertension by young adulthood, as well as potentially adverse cardiac remodeling even when normotensive. To what extent blood pressure elevation affects left ventricular (LV) structure and function in adults born preterm is currently unknown. Objective To investigate whether changes observed in LV structure and function in preterm-born adults make them more susceptible to cardiac remodeling in association with blood pressure elevation. Design, Setting, and Participants This cross-sectional cohort study, conducted at the Oxford Cardiovascular Clinical Research Facility and Oxford Centre for Clinical Magnetic Resonance Research, included 468 adults aged 18 to 40 years. Of these, 200 were born preterm (<37 weeks’ gestation) and 268 were born at term (≥37 weeks’ gestation). Cardiac magnetic resonance imaging was used to characterize LV structure and function, with clinical blood pressure readings measured to assess hypertension status. Demographic and anthropometric data, as well as birth history and family medical history information, were collected. Data were analyzed between January 2012 and February 2021. Main Outcomes and Measures Cardiac magnetic resonance measures of LV structure and function in response to systolic blood pressure elevation. Results The cohort was primarily White (>95%) with a balanced sex distribution (51.5% women and 48.5% men). Preterm-born adults with and without hypertension had higher LV mass index, reduced LV function, and smaller LV volumes compared with term-born individuals both with and without hypertension. In regression analyses of systolic blood pressure with LV mass index and LV mass to end-diastolic volume ratio, there was a leftward shift in the slopes in preterm-born compared with term-born adults. Compared with term-born adults, there was a 2.5-fold greater LV mass index per 1–mm Hg elevation in systolic blood pressure in very and extremely preterm-born adults (<32 weeks’ gestation) (0.394 g/m² vs 0.157 g/m² per 1 mm Hg; P < .001) and a 1.6-fold greater LV mass index per 1–mm Hg elevation in systolic blood pressure in moderately preterm-born adults (32 to 36 weeks’ gestation) (0.250 g/m² vs 0.157 g/m² per 1 mm Hg; P < .001). The LV mass to end-diastolic volume ratio per 1–mm Hg elevation in systolic blood pressure in the very and extremely preterm-born adults was 3.4-fold greater compared with those born moderately preterm (3.56 × 10⁻³ vs 1.04 × 10⁻³ g/mL per 1 mm Hg; P < .001) and 3.3-fold greater compared with those born at term (3.56 × 10⁻³ vs 1.08 × 10⁻³ g/mL per 1 mm Hg; P < .001). Conclusions and Relevance Preterm-born adults have a unique LV structure and function that worsens with systolic blood pressure elevation. Additional primary prevention strategies specifically targeting cardiovascular risk reduction in this population may be warranted.
... [202][203][204][205] The urgency to reduce premature heart failure, stroke, and chronic kidney disease among young adults is increasingly recognized; multiple young adult hypertension trials are in progress. [206][207][208] Several statin trials have found reductions in blood pressure and hypertension incidence in statin-treated patients. 209 Proprotein convertase subtilisin-like/kexin type 9 inhibitors have also recently been shown to improve endothelial function in proportion to the magnitude of LDL-C lowering. ...
Article
Full-text available
Improvements in cardiovascular disease (CVD) rates among young adults in the past 2 decades have been offset by increasing racial/ethnic and gender disparities, persistence of unhealthy lifestyle habits, overweight and obesity, and other CVD risk factors. To enhance the promotion of cardiovascular health among young adults 18 to 39 years old, the medical and broader public health community must understand the biological, interpersonal, and behavioral features of this life stage. Therefore, the National Heart, Lung, and Blood Institute, with support from the Office of Behavioral and Social Science Research, convened a 2‐day workshop in Bethesda, Maryland, in September 2017 to identify research challenges and opportunities related to the cardiovascular health of young adults. The current generation of young adults live in an environment undergoing substantial economic, social, and technological transformations, differentiating them from prior research cohorts of young adults. Although the accumulation of clinical and behavioral risk factors for CVD begins early in life, and research suggests early risk is an important determinant of future events, few trials have studied prevention and treatment of CVD in participants <40 years old. Building an evidence base for CVD prevention in this population will require the engagement of young adults, who are often disconnected from the healthcare system and may not prioritize long‐term health. These changes demand a repositioning of existing evidence‐based treatments to accommodate new sociotechnical contexts. In this article, the authors review the recent literature and current research opportunities to advance the cardiovascular health of today's young adults.
... A weight of evidence has shown that the physiological changes associated with regular exercise can be highly effective for the prevention and treatment of coronary artery disease, hypertension, heart failure, obesity, diabetes mellitus and depression, 2,3 with ongoing studies investigating the additional physiological benefits of these training regimes. 4 Regular exercise subjects the heart to bouts of haemodynamic stresses such as pressure and volume overload. In order to meet the systemic demand for an increased blood supply at the site of the working muscles during prolonged and repeated exercise, the heart undergoes physiological adaptation. ...
... Given the known alterations in the renin-angiotensin system [56] and unique cardiac phenotype associated with preterm birth, it remains to be determined whether aerobic exercise training would have the same benefits in a population of preterm-born young adults and how this intervention might be used to reduce risk of hypertension and heart failure in these individuals. To explore this, the Trial of Exercise to Prevent HypeRtension in young Adults (TEPHRA) has been designed [57]. This randomized control trial aims to determine the effect of 16 weeks' guided aerobic exercise training on the cardiovascular system of n = 200 young adults between the ages of 18 and 35 years, including a subgroup of individuals born preterm. ...
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Purpose of review Around 10% of the global population is born preterm (< 37 weeks’ gestation). Preterm birth is associated with an increased risk of cardiovascular events, with preterm-born individuals demonstrating a distinct cardiac phenotype. This review aims to summarize the main phenotypic features of the preterm heart and directions for future research to develop novel intervention strategies. Recent findings Being born between 28 and 31 weeks’ gestation results in a 4-fold higher risk of heart failure in childhood and adolescence and 17-fold increased risk when born less than 28 weeks’ gestation. In support of this being due to a reduction in myocardial functional reserve, preterm-born young adults have an impaired left ventricular cardiac systolic response to moderate and high intensity physiological stress, despite having a preserved resting left ventricular ejection fraction. Similar impairments under physiological stress were also recently reported regarding the right ventricle in young adults born preterm. Summary Preterm birth relates to a unique cardiac phenotype with an impaired response to stress conditions. These data, combined with the work in animal models, suggest that being born preterm may lead to a novel form of cardiomyopathy. Understanding the driving mechanisms leading to this unique cardiac phenotype is important to reduce risk of future heart failure and cardiovascular events.
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New findings: What is the topic of this review? This review presents evidence that people born preterm have a greater long-term cardiovascular risk, which may be explained in part by their cardiac structural and functional alterations. What advances does it highlight? This review highlights studies using cardiovascular magnetic resonance imaging and echocardiography to investigate cardiac alterations at rest and during exercise-induced physiological stress in adults born preterm. These studies show that people born preterm have potentially adverse alterations in left and right ventricular structure and function that worsens with blood pressure elevation; an impaired myocardial functional reserve; and an increase in diffuse myocardial fibrosis that may drive their lower diastolic function. Abstract: Preterm birth accounts for more than 10% of births worldwide and associates with a long-term increase in cardiovascular disease risk. The period around preterm birth is a rapid and critical phase of cardiovascular development, which might explain why changes in multiple components of the cardiovascular system have been observed in individuals born preterm. These alterations include reduced microvascular density, increased macrovascular stiffness, and higher systolic and diastolic blood pressure. Cardiac alterations have been observed in people born preterm as early as neonatal life and infancy, with potentially adverse changes in both left and right ventricular structure and function extending into adulthood. Indeed, studies using cardiovascular magnetic resonance imaging and echocardiography have demonstrated that preterm-born individuals have structural cardiac changes and functional impairments. Furthermore, myocardial tissue characterization by cardiovascular magnetic resonance imaging has demonstrated an increase in left ventricular diffuse myocardial fibrosis in young adults born preterm and under acute physiological stress, their myocardial functional reserve assessed by echocardiography is reduced. The preterm heart is also more susceptible to chronic systolic blood pressure elevation, with a significantly greater increase in left ventricular mass as systolic blood pressure rises observed in preterm-born compared to term-born young adults. Given these known, potentially adverse acute and chronic cardiac adaptations in the preterm-born population, primary prevention strategies are needed to reduce long-term cardiovascular disease risk in this subgroup of the population. This article is protected by copyright. All rights reserved.
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Cardiovascular diseases represent a major health problem, being one of the leading causes of morbidity and mortality worldwide. Therefore, in this scenario, cardiovascular prevention plays an essential role although it is difficult to establish when promoting and implementing preventive strategies. However, there is growing evidence that prevention should start even before birth, during pregnancy, aiming to avoid the onset of cardiovascular risk factors, since events that occur early in life have a great impact on the cardiovascular risk profile of an adult. The two pillars of this early preventive strategy are nutrition and physical exercise, together with prevention of cardio-metabolic diseases during pregnancy. This review attempts to gather the growing evidence of the benefits of antenatal, perinatal and primordial prevention, discussing also the possibility to reverse or to mitigate the cardiovascular profile developed in the initial stages of life. This could pave the way for future research, investigating the optimal time and duration of these preventing measures, their duration and maintenance in adulthood, and the most effective interventions according to the different age and guiding in the next years, the best clinical practice and the political strategies to cope with cardiovascular disease.
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