A life course approach to cardiovascular ageing
Rebecca Hardy
MRC Unit for Lifelong Health and Ageing at UCL
ICH Seminar
27th January 2016
Life course epidemiology
The study of the “biological, behavioural, and psychosocial
pathways that link physical and social exposures during
gestation, childhood, adolescence and adult life, and across
generations, to adult health, function and disease risk”
(Kuh & Ben-Shlomo 1997, 2004, 2014)
Building a theoretical life course framework
•
•
•
•
More than just the collection of
exposure data across life
Requires the temporal ordering of
variables across life and their interrelationships
Aim to improve understanding of
aetiology and help policy
formulation
Requires understanding of:
• the natural history and
physiological trajectory of
normal biological systems
• theories of human development
and ageing
Life course pathways to respiratory disease
Lower childhood
SEP
Lower educational
attainment
Air pollution
Passive smoking
Poor nutrition
Infant
Respiratory
Infections
Poor
growth
in utero
Lower adult
SEP
Air pollution
Poor adult diet
Smoking
Occupational
hazards
Childhood
chest illness
Rapid decline
in lung function/
adult lung disease
Poor
lung
development
Asthmatic tendency/genetic predisposition
AGE/TIME
Taken from Ben-Shlomo and Kuh Int J Epidemiol 2002
From a theoretical life course framework
to a testable hypothesis
•
Need to break down theoretical frameworks
into testable parts
•
Life course models were originally used to
test the influence of the timing and
duration of exposures across life on later
disease risk:
a. Critical and sensitive period models
b. Accumulation of risk models
o with independent and uncorrelated
insults (a)
o with correlated insults
o risk clustering (b)
o chains of risk (with additive or
trigger effects) (c & d)
•
These models are NOT mutually exclusive
and may operate simultaneously
Taken from Kuh et al JECH 2003;57:778–783
Life course epidemiology: recent developments
• Models continue to evolve and have been extended to consider:
• a wider range of different types of health outcome
• functional trajectories across life
• key ageing phenotypes (i.e. the progressive, generalised impairment
of function)
• inter-generational associations
• reversibility
• resilience
•
Examples of current research questions:
• How do human systems & function change across life? During which
periods of life are important changes observed? Gender, ethnic, birth
cohort differences?
• What are the lifetime determinants of level & change in function ?
• What is the relationship between earlier levels and changes in function
with subsequent disease risk?
Life course epidemiology and functional
trajectories
• Many functions increase in childhood and adolescence and
then plateau in early adulthood and decline with ageing
• Interpretation of the absolute level of function at age given
age in later life requires understanding of the normal agerelated life course trajectory
• Life course factors which might drive deviations from this
norm
Dodds et al PLOS One 2014
Life course blood pressure trajectories
Predicted mean SBP trajectories and
velocities (mmHg/year) (right y-axis) in each cohort
MEN
WOMEN
Wills et al. PloS Med 2011
Challenges: sensitivity analyses
170
Manual versus automated device
160
• use conversion equations
(Stang et al., AJE 2006)
• a constant of +10mmHg to
those on medication (Tobin
et al., Stats in Med 2005)
Decline at older ages
• Exclude those on medication
and who had an MI
Cohort effect
• Adjust for cohort change in
BMI
SBP(mmHg)
Model “true” untreated SBP
150
140
130
120
110
0
10
20
30
40 50
Age (years)
60
70
80
ALL (95% CI)
No treatment for high BP
Additional
exclusion of MI
MRC National Survey of Health and
Development
• MRC National Survey of Health and
Development is a sample of 5362
babies born in 1 week in March 1946
and followed up ever since
• Most recent complete follow up in
2006/10 when study members visited
clinics or were interviewed in their own
homes at ages 60-64
• Currently completing age 69 home visit
Birth
4
2
7
6
9 11
8
10
15
13
20
19
23
22
26
31
36
43
53
60-64
68-69
25
46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 96 98 00 02 04 06 08 10 12 14 16
Life course body size and CV measures in NSHD
• Birth weight
• Weight and height 2, 4, 6, 7, 11, 15, 20, 26,
36, 43, 53, 60-64 years
• Calculate body mass index
• Focus on continuous measures of
cardiovascular structure and function which
change throughout life and can monitor
cardiovascular ageing (rather than CVD)
• BP at 36, 43, 53, 60-64 years
• Lipids at 53, 60-64 years
• Echocardiography and carotid intima-media
thickness (cIMT) at 60-64 years
Midlife acceleration
• WHII acceleration later, widening distribution
• Point of transition/ turning point?
• Heterogeneity in SBP around midlife?
ENTROPY = 0.78
ENTROPY = 0.84
Wills et al. Epidemiology 2012
Change in midlife blood pressure and left
ventricular mass at 60-64 years
Difference in LVMI for a 1SD increase
in conditional SBP change
(adjusted for sex, age, clinic, current BMI,
diabetes status, medication)
Regression models including SBP and HTT
at each age
(adjusted for sex, age, clinic)
Antihypertensive medication (yes v no)
Ghosh et al. Eur Heart J 2014
What influences the shape of trajectories?
• Review of vascular and
metabolic function
across the life course
(Lawlor & Hardy OUP
2014)
Estimates from multilevel models
adjusted for sex
Childhood social class
(manual v. non manual)
unadjusted
4
3
• “few studies have
appropriately modelled
change with age and
explored risk factors for
different patterns of agerelated change”
2
adjusted for adult BMI
1
0
30
35
40
45
50
55
-1
-2
-3
-4
Age (years)
Hardy et al. Lancet 2003
Systolic blood pressure by birth weight and
father’s social class in the NSHD
Birth weight (per kg)
Manual childhood
social class
6
5
4
3
mmHg
2
1
0
-1
36
43
53
36
43
53
-2
-3
-4
-5
-6
Age (years)
Hardy et al. Lancet 2003
• Birth weight and SEP do
not confound each other
– separate pathways
• Birth weight influences
intercept only
• SEP influences intercept
and rate of change
Systolic blood pressure change by adult
height and components of height length
Estimates (per 10cm height) from multilevel models adjusted for sex
Difference in SBP (mmHg)
1
0
30
35
40
45
50
55
Trunk length
-1
-2
-3
Height
-4
Leg length
-5
Age (years)
Langenberg et al. IJE 2005
Blood pressure trajectories across
adolscence: Project HeartBeat!
Labarthe et al Am J Prev Med 2009
Age at puberty and blood pressure
Pubertal age and SBP (mmHg) in men
Reg. coeff. (95% CI)
Age 53
Unadjusted
Adjusted for
body size
Latest
Reference
Reference
2
5.7 (1.3,10.0)
6.0 (1.8,10.2)
3
6.7 (2.3,11.1)
6.5 (2.3,10.8)
Earliest
6.4 (1.8,10.9)
4.8 (0.4,9.2)
P=0.03
P=0.02
Age at menarche not associated with BP in women
Hardy et al. J Hypertens 2006
Age at menarche and CV risk factors
• Age at menarche not
associated with BP
• Early menarche in females
associated with:
• worse lipid profile (Pierce et al
2011)
• increased risk of type 2
diabetes (Pierce et al 2012)
• Mediation through BMI
Pregnancy
• Metabolic changes occur
during pregnancy
• Pregnancy outcomes
associated with later
disease risk in women
• Gestational diabetes
• Hypertension
• Low birth weight
• Pre-term delivery
• Pregnancy a “stress test”
that can reveal
subclinical trajectories
• Opportunity for early
intervention
MacDonald-Wallis et al. Hypertens 2012
Pregnancy or parenthood?
Mean SBP by age at parenthood for
men and women
150
Mean (kg/m2)
• Metabolic changes during
normal pregnancy
• Long term impact of
pregnancy, or confounding or
mediating by lifestyle factors
associated with childrearing?
• Compare the effects in
men with that in women
• Adjust for confounders and
mediators
women
p<0.001
men
p=0.003
145
140
135
30+
25-29
20-24
Teenage
30+
25-29
20-24
• Intervention to promote
healthy lifestyle in young
families?
Teenage
130
Hardy et al. JECH 2007
Number of children and blood pressure change
At least one child versus no child
SBP
3
DBP
3
mmHg
Women
2
2
1
1
0
Women
0
30
35
40
45
50
55
-1
30
35
40
45
-1
Men
-2
-3
Age (years)
50
55
Men
-2
-3
Age (years)
Hardy et al. BJOG 2007
Sex differences and the influence of menopause
Mean sex difference in SBP (men minus women) (mmHg) and
95% CI. Positive values indicate a higher SBP in males. Adjusted for BMI.
Explanation for sex
differences:
• Similar patterns seen
across globe (Lawes et al.,
2006) except isolated
communities with low salt
intake (He et al., 1991)
• Menopause-related effect
on salt sensitivity?
Wills et al PloS Med 2011
Menopause
Kuh et al. BJOG 2005
Cohort differences
Johnson et al. PLOS Med 2015
Predicted mean SBP trajectory and velocity (95% CI) in BMI
adjusted models
MEN
WOMEN
Unadjusted
Wills et al PloS Med 2011
Growth and blood pressure: comparison
with 1958 birth cohort
Li et al. IJE 2015
• Correlation between BMI and SBP greater in 1958 compared
with 1946 cohort despite secular increases in BMI and
decreases in SBP
• Differing body composition at same BMI?
Summary
• Understanding of normal life
course trajectories and
deviations from the norm may
allow early detection of those
not ageing healthily
• Monitor longitudinally e.g.
rapid midlife changes in BP
rather than crossing threshold
• Susceptible periods e.g.
pregnancy or menopause?
Rich-Edwards. Hypertension 2010
Acknowledgements
Diana Kuh & LHA scientific team and collaborators
NSHD data collection team
Medical Research Council
NSHD study members