ancestry differences in hypertension risk, progression and
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Ancestry differences in hypertension
risk, progression and
treatment response
Prof. Kennedy Cruickshank
Cardiovascular Medicine & Diabetes,
King’s College & Health Partners
= Guy’s & St Thomas’ Hospitals,
London, UK
RCP - BHS joint symposium
I have no disclosures
Heart attack and Stroke 20y Incidence by Ethnicity, in west London, 1988-2011
The ‘Sabre’ cohort – Ealing & Brent; Chaturvedi N et al; JACC 2013
N = 2049 630 1517
CHD
STROKE
Frequency distribution of LV mass indexed to
BSA in black vs white women (A) and men (B)
Mark H. Drazner et al.
Hypertension
2005;46:124-129
Representative
samples in the
Dallas Heart study
The ‘null’ hypothesis
More (High) Blood Pressure in W Afrs & Caribbeans but for given BP levels (eg: ‘x’), no difference in outcomes..
- Cruickshank 1989
Inci
den
ce r
ate
o
f o
utc
om
es
Europeans
West African / C’bean
Origins of High Blood Pressure risk
- Genes.. variants?
- Development – life-course exposure..?
- Risk factor burden..?
- Social determinants..?
Trajectories of systolic blood pressure (A) and body mass index (BMI) (B) from 1 to 20 years
of age in offspring of normotensive (blue), pregnancy-induced hypertension (PIH; orange)
and complicated hypertensive (red) pregnancies.
Esther F Davis et al. BMJ Open 2015;5:e008136
©2015 by British Medical Journal Publishing Group
BM
I –kg
/m2
SBP
- m
mH
g
Bogalusa Heart Study: multiple regression
on Longitudinal systolic BP at 15y (n= 182, Af.Am 92)
95 % CI Standard beta
coefficients P value
Birth weight -8.6 to 4.1 - 0.36 <0.01
Height 0.27 to 0.57 0.38 <0.01
BMI 0.30 to 0.85 0.3 <0.01
DWT 04 -1.3 to –0.3 - 0.25 0.01
SBP at 4y 0.08 to 0.44 0.19 <0.01
NB. Ethnic difference in 15y BP ‘accounted for’ by birth weight
Cruickshank et al Circulation 2005;111:1932-37
Adolescence 11-13y & 14-16y, (n=~6000)
CVD, respiratory
& Mental Health
<birth weight linked>
Early life & childhood
+ bio-markers, arterial stiffness, accelerometery, dietary recall, own SEC,
parenting qualitative interviews
21-23y: Pilot study (n=665)
Work life & beyond
health & life trajectories future follow-up linkage of medical data generational studies
DASH - health over the life course, ~1000 in each major ethnic group
100
105
110
115
120
systo
lic B
P (
mm
Hg
)
■ 13.1 - 18.8 kg/m² ♦ 18.8 - 21.9 kg/m² ● 21.9 - 39.5 kg/m²
White Black
Caribbean
Black
African
Indian Pakistani/
Bangladeshi
MixedWhite
Other
Systolic BP by BMI tertiles among adolescent girls
The MRC DASH Study in London Schools 11-13y olds
Harding S, Maynard M, Cruickshank JK. J Hypertension 2006
Systolic blood pressure, by age and ethnicity for males and females: means/percentage and 95% confidence
intervals adjusted for gender and ethnicity
Males Females
100
105
110
115
120
125
130
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
Whites UK BC BA Indian PB Others
Syst
olic
Blo
od
Pre
ssu
re, m
mH
g
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
Whites UK BC BA Indian PB Others
(BC – Black Caribbean, BA – Black African, PB – Pakistani/Bangladeshi)
Systolic blood pressure from adolescence to early adulthood for males and females: association with
longitudinal measures of adiposity* - at ages 21-23y
100
105
110
115
120
11-13y 14-16y 21-23y
Syst
olic
Blo
od
Pre
ssu
re, m
mH
g
Males 95% CI Males
Females 95%CI Females
Coeff 95% CI p-value
Males
Waist to height ratio 32.49 (22.05,42.93) <0.001
BMI, kg/m2 0.17 (0.08,0.26) <0.001
Overweight (Normal weight - Ref)
Overweight/Obese 1.74 (-0.31,3.79) 0.097
Females
Waist to height ratio 32.69 (24.84,40.55) <0.001
BMI, kg/m2 0.54 (0.42,0.65) <0.001
Overweight (Normal weight - Ref)
Overweight/Obese 3.75 (2.00,5.50) <0.001
*Mixed-Effects Linear Regression Model coefficients adjusted for age, ethnicity, waist to height ratio (or BMI, or
overweight status), parental/own employment and currently smoking.
Harding S et al.. Cruickshank JK – in preparation
Relationship of Pulse Wave Velocity with BP
4
6
8
10
12
Pu
lse
Wa
ve
Ve
locity (
m/s
)
80 100 120 140 160 Systolic BP
60 70 80 90 100 Diastolic BP
ρ=0.31 (p<.0001)
ρ=0.18 (p=0.000)
Feasibility Follow-up – ages 22-23y
Many young people
already ‘stiffening’..?
Cruickshank et al Hypertension June 2016
Individual Patient Meta-analysis of Arterial Stiffness and Mortality – an intermediary
outcome not a risk factor..
Ben-Shlomo Y et al, JACC 2014
0
10
20
30
40
%
< 50 60 70 80 90 100 110 120 130 140
Diastolic Blood Pressure mmHg
Manchester 23 Jamaica 15 Cameroon – urban 4.4
% BP (treated)
Cameroon – rural 0.5
Cruickshank et al, J Hypert 2001; 19: 41-46
Age-adjusted blood pressure distributions of
west African-origin populations
Severe childhood malnutrition (SCM) - still a problem…
- 2 distinct forms - based on
presence or absence of nutritional oedema:
Oedematous
(Kwashiorkor & Marasmic-kwashiorkor)
Non-oedematous
(Marasmus)
15
Differences in cardiovascular measures (SD scores)
- controls vs. all Malnutrn survivors at ±30y
16
Measurement
(standardised score)
Controls – all SAM survivors
Difference 95%CI, p-value
Controlled for age and sex
Visceral fat mass -0.09 -0.45 to 0.27, 0.6
Systolic blood pressure -0.22 -0.55 to 0.12, 0.2
Diastolic blood pressure -0.40 -0.71 to -0.08, 0.02
Heart rate 0.21 -0.14 to 0.56, 0.2
Pulse Wave Velocity 0.35 0.06 to 0.65, 0.02
Stroke Volume 0.49 0.15 to 0.82, 0.005
Cardiac Output 0.56 0.23 to 0.90, 0.001
Ejection Fraction -0.41 -0.76 to -0.06, 0.02
LV outflow tract diameter 0.71 0.39 to 1.03, <0.001
Systemic Vascular Resistance -0.69 -1.03 to -0.35, <0.001
LV Mass index -0.02 -0.35 to 0.31, 0.9
Central Systolic BP -0.15 -0.47 to 0.18, 0.4
Tennant-Martin et al – Hypertension 2014
Vascular resistance & LV outflow
tract +/- 30 years after
Malnutrition
17 Tennant-Martin et al – Hypertension 2014
Lifetime transition..?
Recovered
Kwashiorkor, small
baby…
High BP
Type 2 Diabetes
? Population
Risk ?
X 2
Expected
NB
Temperature
difference
Nigerian birth cohort – BP change up to age 3y by maternal
malarial status
Courtesy of Jasmin Farikullah-Mirza, O Ayoola, Clayton P & our team – submitted 2016
Maternal malaria +ve
Unexposed ‘controls’
Increased
Vasc GFs
Sick genes, Sick individuals or
Sick populations with chronic
disease? An example from studying
diabetes & hypertension in African-origin
populations.
JK Cruickshank, J-C Mbanya, R Wilks, B Balkau, N McF Anderson, T Forrester
Int J Epidemiol 2001; 30: 111-117
Developmental & Environmental, rather than genetic-variant, bases for ethnic variation in High Blood Pressure - & Diabetes / Vascular disease
Perspective
1. Natural History of Disease
2. It’s a long way from genome to phenotype:
gene – translation – protein folding, synthesis & turnover – substrate availability & metabolism – tissue lay-down, degradation & repair - individual vs. commonality – social experience & behaviour
- A far cry from genome variants..
What it’s all about is regulation of
gene expression –
not the genome itself
Salt + Aldo excess & remodelling?
Catena C et al, Sechi L
- online, July 2016
PET- CT for Adrenal(micro-)adenoma imaging
Findings: Limited PET with low dose un-enhanced diagnostic CT adrenal glands.
Right Adrenal: >20mm nodule in R adrenal gland, with intense focal tracer uptake
Left Adrenal : Homogenous tracer distribution on the left; no obvious nodularity
IG: 37yo woman, West African descent;
Difficult, poorly controlled BP 3+ line therapy..
R Adrenalectomy - 9/12 later - BP 128/86mmHg on Amlodipine 5mg/d
JKC Guy’s patient – PET-CT courtesy of Morris Brown
NB:
Adrenal Aldosterone-secreting
Adenomas
are somatic, not germ-line
mutations
Beta-blockers ineffective alone for BP in
AfC’bean (& Af) patients
Cruickshank JK et al; BMJ 1988 Nov 5;297:1155-9. Cross-over RCT
Plasma Renin
AfC’bean
Europeans
BP
AfC Eurpns
AfC Eur
Sample of key papers on Ethnic Diffs in Hypert Trtmnt
literature
• Humphreys GS, Delvin DG. Ineffectiveness of propranolol in hypertensive Jamaicans.
Br Med J 1968 ; 2: 601-3.
• Kaplan NM, Kem DC, Holland OB, ..Gomez-Sanchez C. The intravenous furosemide test:
a simple way to evaluate renin responsiveness. Ann Intern Med 1976; 84: 639-45.
• Holland OB, von Kuhnert L, Campbell WB, Anderson RJ. Synergistic effect of captopril
with hydrochlorothiazide for the treatment of low-renin hypertensive black patients.
Hypertension 1983;5:235-9.
• Preston RA, Materson BJ, Reda DJ, Williams DW, Hamburger RJ, Cushman WC, Anderson
RJ. Age-race subgroup compared with renin profile as predictors of blood pressure
response to antihypertensive therapy. Veterans Affairs Coop Study Group on
Hypertensive. JAMA 1998; 280:1168-72.
Heart Failure by ALLHAT treatment
Wright J et al JAMA
2005;293:1595-1608
Systematic review: antihypertensive drug therapy in patients of African and South Asian
ethnicity
Brewster LM, van Montfrans GA, Oehlers GP, Seedat YK
Intern Emerg Med (2016) 11:355–374
32
-20 -10 -5 0 5 10 20 mm Hg
Favours treatment Favours control
(WMD 95%CI)
Effect of different drugs
on
Systolic Blood Pressure in
black people
Ca-blockers
I2 =94%
Diuretics
ACE inhibitors
AT II antagonists
Beta-blockers
-20 -10 -5 0 5 10 20 mm Hg
Favours treatment Favours control Brewster, 2004
Syst Review – RCTs in African-origin Hypertensive pts (only) vs placebo - 1
Brewster LM et al
Syst Review – RCTs in African-origin Hypertensive pts (only) vs placebo – 2, Brewster LM et al
Danish National Registry
Serum K+ and Risk of Death in Hypertension
1. Spironolactone
2. Amiloride ± HCTZ
3+.. Aldosterone synthase antagonism
- every opportunity in African origin patients
‘Simple’ Future Treatments
N. Xiao, J.D. Humphrey, C.A. Figueroa. “Computational Model of 3-D Hemodynamics -
a Full-Body Arterial Network."
Journal of Computational Physics. 2012 DOI: 10.1016/j.jcp.2012.09.016
Flow & Pressure
Variation
across the
Arterial tree..
(modelled)
NB:
Pulse Wave
Velocity
changes
(estimated)
Courtesy of
Dr A Figueroa,
King’s College
The
“Restricted
Vascular
Network”
Hypothesis
for High BP
Intergenerational transmission of CVS RISK -
Examples from Caribbean peoples
Intrauterine Social Position growth early childhood growth adolescent RISK FACTORS Adult Health Outcomes Lifespan--------------------------------------------------------/
maternal
phenotype
genes Individual adaptation Finance
Forces of HISTORY & Society
Slavery & slow escape from post-
emancipation poverty / indentured labour
Nutrition
Upstream & downstream policies to address ethnic inequalities – the heart of public health debate
BP distribution in 35-66y olds –
Kilifi, Kenya; ABPM vs Usual
Etyang, Smeeth, Cruickshank & Scott
BP distribution in 35-66y olds – Kilifi,
Kenya; ABPM vs Usual
Etyang, Smeeth, Cruickshank & Scott
Waist to height ratio by age and ethnicity for males and females: means/percentage and 95% confidence
intervals by gender and ethnicity
0.40
0.42
0.44
0.46
0.48
0.50
0.52
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
Whites UK BC BA Indian PB Others
Wai
st h
eig
ht
rati
o
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
11
-13
y
14
-16
y
21
-23
y
Whites UK BC BA Indian PB Others
Males Females
(BC – Black Caribbean, BA – Black African, PB – Pakistani/Bangladeshi)
Harding S et al.. Cruickshank JK – in preparation
The influence of waist to height ratio at 11-13y and 21-23y on bio-markers at 21-23y
• Allostatic Load: Score derived at 21-23y using high-risk thresholds defined as below the 25th percentile for HDL cholesterol, and above the 75th percentile for all other biomarkers.
• The thresholds were: systolic, 121.0 mmHg; diastolic, 77 mmHg; BMI, 26.8 kg/m2; waist to height ratio male, 0.89, and female, 0.86; total cholesterol, 4.8 mmol/L; HDL cholesterol, 1.8 mmol/L; HbA1c, 37.0 mmol/mol; C-reactive protein, 0.0 mg/L. Linear Regression Model: regression coefficients adjusted for gender, ethnicity, waist to height ratio.
** HbA1c, HDL Cholesterol and Total cholesterol: Linear Regression Model. Regression coefficients adjusted for ethnicity and waist to height ratio at 11-13y and 21-23y.
Allostatic Load HbA1c HDL Cholesterol Total Cholesterol
Coef 95% CI Coef 95% CI Coef 95% CI Coef 95% CI
Males
Waist to height ratio, 11-13y 7.69*** (4.27,11.11) 3.24 (-7.44,13.93) 1.31** (0.49,2.14) -1.47 (-3.55,0.60)
Waist to height ratio, 21-23y - - 0.27 (-9.66,10.21) -1.79*** (-2.55,-1.03) 4.51*** (2.59,6.43)
Females
Waist to height ratio, 11-13y 11.36*** (7.76,17.95) 22.54** (6.36,38.72) 0.25 (-0.90,1.40) -1.95 (-4.31,0.40)
Waist to height ratio, 21-23y - - -0.85 (-11.98,10.28) -1.24** (-2.00,-0.47) 2.93*** (1.31,4.55)
*p<0.05, **p<0.01, ***p<0.001
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