‘Screening for ‘causes’ of

hypertension – needles, haystacks

& mass spec(ulation)?’

Hypertension in the blood - & urine..?

Prof Kennedy Cruickshank

Cardiovascular Medicine & Diabetes

Nutritional Sciences Division

King’s College &

King’s Health Partners (St Thomas’/Guy’s Hosps), UK

London (with Univ. West Indies, Jamaica & Barbados,

Cameroon, Nigeria, Ghana & New Orleans, USA).

N. Xiao, J.D. Humphrey, C.A. Figueroa. "Multi-Scale Computational Model of Three-

Dimensional Hemodynamics within a Deformable Full-Body Arterial Network."

Journal of Computational Physics. DOI: 10.1016/j.jcp.2012.09.016

Variation in

Flow and Pressure

across the

Arterial tree..

(modelled) Note resulting

Pulse Wave

Velocity

changes

(estimated) Courtesy of

Dr A Figueroa,

King’s College

Alteration in arterial parameter

Number of CV events

Arterial biomarker of CV events :

Intermediate end-point

Longitudinal study

Eg:

Pulse wave velocity (PWV)

Central (aortic) BP

Augmentation ?

CVD death rates by Systolic Blood

Pressure

0

50

100

150

200

250

300

<120 120-

139

140-

159

160-

179

180-

199

>200

Systolic BP level (mmHg)

Dea

th r

ate

s p

er 1

0,0

00

perso

n-y

rs

without diabetes

with diabetes

Age adjusted cardiovascular death rates

with and without diabetes at screening

for MRFIT

Alive Died

80 220 4

25

130 160 190

Pu

lse

Wa

ve

Vel

oci

ty (

m/s

)

Arterial Stiffness as Pulse Wave

Velocity (PWV) vs SBP for all

T2 Diabetes & GTTd Controls

Vacarro et al 2003 Cruickshank et al Circulation 2002

Systolic BP mmHg

NB: Accord Trial data 2010

Individual Patient Meta-analysis of Arterial

Stiffness and Mortality – an intermediary

outcome not a risk factor..

Ben-Shlomo 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

Age-adjusted blood pressure distributions of

west African-origin populations

Cruickshank et al, J Hypert 2001; 19: 41-46

Barker hypothesis

• Fetal origins of Adult CVS Disease*

• Consistent, global association of poor fetal growth

Low Birth weight Disproportional

thin baby poor placenta

• ? Nutritional inadequacy

* Barker DJP. Mothers, babies & Disease in later

life. BMJ books, London 1998.

Weight Gain from Birth to 3 months

& Rise in Systolic BP

Bansal et al, J Hypert 2008; 26 (3): 412-18

‘Tracking’ coefficients of children blood pressure: the Brompton study, UK

De Swiet et al, BMJ 1992; 304:23-26

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

UK: systolic BP by BMI tertiles among adolescent girls

The MRC DASH Study in London Schools

Harding, Maynard, Cruickshank, J Hypertension 2006

Ingrid A. Tennant, Debbie S. Thompson,, Alan T. Barnett, Jan Kips*, M Boyne, E Chung, A Chung, C Osmond#, MA. Hanson, PD Gluckman,

P Segers*, J Kennedy Cruickshank, Terrence E. Forrester

Univ. West Indies Mona Jamaica

Univs. Ghent, Belgium, & Southampton, King’s College London, UK

11

Cardiovascular structure and function

in adult survivors of severe acute

malnutrition

Hypertension – accepted May 2014

Differences in cardiovascular measures (SD

scores) between controls vs. all SAM survivors

12

Measurement

(standardised score)

Controls – all SAM survivors

Difference 95%CI, p-value

Controlled for age and sex

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

Hypertension – accepted May 2014

X 2

Expected

NB

Temperature

difference

Initial studies of Arterial function in

Ghana

Factors related to PWV (arterial stiffness) in T2 Diabetes patients

with (n=164) and without ‘High BP’ (n=83), in hypertensives

(n= 78), & in similarly aged Controls (n=62)

Standardised

B

P value

Mean BP 0.38 <0.001

Age 0.34 <0.001

Hypertension status 0.196 0.001

BMI -0.172 0.001

Diabetes status 0.126 0.025

WHR 0.035 0.4

Heart rate 0.035 0.4

FPG 0.016 0.8 Yeboah, Govoni,

JKC, Amoah

‘Diagnosis’ of Hypertension

‘the level of BP above which treatment

does more good than harm’

(Rose 1964)

= need Randomised Clinical Trials of

TREATMENT to decide

Hypertension currently...

• >140/90 mmHg (30+% adults – BUT age-related)

• 98% Primary (essential)

• 2% Secondary: Adrenal gland tumours /

hyperplasia [?]

• Kidney disease

• Renal artery stenosis

• Genetic disorders

• Drugs (OCP) Liquorice

Candidate genes screened for linkage

to (high) BP in African-

Americans, Caribbeans and west Africans:

• Epith. Na+ channel

•TGF- B

• Endothelin-1, Naturetic peptides

• a- receptors

• Glyc389 B1 Rc

• Aldosterone synthase

• NO synthase

• Angiotensinogen etc.

All linked, & not found on repeat sampling in other data.

cf. UK MRC’s ‘BRIGHT’ study

Sick genes, Sick individuals or

Sick populations with chronic

disease? An example from studying

diabetes & hypertension in African-

origin populations.

Kennedy Cruickshank

with J-C Mbanya, R Wilks, B Balkau,

N McF Anderson & T Forrester

Int J Epidemiol 2001; 30: 111-117

What it’s all about is

regulation of gene expression

–

not the genome itself

Primary Hyperaldosteronism (Kaplan NM: In Kaplan’s Clinical Hypertension 2002)

= Conn’s syndrome

- 70% adrenal hyperplasia

- V. rarely adrenal carcinoma

- glucocorticoid suppressible aldosteronism (autosomal dominant)

• Low Prevalence (1-2% of unselected hypertensives)

30% caused by

adrenal adenoma

• Adenomata commoner in women (rare in children)

Adrenal enlargement

‘Normal’ adrenal ‘limbs’ <5mm Johnson et al

Frequency of aldosteronism in

hypertension:

4.8% Aldosterone Producing Adenoma

6.4% Idiopathic Hyperaldosteronism

0

20

40

60

80

100

120

1955 1965 1975 1985 1995

Primary Aldosteronism -- Mayo Clinic

No. of New Cases/yr

Conn’s

syndrome

Spironolactone

discovered

ARR first used

Algorithm for diagnosis and management of PA

CT adrenals (fine

cuts)

Normal OR

Micronodule(s)<1cm

Mass >1cm

Adrenal

Vein

Sampling

Medical

treatmentUnilateral

adrenalectomy

*Suspicious of

adenomatous

PA?

No

lateralizationLateralization

BILATERAL

ADRENAL

HYPERPLASIA

UNILATERAL

PRIMARY

ALDOSTERONISM

Age >40

Age <40

*Clinical features which make adenomatous Primary Aldosteronism

more likely include: hypokalemia / severe hypertension / younger age

/high levels of aldosterone

Part 2-Establish subtype of PA

Morris Brown’s ‘breakthrough’

Variants of aldosterone-producing

adenomas: classical Conn’s may be

tip of the iceberg

.

Brown M J Hypertension. 2014;63:24-26

Azizan E.. Brown MJ. APAs Nat Gen 2013

Azizan E.. Brown MJ. APAs Nat Gen 2013

Functional consequences of somatic mutants in Aldo-p Adenomas

Unusual ‘pure ZG’ Adenoma

Original CT

PET

Overlay

Coronal - PET

‘Searching for Adenomas…’

- Mr KA, 47y; Ghanaian-origin

(via Morris Brown)

Le profilage des stéroïdes d’urine

Courtesy of Dr Norman Taylor

Urinary steroids & Arterial stiffness

Courtesy of Dr Norman Taylor & Ms D Bobeica

r = 0.47,

P=0.02

N= 24

Summary

• Arterial function a genuine candidate

beyond high BP

• Think ‘life-course’ not just ‘adults’

• Gene variants not seriously implicated

for the great majority of HIGH BP

• Aldosteronism.. Moving forwards..?! –

- still not common but..