Vascular compliance as a novel cardiovascular risk factor

Dr Ian B. Wilkinson

Senior Lecturer & BHF Research Fellow

University of Cambridge

Hypertension and the Arterial Waveform

F.A. Mohamed 1874

“ These persons appear to pass through life pretty much as others do and generally do not suffer from their high blood pressure except in their petty ailments

upon which it imprints itself… As age advances the enemy gains accession of strength … the individual has now passed forty years, perhaps fifty of age, his

lungs begin to degenerate, he has a cough in the winter time, but by his pulse you will know him … Alternatively headache, vertigo, epistaxis, and a

passing paralysis, a more severe apopleptic seizure, and then the final blow…”

F.A. Mahomed, 1879

Riva Rocci and Korotkoff, ~1905

“ When you can measure what your are speaking about, and can express it in

numbers, you know something about it; but when you cannot measure it, when you

cannot express it in numbers, your knowledge is of a meagre and unsatisfactory

kind.”

Lord Kelvin, 1891

Actuary Data Relating Blood Pressure to Mortality 1935-1954

Metropolitan Life Insurance Company 1961

Modern Techniques for Assessing Arterial Stiffness

Arterial Stiffness: a definition

Stiffness: the resistance of an elastic body to deflection by an applied force.

The stiffness E of a body that deflects a distance δ under an applied force F is:

       

FE

Elastic Bodies

unstretched springHooke’s Law:Fspring = -kx

Spring constant

kx

F

2F

2x

It takes twice as much force to stretch a spring twice as far

Smooth muscle cells

Elastic lamellae

Endothelium

Lamellar subunit

Schematic Diagram of a Large Artery

Why Have Elastic Arteries

Diastole Systole

Reduces peak pressureMaintains diastolic pressure

Smoothes blood flowImproves efficiency

V

Effect of Arterial Stiffening

Systolic pressure Diastolic pressure

Arterial remodelling Arterial stiffness

NO production

Systolic hypertension

Risk Shear stress

Cyclical stress

Heart failureMyocardial ischaemia

Effect of Aortic Stiffening on Blood Pressure

Saeki et al. Circ Res 1995;76:132-141

Indices of Arterial Stiffness

Mackenzie and Wilkinson. QJM 1999;95:67

Pulse Wave Velocity

Elastic Stiff

Measuring PWV

ApplanationTonometry of the Carotid Artery

Does stiffness matter…..?

Pulse Pressure and Aortic PWV

Haynes et al. Am Heart J 1936;4:385

Isolated Systolic Hypertension is Associated with Increased Aortic Stiffness

169 untreated subjects, 114 controls

6

7

8

9

10

11

12

13

14

ISH Control

Pul

se W

ave

Vel

ocity

(m

/s)

P<0.001

Yasmin et al. ATVB 2004;25:372

Aortic PWV Predicts the Risk of Developing Hypertension

n=499, 4.9 year follow-up

Najjar et al. JACC 2008;51:377

Relationship Between Left Ventricular Mass and Aortic Stiffness in Dialysis Patients

Barenbrock et al. KI 1994;45:1397

Aortic PWV and Cardiovascular Risk

Blacher. Hypertension 1999;33:1111

PWV and Mortality in End-Stage Renal Failuren=241; mean age 51; 6 year follow up

Blacher et al. Circulation 1999;99:2434

The Independent Predictive Value of Arterial Stiffness

Consensus Statement: Eur Heart J 2006; 27:2588

Predictive Value of Aortic PWV for Stroke Death in Hypertensives

n=1715; 8 yr follow up; mean age 51 years

Laurent S Stroke 2003; 34:1203

Predictive Value of Aortic PWV for Stroke Death in Hypertensives

n=1715; 8 yr follow up; mean age 51 years

Laurent S Stroke 2003; 34:1203

Predictive Value of Aortic PWV and PP for Stroke Death After Correcting for Other Risk Factors

n=1715; 8 yr follow up; mean age 51 years

Laurent S Stroke 2003; 34:1203

Hansen et al., Circulation 2006; 113: 664-70

Predictive Value of Aortic PWV & Blood Pressure Danish Monica Study n=1,678, 9.4yr follow-up, 154 events

Predictive Value of Aortic PWV & Blood Pressure Danish Monica Study n=1,678, 9.4yr follow-up, 154 events

Hansen et al., Circulation 2006; 113: 664-70

Predictive Value of Aortic PWV & Blood Pressure Danish Monica Study n=1,678, 9.4yr follow-up, 154 events

Hansen et al., Circulation 2006; 113: 664-70

Addition of Novel Biomarkers Does not Improve Risk Prediction

Wang et al NEJM 2006;355:25

Aortic PWV Improves Risk Prediction

Boutouyrie et al Hypertension 2002;39:10

Arterial Stiffness and Response to TreatmentPWV and Mortality in End-Stage Renal Failure

Guerin et al. Circulation 2001

“Only in the case of young children do we find that the elasticity of the arteries is so perfectly adapted to the requirements of the organism as it is in the case of the lower animals”

Roy: 1880

Age and Aortic Pulse Wave Velocity: UK

Bramwell & Hill. Lancet 1922

Age and Pulse Wave Velocity

McEniery et al JACC 2005;46:1753

Aortic

Arterial Stiffening

Elastin Fatigue

Number of cycles Cyclical stressx

Heart rate Pulse pressurex= =

Relationship Between Rate Pressure Product and aPWV in the Caerphilly Study

McEniery et al Caerphilly Data

Comparison of Aortic PWV in urban and Rural Chinese Communities

Avolio et al. Hypertension 1985; 71:202

Blood Pressure in !Kung Bushmen in Northern Botswana

Truswell et al. Am Heart J 1972;84:5

Factors Influencing Arterial Stiffness

Zieman et al ATVB 2005;25:932

Arterial Calcification

Relationship Between Age and Thoracic Aortic Calcium Content in Man

Elliot et al. Calcif Tissue Int 1994;54:268

Media

Adventitia

Multi Slice CT Quantification of Aortic Calcification

aPWV and Abdo Calcification

Me

an

Ao

rtic

Ab

do

min

al C

alc

ium

Sco

re (

cm3

)2.0

1.5

1.0

0.5

0.0

Quartiles of aPWV4321

McEniery et al Caerphilly Data

Calcification By Blood Pressure

McEniery et al Caerphilly Data

Inflammation

Cardiovascular Disease

Arterial Stiffness

Inflammation and Aortic PWV

4

5

6

7

8

9

10

<1 1 - 3 >3

CRP Category

Ao

rtic

PW

V (

m/s

)

0

P<0.001

Yasmin et al. ATVB 2004;24:969

Rheumatoid Arthritis

• RA is chronic systemic inflammatory disease

• A worldwide distribution• Prevalence increases

with age, approaching 5% in women over age 55

• Rarely involves the large arteries directly

Rheumatoid Arthritis is Associated with Increased Aortic PWV

Maki-Petaja et al; Circulation 2006;114:1184

Anti-TNF- Therapy

Effective Anti TNF- Therapy Normalizes Aortic PWV in Rheumatoid Arthritis

P= 0.004

Maki-Petaja et al; Circulation 2006;114:1184n=9

Simvastatin Prevents Acute Inflammation-Induced Aortic Stiffening

Overall ANOVA P<0.001

P = 0.002

P = NS

5

5.5

6

6.5

7

Placebo Simvastatin

m/s

Day 14

Day 15P = 0.016

Inflammation

Cardiovascular Disease

Arterial Stiffness

Why?

Heritability of Pulse Wave Velocity

Ge et al. Am J HT 2007;20:1065

Matrix Metalloproteinase-9

• Relative selectivity for elastin• Present in the circulation and aortic tissue• Inducible

– Cytokines, pro-inflammatory mediators

• Increased levels in coronary artery disease and inflammatory conditions eg kawasaki disease

Signal/Prodomain Hinge Region

Catalytic Domain Hemopexin

MMP-9 Levels and aPWV

Yasmin et al ATVB 2005; 25: 372-378

MMP-9 Genotype and Aortic PWV

Yasmin et al ATVB 2006; 26: 1799

“In extreme old age, the arteries themselves, the grand instrument of the circulation, by the

continual apposition of earth, become hard, and as if it were bony, till, having lost the power of

contracting themselves they can no longer propel the blood, even through the largest channels, in consequence of which death

naturally ensues.”

John Wesley, 1703-1791

Disparity Between Aortic and Brachial Pressure

Rowell et al. Circulation 1968; 37:954

Peripheral Versus Aortic Pressure

Pauca AL et al. Chest 1992;102:1193

SBP

SBP

MAPDBP

Wave reflection

Elastic Stiff

Central Pulse Pressure Predicts Mortality in ESRF n=180; mean age 25; 4 year follow up

Safar et al, Hypertension 2002;39:735

The Independent Predictive Value of Central Pulse Pressure

Consensus Statement: Hypertension 2007; in press

The TIMES Friday 5th November 2004

ASCOT Studyn=19,257, mean age 63

Dahlof et al. Lancet 2005;366:895

Stroke All cause mortality

Pulse Wave AnalysisNon-invasive Assessment of Arterial Stiffness

Wilkinson et al. Lancet 2006; 367:627

Differential Effect of -blockers/diuretics and ACEi inhibitors/calcium blockers on Blood Pressure in ASCOT

CAFÉ Investigators. Circulation 2006; 113:

Atenolol

Amlodipine

Atenolol

Amlodipine

Variability in Central BP Resulting From Classification Based on Peripheral BP

McEniery et al. Hypertension 2008; in press