Transcript Vascular compliance as a novel cardiovascular risk factor

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
F.A. Mahomed, 1879
“ 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…”
Riva Rocci and Korotkoff, ~1905
Lord Kelvin, 1891
“ 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.”
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:
E
F

Elastic Bodies
Hooke’s Law:
Fspring = -kx
Spring constant
It takes twice
as
unstretched
spring
much force to stretch
a spring twice as far
x
k
2x
F
2F
Schematic Diagram of a Large Artery
Smooth muscle cells
Elastic lamellae
Endothelium
Lamellar subunit
Why Have Elastic Arteries
DV
Diastole
Systole
Reduces peak pressure
Maintains diastolic pressure
Smoothes blood flow
Improves efficiency
Effect of Arterial Stiffening
Systolic hypertension
Heart failure
Myocardial ischaemia
 Risk
 NO production
Arterial remodelling
 Arterial stiffness
 Systolic pressure
 Diastolic pressure
 Shear stress
 Cyclical stress
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
Pulse Wave Velocity (m/s)
14
13
P<0.001
12
11
10
9
8
7
6
ISH
Control
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 Failure
n=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
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
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 Treatment
PWV and Mortality in End-Stage Renal Failure
Guerin et al. Circulation 2001
Roy: 1880
“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”
Age and Aortic Pulse Wave Velocity: UK
Bramwell & Hill. Lancet 1922
Age and Pulse Wave Velocity
Aortic
McEniery et al JACC 2005;46:1753
Elastin Fatigue
Number of cycles
x
Cyclical stress
=
=
Heart rate
x
Pulse pressure
Arterial Stiffening
Relationship Between Rate Pressure Product
and aPWV in the Caerphilly Study
30
25
PWV (m/s)
20
15
10
5
R2 = 0.33, P<0.001
0
0
2000
4000
6000
8000
10000
12000
Rate pressure product
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
Media
Adventitia
Elliot et al. Calcif Tissue Int 1994;54:268
Multi Slice CT Quantification of Aortic
Calcification
Mean Aortic Abdominal Calcium Score (cm3)
aPWV and Abdo Calcification
2.0
1.5
1.0
0.5
0.0
1
2
3
Quartiles of aPWV
4
McEniery et al Caerphilly Data
Calcification By Blood Pressure
McEniery et al Caerphilly Data
Inflammation
Arterial Stiffness
Cardiovascular
Disease
Inflammation and Aortic PWV
10
P<0.001
Aortic PWV (m/s)
9
8
7
6
5
40
<1
1-3
>3
CRP Category
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-a Therapy
Effective Anti TNF-a Therapy Normalizes
Aortic PWV in Rheumatoid Arthritis
P= 0.004
n=9
Maki-Petaja et al; Circulation 2006;114:1184
Simvastatin Prevents Acute InflammationInduced Aortic Stiffening
7
Day 14
P = 0.016
Day 15
P = 0.002
m/s
6.5
P = NS
6
5.5
5
Placebo
Overall ANOVA P<0.001
Simvastatin
Inflammation
Why?
Arterial Stiffness
Cardiovascular
Disease
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
Catalytic Domain
Hinge Hemopexin
Region
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
John Wesley, 1703-1791
“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.”
Disparity Between Aortic and
Brachial Pressure
Rowell et al. Circulation 1968; 37:954
Peripheral Versus Aortic Pressure
SBP
SBP
DBP
MAP
Pauca AL et al. Chest 1992;102:1193
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 Study
n=19,257, mean age 63
Stroke
All cause mortality
Dahlof et al. Lancet 2005;366:895
Pulse Wave Analysis
Non-invasive Assessment of Arterial Stiffness
Wilkinson et al. Lancet 2006; 367:627
Differential Effect of b-blockers/diuretics and ACEi
inhibitors/calcium blockers on Blood Pressure in ASCOT
Atenolol
Amlodipine
Atenolol
Amlodipine
CAFÉ Investigators. Circulation 2006; 113:
Variability in Central BP Resulting From
Classification Based on Peripheral BP
McEniery et al. Hypertension 2008; in press