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:        

It takes twice as much force to stretch a spring twice as far Elastic Bodies Hooke’s Law: Fspring = -kx Spring constant k unstretched spring It takes twice as much force to stretch a spring twice as far 2x x 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  Systolic pressure  Diastolic pressure Heart failure Myocardial ischaemia  Shear stress  Risk  NO production Arterial remodelling  Arterial stiffness  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 Stiff Elastic

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 P<0.001 Yasmin et al. ATVB 2004;25:372

Aortic PWV Predicts the Risk of Developing Hypertension n=499, 4 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

Blacher et al. Circulation 1999;99:2434 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

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

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

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 x = = x Arterial Stiffening Number of cycles Cyclical stress x = = Heart rate x Pulse pressure Arterial Stiffening

McEniery et al Caerphilly Data 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 Media Adventitia Elliot et al. Calcif Tissue Int 1994;54:268

Multi Slice CT Quantification of Aortic Calcification

aPWV and Abdo Calcification McEniery et al Caerphilly Data

Calcification By Blood Pressure McEniery et al Caerphilly Data

Inflammation Arterial Stiffness Cardiovascular Disease

Inflammation and Aortic PWV 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

Maki-Petaja et al; Circulation 2006;114:1184 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 Inflammation-Induced Aortic Stiffening P = NS There was a 0.4m/s increase in aPWV denoting an increase in aortic stiffness following vaccination 8 hours in the placebo group. This was a same change to that seen by Vlachopoulos. Overall ANOVA P<0.001 59

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 Region Hemopexin 62

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 MAP DBP SBP Pauca AL et al. Chest 1992;102:1193

Wave reflection Elastic Stiff

Safar et al, Hypertension 2002;39:735 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 Dahlof et al. Lancet 2005;366:895 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

CAFÉ Investigators. Circulation 2006; 113: Differential Effect of b-blockers/diuretics and ACEi inhibitors/calcium blockers on Blood Pressure in ASCOT Atenolol Amlodipine CAFÉ Investigators. Circulation 2006; 113:

McEniery et al. Hypertension 2008; in press Variability in Central BP Resulting From Classification Based on Peripheral BP McEniery et al. Hypertension 2008; in press