1. Vascular compliance as a novel cardiovascular risk factor
Dr Ian B. Wilkinson
Senior Lecturer & BHF Research Fellow
University of Cambridge

5. Hypertension and the Arterial Waveform
F.A. Mohamed 1874

6. 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…”

7. Riva Rocci and Korotkoff, ~1905

8. 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.”

9. Actuary Data Relating Blood Pressure to Mortality 1935-1954
Metropolitan Life Insurance Company 1961

10. Modern Techniques for Assessing Arterial Stiffness

11. 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:
       

12. 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

13. Schematic Diagram of a Large Artery
Smooth muscle cells
Elastic lamellae
Endothelium
Lamellar subunit

14. Why Have Elastic ArteriesDV
Diastole
Systole
Reduces peak pressure
Maintains diastolic pressure
Smoothes blood flow
Improves efficiency

15. 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

16. Effect of Aortic Stiffening on Blood Pressure
Saeki et al. Circ Res 1995;76:

17. Indices of Arterial Stiffness
Mackenzie and Wilkinson. QJM 1999;95:67

18. Pulse Wave Velocity
Stiff
Elastic

19. Measuring PWV

20. ApplanationTonometry of the Carotid Artery

21. Does stiffness matter…..?

22. Pulse Pressure and Aortic PWV
Haynes et al. Am Heart J 1936;4:385

23. Isolated Systolic Hypertension is Associated with Increased Aortic Stiffness 169 untreated subjects, 114 controls
P<0.001
Yasmin et al. ATVB 2004;25:372

24. 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

25. Relationship Between Left Ventricular Mass and Aortic Stiffness in Dialysis Patients
Barenbrock et al. KI 1994;45:1397

26. Aortic PWV and Cardiovascular Risk
Blacher. Hypertension 1999;33:1111

27. 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

28. The Independent Predictive Value of Arterial Stiffness
Consensus Statement: Eur Heart J 2006; 27:2588

29. 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

30. 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

31. 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

32. 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:

33. 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:

34. 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:

35. Addition of Novel Biomarkers Does not Improve Risk Prediction
Wang et al NEJM 2006;355:25

36. Aortic PWV Improves Risk Prediction
Boutouyrie et al Hypertension 2002;39:10

37. Arterial Stiffness and Response to Treatment PWV and Mortality in End-Stage Renal Failure
Guerin et al. Circulation 2001

38. 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”

39. Age and Aortic Pulse Wave Velocity: UK
Bramwell & Hill. Lancet 1922

40. Age and Pulse Wave Velocity
Aortic
McEniery et al JACC 2005;46:1753

42. Elastin Fatigue x = = x Arterial Stiffening Number of cycles
Cyclical stress x = =
Heart rate x
Pulse pressure
Arterial Stiffening

43. McEniery et al Caerphilly Data
Relationship Between Rate Pressure Product and aPWV in the Caerphilly Study
McEniery et al Caerphilly Data

44. Comparison of Aortic PWV in urban and Rural Chinese Communities
Avolio et al. Hypertension 1985; 71:202

45. Blood Pressure in !Kung Bushmen in Northern Botswana
Truswell et al. Am Heart J 1972;84:5

46. Factors Influencing Arterial Stiffness
Zieman et al ATVB 2005;25:932

47. Arterial Calcification

48. Relationship Between Age and Thoracic Aortic Calcium Content in Man
Media
Adventitia
Elliot et al. Calcif Tissue Int 1994;54:268

49. Multi Slice CT Quantification of Aortic Calcification

50. aPWV and Abdo Calcification
McEniery et al Caerphilly Data

51. Calcification By Blood Pressure
McEniery et al Caerphilly Data

52. Inflammation
Arterial Stiffness
Cardiovascular
Disease

53. Inflammation and Aortic PWV
Yasmin et al. ATVB 2004;24:969

54. 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

55. Rheumatoid Arthritis is Associated with Increased Aortic PWV
Maki-Petaja et al; Circulation 2006;114:1184

56. Anti-TNF-a Therapy

57. 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

59. 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

60. Inflammation
Why?
Arterial Stiffness
Cardiovascular
Disease

61. Heritability of Pulse Wave Velocity
Ge et al. Am J HT 2007;20:1065

62. 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

63. MMP-9 Levels and aPWV
Yasmin et al ATVB 2005; 25:

64. MMP-9 Genotype and Aortic PWV
Yasmin et al ATVB 2006; 26: 1799

65. John Wesley,
“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.”

67. Disparity Between Aortic and Brachial Pressure
Rowell et al. Circulation 1968; 37:954

68. Peripheral Versus Aortic Pressure
SBP
MAP
DBP
SBP
Pauca AL et al. Chest 1992;102:1193

69. Wave reflection
Elastic
Stiff

70. 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

71. The Independent Predictive Value of Central Pulse Pressure
Consensus Statement: Hypertension 2007; in press

72. The TIMES Friday 5th November 2004

73. 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

74. Pulse Wave Analysis Non-invasive Assessment of Arterial Stiffness
Wilkinson et al. Lancet 2006; 367:627

75. 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:

76. 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