1. 10 year follow-up of central pulse pressure components and effect of nitrovasodilating therapy in women Marina Cecelja, Jiang B, K McNeill, Spector T, Chowienczyk P. Department of Clinical Pharmacology St Thomas’ Hospital King’s College London Department of Twin Research & Genetic Epidemiology

2. pPP cPP DBP pSBP cSBP Aortic PressurePeripheral Pressure Pulse pressure

3. CAFE study The CAFÉ Investigators. Differential impact of blood-lowering drugs on central aortic pressure and clinical outcomes: Principle Results of the Conduit Artery Function Evaluation (CAFÉ) Study. Circulation 2006; 113: 1213-1225 Amlodipine +perindopril Atenolol + bendroflumethiazide Central SBP Brachial SBP

4. P1 and AP differentially associated with aortic stiffness Arterial dimensions Augmentation (AP) Forward Pressure Wave P1: Aortic Stiffness ( ↓ distension) Cecelja et al. J Am Coll Cardiol. 2009; 18: 54: 695-703. Inflection Point (P1)

5. Aims 10-year prospective follow-up  Examine the contribution of P1 and AP to age related increase in cPP  Degree to which age-related increase can be reversed by pharmacological vasodilation (Glyceryl Trinitrate) Pulse Pressure Augmentation (AP) Forward Pressure Wave (P1)

6. TWINS UK Registry 411 Female Twins TWINS UK Registry Department of Twin Research & Genetic Epidemiology Visit 1 (1996 – 2001) Visit 2 (2006 – 2010) n = 411 Central BP Carotid BP Arterial stiffness Arterial diameter Visit 2 Central BP Arterial stiffness Arterial diameter n = 40 400 μg GTN

7. Aortic Pressure Waveforms: Baseline and Follow-up Applanation tonometry Applanation tonometry High fidelity pressure transducer (Millar Instruments, Texas) High fidelity pressure transducer (Millar Instruments, Texas) SphygmoCor System SphygmoCor System Calibrated to brachial BP Calibrated to brachial BP

8. Carotid pressure waveforms Quality control – variation in recorded waveform n = 477 Inconclusive - excluded

9. d t1 t2 Pulse wave velocity (PWV) Femoral Carotid PWV = distance transit time SphygmoCor

10. Ultrasonography Arterial dimensions Arterial dimensions Abdominal aortic diameter Femoral artery diameter Arterial diameter change expressed as a ratio: femoral/abdominal diameter Carotid and brachial diameters

11. Visit 1 (n = 411) Visit 2 (n = 411) P Age (years) 47.6 ± 9.4 58.2 ± 9.0< 0.0001 Height (cm)161.8 ± 6.0161.4 ± 6.0< 0.0001 Weight (kg)66.0 ± 11.569.8 ± 12.5< 0.0001 HR (bpm)72.6 ± 11.163.6 ± 9.5< 0.0001 Peripheral SBP (mm Hg)118.9 ± 15.8125.0 ± 15.9< 0.0001 Peripheral DBP (mm Hg)76.1 ± 11.173.0 ± 8.3< 0.0001 MAP (mm Hg)92.4 ± 13.192.3 ± 10.6NS Central SBP(mm Hg) 110.3 ± 16.0117.1 ± 15.7< 0.0001 Central DBP (mm Hg)77.4 ± 11.373.9 ± 8.3< 0.0001 Total cholesterol (mmol/L)5.5 ± 1.15.6 ± 1.0< 0.05 HDL (mmol/L)1.5 ± 0.41.8 ± 0.5< 0.0001 Glucose (mmol/L)4.6 (4.27 - 4.97)5 (4.7 - 5.3)< 0.0001 TG (mmol/L)1.0 (0.75 - 1.37)0.98 (0.72 - 1.31)NS Subject characteristics

12. ∆ Pressure (mm Hg) P<0.0001 P = NS Greater increase in cPP compared to pPP in younger subjects <50 years at baseline ≥50 years at baseline

13. AP contributed more than P1 to age-related increase in cPP ≥50 years at baseline <50 years at baseline

14. Carotid pressure waveform: P1 and AP

15. Variable betaR2R2 P Carotid P1 Age0.150.01<0.0001 MAP0.460.36<0.0001 HR-0.170.03<0.0001 PWV 0.290.07<0.0001 Carotid AP Age0.330.09<0.0001 MAP0.60.32<0.0001 HR-0.450.18<0.0001 TG0.070.01<0.05 Abd Diameter-0.160.12<0.0001 Fem/Abd diameter-0.220.18<0.0001 Multivariate regression analysis

16. Glyceryl Trinitrate (400 μg) Diameter Change All P<0.0001 % Diameter Change

17. Glyceryl Trinitrate: P1 and AugP ∆ 9.3 mm Hg ≈ 10 years ageing

18. Glyceryl trinitrate: PWV and heart rate PWV (m/sec) NS Errors bars = 1 SD P<0.05 Heart Rate (bpm)

19. Conclusion  Augmentation pressure is an important determinant of the progression in central pulse pressure  AugP is not associated with PWV but is associated with attenuation of arterial diameter  AugP can be effectively reduced by vasodilation, independently of an effect on PWV

20. Discussion   Our findings challenge the conventional view that cPP is influenced predominantly by irreversible stiffening of the proximal aorta.  Suggest that drugs that dilate muscular arteries may be effective in reducing age-related widening in cPP.

21. Acknowledgements British Heart Foundation British Research Council Twins UK Department of Twin Research & Genetic Epidemiology

22. Age –related change in P1 and AP AIx = AP/AP+P1

23. P1 and AP differentially associated with aortic stiffness Arterial dimensions Augmentation (AP): Forward Pressure Wave P1: Aortic Stiffness ( ↓ distension) Cecelja et al. J Am Coll Cardiol. 2009; 18: 54: 695-703. Augmentation Index (AIx) = AP/cPP * 100 Inflection Point (P1)

24. P1 and AP differentially associate with age? McEniery, et al. J Am Coll Cardiol 2005;46:1753-1760 Augmentation Pressure Augmentation Index AP/AP+P1

26. Measurement of ascending aortic (top) and brachial (bottom) pressure waves at diagnostic cardiac catheterization in an older patient, by Millar micromanometer before (control) and after administration of 0.3 mg nitroglycerin (GTN) sublingually. O'Rourke M F, Seward J B Mayo Clin Proc. 2006;81:1057- 1068 © 2006 Mayo Foundation for Medical Education and Research

27. Copyright ©1996 American Heart Association Chen, C.-H. et al. Hypertension 1996;27:168-175 Tracings from all four group B patients illustrate simultaneously recorded invasively (micromanometer) and noninvasively (tonometer) obtained carotid artery waveforms as well as the invasive (AIm) and noninvasive (AIt) augmentation indexes (expressed as percent)‏

29. Carotid pressure waveform: P1 and AP