1. Mechanistic insights into the relationship between wave reflection and retinal artery flow pulsatility. McDonnell BJ *, Coulson J **, Zagura M***, Munnery I **, Munnery M **, Stohr E*, Shave R*, McEniery CM ¶, Wilkinson IB ¶, Cockcroft JR**. *University of Wales Institute, Cardiff. **Wales Heart Research Institute, Heath Hospital, Cardiff. ***University of Tartu, Tartu, Estonia. ¶ Department of Clinical Pharmacology, Addenbrooke’s Hospital, Cambridge.

2. Small arteries Large arteries ArteriolesCapillariesVeins 120 Blood Pressure (mmHg) 80 Pulsatile to smooth flow/pressure in the arterial system

3. Large artery stiffness and microvascular damage Increased Large artery stiffness Increased damage to end organs High PP transmitted to micro-circulation Increased Pulsatility (PP)

4. Decline in GFR is More Closely Related to Pulse Pressure than MAP Fesler et al. J Hypertens 2007;25:1796

5. Sato et al. Graefe’s Arch Clin Exp Opthalmol. 2006;244:963 Age-related Macular Degeneration is Associated with Increased Central Pressure

6. What are the determinants of pulsatility????

7. Determinants of pulsatility Q: AIx? -The degree to which the incident wave is reflected?? Physiology, Berne and Levy Systolic Pressure Diastolic Pressure Large Artery Stiffness Stroke Volume

8. Large artery stiffness and microvascular damage Increased Large artery stiffness Increased damage to end organs High PP transmitted to micro-circulation Increased Pulsatility (PP)

9. Large artery stiffness and microvascular damage Increased Large artery stiffness Decreased damage to end organs Decrease PP transmitted to micro-circulation Increased Pulsatility (PP) AIx

10. Relationship between Pulse Pressure and Wave Reflection on retinal artery Pulsatility Ratio N=64

11. Difference in PR between highest and lowest of AIx.

12. An increased AIx may have a potentially beneficial effect in reflecting an otherwise high pulsatile flow wave travelling to the micro-circulation

13. Step 2: Aim of study: To investigate if wave reflection is directly related to degree of pulsatility in the retinal artery. By reducing/manipulating wave reflection via administration of sublingual GTN.

14. The Effects of GTN

15. Methods Vascular Measurements: –(Peripheral and Central BP and HR, (using Mobilograph, IEM) –CBP and AIx (using SphygmoCor) Retinal Artery Flow Measurements: –(PI using Doppler Ultrasound, GE). Participants: 9 individuals, aged 63±6 years (3 Males, 6 Females) -free from CVD and ocular disease and free from taking sympathomimetic compounds.

16. Measuring of flow oscillations in the retinal artery using: Pulsatility Index as a measure of flow wave pulsatility. PI takes into account Peak Systolic Velocity (PSV), End Diastolic Velocity (EDV) of the flow wave, whilst accounting for Mean Flow Velocity (MV).

17. Pulsatility Index: PI = (PSV/EDV) / MV PSV EDV Mv Doppler ultrasound to measure arterial blood flow in the retinal artery

18. GTN Protocol All measurements were recorded simultaneously at: Baseline ADMINISTRATION OF 500µg of GTN 1min 3min 5min 10min 15mins

19. Results

20. Baseline Group Demographics Age (Years)63.4 ± 6 Males/females3/6 Ht (m)1.60±0.04 Wt (Kg)75.4± 9.7 BMI (Kg/m 2 )29.5±3.4 HR (bpm)64±6 SBP (mmHg)140±19 DBP (mmHg)85±13 MAP (mmHg)106±14 AIx (%)38.2±7 aPWV (m/sec)8.1±1.4

21. P<0.05

22. Relationship between AIx and PI

23. Summary Evidence suggesting a direct inverse relationship between changes in Wave Reflection and changes in flow Pulsatility in the retinal artery.

24. Conclusion Wave reflection may have a protective effect on the pulsatile flow wave transmitted to the microvasculature.

25. Acknowledgements : Prof John Cockcroft Mrs Margaret Munnery Dr James Coulson Mr Iain Munnery Maksim Zagura Dr Ian Wilkinson Dr Carmel McEniery Dr Kaisa Maki-Petaja Wales Heart Research Institute, Heath Hospital, Cardiff: Vascular Research Unit, Addenbrooke’s Hospital, Cambridge:

26. McEniery CM. Curr Hypertens Rep. 2009;11:253-9 Effects of Antihypertensive Drugs on Central Pressure, Wave Reflection and Aortic PWV

27. High PWV with High Wave Reflection = Low Pulsatility in Microcirculation

28. High PWV with Low Wave Reflection = HIGH Pulsatility in Microcirculation

29. Effect of aortic stiffness on retinal artery Pulsatility Ratio

30. Percentage change in PI and AIx from baseline

31. * * P<0.05

32. Effect of aPWV and AIx on the microvasculature Elastic SegmentMuscular Segment MacrocirculationMicrocirculation

33. Elastic SegmentMuscular Segment Macrocirculation Microcirculation Effect of aPWV and AIx on the microvasculature

34. Elastic SegmentMuscular Segment Macrocirculation Microcirculation Effect of aPWV and AIx on the microvasculature

35. Aims and objectives: 1.To determine the relationship between aPWV, AIx and pulsatility in the retinal artery. 2.To investigate whether individuals with high PWV’s and low AIx have higher pulsatility in the microcirculation than individuals with low PWV’s and high AIx.

36. Aims and objectives: 1.To determine the relationship between aPWV, AIx and pulsatility in the retinal artery.

38. Microvascular damage Large vessel stiffening ↑ MAP ↑ PP

39. Increased PWV was associated with increased microalbuminuria in the general population Hoorn study

40. Methods Participants: 62 individuals, aged 39-83 years –free from CVD and ocular disease –and free from taking sympathomimetic compounds. Macrovascular measurements: Peripheral and Central BP Augmentation Index (SphygmoCor) Aortic PWV (carotid – femoral) (SphygmoCor) Microvascular measurements: Retinal Artery Pulsatility Ratio (PR) Retinal Artery Resistance Index (RI) (Retinal Artery Doppler Ultrasound)

41. Methods II Doppler ultrasound to measure arterial blood flow in the retinal artery Pulsatility Index: PI = (PSV/EDV) / mean flow velocity Resistance index: RI = (Peak systolic velocity- End diastolic velocity)/Peak systolic velocity Peak Systolic Velocity End Diastolic Velocity Taken from Baxter et al. Opthalmol. Vis. Sci.1992

42. Results

43. Summary Significant relationship between increased CF PWV and increased pulsatility in the retinal artery. Increased wave reflection was inversely related to increased pulsatility in the retinal artery. Individuals with high PWV and low AIx had significantly higher pulsatility in the retinal artery compared to individuals with low PWV and high AIx.

44. Future Research Effects of Atenolol on PI and AIx ??? ???