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.

Small arteries

Large arteries

Arterioles Capillaries Veins

120

Blood

Pressure

(mmHg)

80

Pulsatile to smooth flow/pressure in the arterial system

Large artery stiffness and microvascular damage

Increased Large artery stiffness

Increased damage to end organs

High PP transmitted to micro-circulation

Increased Pulsatility (PP)

Decline in GFR is More Closely Related to Pulse Pressure than MAP

Fesler et al. J Hypertens 2007;25:1796

Sato et al. Graefe’s Arch Clin Exp Opthalmol. 2006;244:963

Age-related Macular Degeneration is Associated with Increased Central Pressure

What are the determinants of pulsatility????

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

Large artery stiffness and microvascular damage

Increased Large artery stiffness

Increased damage to end organs

High PP transmitted to micro-circulation

Increased Pulsatility (PP)

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

Relationship between Pulse Pressure and Wave Reflection on retinal artery Pulsatility Ratio

0 10 20 30 40 50 600

0.5

1

1.5

2

2.5

3

3.5

4

PR

AIx (%)

R=-0.33, P=0.011

30 40 50 60 70 80 90 1001

1.5

2

2.5

3

3.5

4

PP (mmHg)

R=0.26, P = 0.04

PR

N=64

Difference in PR between highest and lowest of AIx.

Low AIx High AIx0

0.5

1

1.5

2

2.5

PR

P= 0.032

An increased AIx may have a potentially

beneficial effect in reflecting an otherwise high pulsatile flow wave travelling to the

micro-circulation

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.

The Effects of GTN

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.

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).

Pulsatility Index: PI = (PSV/EDV) / MV

PSV

EDV

Mv

Doppler ultrasound to measure arterial blood flow in the retinal artery

GTN Protocol

All measurements were recorded simultaneously at:

Baseline

ADMINISTRATION OF 500µg of GTN

1min

3min

5min

10min

15mins

Results

Baseline Group Demographics

Age (Years) 63.4 ± 6

Males/females 3/6

Ht (m) 1.60±0.04

Wt (Kg) 75.4± 9.7

BMI (Kg/m2) 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

BL 1min 3min 5min 10min 15min20

22

24

26

28

30

32

34

36

38

40

1.4

1.45

1.5

1.55

1.6

1.65

Relationship between changes in AIx and Pulsatility Index

Mean PI

Mean AIx

AIx (%)

PI

P<0.05

P<0.05

10 15 20 25 30 35 40 45 50 550

0.5

1

1.5

2

2.5

3

3.5

4

PI

AIx (%)

R= -0.27, P<0.05

Relationship between AIx and PI

Summary

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

Conclusion

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

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:

McEniery CM. Curr Hypertens Rep. 2009;11:253-9

Effects of Antihypertensive Drugs on Central Pressure, Wave Reflection and Aortic PWV

High PWV with High Wave Reflection = Low Pulsatility in Microcirculation

High PWV with Low Wave Reflection = HIGH Pulsatility in Microcirculation

Effect of aortic stiffness on retinal artery Pulsatility Ratio

4 6 8 10 12 14 16 18 200

0.5

1

1.5

2

2.5

3

3.5

4

R² = 0.285596292950341

PR

aPWV (m/s)

Percentage change in PI and AIx from baseline

AIx@5mins PI@5mins

-180

-130

-80

-30

20

Percentage change in PI and AIx from baseline

%

P=0.04

1min 3min 5min 10min 15min

-14

-12

-10

-8

-6

-4

-2

0

0

0.02

0.04

0.06

0.08

0.1

0.12

0.14

0.16

The Relationship Between Changes in AIx and PI from Base-line

DPI DAIx

Del

ta A

Ix

Delta P

I

*

*

* P<0.05

Effect of aPWV and AIx on the microvasculature

Elastic Segment Muscular Segment

Macrocirculation Microcirculation

Elastic Segment Muscular Segment

Macrocirculation Microcirculation

Effect of aPWV and AIx on the microvasculature

Elastic Segment Muscular Segment

Macrocirculation Microcirculation

Effect of aPWV and AIx on the microvasculature

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.

Aims and objectives:

1. To determine the relationship between aPWV, AIx and pulsatility in the retinal artery.

Microvasculardamage

Large vessel stiffening

↑ MAP ↑ PP

Increased PWV was associated with increased microalbuminuria in the general population

Hoorn study

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)

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

Results

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.

Future Research

Effects of Atenolol on PI and AIx??????

BL 1min 3min 5min 10min 15min0

5

10

15

20

25

30

35

40

0

100

200

300

400

500

600

700

Relationship between AIx and acceleration to peak systolic velocity

Mean Accel

Mean AIx

AIx (%) Mean Accel (cm/s)

BL 1min 3min 5min 10min 15min1.35

1.4

1.45

1.5

1.55

1.6

1.65

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Relationship between PI and PVR

Mean PVR

Mean PI

PI PVR

BL 1min 3min 5min 10min 15min0

5

10

15

20

25

30

35

40

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Relationship between AIx and PR

Mean PR

Mean AIx

AIx (%) PR

BL 1min 3min 5min 10min 15min0

5

10

15

20

25

30

35

40

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Relationship between AIx and PR

Mean PR

Mean AIx

AIx (%) PR

BL 1min 3min 5min 10min 15min0

5

10

15

20

25

30

35

40

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Relationship between AIx and PVR

Mean PVR

Mean AIx

AIx (%) PVR

BL 1min 3min 5min 10min 15min7.8

7.9

8

8.1

8.2

8.3

8.4

8.5

1.35

1.4

1.45

1.5

1.55

1.6

1.65

Relationship between aPWV and PI

Mean PI Mean CFPWV

aPWV PI

BL 1min 3min 5min 10min 15min0

1

2

3

4

5

6

1.35

1.4

1.45

1.5

1.55

1.6

1.65

Relationship between CO and PI

Mean PI Mean CO

CO (l/min) PI