Ernest Orlando Lawrence Berkeley National Laboratory

Instrument for the non-invasive evaluation of human arterial endothelial function via measurement of changes in the transit time of an artificial pulse

Jonathan S. Maltz, Ph.D.(jon@eecs.berkeley.edu)

Thomas F. Budinger, MD, PhD(tfbudinger@lbl.gov)

Department of Nuclear Medicine and Functional ImagingBerkeley Lab, University of California, Berkeley

http://muti.lbl.gov/relaxoscope/isbi2004.ppt

Ernest Orlando Lawrence Berkeley National Laboratory

Instrument for the non-invasive evaluation of human arterial endothelial function via measurement of changes in the transit time of an artificial pulse

1. Motivation

2. Quantifying endothelial function

3. Design of new instrument:

“The Relaxoscope”

4. Evaluation in human subjects

5. Future enhancements

Ernest Orlando Lawrence Berkeley National Laboratory

-Kills 960,000 Americans each year -40% of all deaths-Disables 11 million Americans over age 65 -Costs $286.5 billion a year

Source: US Centers for Disease Control and Prevention (1999).

Cardiovascular disease

Ernest Orlando Lawrence Berkeley National Laboratory

Routine evaluation of arterial system would allow:

•Detection of developing cardiovascular disease at a preclinical stage•Monitoring of the effects on arterial function of:

-statin therapy-dietary modification-vitamin supplementation-smoking cessation-exercise therapy

Cardiovascular disease

Ernest Orlando Lawrence Berkeley National Laboratory

Currently the only routine physical method for monitoring the health of the arterial system is the Riva-Rocci spygmomanometer (1896):

Blood pressure cuff

Ernest Orlando Lawrence Berkeley National Laboratory

Evaluation of endothelial function is logical target for routine monitoring

Endothelial dysfunction:•Is an early sign of developing artherosclerosis

•Correlates with all major cardiovascular disease risk factors

•Is a strong predictor of cardiovascular events such as heart attack and stroke

•Is ameliorated by factors that benefit cardiovascular health: exercise, quitting smoking, vitamin supplementation

Ernest Orlando Lawrence Berkeley National Laboratory

Flow-mediated vasodilation

Ernest Orlando Lawrence Berkeley National Laboratory

Ultrasonic imaging of brachial artery diameter

Measurement of vasodilation response by ultrasonic imaging of arterial diameter:

Ernest Orlando Lawrence Berkeley National Laboratory

1. The procedure requires an experienced ultrasound technician to produce a high quality image.

2. The equipment is costly (> $50,000).

3. Measurements are highly variable (reported coefficients of variation 1.5% - 50%).

Ultrasonic imaging of brachial artery diameter

Not routinely performed because:

Ernest Orlando Lawrence Berkeley National Laboratory

Key idea:

Measure flow-mediated vasorelaxation rather than flow-mediated vasodilation.

Theoretically greater sensitivity Potentially easier to measure Lower instrument cost

The Relaxoscope

Ernest Orlando Lawrence Berkeley National Laboratory

Key principle:Quantify endothelium-mediated vasorelaxation by measuring the transit time of an artificial pulse before and after endothelial stimulus

By the Moens-Korteweg equation:

The Relaxoscope

Ernest Orlando Lawrence Berkeley National Laboratory

After vasorelaxation: increased diameter, decreased wall thickness, decreased wall stiffness.

The Relaxoscope

Ernest Orlando Lawrence Berkeley National Laboratory

The Relaxoscope

Ernest Orlando Lawrence Berkeley National Laboratory

The Relaxoscope

Pulse-inducing actuator

Doppler

stethoscope

Ernest Orlando Lawrence Berkeley National Laboratory

Force applied over artery

Ultrasound audio output

Artery compression begins

Rising edge of received artificial pulse

Ernest Orlando Lawrence Berkeley National Laboratory

Refinement

Ernest Orlando Lawrence Berkeley National Laboratory

Refinement

Auto-detecting an artificial pulse signature

Ernest Orlando Lawrence Berkeley National Laboratory

Ernest Orlando Lawrence Berkeley National Laboratory

The Relaxoscope

Ernest Orlando Lawrence Berkeley National Laboratory

Preliminary testing: PTT versus distance

Subject 1 Subject 2

Ernest Orlando Lawrence Berkeley National Laboratory

Comparison with arterial diameter measurements

Diameter measurement Relaxoscope1. Image baseline diameter (radius )

1. Record baseline PTT:

2. Occlude brachial artery for 5 minutes with cuff to generate maximal post occlusion reactive hyperemia3. Release cuff and resume measurement process.for 5 minutes. Yields:

4. Calculate: 4. Calculate:

Experimental protocol I

Objective: Compare to in same subjects.

Ernest Orlando Lawrence Berkeley National Laboratory

Diameter measurement apparatus

Photograph courtesy P

ie M

edical

Ernest Orlando Lawrence Berkeley National Laboratory

Results

Ernest Orlando Lawrence Berkeley National Laboratory

• is correlated with :

• A straight line fit yields:

• Thus, is 37% more sensitive to flow-mediated vasodilation than

Results

Ernest Orlando Lawrence Berkeley National Laboratory

Sensitivity to pharmacological vasodilators

1. Record baseline PTT for 1 minute2. Administer 0 or 0.6mg of sublingual

nitroglycerin.3. Measure PTT continuously for 7 minutes.

Experimental protocol II

Objectives: 1. Ensure relaxoscope is sensitiveto arterial wall tone

2. Evaluate repeatability: endothelium-mediated relaxation has much higher day-to-day variability than NG-induced relaxation.

Ernest Orlando Lawrence Berkeley National Laboratory

Results

No dose of nitroglycerin (NG) given:

0.6mg sublingual NG at t=1 minute:

Ernest Orlando Lawrence Berkeley National Laboratory

Results

Nitroglycerin study

Four subjects examined: • 3 times with no NG• 3 times with 0.6mg sublingual NG

Measured quantities:•

•

• initial blood pressure (t < 0 min.)• final blood pressure (t = 7 min.)

Analysis: • MANOVA of each measured variable with each trial contributing a dependent variable. • Lawley-Hotelling trace test with =0.05

Ernest Orlando Lawrence Berkeley National Laboratory

Results

Nitroglycerin study: Effect of treatment with NG

Mean fractional change (N=12) 0mg NG SEM

0.6mg NG

Maximum PTT / baseline 5.26 1.76% 21.24 1.90%

Final PTT / baseline 0.53 2.60% 6.20 2.4%

Final systolic BP / baseline -1.05 1.88% -2.46 2.25%

Final diastolic BP / baseline -5.78 3.46% -10.10 3.57%

Ernest Orlando Lawrence Berkeley National Laboratory

Results

Nitroglycerin study: MANOVA

• The effect of NG on was highly significant. (p=0.0036 < 0.05)

• The effect of NG on was significant. (p=0.0433 < 0.05)

• The effects of NG on systolic and diastolic blood pressuresat the final time points of the studies were not significant. (p=0.3325 > 0.05 and p=0.0634 > 0.05, respectively)

Considering all 4 subjects x 2 treatments x 3 trials

Ernest Orlando Lawrence Berkeley National Laboratory

Results

Nitroglycerin study: Within-subject coefficient of variation (CV)

Within-subject day-to-daymean CV SEM

0mg NG studies 4.0 1.7% (N=3)

0.6mg NG studies 4.1 0.9% (N=3)

Pooled studies 4.1 0.9% (N=6)

Ernest Orlando Lawrence Berkeley National Laboratory

Conclusion

1. The relaxoscope PTT measurements are directly proportional to propagation distance.

2. The relaxoscope appears to be 37% more sensitive to endothelium-mediated vasorelaxation than artery diameter measurements.

3. The relaxoscope PTT measurements increase after sublingual nitroglycerin, confirming that extravasation during occlusion is not the principal contributor to the decreases in PTT observed.

4. CV compares very favorably with most reported brachial artery diameter studies.

Ernest Orlando Lawrence Berkeley National Laboratory

Future work

1. Build high frequency switchable continuous wave (CW) / pulsed wave (PW) flowmeter optimized for artificial pulse rising edge detection (software ultrasound).

2. More ergonomic design to accommodate different size arms.

3. More convenient methods of pulse application: wristband, hydraulic coupling

4. Better tolerated methods of endothelial stimulation than 5 minute cuff occlusion: 2-adrenergic agonists such as inhaled albuterol or salbutamol (Hayward et al. 2002, Wilkinson et al. 2002)

Ernest Orlando Lawrence Berkeley National Laboratory

Ernest Orlando Lawrence Berkeley National Laboratory

Acknowledgements

This work was supported by the US Department of Energy, the National Institute on Aging and the National Heart, Lung and Blood Institute.

http://muti.lbl.gov/relaxoscope/isbi2004.ppt