ernest orlando lawrence berkeley national laboratory instrument for the non-invasive evaluation of...

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.([email protected])

Thomas F. Budinger, MD, PhD([email protected])

Department of Nuclear Medicine and Functional ImagingBerkeley Lab

University of California, Berkeley

http://muti.lbl.gov/relaxoscope/embs2003.ppt


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


-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


Routine evaluation of arterial system would allow:

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

function of:-cholesterol lowering therapy-vitamin supplementation-quitting smoking-exercise therapy

Cardiovascular disease


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

Blood pressure cuff


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


Flow-mediated vasodilation


Ultrasonic imaging of brachial artery diameter

Measurement of vasodilation response by ultrasonic imaging of arterial diameter:


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:


Key idea:

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

Theoretically greater sensitivity Potentially easier to measure Lower instrument cost

The Relaxoscope


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


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

The Relaxoscope


The Relaxoscope


The Relaxoscope

Pulse-inducing actuator

Doppler

stethoscope


Force applied over artery

Ultrasound audio output

Artery compression begins

Rising edge of received artificial pulse


Refinement


Refinement

Auto-detecting an artificial pulse signature


Time-frequency analysis using Wigner-Ville transform


The Relaxoscope


Preliminary testing: PTT versus distance

Subject 1 Subject 2


Comparison with arterial diameter measurements

Diameter measurement Relaxoscope

1. Image baseline diameter (radius )

1. Record baseline PTT:

2. Occlude brachial artery for 5 minutes with cuff to generate maximal post occlusion reactive hyperemia

3. Release cuff and resume measurement process.

for 5 minutes. Yields:

4. Calculate: 4. Calculate:

Experimental protocol I

Objective: Compare to in same subjects.


Diameter measurement apparatus

Photograph courtesy P

ie M

edical


Results


• is correlated with :

• A straight line fit yields:

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

Results


Sensitivity to pharmacological vasodilators

1. Record baseline PTT for 1 minute

2. Administer 0 or 0.6mg of sublingual nitroglycerin.

3. Measure PTT continuously for 7 minutes.

Experimental protocol II

Objectives: Ensure relaxoscope is sensitiveto arterial wall relaxation


Results

No dose of nitroglycerin (NG) given:

0.6mg sublingual NG at 1 minute:


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.


Future work

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

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)


Acknowledgements

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

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