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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
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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
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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
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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:-cholesterol lowering therapy-vitamin supplementation-quitting smoking-exercise therapy
Cardiovascular disease
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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
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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
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Ernest Orlando Lawrence Berkeley National Laboratory
Flow-mediated vasodilation
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Ernest Orlando Lawrence Berkeley National Laboratory
Ultrasonic imaging of brachial artery diameter
Measurement of vasodilation response by ultrasonic imaging of arterial diameter:
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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:
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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
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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
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Ernest Orlando Lawrence Berkeley National Laboratory
After vasorelaxation: increased diameter, decreased wall thickness, decreased wall stiffness.
The Relaxoscope
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Ernest Orlando Lawrence Berkeley National Laboratory
The Relaxoscope
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Ernest Orlando Lawrence Berkeley National Laboratory
The Relaxoscope
Pulse-inducing actuator
Doppler
stethoscope
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Ernest Orlando Lawrence Berkeley National Laboratory
Force applied over artery
Ultrasound audio output
Artery compression begins
Rising edge of received artificial pulse
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Ernest Orlando Lawrence Berkeley National Laboratory
Refinement
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Ernest Orlando Lawrence Berkeley National Laboratory
Refinement
Auto-detecting an artificial pulse signature
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Ernest Orlando Lawrence Berkeley National Laboratory
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Ernest Orlando Lawrence Berkeley National Laboratory
Time-frequency analysis using Wigner-Ville transform
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Ernest Orlando Lawrence Berkeley National Laboratory
The Relaxoscope
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Ernest Orlando Lawrence Berkeley National Laboratory
Preliminary testing: PTT versus distance
Subject 1 Subject 2
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Ernest Orlando Lawrence Berkeley National Laboratory
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.
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Ernest Orlando Lawrence Berkeley National Laboratory
Diameter measurement apparatus
Photograph courtesy P
ie M
edical
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Ernest Orlando Lawrence Berkeley National Laboratory
Results
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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
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Ernest Orlando Lawrence Berkeley National Laboratory
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
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Ernest Orlando Lawrence Berkeley National Laboratory
Results
No dose of nitroglycerin (NG) given:
0.6mg sublingual NG at 1 minute:
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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.
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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.
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)
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Ernest Orlando Lawrence Berkeley National Laboratory
Acknowledgements
This work was supported by the US Department of Energy and by the National Institute on Aging.