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. Thomas F. Budinger, MD, PhD Department of Nuclear Medicine and Functional Imaging Berkeley Lab University of California, Berkeley

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: -cholesterol lowering therapy -vitamin supplementation -quitting smoking -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

Time-frequency analysis using Wigner-Ville transform

Ernest Orlando Lawrence Berkeley National Laboratory The Relaxoscope

Ernest Orlando Lawrence Berkeley National Laboratory Preliminary testing: PTT versus distance Subject 1Subject 2

Ernest Orlando Lawrence Berkeley National Laboratory Comparison with arterial diameter measurements Diameter measurementRelaxoscope 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: Experimental protocol I Objective: Compare to in same subjects.

Ernest Orlando Lawrence Berkeley National Laboratory Diameter measurement apparatus Photograph courtesy Pie Medical

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 minute 2.Administer 0 or 0.6mg of sublingual nitroglycerin. 3.Measure PTT continuously for 7 minutes. Experimental protocol II Objectives: Ensure relaxoscope is sensitive to arterial wall relaxation

Ernest Orlando Lawrence Berkeley National Laboratory Results No dose of nitroglycerin (NG) given: 0.6mg sublingual NG at 1 minute:

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.

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)

Ernest Orlando Lawrence Berkeley National Laboratory Acknowledgements This work was supported by the US Department of Energy and by the National Institute on Aging.