1. Non-Invasive Blood Pressure Waveform Monitoring in Mice By Andrew McClellan Laura Miller

2. The Need for Blood Pressure Measurements Baseline levels Effects of pharmacological drug administration Exercise or Food Studies Behavioral Response Studies Effects of genetic alterations

3. Need for Continuous Waveform Measurements vs. Single Measurements Single measurements only give max and min (systolic / diastolic) Continuous waveforms needed for frequency analysis –autonomic nervous system responses –blood pressure variability –baroreceptor function Examining blood pressure changes over time, like during behavioral tests

4. What Currently Exists MouseHuman Beat-to-beatTail CuffArm Cuff Continuous Arterial Line Implanted Catheter/ Transmitter Finger Cuff (Finapres)

5. Beat to beat BP measurements: Korotkoff Method Mouse: inflatable tail cuff www.TSE-systems.com Human: inflatable arm cuff http://www.geocities.com/lorijean_2002/academia /sphygmomanometer.jpg

6. What Currently Exists MouseHuman Beat-to-beatTail CuffArm Cuff Continuous Arterial Line Implanted Catheter/ Transmitter Finger Cuff (Finapres)

7. What Currently Exists for Mice: Implantable transmitters Catheter pressure transducers (Data Sciences International) Continuous waveform Require surgical implantation into carotid artery Mice need at least 3 weeks post-surgery recovery time for stabilization of BP/HR Transmitters are expensive and require corresponding receiver hardware and analysis software ($600/transmitter + $100/each battery exchange + $1000s in receivers and software) Mills P, et al. The design and performance of an implantable device for monitoring blood pressure, heart rate, and movement activity from conscious freely moving laboratory mice. 2nd International Conference on Methods and Techniques in Behavioral Research, 1998. Mills PA, et al A new method for measurement of blood pressure, heart rate, and activity in the mouse by radiotelemetry. J Appl Physiol. 2000 May;88(5):1537-44

8. What Currently Exists MouseHuman Beat-to-beatTail CuffArm Cuff Continuous Arterial Line Implanted Catheter/ Transmitter Finger Cuff (Finapres)

9. What Currently Exists: finger cuff measurements Finapres Non-invasive Continuous waveform Finger cuff Bogert LW, et al. Non-invasive pulsatile arterial pressure and stroke volume changes from the human finger. Exp. Physiol 90.4 pp 437-446. 2005

10. What Currently Exists MouseHuman Beat-to-beatTail CuffArm Cuff Continuous Arterial Line Implanted Catheter/ Transmitter Finger Cuff (Finapres) Problem: There are no blood pressure devices that non- invasively measure a continuous waveform in mice

11. Our project goal Non-invasive, continuous blood pressure waveform measurement in mice

12. Challenges From Adapting a Human Device Size – mice are much smaller Physiological Parameters – HR = 500-700bpm, BP = 100-250mmHg Cuff – must work for above pressures System response – high frequency

13. Peňáz Method Dynamic pulsatile unloading of the arterial walls Volume clamp method Pressure needed to maintain mean arterial volume equals the blood pressure waveform

14. Plethysmographic Signal Obtained through measuring optical impedance through blood vessel in tail Optical impedance corresponds to volume of blood in artery

15. How it Works Blood volume α blood pressure Blood volume α optical impedance (plethysmographic signal) Use optical impedance to determine necessary pressure to maintain mean arterial volume

16. Transduction Blood Volume = Blood Pressure P-signal (voltage) (photosensor) Pressure Wave invert & offset (speaker) (tail cuff)

17. Tail Cuff with Photosensor www.TSE-systems.com

18. Peňáz Method 1.Obtain plethysmographic signal 2.Ramp up cuff-pressure until V p-p of plethymographic signal is max (offset) 3.Invert plethysmographic signal 4.Convert electrical signal to a pressure waveform in the tail cuff 5.Increase gain until p-signal fluctuations in plethysmographic signal are minimal max ramp-up increase gain ramp-up

19. Peňáz Method max ramp-up increase gain ramp-up

20. Circuit buffergain offsetaudio amp

21. Schematic tail cuff Harvard plethysmogram / pressure monitor computer pump speaker amplifyoffset plethysmographic signal pressure signal analog circuit

22. Lab Setup

23. Economic Analysis Device: Tail Cuff with Photosensor $400 Circuit components $10 Speaker $5 Power Source $100 Air pump $50 Pressure Sensor$100 $665 Acquisition software/hardware Windaq $2000

24. Plan of Attack Use existing tail cuff Obtain a plethysmographic signal Build an analog circuit to amplify and offset the signal Use speaker to transduce voltage to pressure Obtain blood pressure waveform Check waveform against catheter transducer