Assessing endothelial function and providing calibrated UFMD data using a blood pressure cuff

• US 10,292,597 B2
• Filed: 07/23/2018
• Issued: 05/21/2019
• Est. Priority Date: 08/14/2015
• Status: Active Grant

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Maltz, Jonathan S.
• Primary Examiner(s): Messersmith, Eric J
• Application Number:
  US16/042,936
• Publication Number:
  US 20180325389A1
• Time in Patent Office: 302 Days
• CPC Class Codes: A61B 17/1355 Automated control means therefor
• CPC Class Codes: A61B 5/02021 Determining capillary fragility
• CPC Class Codes: A61B 5/02116 of pulse wave amplitude A61B5/02225 takes precedence
• CPC Class Codes: A61B 5/02208 using the Korotkoff method
• CPC Class Codes: A61B 5/02225 using the oscillometric method
• CPC Class Codes: A61B 5/02233 Occluders specially adapted therefor tourniquets A61B17/132
• CPC Class Codes: A61B 5/0225 the pressure being controlled by electric signals, e.g. derived from Korotkoff sounds
• CPC Class Codes: A61B 5/1075 for measuring dimensions by non-invasive methods, e.g. for determining thickness of tissue layer A61B8/0858 takes precedence
• CPC Class Codes: A61B 5/7225 Details of analog processing, e.g. isolation amplifier, gain or sensitivity adjustment, filtering, baseline or drift compensation A61B5/30, A61B5/316 take precedence; transformers for specific applications H01F38/00; amplifiers H03F
• CPC Class Codes: A61B 5/7278 Artificial waveform generation or derivation, e.g. synthesising signals from measured signals A61B5/327 takes precedence
• CPC Class Codes: A61B 8/04 Measuring blood pressure
• CPC Class Codes: A61B 8/06 Measuring blood flow measuring volume flow in general G01F, e.g. G01F1/66, G01F1/72; measuring speed of fluids in general G01P5/00
• CPC Class Codes: A61B 8/5223 for extracting a diagnostic or physiological parameter from medical diagnostic data for algorithms to analyse biomedical images G06T7/0012
• CPC Class Codes: A61B 8/58 Testing, adjusting or calibrating the diagnostic device
• CPC Class Codes: G16H 50/30 for calculating health indices; for individual health risk assessment
• CPC Class Codes: Y02A 90/10 Information and communication technologies [ICT] supporting adaptation to climate change, e.g. for weather forecasting or climate simulation

Abstract

Methods and apparatus are provided for assessing endothelial function in a mammal. In certain embodiments the methods involve using a cuff to apply pressure to an artery in a subject to determine a plurality of baseline values for a parameter related to endothelial function as a function of applied pressure (P_m); b) applying a stimulus to the subject; and applying external pressure P_m to the artery to determine a plurality of stimulus-effected values for the parameter related to endothelial function as a function of applied pressure (P_m); where the baseline values are determined from measurements made when said mammal is not substantially effected by said stimulus and differences in said baseline values and said stimulus-effected values provide a measure of endothelial function in said mammal.

Claims

1. A method of assessing cardiovascular function in a mammal, said method comprising:

a) determining the systolic and diastolic blood pressure of said mammal wherein said determining the systolic and diastolic blood pressure comprises determining the pulse height as a function of applied external pressure P_m to an artery;

b) applying a substantially constant external pressure P_m to an artery for a first period of time T_m, to provide a reduced transmural pressure, and determining, over the course of one or more cardiac cycles in said first period of time T_m, changes in pressure in said artery resulting from cardiac activity of said mammal, or an artificially induced arterial pulse, to establish a baseline value for a parameter related to endothelial function in said mammal;

c) applying an arterial stimulus to said mammal; and

d) applying said substantially constant external pressure P_m to said artery for a second period of time T_m, to provide a reduced transmural pressure, and determining, over the course of one or more cardiac cycles in said second period of time T_m, changes in pressure in said artery resulting from cardiac activity of said mammal, or an artificially induced arterial pulse, to provide a stimulus-affected parameter related to endothelial function in said mammal;

e) determining a second the systolic and diastolic blood pressure of said mammal, wherein said determining a second systolic and diastolic blood pressure comprises determining the pulse height as a function of applied external pressure P_m to an artery;

f) fitting the data obtained in step (a) to determine a first model relating pulse height to transmural pressure and using said first non-linear model to convert said baseline value for a parameter related to endothelial function to a baseline value for a parameter related to endothelial function at a reference pressure;

g) fitting the data obtained in step (e) to determine a second non- linear model relating pulse height to transmural pressure and using said second model to convert said stimulus-affected value for a parameter related to endothelial function to a stimulus-affected parameter related to endothelial function at said reference pressure;

h) using said baseline value for a parameter related to endothelial function at said reference pressure to calculate baseline arterial lumen area (A_b) or a measure proportional to the area A_b at said reference pressure;

i) using said stimulus-affected value for a parameter related to endothelial function at said reference pressure to calculate stimulus-affected arterial lumen area (A_r) or a measure proportional to the area A_r at said reference pressure; and

j) determining the equivalent ultrasound-based flow-mediated dilation FMD (uFMD) measure where uFMD is proportional to the square root of the ratio A_r/A_b, and where said baseline values are determined from measurements made when said mammal is not substantially affected by said stimulus and uFMD provides a measure of cardiovascular function in said mammal.

2. The method of claim 1, wherein said substantially constant external pressure P_m is lower than the diastolic pressure determined in step (a).

3. The method of claim 1, wherein said reference pressure is substantially equal to the systolic pressure determined in step (a) or in step (e).

4. The method of claim 1, wherein said reference pressure is substantially equal to the mean arterial pressure determined in step (a) or in step (e).

5. The method of claim 1, wherein said reference pressure is substantially equal to the diastolic pressure determined in step (a) or in step (e).

6. The method of claim 1, wherein said reference pressure is between the systolic and diastolic pressure determined in step (a) or in step (e).

7. The method of claim 1, wherein said substantially constant external pressure is no more than about 10 mm Hg below the average diastolic pressure for said subject.

8. The method of claim 1, comprising outputting said uFMD measure to a display, printer, or computer readable medium.

9. The method of claim 1, wherein the equivalent ultrasound-based FMD is given as

uFMD%=[√

{square root over ((A_r/A_b)}−

1]×

100.

10. The method of claim 1, wherein said first non-linear model and said second non-linear model are three parameter models.

11. The method of claim 1, wherein baseline values and stimulus-affected values are determined for the same limb or region.

12. The method of claim 1, wherein baseline values are determined for a limb or region contralateral to a limb or region used for determining the stimulus-affected values.

13. The method of claim 12, wherein said contralateral limb or region is used for determining the systolic and diastolic blood pressure in steps (a) and/or (e).

14. The method of claim 1, wherein:

said providing stimulus-affected values comprises providing values for changes in pressure resulting from an artificially induced arterial pulse;

or

said providing stimulus-affected values comprises providing values for changes in pressure resulting from cardiac activity of said mammal.

15. The method of claim 1, wherein step d) is performed at least about 30 seconds after stimulus up to about 5 minutes after said stimulus.

16. The method of claim 1, wherein:

step d) further comprises integrating the value of a pressure change over time (calculating the area under a pressure/time curve) for said one or more cardiac cycles to determine an integrated pressure value; and

/or step d) further comprises determining a maximum, or a certain percentile rank, of a derivative of a pressure versus time waveform on a rising edge of a pressure pulse said one or more cardiac cycles to determine a compliance value.

17. The method of claim 16, wherein said integrated pressure value and/or said compliance value is determined for a single cardiac cycle.

18. The method of claim 17, wherein

said single cardiac cycle is a cardiac cycle selected for the maximum change in said value in a plurality of cardiac cycles;

or

said single cardiac cycle is a cardiac cycle selected for the maximum change in said value between a baseline measurement and a stimulus-affected measurement.

19. The method of claim 1, wherein step d) further comprises determining the pressure in said cuff as a function of time to provide a cardiac pulse waveform while the cuff inflates and/or while said cuff deflates.

20. The method of claim 19, wherein the cardiac pulse waveform(s) are compared between baseline and post-stimulus conditions by direct comparison of pulse characteristics at corresponding pressure levels;

or the cardiac pulse waveform(s) are compared between baseline and post-stimulus conditions by first fitting models to the set of baseline cardiac pulse waver forms and to the set of post-stimulus cardiac pulse waveforms and comparing parameters generated by the two models.

21. The method of claim 1, wherein, in steps (a) or (e):

the systolic BP and MAP are measured and the diastolic blood pressure (DBP) is calculated using an oscillometric analysis;

or

the systolic BP and MAP are measured and the DBP is determined by analyzing Korotkoff sounds obtained using an audio sensor or ultrasound probe.

22. The method of claim 1, wherein measurements to calculate systolic BP, and/or MAP, and/or DBP are obtained during inflation or deflation of a sphygmomanometer cuff.

23. The method of claim 1, wherein applying the stimulus comprises restricting flow of blood to the limb by occlusion of a blood vessel, or administering a drug to said mammal or applying low intensity ultrasound and/or acoustic/mechanical tissue vibration to said mammal.