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

• US 10,028,664 B2
• Filed: 08/17/2017
• Issued: 07/24/2018
• 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): Cheng, Jacqueline
• Assistant Examiner(s): MESSERSMITH, ERIC J
• Application Number:
  US15/680,082
• Publication Number:
  US 20170367592A1
• Time in Patent Office: 341 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) applying external pressure P_m to an artery for a period of time T_m, and determining, over the course of one or more cardiac cycles in said period Tm, changes in pressure in said artery resulting from cardiac activity of said mammal, or an artificially induced arterial pulse, to provide values for a baseline parameter related to endothelial function in said mammal, where said baseline parameter is provided for at least three different external pressures (P_m) by varying the external pressure P_m during period of time T_m, and/or by measuring said baseline parameter over a plurality of time periods Tm having different external pressures (P_m), to provide a plurality of baseline values for said parameter related to cardiovascular function as a function of said external pressure (P_m);

b) applying a stimulus to said mammal; and

c) applying external pressure P_m to an said artery for a period of time T_m, and determining over the course of one or more cardiac cycles in said period T_m, changes in pressure in said artery resulting from cardiac activity of said mammal, or an artificially induced arterial pulse, to provide values for a stimulus-effected parameter related to endothelial function in said mammal, where said stimulus-effected parameter is provided for at least three different external pressures (P_m) by varying the external pressure P_m during period of time T_m, and/or by determining said parameter over a plurality of time periods Tm having different external pressures (P_m), to provide a plurality of stimulus- effected values for said parameter related to cardiovascular function as a function of applied pressure (P_m);

d) determining the area, or a measure proportional to the area, of the arterial lumen calculated from the baseline measured pressures as a function of transmural pressure P_tm, where transmural pressure is determined as the difference between the baseline measured pressures and the external pressure P_m and fitting these data with a first non-linear model to provide a first function describing baseline arterial lumen area as function of transmural pressure;

e) determining the area, or a measure proportional to the area, of the arterial lumen calculated from the stimulus-effected measured pressures as a function of transmural pressure P_tm, where transmural pressure is determined as the difference between the measured stimulus-effected pressures and the external pressure P_m and fitting these data with a second non-linear model to provide a second function describing stimulus-effected arterial lumen area as function of transmural pressure;

f) using said first function to calculate baseline arterial lumen area (A_b) or a measure proportional to the area A_b at a transmural pressure substantially equal to the systolic blood pressure (SBP);

g) using said second function to calculate stimulus-effected arterial lumen area (A_r) or a measure proportional to the area A_r at a transmural pressure substantially equal to the systolic blood pressure; and

h) determining the equivalent ultrasound-based flow mediated dilation (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 effected by said stimulus and uFMD provides a measure of cardiovascular function in said mammal.

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

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

uFMD %=[√

{square root over ((A_r/A_b)}−

1]×

100.

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

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

6. 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 effected values.

7. The method of claim 6, wherein said contralateral limb or region is used for monitoring blood pressure during measurement.

8. The method of claim 7, wherein monitored blood pressure is used to adjust the measurement pressure if blood pressure changes during the measurement.

9. The method of claim 1, wherein

said applying external pressure P_m to said artery for a period of time T_m, comprises applying a substantially constant external pressure P_m for a period of time T_m.

10. The method of claim 1, wherein said method comprises:

providing said baseline parameter for at least three different external pressures (P_m) by measuring said baseline parameter over a plurality of time periods T_m having different external pressures (P_m) to provide at least three baseline values for said parameter related to cardiovascular function as a function of said external pressure (P_m); and

providing said values for a stimulus-effected parameter for at least three different external pressures (P_m) by measuring said stimulus-effected parameter over a plurality of time periods T_m having different external pressures (P_m) to provide at least three stimulus-effected values for said parameter related to cardiovascular function as a function of applied pressure (P_m);

or said method comprises;

providing said baseline parameter for at least three different external pressures (P_m) by continuously varying the external pressure P_m during period of time T_m to provide at least three baseline values for said parameter related to cardiovascular function as a function of said external pressure (P_m); and

providing said values for a stimulus-effected parameter for at least three different external pressures (P_m) by continuously varying the external pressure P_m during period of time T_m, to provide at least three stimulus-effected values for said parameter related to cardiovascular function as a function of applied pressure (P_m).

11. The method of claim 1, wherein:

said external pressure is less than the mean arterial pressure;

or

said external pressure is less than the mean diastolic pressure.

12. The method of claim 1, wherein:

said baseline parameter and/or said stimulus-effected parameter is provided for at least three different external pressures (P_m) by varying the external pressure P_m during period of time T_m;

or

said baseline parameter and/or said stimulus-effected parameter is provided for at least three different external pressure points (P_m) by determining said baseline parameter over a plurality of time periods T_m having different external pressure points (P_m).

13. The method of claim 1, wherein during said time interval(s) said external pressure is maintained substantially constant and held at different levels in different time intervals.

14. The method of claim 1, wherein said external pressure is adjusted to different levels during a single time period (T_m).

15. The method of claim 1, wherein:

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

or

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

16. the method of claim 1, wherein said substantially external pressure is below the average diastolic pressure measured for said subject or below an expected diastolic pressure for said subject.

17. The method of claim 1, wherein the providing stimulus-effected values is performed at least about 30 seconds after stimulus up to about 5 minutes after said stimulus.

18. The method of claim 1, wherein said providing over the course of one or more cardiac cycles, changes in pressure in said cuff resulting from cardiac activity of said mammal comprises determining the pressure in said cuff as a function of time.

19. The method of claim 18, wherein:

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

/or

said providing comprises determining the maximum, or a certain percentile rank of the derivative of the pressure versus time wave form on the rising edge of a pressure pulse for one or for a plurality of cardiac cycles to determine a compliance value.

20. The method of claim 19, wherein said integrated pressure value and/or said compliance value is determined for a single cardiac cycle.

21. The method of claim 20, 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-effected measurement.

22. The method of claim 18, wherein said providing, over the course of one or more cardiac cycles, changes in pressure in said cuff resulting from cardiac activity of said mammal comprises determining the pressure in said cuff as a function of time to provide a cardiac pulse waveform.

23. The method of claim 22, wherein said providing, over the course of one or more cardiac cycles, changes in pressure in said cuff resulting from cardiac activity of said mammal 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.

24. The method of claim 23, wherein

the cardiac pulse waveforms are compared between baseline and post-stimulus conditions by direct comparison of pulse characteristics at corresponding pressure levels;

or

the cardiac pulse waveforms 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.

25. The method of claim 23, wherein said external pressure is a pressure in excess of the peak of the cardiac pulse waveform.

26. The method according of claim 23, wherein:

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

or the systolic blood pressure and mean arterial pressure are measured and the DBP is determined by analyzing Korotkoff sounds obtained using an audio sensor or ultrasound probe.

27. The method of claim 23, wherein measurements to calculate cuff-based flow-mediated vasodilation (cFMD) and/or mean arterial pressure, and/or diastolic blood pressure are obtained during inflation or deflation of a sphygmomanometer cuff.

28. The method according of claim 23, wherein:

systolic blood pressure and/or diastolic blood pressure is determined and for cuff-based flow-mediated vasodilation (cFMD) determination, comparison of pulse waveform characteristics between baseline and post-stimulus intervals at corresponding pressures is a comparison made where the corresponding pressures are transmural pressures calculated using the determined systolic and/or diastolic blood pressure values;

or comparison of pulse waveform characteristics between baseline and post-stimulus intervals at corresponding pressures is a comparison made based on the transmural pressure determined by the models.

29. 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.

30. The method of claim 1, wherein said applying external pressure P_m to said artery for a period of time T_m comprises applying a continuously varying external pressure P_m for a period of time T_m.