Noninvasive detection of rejection in heart transplant patients

• US 5,285,793 A
• Filed: 05/21/1992
• Issued: 02/15/1994
• Est. Priority Date: 05/21/1992
• Status: Expired due to Fees

• Current Assignee: Regents of The University of Minnesota (University of Minnesota)
• Original Assignee: Regents of The University of Minnesota (University of Minnesota)
• Inventors: Slovut, David P., Wenstrom, John C., Bianco, Richard W., Bolman, R. M. III
• Primary Examiner(s): Kamm, William E.
• Assistant Examiner(s): MANUEL, GEORGE C
• Application Number:
  US07/886,727
• Time in Patent Office: 635 Days
• Field of Search: 128/696, 128/702, 128/697, 128/704, 128/708, 128/660.03
• US Class Current: 600/519
• CPC Class Codes: A61B 5/364 Detecting abnormal ECG interval, e.g. extrasystoles, ectopic heartbeats
• CPC Class Codes: A61B 5/413 Monitoring transplanted tissue or organ, e.g. for possible rejection reactions after a transplant
• CPC Class Codes: Y10S 128/925 Neural network

Abstract

A method and apparatus for diagnosing heart rejection is disclosed. Heart rejection is diagnosed based on the pattern of interbeat intervals. The interbeat intervals of the heart are measured shortly after transplant to establish a baseline pattern. The patterns of interbeat intervals from subsequent measurements are compared to the baseline to detect changes from the baseline indicating rejection. The apparatus of the invention measures the interbeat intervals using a Schmidt trigger that detects the upstroke of the QRS and produces a corresponding pulse. The intervals between pulses are timed to produce a series of interbeat interval measurements that are stored and analyzed. Software provides for automated pattern analysis.

Claims

1. A method for diagnosing heart rejection in a mammal with a transplanted heart, wherein the time interval between heart beats is an interbeat interval, and a series of interbeat intervals has an associated pattern, comprising the steps of:

(a) measuring the interbeat intervals in the transplanted heart and obtaining a pattern associated with its intervals; and

(b) diagnosing heart rejection based on the pattern of interbeat intervals using nonlinear dynamical systems analysis.

5. The method according to claim 1, 2, 3 or 4 wherein the interbeat intervals are measured with a precision equal to or greater than 1 millisecond resolution.

6. The method of claim 1, 2, 3, 4 or 5 wherein the step of diagnosing heart rejection includes using a differential time interval plot to reveal the pattern of interbeat intervals.

7. The method of claim 1, 2, 3, 4 or 5 wherein the step of diagnosing heart rejection includes using a recurrence plot to reveal the pattern of interbeat intervals.

8. The method of claim 1, 2, 3, 4 or 5 wherein the steps of diagnosing heart rejection includes using a method of delays to create a data set for plotting to reveal the pattern of interbeat intervals.

2. A method for diagnosing and treating heart rejection in a manual with a transplanted heart, wherein the time interval between heart beats is an interbeat interval, and a series of interbeat intervals has an associated pattern, comprising the steps of:

(a) measuring the interbeat intervals in the transplanted heart and obtaining a pattern associated with the intervals; and

(b) diagnosing heart rejection based on the pattern of interbeat intervals using nonlinear dynamical systems analysis; and

(c) administering pharmaceutical agents to control rejection based on the diagnosis made in step (b).

3. A method for diagnosing heart rejection in a mammal with a transplanted heart wherein the time interval between heart beats is an interbeat interval, and a series of interbeat intervals has an associated pattern, comprising the steps of:

(a) measuring the interbeat intervals in the transplanted heart shortly after the heart is transplanted to establish a baseline reference for future comparison to provide a baseline measurement;

(b) measuring the interbeat intervals in the transplanted heart and obtaining a pattern associated with the intervals at a point later in time than the baseline measurement to provide a later measurement; and

(c) diagnosing heart rejection based on comparing the pattern of interbeat intervals of the later measurement to the baseline measurement using nonlinear dynamical systems analysis.

9. The method according to claim 3 or 4 wherein the pattern from the later obtained measurements are compared to the baseline measurements using automated software driven pattern analysis.

10. The method according to claim 3 or 4 wherein the pattern from the later obtained measurements are compared to the baseline measurements using weighted values obtained from a neural network trained to recognize changes in patterns associated with rejection.

4. A method for diagnosing and treating heart rejection in a mammal with a transplanted heart, wherein the time interval between heart beats is an interbeat interval, and a series of interbeat intervals has an associated pattern comprising the steps of:

(a) measuring the interbeat intervals in the transplanted heart shortly after the heart is transplanted to establish a baseline reference for future comparison to provide a baseline measurement;

(b) measuring the interbeat intervals in the transplanted heart and obtaining a pattern associated with the intervals at a point later in time than the baseline measurement to provide a later measurement;

(c) diagnosing heart rejection based on comparing the pattern of interbeat intervals of the later measurement to the baseline measurement using nonlinear dynamical systems analysis; and

(d) administering pharmaceutical agents to control rejection based on the diagnosis made in step (c).

11. Apparatus for diagnosing heart rejection in a mammal with a transplanted heart, wherein the time interval between heart heats is an interbeat interval, and a series of interbeat intervals has an associated pattern, comprising:

an amplifier for amplifying an EKG signal from leads attached to the chest of the mammal;

a level detector receiving the amplified EKG and set to detect a component of the QRS complex of the EKG to produce a signal indicating the occurrence of a heart beat, whereby the detector produces a series of signals corresponding to the occurrence of heart beats;

a timer means for responsive to said series of signals for timing the intervals between heart beats to produce a series of interbeat interval measurements;

means for obtaining a pattern of interbeat interval measurements;

means for analyzing the pattern of interbeat interval measurements using nonlinear dynamical systems analysis for an indication of rejection; and

an indicator for indicating to a user of the apparatus whether or not rejection has been detected by the means for analyzing.

12. The apparatus of claim 11 wherein said timer has a precision of 1 millisecond or greater.

13. The apparatus of claim 11 wherein the level detector is an electronic trigger, and the signal is a pulse.

14. Apparatus for diagnosing heart rejection in a manual with a transplanted heart, wherein the time interval between heart beats is an interbeat interval, and a series of interbeat intervals has an associated pattern, comprising:

an amplifier for amplifying an EKG signal from leads attached to the chest of the mammal;

means for timing the intervals between heart beats and producing a series of interbeat interval measurements;

means for obtaining a pattern of interbeat interval measurements; and

means for analyzing the pattern of interbeat interval measurements using nonlinear dynamical systems analysis for an indication of rejection;

an indicator for indicating to a user of the apparatus whether or not rejection has been detected by the means for analyzing.

15. The apparatus of claim 14 wherein said timing means has a precision of 1 millisecond or greater.

16. A method of ambulatory monitoring for an ambulatory mammal, comprising the steps of:

(1) providing a monitoring apparatus comprising

(a) an amplifier for amplifying an EKG signal from leads adapted for attachment to the chest of the mammal;

(b) a level detector receiving the amplified EKG and set to detect the R wave upstroke of the QRS complex of the EKG to produce a signal indicating the occurrence of the upstroke, whereby the detector produces a series of signals corresponding to the occurrence of R waves;

(c) a timer responsive to said series of signals for timing the intervals between R waves to produce a series of RR interval measurements in digital form;

(d) an analog to digital converter for sampling the analog EKG to produce a digitized EKG;

(e) a storage device for storing the series of RR interval measurements and the digitized EKG; and

(f) a battery for supplying power to the amplifier, level detector, timer, analog to digital converter and storage device;

(2) attaching the monitoring apparatus and said leads to the ambulatory mammal for a period of time and storing a series of RR interval measurements obtained from the mammal'"'"'s EKG signal, said RR interval measurements being stored in said storage device, and obtaining a pattern associated with the interval measurements; and

(3) diagnosing heart rejection based on an analysis of the pattern of RR interval measurements stored in said storage device using nonlinear dynamical systems analysis.

17. A method for diagnosing heart rejection in a mammal with a transplanted heart comprising the steps of:

(a) measuring the interbeat intervals in the transplanted heart shortly after the heart is transplanted to establish a baseline reference for future comparison;

(b) measuring the interbeat intervals in the transplanted heart at a point later in time than the baseline measurement, and obtaining a pattern associated with the intervals and diagnosing heart rejection based on comparing the pattern of interbeat intervals of the later measurement to the baseline measurement wherein the pattern from the later obtained measurements are compared to the baseline measurements using weighted values obtained from a neural network trained to recognize changes in patterns associated with rejection.

18. A method for diagnosing and treating heart rejection in a mammal with a transplanted heart, comprising the steps of:

(a) measuring the interbeat intervals in the transplanted heart shortly after the heart is transplanted to establish a baseline reference for future comparison;

(b) measuring the interbeat intervals in the transplanted heart at a point later in time than the baseline measurement and obtaining a pattern associated with the intervals;

(c) diagnosing heart rejection based on comparing the pattern of interbeat intervals of the later measurement to the baseline measurement, wherein the pattern from the later obtained measurements are compared to the baseline measurements using weighted values obtained from a neural network trained to recognize changes in patterns associated with rejection.; and

(d) administering pharmaceutical agents to control rejection based on the diagnosis made in step (c).