Modulation of intracellular calcium concentration using non-excitatory electrical signals applied to the tissue

• US 8,825,152 B2
• Filed: 04/03/2002
• Issued: 09/02/2014
• Est. Priority Date: 01/08/1996
• Status: Expired due to Fees

• Current Assignee: Impulse Dynamics NV
• Original Assignee: Impulse Dynamics NV
• Inventors: Shemer, Itzik, Felzen, Bella, Darvish, Nissim, Mika, Yuval, Haddad, Walid, Haham, Yaakov, Aviv, Richardo
• Primary Examiner(s): BOCKELMAN, MARK
• Application Number:
  US10/116,201
• Publication Number:
  US 20030040777A1
• Time in Patent Office: 4,535 Days
• Field of Search: 607/2, 607/9, 607/25
• US Class Current: 607/2
• CPC Class Codes: A61N 1/3627 for treating a mechanical deficiency of the heart, e.g. congestive heart failure or cardiomyopathy
• CPC Class Codes: A61N 1/3628 using sub-threshold or non-excitatory signals
• CPC Class Codes: A61N 1/368 comprising more than one electrode co-operating with different heart regions A61N1/3622, A61N1/3627 take precedence

Abstract

According to a method and device for modulating intracellular calcium concentration in biological tissue, a stimulation probe is applied to the tissue, a non-excitatory stimulation pulse is generated, and the pulse is conveyed to the stimulation probe. In one embodiment concerning cardiac tissue, a stimulation probe is applied to a patient'"'"'s heart, a signal is received from at least one sensor responsive to the patient'"'"'s cardiac muscle activity, a non-excitatory stimulation pulse responsive to the signal is generated, and the pulse is conveyed to the stimulation probe.

Claims

1. A method of intentionally modulating the intracellular calcium properties in cardiac tissue, comprising:

(a) applying a stimulation probe to cardiac tissue in a subject'"'"'s body;

(b) selecting a desired effect on intracellular calcium properties in said cardiac tissue;

(c) providing pulse parameters of non-excitatory stimulation designed to achieve said desired effect on said intracellular calcium properties;

(d) using said parameters to generate an electrical signal comprising said non-excitatory stimulation; and

(e) conveying said electrical signal to the stimulation probe during a refractory period for the tissue, thereby applying said non-excitatory stimulation to said cardiac tissue.

2. The method of claim 1, wherein the stimulation probe comprises one or more stimulation probes.

3. The method of claim 1, wherein the desired effect comprises increasing the intracellular calcium concentration.

4. The method of claim 1, wherein said desired effect comprises decreasing the intracellular calcium concentration.

5. The method of claim 1, wherein the desired effect is an increase in intracellular calcium ion flux.

6. The method of claim 1, wherein the desired effect includes a return to a base line value for the intracellular calcium property.

7. The method of claim 1, wherein the desired effect includes a return to a base line level of the intracellular calcium property between heart beats.

8. The method of claim 1, wherein the parameters include applying said non-excitatory stimulation beginning between 0 and 100 milliseconds after local activation.

9. The method of claim 1, wherein said selecting comprises selecting a desired long term consequence.

10. The method of claim 9, wherein said long term consequence comprises gene transcription and/or post translation modification.

11. The method of claim 1, wherein said selecting a desired effect comprises selecting a transient effect.

12. The method of claim 1, wherein said desired effect is release or re-uptake of calcium from a sarcoplasmic reticulum.

38. The method of claim 1, wherein said desired effect comprises desired effects on calcium concentration and/or trans-membranal calcium ion flux and/or intracellular stores content.

39. The method of claim 38, wherein the property is ion flux.

40. The method of claim 38, wherein the property is intracellular stores content.

41. The method of claim 38, wherein the property is increased.

42. The method of claim 1 wherein the desired effect comprises increase of the property.

43. The method of claim 1 wherein the desired effect comprises decrease of the property.

44. The method of claim 1 wherein the pulse parameters comprise timing and/or voltage, current, duration, polarity, waveform, and frequency of the waveform of the stimulation.

45. The method of claim 1 wherein the parameters are selected for an individual subject.

13. A method of intentionally modulating intracellular calcium properties in cardiac tissue, comprising:

(a) applying a stimulation probe comprising one or more stimulation electrodes to a subject'"'"'s heart;

(b) applying to said subject'"'"'s body at least one sensor responsive to said subject'"'"'s cardiac muscle activity;

(c) receiving a sensing signal from said at least one sensor;

(d) selecting a desired effect on intracellular calcium properties in said subject'"'"'s heart;

(e) determining parameters of a non-excitatory stimulation pulse for modulation of intercellular calcium concentration to achieve said desired effect, depending on said sending signal;

(f) generating an electrical signal comprising said non-excitatory stimulation pulse responsive to said sensing signal; and

(g) conveying said electrical signal to at least one of said one or more electrodes during a refractory period for the cardiac tissue thereby applying said non-excitatory stimulation pulse to said cardiac tissue.

14. The method of claim 13, wherein said desired effect comprises increasing the intracellular calcium concentration.

15. The method of claim 13, wherein said desired effect comprises decreasing the intracellular calcium concentration.

16. The method of claim 13, wherein the sensor is an electrode introduced into the heart, said sensor measuring said heart'"'"'s electrical activity, and wherein generating the electrical signal comprises generating an electrical signal synchronized with said electrical activity sensed by said sensing electrode.

17. The method of claim 13, wherein the sensor is an external electrode attached to the subject'"'"'s body surface, said electrode measuring an ECG signal, and wherein generating the electrical signal comprises generating an electrical signal synchronized with said ECG signal.

18. The method of claim 13, wherein at least one of the one or more of the stimulation electrodes also functions as a sensing electrode.

19. The method of claim 13, wherein generating the electrical signal comprises generating an electrical signal having a predetermined delay relative to the signal.

20. The method of claim 13, wherein applying the stimulation probe comprises applying a probe comprising a plurality of stimulation electrodes, and wherein generating and conveying the electrical signal comprises generating a sequence of electrical signals and applying each electrical signal in said sequence to a different one of said plurality of stimulation electrodes.

21. The method of claim 13, wherein generating and conveying the electrical signal comprises generating and conveying said electrical signal selectively, based on a characteristic of the signals received from the at least one sensor.

22. The method of claim 21, wherein generating and conveying the electrical signal comprises generating and applying said electrical signal at a rate dependent on the heart rate, but not equal to the heart rate.

23. The method of claim 21, wherein generating and conveying the electrical signal comprises detecting a cardiac arrhythmia and adjusting the application of said electrical signal responsive thereto.

24. The method of claim 21, wherein generating and conveying the electrical signal comprises detecting a QT interval in the signals received from the at least one sensor and generating pulses responsive thereto.

25. The method of claim 13, wherein generating the electrical signal comprises varying one or more parameters of the non-excitatory stimulation pulse, selected from the group consisting of the pulse voltage, current, duration, delay, and waveform frequency.

26. The method of claim 13, wherein the non-excitatory stimulation comprises a baseline pulse and a waveform of substantially higher frequency than the baseline pulse superimposed thereon.

27. The method of claim 26, wherein the waveform comprises a square wave.

28. The method of claim 13, further comprising, after step (g), another step (h) generating and conveying another electrical signal of opposite polarity thereto.

29. The method of claim 13, wherein applying the non-excitatory stimulation pulse comprises varying the extent of a portion of the area of the heart segment to which said stimulation pulse is applied.

30. The method of claim 29, wherein varying the extent comprises selectively addressing a net of stimulation electrodes implanted in the heart.

31. The method of claim 13, wherein applying the stimulation probe comprises inserting the one or more stimulation electrodes into multiple chambers of the heart.

32. The method of claim 13, wherein applying the stimulation probe comprises inserting at least one of the one or more stimulation electrodes into a blood vessel of the heart.

33. The method of claim 32, wherein inserting the at least one stimulation electrode comprises inserting the electrode into the coronary sinus.

34. The method of claim 13, wherein generating and conveying the electrical signal comprises generating and conveying electrical signals at selected times of the day.

35. The method of claim 13, wherein generating and conveying the electrical signal comprises generating and conveying electrical signals which increase the subject'"'"'s cardiac output.

36. The method of claim 13, wherein generating and conveying the electrical signal comprises generating and conveying electrical signals which decrease the subject'"'"'s cardiac output.

37. The method of claim 13, wherein generating and conveying the electrical signal comprises generating and conveying electrical signals which increase the efficiency of contraction of the heart.

46. The method of claim 13, wherein the properties include calcium concentration and/or trans-membranal calcium ion flux and/or intracellular stores content.

47. The method of claim 13, wherein the pulse parameters comprise timing and/or voltage, current, duration, polarity, waveform, and frequency of the waveform of the stimulation.

48. The method of claim 13, wherein said desired effect comprises an increase in intracellular calcium ion flux.

49. The method of claim 13, wherein the parameters include applying said non-excitatory stimulation beginning between 0 and 100 milliseconds after local activation.

50. The method of claim 13, wherein said selecting comprises selecting a long term consequence.

51. The method of claim 13, wherein said selecting a desired effect comprises selecting a transient effect.

52. The method of claim 13, wherein said desired effect is release or re-uptake of calcium from a sarcoplasmic reticulum.

53. A method for regulating the intracellular calcium properties in cardiac tissue, comprising:

a. applying a stimulation probe to cardiac tissue in a subject'"'"'s body;

b. determining a desired intracellular calcium property of said tissue;

c. generating an electrical signal comprising non-excitatory stimulation which has an effect on said intracellular calcium property commensurate with said desired regulation; and

d. conveying said non-excitatory stimulation pulse to said cardiac tissue during a refractory period for said tissue.

54. The method of claim 53, wherein steps (c) and (d) are repeated as often as necessary to regulate the intracellular calcium properties in the cardiac tissue by the signal according to the desired regulation.

55. The method of claim 53, wherein the properties include calcium concentration and/or trans-membranal calcium ion flux and/or intracellular stores content.

56. The method of claim 53, wherein the desired regulation comprises increase of the property.

57. The method of claim 53, wherein the desired regulation comprises decrease of the property.

58. The method of claim 53, wherein modulating comprises increase of the property.

59. The method of claim 53, wherein modulating comprises decrease of the property.

60. The method of claim 53, wherein the desired calcium property comprises an increase in intracellular calcium ion flux.

61. The method of claim 53, wherein the conveying comprises applying said non-excitatory stimulation beginning between 0 and 100 milliseconds after local activation.

62. The method of claim 53, wherein said desired effect is release or re-uptake of calcium from a sarcoplasmic reticulum.