Methods for In Vivo Evaluation of Pulmonary Physiology And/Or Function Using NMR Signals of Polarized 129Xe

• US 20070110669A1
• Filed: 01/16/2007
• Published: 05/17/2007
• Est. Priority Date: 09/20/2001
• Status: Active Grant

• Current Assignee: Polarean, Inc. (Polarean Imaging Plc)
• Original Assignee: Medi-Physics Incorporated (General Electric Company)
• Inventors: Marelli, Claudio, Driehuys, Bastiaan, Wolber, Jan, Hall, Margaret, Mansoon, Sven
• Granted Patent: US 7,867,477 B2
• Time in Patent Office: Days
• US Class Current: 424/9.300
• CPC Class Codes: A61B 5/02755 Radioactive tracers
• CPC Class Codes: A61B 5/055 involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
• CPC Class Codes: A61B 5/0813 Measurement of pulmonary parameters by tracers, e.g. radioactive tracers
• CPC Class Codes: A61B 5/411 Detecting or monitoring allergy or intolerance reactions to an allergenic agent or substance
• CPC Class Codes: A61B 5/413 Monitoring transplanted tissue or organ, e.g. for possible rejection reactions after a transplant
• CPC Class Codes: A61K 49/06 Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
• CPC Class Codes: G01N 24/08 by using nuclear magnetic resonance G01N24/12 takes precedence
• CPC Class Codes: G01R 33/46 NMR spectroscopy
• CPC Class Codes: G01R 33/485 based on chemical shift information [CSI] or spectroscopic imaging, e.g. to acquire the spatial distributions of metabolites
• CPC Class Codes: G01R 33/5601 involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent
• CPC Class Codes: G01R 33/563 of moving material, e.g. flow contrast angiography
• CPC Class Codes: G01R 33/56308 Characterization of motion or flow; Dynamic imaging

Abstract

In certain embodiments, methods of the present invention obtain dynamic data sets of an NMR spectroscopy signal of polarized ¹²⁹Xe in a selected structure, environment, or system. The signal data can be used to evaluate: (a) the physiology of a membrane or tissue; (b) the operational condition or function of a body system or portion thereof (when at rest or under stimulation); and/or (c) the efficacy of a therapeutic treatment used to treat a diagnosed disorder, disease, or condition. Thus, the present invention provides methods for screening and/or diagnosing a respiratory, cardiopulmonary disorder or disease such as chronic heart failure, and/or methods for monitoring the efficacy of therapeutics administered to subject to treat the disorder or disease.

Claims

1-39. -39. (canceled)

40. An in vivo method for evaluating whether a subject has a respiratory disorder, or a cardiopulmonary disorder such as chronic heart failure, comprising:

delivering polarized ¹²⁹Xe in vivo to a subject such that the polarized ¹²⁹Xe travels across the alveolar-capillary membrane to be taken up in the blood across the membrane, the polarized gas in the blood having a polarized ¹²⁹Xe NMR chemical shift signal frequency;

destroying the polarization of the polarized ¹²⁹Xe in the blood and the membrane;

obtaining an NMR spectroscopic signal of the polarized gas in the subject over time at the blood and/or tissue resonant frequency to generate at least one dynamic data set to generate at least one NMR ¹²⁹Xe uptake curve at at least one chemical shift frequency of interest of signal strength values over time; and

evaluating the NMR derived dynamic data set to assess whether the subject has a respiratory or cardiopulmonary disorder.

41. A method according to claim 40, wherein the subject is evaluated for chronic heart failure.

42. A method according to claim 40, further comprising:

calculating a time constant associated with the time it takes the polarized gas to travel across the membrane and then enter the blood after said destroying step; and

determining a diffusion thickness based on data provided by said obtaining and calculating steps.

43. A method according to claim 42, wherein the step of obtaining comprises obtaining a plurality of signal data points over a time which is greater than about twice the time constant.

44. A method according to claim 42, wherein said obtaining step is carried out when the subject is at rest and then repeated while the subject is exposed to conditions of actual or chemically induced exercise, and wherein said method further comprises comparing the time constants associate therewith to thereby assess the function of the alveolar-capillary membrane.

45. A method according to claim 43, further comprising calculating asymptotes and intercepts of the NMR ¹²⁹Xe signal uptake curves from the NMR data and determining the membrane thickness, wherein the membranes have a thickness in the range of between about 1 micron to about 100 microns.

46. A method according to claim 40, wherein the obtaining step is carried out a plurality of times, including at least once while the subject is at rest and at least once when the subject is under or just after actual or simulated physical activity when the heart rate is elevated.

47. A method according to claim 40, wherein the obtaining step is performed after a therapeutic agent is administered to the subject to evaluate the efficacy in treating the disorder or to evaluate its impact on the thickness of the alveolar-capillary membrane.

48. A method according to claim 47, wherein the obtaining step is carried out both before and after the administration of the therapeutic to the subject.

49. A method according to claim 40, wherein the evaluating step comprises evaluating at least one of thickness of the alveolar-capillary membrane, perfusion in the pulmonary blood, , and ejection fraction, based on said obtaining step.

50. A method according to claim 40, further comprising providing a predetermined diffusion model of alveolar gas exchange employing an alveolar gas compartment, a tissue compartment, and a capillary compartment;

and

calculating a plurality of selected bioparameters related to lung function and/or physiology using NMR-derived data associated with ¹²⁹Xe uptake curves and the predetermined diffusion model.

51. A method according to claim 50, further comprising computing a total diffusion length “

L”

associated with the combined tissue compartment thickness and the capillary compartment thickness by the equation;

L≈

π

/2√

{square root over (Dτ

₁)}

where D is a diffusion coefficient of xenon in the tissue and/or capillary and τ

₁ is an uptake time constant associated with an initial portion of the uptake curve of the NMR signal of the polarized ¹²⁹Xe in the combined tissue and capillary compartment.

52. A method according to claim 50, wherein the calculating step is carried out by combining the tissue and capillary compartments into a single compartment using a common ¹²⁹Xe concentration value.

53. A method according to claim 50, further comprising:

defining equations representing the NMR signals associated with each of tissue, plasma and red blood cells using a respective Ostwald solubility coefficient for each compartment; and

computing at least one of a time constant, intercept and slope of an asymptote derived from the signal build up curve of polarized ¹²⁹Xe associated with the tissue and capillary compartments derived from the NMR dynamic data set to determine a plurality of selected parameters related to perfusion and/or diffusion.

54. A method according to claim 53, wherein the computing step computes the intercept and slope asymptote values for both the tissue uptake curve and the blood compartment uptake curve based on the NMR data.

55. A method according to claim 53, further comprising evaluating the dynamic NMR data set to determine the NMR uptake curve signal of the ¹²⁹Xe associated with the tissue, plasma and red blood cells.

56. A method according to claim 50, further comprising concurrently assessing diffusing capacity and pulmonary perfusion using the ¹²⁹Xe NMR data set.

57. A method according to claim 50, wherein the concurrently determined parameters include at least two of:

tissue thickness, capillary thickness, perfusion, mean transit time and alveolar radius.

58. A method according to claim 57, wherein the parameters comprise at least two of hematocrit, perfusion, and mean transit time.

59. A method according to claim 57, wherein the parameters comprise pulmonary perfusion.

60. A method according to claim 50, further comprising determining a hematocrit value based on the ¹²⁹Xe-NMR data set.

61. A method according to claim 50, wherein the parameters include at least two of the alveolar radius, the alveolar volume, and the relative blood volume based on the ¹²⁹Xe NMR data set.

62. A method according to claim 40, further comprising evaluating the subject for indications of a drug-induced lung disorder and/or injury.

63. A method according to claim 50, further comprising evaluating the subject for an environmentally induced lung injury based on the NMR-derived dynamic data set.

64. A method according to claim 50, further comprising evaluating the subject for at least one of pulmonary inflammation, pulmonary edema, pulmonary hypertension, and pneumonitis/pulmonary fibrosis based on the ¹²⁹Xe NMR data set.

65. A method according to claim 40, further comprising monitoring the subject for indications of a transplant rejection based on the ¹²⁹Xe NMR data set.

66. An in vivo method for evaluating a subject for chronic heart failure comprising:

(a) delivering polarized ¹²⁹Xe in vivo to a subject such that the polarized ¹²⁹Xe moves across the alveolar-capillary membrane to be taken up in the blood across the membrane, the polarized gas in the blood having a corresponding polarized gas NMR chemical shift signal frequency;

(b) destroying the polarization of the polarized ¹²⁹Xe in the blood and the membrane;

(c) obtaining an NMR spectroscopic signal of the polarized ¹²⁹Xe in the subject over time at the blood chemical shift frequency to generate at least one dynamic data set of the NMR spectroscopic signal strength over time;

(d) evaluating the dynamic data; and

(e) determining whether the subject has chronic heart failure based on the obtaining and evaluating steps.

67-124. -124. (canceled)