Methods for in vivo evaluation of pulmonary physiology and/or function using nmr signals of polarized 129xe

Abstract

In certain embodiments, methods of the present invention obtain dynamic data sets of an NMR spectroscopy signal of polarized 129 Xe 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.

1 .- 67 . (canceled) 
     
     
         68 . An in vivo method for evaluating respiratory, pulmonary and/or cardiopulmonary physiology and/or function, comprising:
 (a) delivering polarized  129 Xe in vivo to a subject such that the polarized  129 Xe moves serially from an alveolar gas compartment through a tissue compartment with thickness L T , a capillary compartment with thickness L C  comprising plasma and red blood cells, and is then taken away in the blood stream;   (b) obtaining NMR spectroscopic signals of the polarized  129 Xe in the subject over time at selected chemical shift frequencies to generate at least one dynamic data set of the NMR spectroscopic signal strength over time after successively destroying the polarization of the  129 Xe repetitively at predetermined delays in the compartments; and   (c) calculating a plurality of selected parameters associated with lung function and/or physiology according to a predetermined mathematical diffusion model of alveolar gas exchange using the NMR-derived dynamic data set.   
     
     
         69 . A method according to  claim 68 , further comprising evaluating the calculated parameters to determine a pulmonary condition of a patient to thereby assess respiratory, pulmonary, and/or cardiopulmonary function or associated physiology. 
     
     
         70 . A method according to  claim 68 , further comprising assessing both membrane diffusion and pulmonary perfusion based on the NMR data set. 
     
     
         71 . A method according to  claim 69 , further comprising identifying whether the subject exhibits gas-exchange that is perfusion or diffusion limited. 
     
     
         72 . A method according to  claim 71 , wherein the NMR signals include at least one signal associated with dissolved  129 Xe, the dissolved-phase NMR signal having an associated signal build up curve with an initial exponential build-up portion and a dynamic equilibrium portion, wherein the build-up curve has an uptake time constant associated with the initial build-up portion of the NMR signal, the method further comprising taking the ratio of the uptake time constant and mean transit time to determine whether the gas exchange is perfusion or diffusion limited. 
     
     
         73 . A method according to  claim 68 , wherein the NMR signals include signals at a frequency associated with dissolved-phase  129 Xe, the dissolved-phase signals having signal uptake curves with an initial exponential build-up portion and a dynamic equilibrium portion, the dynamic equilibrium portion of the uptake curves having an associated asymptote slope and intercept, wherein the slopes and intercepts of the asymptotes of the dissolved-phase  129 Xe NMR uptake curves are used to calculate mean transit time, perfusion and relative blood volume. 
     
     
         74 . A method according to  claim 68 , wherein at least one of the NMR signals is a dissolved-phase  129 Xe NMR signal that has a signal uptake curve with an initial exponential build-up portion and a dynamic equilibrium portion in a time period of interest, the signal having an associated asymptote slope and intercept after the initial exponential build-up portion, wherein the uptake curve has an uptake diffusing time constant associated with the initial build-up portion of the NMR signal, and wherein total diffusing thickness “L” is calculated directly from the uptake time constant τ 1 , using the equation: 
       
         
           
             
               L 
               = 
               
                 
                   π 
                   2 
                 
                  
                 
                   
                     D 
                      
                     
                         
                     
                      
                     
                       τ 
                       1 
                     
                   
                 
               
             
           
         
       
       where D is the diffusion coefficient of xenon. 
     
     
         75 . A method according to  claim 74 , further comprising mathematically transforming selected variables in a predetermined equation associated with the thickness of at least one compartment in the predetermined diffusion model and using data associated with a time constant determined from the signal build up curve of polarized  129 Xe in the tissue and/or capillary compartment derived from the NMR dynamic data set to measure a pathological and/or physiological structure and/or condition. 
     
     
         76 . A method according to  claim 75 , wherein the pathological condition is thickening or thinning of a patient's alveolar membrane. 
     
     
         77 . A method according to  claim 68 , further comprising concurrently assessing alveolar diffusion and pulmonary perfusion using the NMR data set. 
     
     
         78 . A method according to  claim 68 , further comprising providing data that identifies the presence or absence of an environmentally induced lung disorder. 
     
     
         79 . A method according to  claim 68 , further comprising data that identifies the presence or absence of a drug-induced lung injury. 
     
     
         80 . A method according to  claim 68 , further comprising monitoring a patient's response to a therapeutic drug. 
     
     
         81 . A method according to  claim 80 , wherein the monitoring is carried out to assess whether the patient is exhibiting an undesirable response to a therapeutic agent. 
     
     
         82 . A method according to  claim 68 , wherein the predetermined mathematical diffusion model of alveolar gas exchange includes an alveolar gas compartment, a tissue compartment, and a capillary compartment. 
     
     
         83 . A method according to  claim 82 , wherein the predetermined diffusion model defines three boundaries, an alveoli-tissue boundary, a tissue-capillary boundary, and an outer capillary boundary. 
     
     
         84 . A method according to  claim 68 , wherein the NMR data set includes data for NMR signals associated with the polarized  129 Xe in the alveolar compartment, the tissue compartment, and the capillary or blood compartment at corresponding polarized gas NMR chemical shift signal frequencies. 
     
     
         85 . A method according to  claim 84 , further comprising destroying the polarization of the polarized  129 Xe in the tissue and capillary compartments prior to acquisition of the NMR data set. 
     
     
         86 . A method according to  claim 82 , wherein the calculating step is carried out by combining the tissue and capillary compartments of the model into a single compartment with a common  129 Xe concentration value. 
     
     
         87 . A method according to  claim 68 , wherein the predetermined mathematical diffusion model comprises a capillary compartment and a tissue compartment, the method further comprising evaluating the NMR signal from the capillary compartment and the tissue compartment to determine a hematocrit value. 
     
     
         88 . A method according to  claim 68 , further comprising evaluating the dynamic NMR data set to determine signal build-up curves of the NMR signals of the  129 Xe associated with each of tissue, plasma and red blood cells. 
     
     
         89 . (canceled) 
     
     
         90 . A method according to  claim 89 , wherein at least one of the parameters is selected from the group of: hematocrit, lung perfusion, and mean transit time. 
     
     
         91 . A method according to  claim 89 , wherein one of the parameters is pulmonary perfusion. 
     
     
         92 . A method according to  claim 68 , wherein the calculating step is carried out to determine a plurality of different parameters including at least two of alveolar radius, alveolar volume, and relative blood volume based on the  129 Xe NMR data set. 
     
     
         93 . A method according to  claim 68 , further comprising evaluating the subject for indications of a drug-induced lung disorder and/or injury based on the calculating step. 
     
     
         94 . A method according to  claim 68 , further comprising evaluating the subject for an environmentally induced lung injury based on the calculating step. 
     
     
         95 . A method according to  claim 68 , further comprising evaluating the subject for at least one of pulmonary inflammation, pulmonary edema, pulmonary hypertension, and pneumonitis/pulmonary fibrosis based on the  129 Xe NMR data set. 
     
     
         96 . A method according to  claim 68 , further comprising monitoring the subject for indications of a transplant rejection based on the  129 Xe NMR data set. 
     
     
         97 . A method according to  claim 69 , wherein the evaluating step is carried out to provide data that identifies the presence or absence of a diffuse lung disorder. 
     
     
         98 . A method according to  claim 68 , further comprising evaluating the subject using the dynamic data set and/or the calculated selected parameters to identify whether the subject has at least one of the conditions selected from the group: pulmonary inflammation, pneumonitis/fibrosis, transplant rejection response, interstitial lung disease, pulmonary edema, pulmonary hypertension and interstitial and/or alveolar inflammation. 
     
     
         99 . A method according to  claim 98 , wherein the evaluating step is carried out during clinical evaluation of a drug in drug discovery or clinical trials. 
     
     
         100 . A method according to  claim 98 , wherein the evaluating step is carried out to allow for intervention of a negative or adverse response to a therapeutic drug. 
     
     
         101 - 124 . (canceled)