Abstract:
A method employing pattern recognition techniques for identifying the functional status of patients with Pulmonary Hypertension is described. This method describes a process by which sets of cardiopulmonary exercise gas exchange variables are measured during rest, exercise and recovery and stored as unique data sets. The data sets are then analyzed by a series of feature extraction steps, yielding a multi-parametric index (MPI PH ) which reflects the current functional status of a patient. The method also employs a description scheme that provides a graphical image that juxtaposes the measured value of MPI to a reference classification system. An additional description scheme provides a trend plot of MPI values measured on a patient over time to provide feedback to the physician on the efficacy of therapy provided to the patient. The method will enable physicians to gather, view, and track complicated data using well-understood visualization techniques to better understand the consequences of their therapeutic actions.

Description:
CROSS-REFERENCED TO RELATED APPLICATIONS 
       [0001]    This application is a Continuation-In-Part of application Ser. No. 12/209,376, filed Sep. 12, 2008, which is a non-provisional application of Application No. 60/993,998, filed Sep. 17, 2007, and this application claims priority from those applications which are also deemed incorporated by reference in their entirety in this application. 
     
    
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT 
       [0002]    Not applicable 
       BACKGROUND OF THE INVENTION 
       [0003]    I. Field of the Invention 
         [0004]    The present invention relates generally to the field, including pulmonary arterial and pulmonary vascular hypertension, of medical diagnosis and specifically to a process of identifying patients with Pulmonary Hypertension (PH), including pulmonary arterial and pulmonary vascular hypertension and classifying the functional status of these patients to assess the severity of the disease. The present method provides a more sensitive, physiologic, and easier to use method than currently available classification systems. In addition, the present invention provides feedback during long-term follow-up and treatment in patients with PH. 
         [0005]    II. Related Art 
         [0006]    The early symptoms of PH—such as Dyspnea, dizziness and fatigue—are often mild and are common to many other conditions. At rest there are often no symptoms and no apparent signs of illness. As a result, diagnosis can be delayed for months or even years meaning that PH is frequently not recognized until the disease is relatively advanced. 1  PH is often diagnosed only once other conditions have been investigated and ruled out. 
         [0007]    The non-specific nature of symptoms associated with PH means that the diagnosis cannot be made on symptoms alone. A series of investigations is required to make an initial diagnosis, to refine that diagnosis in terms of clinical class of pulmonary hypertension, and to evaluate the degree of functional and hemodynamic impairment. Current PH evaluation and classification (type, functional capacity, hemodynamics) methods include blood tests and immunology, HIV test, abdominal ultrasound scan, 6-minute walk test (6-MWT), peak VO 2 , right heart catheterization, and vaso-reactivity testing. It is with exercise that the sympathetic and neuro-hormonal systems trigger increased vasoconstriction of the pulmonary arteriolar vascular beds, thus causing an elevation in pulmonary vascular resistance and reduced blood flow through the pulmonary vascular circuit. The reduced blood flow is mismatched to the air flow in the bronchioles and alveoli. 
         [0008]    It is often that the exercise state is not evaluated by any pulmonary function parameters that truly represent gas exchange in the lungs. Instead, walking distance and peak oxygen uptake are measured. 
         [0009]    A well-known current classification system was formulated by the New York Heart Association (NYHA) and the World Health Organization (WHO). The NYHA system places patients in one of four categories based on how much they are limited during physical activity. 
         [0000]    
       
         
               
             
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 NYHA/WHO Classification of Functional Status 
               
               
                 of Patients with Pulmonary Hypertension 1   
               
             
          
           
               
                 Class 
                 Symptomatic profile 
               
               
                   
               
               
                 Class I 
                 Patients with pulmonary hypertension but without 
               
               
                   
                 resulting limitation of physical activity. Ordinary 
               
               
                   
                 physical activity does not cause Dyspnoea or fatigue, 
               
               
                   
                 chest pain or near syncope 
               
               
                 Class II 
                 Patients with pulmonary hypertension resulting in slight 
               
               
                   
                 limitation of physical activity. They are comfortable at 
               
               
                   
                 rest Ordinary physical activity causes undue dyspnoea or 
               
               
                   
                 fatigue. chest pain or near syncope 
               
               
                 Class III 
                 Patients with pulmonary hypertension resulting in marked 
               
               
                   
                 limitation of physical activity. They are comfortable at rest. 
               
               
                   
                 Less than ordinary activity causes undue dyspnoea or 
               
               
                   
                 fatigue, chest pain or near syncope 
               
               
                 Class IV 
                 Patients with pulmonary hypertension with inability to carry 
               
               
                   
                 out any physical activiry without symptoms. These patients 
               
               
                   
                 manifest signs of right heart failure. Dyspnoea and/or fatigue 
               
               
                   
                 may even be present at rest. Discomfort is increased by any 
               
               
                   
                 physical activity. 
               
               
                   
               
             
          
         
       
     
         [0010]    The major shortcoming of the NYHA/WHO system is that it relies on subjective observations by the patient and interpretation of those observations by the physician. 
         [0011]    The 6-minute walk test, while simple and convenient, has many limitations including issues relating to reproducibility, sensitivity, and essentially a plateau in functional assessment when patients have less functional impairment. 
         [0012]    The logistics of performing an exercise test to maximal exertion, including laboratory staffing, direct physician supervision and test duration, in addition to the increased level of patient discomfort, does not lend to conducting this procedure in a serial fashion over short time intervals (i.e. several weeks-months). In addition, it has been found that maximum exercise levels are not representative of lower level, activities of daily living. 
       SUMMARY OF THE INVENTION 
       [0013]    The present advance, to a large extent, obviates the problems discussed in the foregoing for the NYHA/WHO Classification system, for peak VO 2  testing for functional classification, and for the 6-minute hall walk for therapy tracking. In accordance with the present invention, it has been found that a continuous, numeric multiparametric ranking score will provide a functional classification for PH patients that is easier to visualize and interpret. Moreover, this multiparametric score is obtained by either exercising the patient to a maximal value, or by utilization of gas exchange variables commonly measured during submaximal exercise indicative of everyday patient activity. The MPI provides multiparametric representation regarding PH that is clear and easy to understand. 
         [0014]    The present invention involves the use of exercise-related data in a method of pattern recognition for diagnosing the presence of Pulmonary Hypertension and classifying the functional status of patients with chronic PH using a multiparametric index (MPI PH ). 
         [0015]    The present invention provides a single multiparametric score that can be used to quantify the degree of severity of a patient with PH by combining certain Feature Extraction Steps, for example, steps 1-8, explained below, with an additional term, A-35 mmHg, as will be explained. In combination, the value for MPI PH  may be expressed as follows: 
         [0000]      MPI PH =( A− 35 mmHg)+ G*W 1+ H*W 2 +I*W 3+ J*W 4+ K*W 5+ L*W 6 
         [0000]    Where A-L are individual ranking parameters derived from exercise data and W 1 -W 6  are weighting factors. 
         [0016]    The values for A-L having been derived previously in Feature Extraction Steps 1-8 (see FIGS.  7 , 8 , for example). One objective in formulating the value for MPI PH  in the manner of the present invention is to obtain a negative value for patients with PH, and to obtain a value the magnitude of which is larger with increasing severity of the disease. This is also evident from the table in  FIG. 8 . Because the term “G” represents an appropriate directional change in ETCO 2  in response to exertion, although transient, this may be indicative of pulmonary venous hypertension, rather than pulmonary arterial hypertension. Therefore, it has been determined that a relatively larger value for G (first rise) is indicative of lower severity; thus, a positive value of G reduces the negative total MPI PH . Because the term “H” represents an increase in pulmonary blood flow or improved matching of ventilation to perfusion, it has been determined that a relatively larger value for H (delay) is indicative of lower severity; thus, a positive value of H reduces the negative total MPI PH  value. Similarly, it has been determined that the presence of a rebound K, during exercise, is also indicative of lower severity, thus a positive value of K also reduces the negative total MPI PH  value. 
         [0017]    The values for W 1 -W 6  in the above equation are statistical weighting factors that may or may not equal 1 (a value of 1, of course will not alter the total value of MPI PH ). A value of 1 was used for all the weighting factors in conjunction with  FIG. 7  and  FIG. 8 . By conducting clinical trials involving PH patients with known PH disease, confirmed by right heart catheterization, individual weighting factors can be determined to fine tune the computation of MPI PH . 
         [0018]    The data utilized in the present invention, cardiopulmonary exercise gas exchange measurements, is obtained 1) at rest, 2) during physical exercise testing performed in accordance with a standardized workload protocol as the forcing function to elicit physiologic changes resulting from the workload, and 3) during a short recovery period following exercise termination. 
         [0019]    Physiologic changes are measured using a cardiopulmonary exercise testing system (CPX) to measure selected variables (parameters) associated with oxygen consumption, VO 2 , carbon dioxide production, VCO 2 , end tidal CO 2 , ETCO 2 , ventilation, VE, and heart rate, HR. 
         [0020]    In accordance with a preferred method, a cardiopulmonary exercise gas exchange analysis is made for each test data set. 
         [0021]    Whereas, the data gathering aspect involves known techniques and analysis, and the calculations for formulating predictive assessments are available in the scientific literature (see the bibliography in References), it is aspects of the feature extraction mechanism and the classification scheme from which the invention enables an observer to gain new and valuable insight into the present condition and condition trends in patients. 
         [0022]    Importantly, it has been discovered that the change in end tidal CO 2  (ETCO 2 ) during and related to submaximal or peak exercise can be used as a key prognostic indicator in the evaluation of Pulmonary Hypertension. 
         [0023]    This has been used as a basis for deriving a novel MPI PH  score as described that offers a simplified, easier to interpret quantitative means for the diagnosis and the classification of the functional status of PH. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0024]    In the drawings: 
           [0025]      FIG. 1  is a schematic drawing that illustrates the functional components of a CPX testing system usable with the present invention; 
           [0026]      FIG. 2  is a schematic drawing that illustrates one form of exercise protocol that is used to place a volume load on the cardiopulmonary system; 
           [0027]      FIG. 3  illustrates an organization of the measured data once it is acquired from the cardiopulmonary exercise gas exchange analyzer; 
           [0028]      FIG. 4  illustrates a normal ETCO 2  response to exercise. 
           [0029]      FIG. 5  illustrates the calculation of the areas over the resting ETCO 2  baseline during exercise (Area O) and the area under the resting ETCO 2  baseline during exercise (Area U); 
           [0030]      FIG. 6  illustrates features extracted from the ETCO 2  vs. time plot; 
           [0031]      FIG. 7  illustrates an analysis flow chart to compute MPI PH ; 
           [0032]      FIG. 8  illustrates sample calculations from Yasunobu; 
           [0033]      FIG. 9  illustrates a description scheme employed by the present invention for displaying the resultant MPI PH  values with the NYHA/WHO Class juxtaposed onto the scale; and 
           [0034]      FIG. 10  illustrates a trend plot of test time-sequential MPI PH  values. 
       
    
    
     DETAILED DESCRIPTION 
       [0035]    The following detailed description, including the use of patient data, is intended to be exemplary of a preferred method of utilizing the concepts of the present invention and is not intended to be exhaustive or limiting in any manner with respect to similar methods and additional or other steps which might occur to those skilled in the art. The following description further utilizes illustrative examples, which are believed sufficient to convey an adequate understanding of the broader concepts to those skilled in the art, and exhaustive examples are believed unnecessary. 
         [0036]    It is becoming increasingly clear in the literature that the change in ETCO 2  during submaximal exercise is a valuable prognostic indicator. 2    
         [0037]    “While both VE/VCO 2  and (ETCO 2 ) were significant univariate prognostic markers, the latter CPX variable appears to provide superior prognostic information during low-intensity exercise”. 
         [0038]    Another study 3  concluded that “Resting ETCO 2  appears to add prognostic value to variables that are well established and commonly collected in clinical practice. 
         [0039]    The fact that resting PetCO 2  is easily, cheaply, and noninvasively obtained portends high clinical promise for this measurement”. 
       ADVANTAGES 
       [0040]    Recently Yasanobu and colleagues 4  have demonstrated the detection of PH by functional evaluation using cardiopulmonary gas exchange measurements. They eloquently demonstrated that the real time monitoring of end-expired CO 2  was able to confirm the existence of PH when a reverse decrease in end tidal ETCO 2  occurred during mild to moderate exercise as assessed up to the anaerobic threshold (AT) with a typical rebound in ETCO 2  upon the cessation of exercise. Of interest was the high correlation between the decrease in ETCO 2  and mean Pulmonary Artery Pressure (PAP). 
         [0041]    However, no method for a systematic, computerized analysis of the breath-by-breath ETCO 2  response curve during rest, exercise, and recovery is presented or suggested. Furthermore, how such data can be used to track therapy is not addressed. 
         [0042]    Using the method described below in accordance with the invention, the MPI PH  was computed for each of the four patient tests represented in the Yasunobu study. The feature extraction method performed on the ETCO 2  vs. time plot is depicted in  FIG. 6 . In reference to  FIG. 6 , measurements A through F represent the following physiologic phenomena. Resting ETCO 2  represents the matching of ventilation to pulmonary perfusion and typically will not disclose any type of significantly elevated PVR, until during an exercise stimulus. As PH worsens, an elevated Pulmonary Vascular Resistance (PVR) will exist even at rest. Measurement H represents the “delay time” in sympathetic and neurohormonal induced Measurements A and B, depending on the degree/severity of pulmonary vasoconstriction, represents the severity of PH. Measurement G represents a transient, normal response to exercise whereby the ETCO 2  begins to increase at the start of exercise. It is believed that this transient rise, then fall, of ETCO 2  is reflective of pulmonary venous, rather than pulmonary arterial, hypertension. The slope, measurement I, of the ETCO 2  drop following exercise onset reflects the rate of increased PVR. Measurement E represents the degree of mismatching and expiration of CO 2  (partial pressure) just at the end of exercise while measurement F reflects the degree of attenuation in PVR due to the sympathetic exercise stimulus being withdrawn. The potential increase in ETCO 2  at end exercise, as compared to the lowest ETCO 2  value at point “D” or the nadir, represents an increase in pulmonary blood flow or improved matching of ventilation to perfusion. 
         [0043]    General Considerations—The present invention includes a pattern recognition system consisting of a) a cardiopulmonary exercise gas exchange analyzer that gathers the observations to be classified or described, b) a feature extraction mechanism that computes numeric information from the observations, and c) a classification or description scheme that does the actual job of classifying or describing observations based on the extracted features. 
         [0044]    Data Gathering: As indicated and shown in  FIG. 2 , the general class of data utilized in the present invention, cardiopulmonary exercise gas exchange measurements, is obtained 1) at rest, 2) during physical exercise testing performed in accordance with a standardized workload protocol as the forcing function to elicit physiologic changes resulting from the workload, and 3) during a short recovery period following exercise termination. The data measured during exercise quantifies how an individual is able to function in the physical world in terms of the physiologic changes that the individual experiences when engaged in the performance of daily physical work. 
         [0045]    The physiologic changes are measured using a cardiopulmonary exercise testing system (CPX) to measure selected variables associated with oxygen consumption, VO 2 , carbon dioxide production, VCO 2 , end tidal CO 2 , ETCO 2 , ventilation, VE, and heart rate, HR. 
         [0046]    As indicated, the data gathering aspect of the invention involves known techniques and analyses, and the calculations for formulating predictive assessments are readily available in the scientific literature (see the bibliography in References). However, by means of aspects of the feature extraction mechanism and the classification scheme, the present invention enables an observer to gain new and valuable insight into the present condition and condition trends in patients. Thus, in accordance with a preferred method, a cardiopulmonary exercise gas exchange analysis is made for each test data set. The performance of such a test is well understood by individuals skilled in the art, and no further explanation of this is believed necessary. 
         [0047]    Equipment—With this in mind typical hardware is shown in  FIG. 1 , which illustrates typical equipment whereby a cardiopulmonary exercise test (CPX) may be conducted and the results displayed in accordance with the method of the present invention. The system is seen to include a data processing device, here shown as a personal computer of PC  12 , which comprises a video display terminal  14  with associated mouse  16 , report printer  17  and a keyboard  18 . The system further has a floppy disc handler  20  with associated floppy disc  22 . As is well known in the art, the floppy-disc handler  20  input/output interfaces comprise read/write devices for reading prerecorded information stored, deleting, adding or changing recorded information, on a machine-readable medium, i.e., a floppy disc, and for providing signals which can be considered as data or operands to be manipulated in accordance with a software program loaded into the RAM or ROM memory (not shown) included in the computing module  12 . 
         [0048]    The equipment used in the exercise protocol can be a simple stair step of a known height. A CPX testing system  34  interfaces with the subject  30  during operation of the exercise test. The physiological variables may be selected from heart rate (HR), ventilation (VE), rate of oxygen uptake or consumption (VO 2 ) and carbon dioxide production (VCO 2 ) end tidal CO 2  (ETCO 2 ) or other variables derived from these basic measurements. Physiological data collected is fed into the computing module  12  via a conductor  31 , or other communication device. 
         [0049]    The workload protocol is illustrated in  FIG. 2  and is organized in to a rest phase  50 , and exercise phase  52 , and a recovery phase  54 . Although not required, the workload may also be quantified by requiring the patient to maintain a desired stepping cadence by the addition of an audible metronome that guides the frequency of the steps taken during the exercise phase. 
         [0050]    All data acquired by the CPX system is stored in a relational database as illustrated in  FIG. 3 . Most importantly, data for each patient and each test is stored into separate subsets of data representing the rest phase  386 , the exercise phase  387 , and the recovery phase  388  for use by the feature extraction mechanism. 
       Feature Extraction Steps 
       [0051]    Step 1—Detection—An impetus for the use of statistical pattern recognition comes from new methods of analyzing cardiopulmonary data published in the scientific literature over the past five years. From the bibliography in References (2), statistical values for the normal value and cutoff point for the difference between the last 30 second average value of ETCO 2  or PetCO 2  pressure in mmHg during rest (point A in  FIG. 6 ) and the last 30 second average of ETCO 2  (mmHg) during exercise (point E in  FIG. 6 ) can be obtained. If the difference in these two values is greater than or equal to 1.8 (mmHg, the patient exhibits no increased risk of death and no presence of PH; thus, the remaining analysis is not and need not be performed. As a further test of whether any given patient test exhibits PH, two areas are computed: 1) Area O (see  FIGS. 5 and 6 ) is the area over the resting ETCO 2  baseline bounded by the measured ETCO 2  waveform during the exercise phase or period; 2) Area U (see  FIGS. 5 and 6 ) is the area under the resting ETCO 2  baseline bounded by the measured ETCO 2  waveform during the exercise phase. If the ratio of Area O/Area U is greater than 1, the patient exhibits no presence of PH; thus, the remaining analysis is not and need not be performed. In accordance with the present method, the following steps 2-8 are used to determine the severity of PH in others, and, with respect to steps 2-8, reference is also made to  FIG. 6 . 
         [0052]    Step 2—Delay time—The delay time (H) is calculated by first determining inflection point C, the first ETCO 2  value during exercise that is less than A. The delay time is calculated by subtracting the time value for C from the starting time of the exercise phase. 
         [0053]    Step 3—First rise—The first rise, measurement G, is calculated by subtracting the average resting value of ETCO 2  (A) from inflection point B, the maximum ETCO 2  value greater than A and which occurs prior to reaching inflection point C. 
         [0054]    Step 4—Nadir—The smallest value of ETCO 2  occurring after point C is then determined as inflection point D. 
         [0055]    Step 5—Slope—The next step is to compute the regression line through those data points for ETCO 2  from inflection point C to D. The general form for the regression equation is 
         [0000]    
       
      
       y=a+bx  
      
     
         [0056]    The constant a is the intercept, b is the slope. The a and b values are chosen so that the sum of squared deviations from the line is minimized. The best line is called the regression line, and the equation describing it is called the regression equation. 
         [0057]    In  FIG. 6 , an example illustrates the measured data for the cardiopulmonary data pairs with the plot of the dashed regression line and the slope value I. 
         [0058]    Step 6—Drop—The next step is to compute the maximum drop in ETCO 2 , J, by subtracting the inflection point D from inflection point C. 
         [0059]    Step 7—Intra-exercise rebound—The next step is to compute the value of the intra-exercise rebound. This step may yield a value of 0 in the case where ETCO 2  continues to drop until the end of the exercise phase. The value of K is computed by subtracting inflection point D from E. 
         [0060]    Step 8—Recovery rebound—The final step is to compute the value of the recovery rebound 
         [0000]    L by subtracting the value of the last ETCO 2  data point during recovery, F, from E. 
       Description Scheme 
     MPI PH  Score 
       [0061]    In  FIG. 8 , 4 patient tests representing different degrees of severity are presented. As can be seen, the patterns are similar to that illustrated in  FIG. 6 . However, the values for A, as derived in Step 1 above, are shifted downward from the normal value for ETCO 2  at rest (estimated to be 35 mmHg based on previous studies to date). In order to provide a single, multiparametric score that can be used to quantify the degree of severity of a patient with PH, the present invention combines the Feature Extraction Steps 1-8 with an additional term, A-35 mmHg. In combination, the value for MPI PH  is then expressed as 
         [0000]      MPI PH =( A− 35 mmHg)+ G*W 1+ H*W 2 +I*W 3+ J*W 4+ K*W 5+ L*W 6 
         [0062]    The values for A-L have been described previously in Feature Extraction, Steps 1-8. The basic objective in formulating the value for MPI PH  in this way is to obtain a negative value for patients with PH, and to obtain a value the magnitude of which is larger with increasing severity of the disease. As indicated above, because the term G represents an appropriate directional change in ETCO 2  in response to exertion, although transient, it has been determined that the presence of first rise G is indicative of lower severity, thus a positive value of G reduces the negative total MPI PH  value. Similarly, because the term H represents an increase in pulmonary blood flow or improved matching of ventilation to perfusion, it has been determined that a relatively larger value for H (delay) is indicative of lower severity, thus a positive value of G reduces the negative total MPI PH  value. Similarly, it has been determined that the presence of an intra-exercise rebound K is also indicative of lower severity, thus a positive value of K reduces the negative total MPI PH  value. 
         [0063]    A flowchart for computing MPI PH  is depicted in  FIG. 7  in which the MPI PH  score is computed for  FIG. 6 . Using this same flowchart, the MPI PH  values for  FIG. 8  are computed and displayed on the left side of  FIG. 8 . 
         [0064]    The values for W 1 -W 6  in the above equation are weighting factors that may or may not equal 1 (a value of 1 not altering the total value of MPI PH ). As indicated by conducting clinical trials involving PH patients with known PH disease, pulmonary vascular or pulmonary arterial, and confirmed by right heart catheterization, individual weighting factors can be determined to fine tune the computation of MPI PH  for determining severity and type. 
       Description Scheme 
     MPI PH  Based Classification System 
       [0065]    In order to introduce the objectively measured value of MPI PH  into the more familiar NYHA/WHO classification system, the two are juxtaposed as illustrated in  FIG. 9 . The addition of the top line for an objective, non-invasive determination of the presence of PH extends the classification system to include a diagnostic indicator for the disease itself. When combined with other cardiopulmonary exercise test variables, such as ventilatory efficiency (VE/VCO 2  slope and ratio) and change in oxygen saturation (SpO 2 ), the present invention provides further diagnostic information to confirm or rule out the presence of PH. 
       Description Scheme 
     Trend Plot 
       [0066]    In order to provide a rapid assessment of the effect of any given therapy for PH over time, one example of a trend plot for MPI PH  values over time is illustrated in the graph in  FIG. 10 . In this example, the individual values of MPI PH  for each test date are plotted serially. However, there is no limitation intended in terms of the type of graph utilized or the visual effects employed. Alternatively, the Area O/Area U ratio can be plotted similarly in a time-sequential manner. 
         [0067]    When combined with other submaximal cardiopulmonary exercise variables (VE/VCO 2  slope, oxygen saturation (SPO 2 )) that have been demonstrated to change with drug therapy 5 , trend plotting of all will allow physicians to manage PH treatment for their patients. 
         [0068]    The invention has been described in considerable detail in order to comply with the Patent Statutes and to provide those skilled in the art with the information needed to apply the novel principles and to construct and use such specialized components as are required. However, it is to be understood that the invention can be carried out by specifically different equipment and devices, and that various modifications, both as the equipment details and operating procedures can be accomplished without departing from the scope of the invention itself. 
       REFERENCES 
       [0000]    
       
         1. Primary Pulmonary Hypertension. Lancet 1998; 352: 719-25-Gaine S P, Rubin L J 
         2. Ventilatory Expired Gas at Low-Intensity Exercise Predicts Adverse Events and Is Related To Neurohormonal Markers in Patients with Heart Failure, Ross Arena, PhD, PT, Dean MacCarter, PhD, Thomas P. Olson PhD, Sophie Lalande PhD, Maile L. Ceridon PhD, Lyle J. Olson, MD and Bruce Johnson, PhD  J Card Fail  2009 August; 15(6):482-8. Epub 2009 Feb. 10 
         3. The partial pressure of resting end-tidal carbon dioxide predicts major cardiac events in patients with systolic heart failure, Ross Arena, PhD, PT, Jonathan Myers, PdD, Mary Ann Peberdy, MD, Daniel Bensimhon, MD, Paul Chase, Med, and Marco Guazzi, MD, PhD Am Heart J 2008; 156:982-88 
         4. End-tidal PCO2 Abnormality and Exercise Limitation in Patients with Primary Pulmonary Hypertension. Yuji Yasunobu, et al. Chest 2005; 127:1637-1646 
         5. Ventilatory Efficiency and Dyspnea on Exertion Improvements are Related to Reduced Pulmonary Pressure in Heart Failure Patients Receiving Sildenafil,  Int J Cardiol.  2009 Mar. 27. [Epub ahead of print] PMID: 19329196, Guazzi M, Myers J, Peberdy M A, Bensimhon D, Chase P, Arena R