Patent Publication Number: US-9883850-B2

Title: Assessment of right ventricular function using contrast echocardiography

Description:
RELATED APPLICATIONS 
     This application claims priority from U.S. Provisional Application Nos. 61/839,594, filed Jun. 26, 2013 and 61/977,344, filed Apr. 9, 2014, both entitled ASSESSMENT OF RIGHT VENTRICULAR FUNCTION USING CONTRAST ECHOCARDIOGRAPHY, the subject matter of which is incorporated herein by reference in its entirety. 
    
    
     TECHNICAL FIELD 
     This invention relates to medical diagnostic systems, and more particularly, to systems and methods for assessing right ventricular function using contrast echocardiography. 
     BACKGROUND 
     Right heart dysfunction is associated with poor outcomes in patients with valvular disease, cardiomyopathy, diastolic dysfunction, and pulmonary arterial hypertension, as well as patients having recent heart transplants. Conversely, preserved right ventricular function, even in the setting of elevated pulmonary arterial pressure, is associated with improved survival, decreased hospitalization, and improved exercise capacity in patients with chronic heart failure. Early diagnosis of right ventricular dysfunction could lead to more effective treatment and, ultimately, better outcomes. 
     SUMMARY OF THE INVENTION 
     In accordance with an aspect of the present invention, a method is provided for determining a right ventricular transit time for a patient. An echodense contrast agent is injected into a patient. A first representative region, representing the right ventricle of the patient, is selected. A second representative region, representing the bifurcation of the main pulmonary artery, is selected. Respective first and second time series of intensity values for the first and second representative regions are generated via echocardiography. The right ventricular transit time is determined from the first and second time series of intensity values. The right ventricular transit time is displayed to a user. 
     In accordance with another aspect of the present invention, a method is provided for determining a transit time for a patient. An echodense contrast agent is injected into a patient. First and second representative regions are selected. Respective first and second time series of intensity values are generated for the first and second representative regions via echocardiography. At least one inflection point is located in each of the first and second time series of intensity values. The transit time is determined from the at least one inflection point located in each of the first and second time series of intensity values and displayed to a user. 
     In accordance with yet another aspect of the present invention, a system is provided for non-invasive evaluation of right ventricular function using contrast-enhanced echocardiography. An ultrasound assembly is configured to image a region containing at least the right ventricle and the bifurcation of the main pulmonary artery to provide a first time series of intensity values representing the right ventricle and a second time series of intensity values representing the first branch of the main pulmonary artery. A parameter calculation component is configured to determine at least a right ventricular transit time (RVTT) from the first and second time series of intensity values. A modeling component is configured to provide a parameter representing the right ventricular function of the patient from at least the determined RVTT. An output device is configured to provide the parameter provided by the modeling component to a user in a human comprehensible form. 
     In accordance with still another aspect of the present invention, a method is provided for determining a transit time for a patient. An echodense contrast agent is injected into a patient. First and second representative regions are selected. Respective first and second time series of intensity values for the first and second representative regions are generated via echocardiography. A point of largest change is located in each of the first and second time series of intensity values. The point of largest change represents a time, m, that minimizes the following function of m: 
     
       
         
           
             
               
                 
                   
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     In this function, n is an number of intensity values in a given time series and I i , is an i th  intensity value in the given time series. The transit time is determined from the point of largest change located in each of the first and second time series of intensity values and displaying to a user. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  illustrates a system for non-invasive evaluation of right ventricular function using contrast-enhanced echocardiography in accordance with an aspect of the present invention; 
         FIG. 2  illustrates one example of a method for determining a right ventricular transit time in accordance with an aspect of the present invention; 
         FIG. 3  illustrates one method for determining a transit time via echocardiography in accordance with an aspect of the present invention; 
         FIG. 4  illustrates another method for determining a transit time via echocardiography in accordance with an aspect of the present invention; 
         FIG. 5  illustrates a first method for locating inflection points in a time series of intensity values; 
         FIG. 6  illustrates a second method for locating inflection points in a time series of intensity values; and 
         FIG. 7  is a schematic block diagram illustrating an exemplary system of hardware components for implementing the systems and methods described herein. 
     
    
    
     DETAILED DESCRIPTION 
     In accordance with an aspect of the present invention, a non-invasive and reproducible method of assessing the function of the right ventricle is provided. The complex morphology of the right ventricle and its location adjacent to the chest wall make thorough assessment of global right ventricular function via echocardiography difficult. Due to these limitations, ejection fraction, the clinical gold standard measurement of left ventricular function, cannot be accurately measured in the right ventricle by echocardiography. Surrogate measures of RV function such as Tricuspid Annular Plane Systolic Excursion, Right ventricular Index of Myocardial Performance, and tissue Doppler imaging are often employed as adjuncts to 2-D echocardiography, but are not ideal because their measurement is dependent on high quality images and adequate alignment with the ultrasound beam. In addition, these parameters vary based on cardiac loading conditions. Other options include cardiac MRI and right-heart catheterization. However, the former is expensive and not widely available and the latter is invasive and carries the inherent attendant risks. 
     To this end,  FIG. 1  illustrates a system  10  for non-invasive evaluation of right ventricular function using contrast-enhanced echocardiography in accordance with an aspect of the present invention. Specifically, the system  10  is configured to calculate at least a right ventricle transit time, that is, the amount of time that it takes blood to pass from the right ventricle to the first branch point (bifurcation) of the main pulmonary artery, as a metric for evaluating right ventricular function. The system  10  uses an echodense contrast agent, such as Definity or Optison, to facilitate this measurement. 
     The system  10  includes an ultrasound assembly  12  configured to image a region containing at least the right ventricle and the bifurcation of the main pulmonary artery. Specifically, the ultrasound assembly  12  is positioned with respect to a patient as to image at least a first representative region within the right ventricle and a second representative region at the bifurcation of the main pulmonary artery. In one implementation, the first representative region can be located between one and two millimeters from the coaptation point of the tricuspid valve and centered between the right ventricular free wall and the interventricular septum. In some applications, a third representative region can be provided in the left atrium as well to facilitate calculation of a pulmonary transit time (PTT). For example, the third representative region can be located one centimeter posterior to the mitral annulus and centered between the lateral left atrial wall and the interatrial septum. Accordingly, the ultrasound assembly  12  can provide intensity values over time for the first and second regions of interest. It will be appreciated that, when the representative regions are larger than one pixel, the intensity value for the regions can be an average (e.g., mean or median) of the intensity values of the individual pixels. 
     The determined intensity values are provided to a parameter calculation component  14  that determines at least a right ventricular transit time (RVTT) from the ultrasound intensity values. It will be appreciated that, when the echodense contrast agent is within a representative region, the intensity of the reflected ultrasound signal from that region will increase noticeably. The parameter calculation component  14  can be fully automated or can utilize an associated user interface in guiding a user in the calculation of the RVTT. In the illustrated implementation, the parameter calculation component  14  is implemented as machine readable instructions on a non-transitory computer readable medium, but it will be appreciated that the parameter calculation component can also be implemented as dedicated hardware (e.g., an application specific integrated circuit [ASIC] or a field programmable gate array [FPGA]) or a combination of software and dedicated hardware. 
     In one implementation, the parameter calculation component  14  can analyze a time series of intensity values for each representative region to determine a time interval between peak intensities of the first and second representative regions, representing the RVTT. Alternatively, a time at which the intensity exceeds a threshold value at a given representative region can be determined to be a “time of first appearance” for the contrast agent at that region, and the RVTT can be calculated as a time interval between the times of first appearance of the first and second representative regions. In still another implementation, inflection points representing a rise in signal intensity are determined from a time series of intensity values, with the RVTT determined from the inflection points. Methods for determining a transit time via location of inflection points is discussed in detail in  FIGS. 4-6  below. 
     In one implementation, multiple time intervals can be determined, for example, via repeated contrast injections, representing multiple transits of contrast agent through the right ventricle, and one of a median value, a mean value, and a weighted combination of the determined values can be utilized for the RVTT. In another implementation, a time interval between peak intensities of the first and third representative regions can be determined to provide a PTT. Each of the RVTT, the PIT, and a ratio of the RVTT to the PTT can be calculated and provided to a modeling component  16 . 
     The inventors have determined that a prolonged RVTT is indicative of right ventricular dysfunction. Accordingly, the modeling component  16  is configured to evaluate the right ventricular function of a patient based on at least one of the RVTT and the RVTT/PVT ratio to provide a parameter representing the right ventricular function. It will be appreciated that this evaluation can be diagnostic, where the parameter output from the modeling component  16  represents a likelihood that a patient currently has a particular defect in right ventricular function, such as an impairment in RV ejection fraction. Alternatively, the evaluation can be prognostic, with the output parameter representing the likelihood of a particular outcome in a given time frame or an expected time before a particular outcome. The predicted outcome can include, for example, a general diagnosis of heart disease, a specific cardiac disorder, death, or a need for a heart transplant. Further, it will be appreciated that the modeling component  16  can utilize additional relevant features associated with the patient, such as parameters representing systolic and diastolic function of the left ventricle, age, sex, medical history, family history, weight, height, and blood pressure. 
     The modeling component  16  can be implemented as any appropriate classification or regression model, such as a polynomial model provided via least squares regression procedure, an artificial neural network, a statistical classifier, a support vector machine, or a comparable model. Such a model can be trained on a set of calculated right ventricle transit times validated by existing methods, such as cardiac MRI or catheterization of the right heart, or observed outcomes. In the illustrated implementation, the modeling component  16  is implemented as machine readable instructions on a non-transitory computer readable medium, but it will be appreciated that the parameter calculation component can also be implemented as dedicated hardware or a combination of software and dedicated hardware. The results of the model are then provided to an output device  18  configured to provide the calculated parameter to a user in a human comprehensible form. The output device  18  can include one or more of a display, printer, speaker, or other appropriate device capable of providing the parameter representing the right ventricular function of the patient. 
     The determination of the RVTT and the RVTT/PTT ratio via contrast ultrasound provides a number of advantages. Echocardiography is inexpensive, widely available, and, while it requires some degree of training to perform accurately, there are a reasonably large number of technicians with the necessary training. This convenience allows contrast echocardiography to be readily used for serial measurements. Particularly when compared to cardiac MRI, determining the RVTT via contrast ultrasound takes less time, doesn&#39;t require gadolinium-based contrast, which is contraindicated for patients with renal insufficiency, and is freely available to patients with pacemakers, defibrillators, and other implanted devices. Further, the RVTT directly represents the function of the right ventricle, while alternate echocardiographic measures of RV function, such as TAPSE, RV fractional area chance, RV tissue Doppler imaging, or RV strain are either extrapolations of regional measurements to the entire RV or are often limited by the technical quality of the echocardiographic imaging. Even PTT is a relatively non-specific marker of RV pump function as it encompasses additional factors such as pulmonary vascular resistance and the pressure in the left atrium, thus diluting the relevance of these parameters to right ventricular function. 
     Having a safe, rapid, and reproducible measurement of global RV-pulmonary vascular function, as provided herein, will be of immense value to clinicians when making treatment decisions. The system is relatively straightforward to measure, non-invasive, and utilizes an imaging modality conducive to serial or ‘point-of-care’ measurements. The applications for echocardiographically derived RVTT and RVTT/PTT are plentiful. Several examples include serial measurements to gauge prognosis and response to treatment of pulmonary hypertension, distinguishing non-invasively PAH from PVH, pre-operative risk stratification (particularly for cardiac surgery), and assessment of RV function in left-heart failure. 
     In view of the foregoing structural and functional features described above in  FIG. 1 , example methods will be better appreciated with reference to  FIGS. 2-5 . While, for purposes of simplicity of explanation, the methods of  FIGS. 2-5  are shown and described as executing serially, it is to be understood and appreciated that the present invention is not limited by the illustrated order, as some actions could in other examples occur in different orders and/or concurrently from that shown and described herein. 
       FIG. 2  illustrates one example of a method  50  for determining a right ventricular transit time in accordance with an aspect of the present invention. At  52 , an echodense contrast agent is injected into a patient, for example, via a peripheral vein. The contrast agent can include any appropriate contrast material for contrast echocardiography. For example, a perflutren lipid microsphere, such as Definity or Optison, can be used. At  54 , first and second representative regions are selected, representing the right ventricle of the patient and the bifurcation of the main pulmonary artery, respectively. For example, the first representative region can be selected as a region between one and two millimeters from the coaptation point of the tricuspid valve and centered between the right ventricular free wall and the interventricular septum. In one implementation, a third representative region, representing the left atrium of the patient is also selected. 
     At  56 , respective first and second time series of intensity values for the first and second representative regions are generated via echocardiography. It will be appreciated that, since the echodense contrast agent will increase the intensity of the returned ultrasound signal when it passes through each region, the presence, absence, and relative intensity of the contrast agent at any given time can be effectively determined from these time series. In one implementation, a third time series of intensity values for the third representative region is also generated, representing the passage of the contrast agent through the left atrium. 
     At  58 , the right ventricular transit time is determined from the first and second time series of intensity values. For example, a time interval between a peak intensity in the first time series of intensity values and a corresponding peak intensity in the second time series of intensity values can be determined as the right ventricular transit time. Alternatively, the right ventricular transit time can be determined as a time interval between a first time at which the first time series of intensity values exceeds a first threshold intensity value and a first time at which the second time series of intensity values exceeds a second threshold intensity value. Where the third time series of intensity values is available, a pulmonary transit time can be determined in a similar manner from the first and third time series of intensity values. At  60 , the right ventricular transit time is displayed to a user. Where the pulmonary transit time is available, a ratio between the right ventricular transit time and the pulmonary transit time can be calculated as well and displayed to the user. In one implementation, any or all of the right ventricular transit time, the pulmonary transit time, and the calculated ratio can be provided as features to a statistical model configured to evaluate the function of the right ventricle of the patient. 
       FIG. 3  illustrates one method  100  for determining a transit time via echocardiography in accordance with an aspect of the present invention. At  102 , an echodense contrast agent is injected into a patient. At  104 , first and second representative regions are selected. For example, where the transit time is a pulmonary transit time, a first representative region could represent a right ventricle of the patient and a second representative region could represent a left atrium of the patient. Where the transit time is right ventricular transit time, a first representative region could represent a right ventricle of the patient and a second representative region could represent a bifurcation of the main pulmonary artery. 
     At  106 , respective first and second time series of intensity values for the first and second representative regions via echocardiography. At  108 , the data is filtered, for example, using a Savitzky-Golay filter. At  110 , a signal offset is determined and the signal is adjusted to remove the determined offset from all values. In the illustrated implementation, the offset is calculated such that the portion of the signal prior to the introduction of the contrast agent is reduced to approximately zero. At  112 , a cumulative sum statistic is calculated. The cumulative sum at a given intensity measurement, S i , is comprised of sequential additions of the difference between the observed signal intensities, and the signal mean, Ī, such that:
 
 S   i   =S   i-1 ( I   i   =Ī )  Eq. 2
 
     where I i  is an i th  intensity measurement in the time series and S 0 =0. 
     After the cumulative sum statistic is generated for the length of each time series, N, a largest change point for each series, that is, a point at which the signal exhibits a large change associated with the appearance of the contrast at the representative region is determined at  114  by identifying the point m which minimizes the mean squared error, MSE(m) when the signal is divided into two subsets, where: 
     
       
         
           
             
               
                 
                   
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     In one implementation, this point can be verified by inspection by a human operator. If, upon visual inspection, m does not appear to be coincident with the signal onset, for example, if a more abrupt change-point is identified elsewhere, such as on the decay portion of the IDC, the signal subset containing the initial rise is extracted, and the cumulative sum statistic is recalculated on this region. This is repeated until it is confirmed that m corresponds with the appearance of contrast. At  116 , the transit time is determined from the largest-change point located in each of the first and second time series of intensity values. The transit time is determined as a time interval between a first time, associated with a largest change point on the first time series of intensity values, and a second time, associated with the a largest change point on the second time series of intensity values. The transit time is displayed to a user at  118 . 
       FIG. 4  illustrates another method  130  for determining a transit time via echocardiography in accordance with an aspect of the present invention. At  132 , an echodense contrast agent is injected into a patient. At  134 , first and second representative regions are selected. For example, where the transit time is a pulmonary transit time, a first representative region could represent a right ventricle of the patient and a second representative region could represent a left atrium of the patient. Where the transit time is right ventricular transit time, a first representative region could represent a right ventricle of the patient and a second representative region could represent a bifurcation of the main pulmonary artery. 
     At  136 , respective first and second time series of intensity values for the first and second representative regions via echocardiography. At  138 , at least one inflection point in each of the first and second time series of intensity values is located. At  140 , the transit time is determined from the at least one inflection point located in each of the first and second time series of intensity values. For example, representative first and second inflection points, representing an initial rise in signal intensity to their associated time series, can be selected from the at least one inflection points for each time series of intensity values. The transit time is determined as a time interval between a first time, associated with the first representative inflection point, and a second time, associated with the second representative inflection point. The transit time is displayed to a user at  142 . 
       FIG. 5  illustrates a first method  150  for locating inflection points in a time series of intensity values. At  152 , a signal offset is determined and the signal is adjusted to remove the determined offset from all values. In the illustrated implementation, the offset is calculated such that the portion of the signal prior to the introduction of the contrast agent is reduced to approximately zero. At  154 , the data is filtered, for example, using a Savitzky-Golay filter. A Savitzky-Golay filter fits a polynomial of a given order to a frame size of a given number of data points, and in one implementation, a second order polynomial with a frame size of forty-one can be used. 
     At  156 , the data is then windowed to include only the baseline data and a ramp up in signal intensity upon appearance of the contrast agent. The data can be windowed either manually via user input or by an automated program. At  158 , a specified model is fit to the portion of the data that describes the rise in signal. In one implementation, the data fitting is performed via a non-linear least squares regression, such as the Levenberg-Marquardt method. In one implementation, the non-linear least squares regression fits the data to a sigmoidal function: 
     
       
         
           
             
               
                 
                   
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     where I(t) is the time series of intensity values and A, B, C, and D are parameters fit in the regression. 
     In another implementation, the non-linear least squares regression fits the data to a local-density random walk model: 
     
       
         
           
             
               
                 
                   
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     where I(t) is the time series of intensity values and m/Q, λ, μ are parameters fit in the regression. 
     At  160 , the derivative of the model fit is taken and a maximum of the derivative is located. The maximum value of this derivative corresponds with the inflection point of the signal rise of the model fit, 
       FIG. 6  illustrates a second method  170  for locating inflection points in a time series of intensity values. At  172 , the data is filtered, for example, using a Savitzky-Golay filter. At  174 , a derivative of the time series is calculated, for example, utilizing an appropriate numerical differentiation algorithm. At  176 , the calculated derivative is then windowed to provide a region of interest including only the baseline data and a ramp up in signal intensity upon appearance of the contrast agent. The data can be windowed either manually via user input or by an automated program. At  178 , a maximum value of the time-derivative is identified. At  180 , all location maxima within the region of interest are determined. For example, a peak-finding algorithm can be employed to locate the local maxima. At  182 , an inflection point is selected from the maximum value and the local maxima. In one implementation, the selection is made by a user, but it will be appreciated that an automated process could be used to select the inflection point. 
       FIG. 7  is a schematic block diagram illustrating an exemplary system  200  of hardware components capable of implementing examples of the systems and methods disclosed in  FIGS. 1-6 . The system  200  can include various systems and subsystems. The system  200  can be a personal computer, a laptop computer, a workstation, a computer system, an appliance, an application-specific integrated circuit (ASIC), a server, a server blade center, a server farm, etc. 
     The system  200  can include a system bus  202 , a processing unit  204 , a system memory  206 , memory devices  208  and  210 , a communication interface  212  (e.g., a network interface), a communication link  214 , a display  216  (e.g., a video screen), and an input device  218  (e.g., a keyboard and/or a mouse). The system bus  202  can be in communication with the processing unit  204  and the system memory  206 . The additional memory devices  208  and  210 , such as a hard disk drive, server, stand alone database, or other non-volatile memory, can also be in communication with the system bus  202 . The system bus  202  interconnects the processing unit  204 , the memory devices  206 - 210 , the communication interface  212 , the display  216 , and the input device  218 . In some examples, the system bus  202  also interconnects an additional port (not shown), such as a universal serial bus (USB) port. 
     The processing unit  204  can be a computing device and can include an application-specific integrated circuit (ASIC). The processing unit  204  executes a set of instructions to implement the operations of examples disclosed herein. The processing unit can include a processing core. 
     The additional memory devices  206 ,  208  and  210  can store data, programs, instructions, database queries in text or compiled form, and any other information that can be needed to operate a computer. The memories  206 ,  208  and  210  can be implemented as computer-readable media (integrated or removable) such as a memory card, disk drive, compact disk (CD), or server accessible over a network. In certain examples, the memories  206 ,  208  and  210  can comprise text, images, video, and/or audio, portions of which can be available in formats comprehensible to human beings. 
     Additionally or alternatively, the system  200  can access an external data source or query source through the communication interface  212 , which can communicate with the system bus  202  and the communication link  214 . 
     In operation, the system  200  can be used to implement one or more parts of a medical diagnostic system in accordance with the present invention. Computer executable logic for determining the right ventricle transit time resides on one or more of the system memory  206 , and the memory devices  208 ,  210  in accordance with certain examples. The processing unit  204  executes one or more computer executable instructions originating from the system memory  206  and the memory devices  208  and  210 . The term “computer readable medium” as used herein refers to a set of one or more non-transitory media that participate in providing instructions to the processing unit  204  for execution. These media can be local to the process or connected via a local network or Internet connection. 
     What have been described above are examples of the present invention. It is, of course, not possible to describe every conceivable combination of components or methodologies for purposes of describing the present invention, but one of ordinary skill in the art will recognize that many further combinations and permutations of the present invention are possible. Accordingly, the present invention is intended to embrace all such alterations, modifications, and variations that fall within the scope of the appended claims.