Methods for quantifying myocardial blood flow from nuclear medicine tomography images.

Abstract

A method for quantifying myocardial blood flow (F) from a single static tomographic image in nuclear medicine, comprising the steps of processing the tomographic image and calculating the myocardial blood flow, the integral of the activity versus time concentration curve of the blood concentration of the radioactive tracer from a single time sampling point.

Description

Detailed Description of the Invention

[0001] The present invention relates to a method for quantifying myocardial blood flow (F) from nuclear medicine tomography images, such as Positron Emission Tomography (PET), Single Photon Emission Computed Tomography (SPECT), and other nuclear imaging modalities capable of reconstructing images of the radioactivity concentration of a radioactive tracer.

[0002] The present invention makes it possible to quantify F from nuclear medicine static tomography images. TECHNICAL FIELD OF THE PRESENT APPLICATION

[0003] The technical field to which the invention pertains is the quantification of physiological parameters in animals, and in particular in humans, based on diagnostic images in nuclear medicine. [Current state of technology and problems to be solved]

[0004] The state of the art for quantifying myocardial blood flow (F) uses compartmental modeling to estimate this kinetic parameter (milliliters of blood per gram of tissue per minute). A compartmental model consists of a set of coupled differential equations, where each compartment represents a chemical state or spatial location of a tracer (e.g. extracellular space, intracellular space, free tracer, metabolic tracer, etc.). For each specific study, transfer coefficients between compartments (kinetic parameters: K1, K2, K3, K4, etc.) are estimated that minimize the error between the model predictions and the measured data. An example of a two compartment model is shown in Figure 1.

[0005] These models require knowledge of the input and output functions (activity concentration vs. time curves) of the model. The input curve typically represents the arterial blood concentration (Ca) and the output curve represents the concentration in the region of interest where one wishes to estimate blood flow, and these are obtained from dynamic imaging.

[0006] In nuclear medicine, dynamic PET or SPECT tomographic imaging (temporal sequences of 3D imaging) is used in myocardial perfusion studies to quantify Ca(t) and myocardial concentrations (Cm(t)) over time from measurements of the respective radioactivity concentrations in the left ventricular and myocardial imaging (i.e. regions of interest). An example of an activity-time concentration curve is shown in Figure 2.

[0007] The complete solution of the compartment model can be simplified by considering a single compartment model with K2 = 0 [Yoshida K, Mullani N and Gould KL 1996 Coronary flow and flow reserve by PET simplified for clinical applications using rubidium-82 or nitrogen-13-ammonia J. Nucl.Med.37 1701-12]. In this case, the following equation is proposed: Formula 1:

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[0008] where E is the extraction fraction of the radiotracer in the myocardium, F is the myocardial blood flow, Cm(t) is the uptake of the radiotracer in the myocardium at time t after administration of the radiotracer, and Ca(t) is the activity concentration of the radiotracer in the blood as a function of time (i.e., the arterial activity concentration). The extraction fraction E depends on the tissue permeability (PS) of the radiotracer used and is a function of blood flow. E can be modeled using the Renkin-Crone model based on the following equation: Formula 2:

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[0009] Myocardial blood flow can be obtained from K1, which takes into account the extraction rate E, based on the following formula [Bailing Hsu. PET tracers and techniques for myocardial blood flow measurement in patients with coronary artery disease. The Journal of Biomedical Research, 2013, 27(6):452-459. doi:10.7555 / JBR.27.20130136]: Formula 3:

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[0010] This simplified model showed good correlation with more complex compartment models and can be further simplified based on [Chang CY, Hung GU, Hsu B., Yang BH, Chang CW, Hu LH, Huang WS, Wang HE, Wu TC and Liu RS 2020.Simplified quantification of 13N-ammonia PET myocardial blood flow: A comparative study with the standard compartment model to facilitate clinical use. J. Nucl.Cardiol.27.819-28: doi.org / 10.1007 / s12350-018-1450-1].

[0011] In this paper, we use still images between t = 0 and t = 2 min to estimate the integral of Ca(t), and other still images between t = 2 and t = 5 min to estimate Cm(t), using the commercially available software HeartSee R We used the implementation available in. This simplification also showed good correlation with blood flow values ​​estimated by a more complex compartmental model.

[0012] In fact, there are already SPECT systems in which the detectors are arranged on a 180 degree (or more) arc, making it possible to acquire dynamic tomographic images of the heart at all angles simultaneously [patents: TWI611795B, US7683331B2, CN100374877C, US6504157B2, US7968851B2, US7705316B2, etc.]. Most conventional SPECT systems with one or two heads currently in use or on the market are either unable to acquire dynamic tomographic images or have very limited time resolution due to detector movement. This makes it difficult to acquire dynamic tomographic images and quantify myocardial blood flow with conventional SPECT systems.

[0013] In patent no. 4895080B2 a solution to this problem is proposed in which two stationary SPECT images of the heart taken at different times (t1, t2) are used for the determination of Cm(t) and Ca(t) is obtained from successive extractions of blood from the patient corrected for the activity concentration of the radioactive tracer in the plasma.

[0014] It should be noted that taking blood samples is an invasive and impractical procedure for clinical use.Against this background, in the present invention, the measurement of Ca(t) and Cm(t) is performed from a single static tomographic image at a given time, thus simplifying the imaging technique procedure.

[0015] In [van den Hoff J., Lougovski A., Schramm G., Maus J., Oehme L., Petr J., Beuthien-Baumann B., Kotzerke J. and Hofheinz F. 2014.Correction of scan time dependence of standard uptake values ​​in oncological PET EJNMMI Res. 4 1-14] the authors demonstrated that the shape of the 18F-FDG radiotracer input function curve (tracer concentration in blood) has an invariant shape between patients, since only the scale changes. In particular, the type of function that best describes the shape of the curve after the peak radioactivity concentration is a potential function of the form based on the following equation:

[0016] Formula 4:

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[0017] In patent application CN111436959A, dynamic PET images of the myocardium are used to determine the Ca(t) curve. A static image formed from the sum of all frames of the dynamic images is used for image processing (segmenting the heart and obtaining the Ca(t) and Cm(t) curves). A compartment model of multiple compartments is used to determine the motion parameters. Against this background, in the present invention, image acquisition and image processing are performed based on a single static tomographic image at a given time (T), and the motion parameter K1 is determined using Equation 3. OBJECTS OF THEINVENTION

[0018] The object of the present invention is a method for quantifying myocardial blood flow using a single (volumetric / three-dimensional) static tomographic image of cardiac nuclear medicine, avoiding the acquisition of standard dynamic tomographic images and the implementation of the complex procedures involved with dynamic tomography. The method is based on being able to calculate the integral of the activity concentration versus time curve of the blood concentration of a radioactive tracer from a single temporal sampling point (i.e. time point), as shown in Figure 4.

[0019] The arterial radioactivity concentration Ca(T) and myocardial concentration Cm(T) of the radiotracer are measured using static tomographic images, which avoid the acquisition of standard dynamic tomographic images and are acquired only once at a specific time T after administration of the radiotracer. Description of the drawings

[0020] For clarity and understanding of the purpose of the present invention, the following figures are provided:

[0021] Figure 1: A two compartment model belonging to the prior art and one of the differential equations describing said model. Ca(t): Concentration of arterial radioactivity as a function of time. K1: Transfer coefficient between arterial blood and compartment 1. K2: Transfer coefficient between compartment 1 and arterial blood. K3: Transfer coefficient between compartment 1 and compartment 2. K4: Transfer coefficient between compartment 2 and compartment 1. C1(t): Radioactivity concentration in compartment 1 as a function of time. C2(t): Radioactivity concentration in compartment 2 as a function of time.

[0022] FIG. 2: Radioactivity concentration curves (Bq / ml) of the 13N-ammonia radiotracer in the left ventricle (Ca(t)) and in the myocardium (Cm(t)) as a function of time (t) belonging to the prior art.

[0023] Figure 3: FIG. 13. Input curves of an exemplary embodiment of a radiotracer (13N-ammonia) in the left ventricle (Ca(t)) after the maximum concentration peak for different individuals. linear axis. Input curves of the radiotracer (13N-ammonia) of the exemplary embodiment in the left ventricle (Ca(t)) after the maximum concentration peak for different individuals. Logarithmic axis.

[0024] Figure 4: Graphical representation of the object of the present invention. Estimation of the integral of the radioactivity concentration vs. time curve of the blood concentration of a radioactive tracer from a single temporal sampling point (i.e., time point). The straight line corresponds to the integral (area under the curve) between time 0 and T.

[0025] Figure 5: For 34 tests of the exemplary embodiment, K 1c and

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[0026] FIG. 6: Segmentation of the left ventricle (LV) and myocardium (M) in static tomographic imaging axial tomography of the heart using PET / CT (Positron Emission Tomography / Multi-Cut Computed Tomography) technology according to an exemplary embodiment.

[0027] Figure 7: Analysis of agreement by the Bland-Altman method between the K1 values ​​obtained with an exemplary embodiment of the method of the present invention (K1) and the validated method described in the exemplary embodiment section (K1c). The solid line indicates the mean difference (dm = -0.01) and the dashed lines indicate the limits of agreement (dm ± 1.96 * SD) is indicated. Bland-Altman analysis of agreement between the F values ​​obtained by the exemplary embodiment of the method of the present invention (F) and the validated method described in the exemplary embodiment section (Fc). The solid line indicates the mean difference (dm = 0.12) and the dashed lines indicate the limits of agreement (dm ± 1.96 * SD) is indicated. Detailed Description of the Invention

[0028] Before proceeding to the description of the method proposed in the present invention, the preliminary steps of preparing the individual and acquiring and reconstructing the tomographic images are described below, which are not part of the object of the present invention and which are necessary as the same initial data ("input"). Preliminary step A of preparing the individual (not part of the object of the invention):

[0029] According to the recommendations of good clinical practice for the performance of myocardial perfusion studies using radioactive tracers (e.g., Argentine Association of Nuclear Biology and Medicine, European Association of Nuclear Medicine, Society of Nuclear Medicine and Molecular Imaging of the United States), a possible form of individual preparation would include the following steps:

[0030] Determining the conditions under which the myocardial perfusion test will be performed: at rest, during exercise, during pharmacological stress, during cold testing, etc.; placing the individual, with the heart in view, on a PET scanner (or hybrid modified PET / CT, PET / MRI (magnetic resonance imaging)), SPECT (or hybrid modified SPECT / CT, SPECT / MRI), or other nuclear imaging device capable of reconstructing an image of the activity concentration of a radioactive tracer; administering to the individual a radioactive tracer for intravenous myocardial perfusion; Wait sufficient time (at least 1 min after injection) to ensure the first passage of the radiotracer through the cardiopulmonary circuit before acquiring static tomographic images; Preliminary step B of the acquisition and reconstruction of tomographic images (not part of the object of the present invention):

[0031] A volumetric tomographic (3D) image of the individual's heart is acquired with a duration based on the detection sensitivity of the equipment used and the expected noise level in the reconstructed images, the latter affecting the level of uncertainty (standard deviation / mean value) of the final calculation; Record the time T (seconds) that elapses from the start of the radiotracer injection in step A3) to the start of the acquisition of static tomographic images in step B1); Reconstruct the images acquired in step B1) using an algorithm that includes a full physical model of the imaging process using attenuation correction, scatter correction, dead time, radioactive decay, detector sensitivity, and, in the case of PET, random matching, and optionally system spatial resolution and partial volume corrections.

[0032] Once the preliminary steps of preparing the individual and acquiring and reconstructing static tomographic images have been completed, the steps relevant for the purposes of the method of the present invention are described below:

[0033] Stage C of processing the tomographic images Depending on the clinical application, in the reconstructed image of step B3), segment the left ventricle, ascending aorta, or other regions of interest where blood radioactivity concentration can be sampled with minimal interference from adjacent tissues, and segment the myocardium based on step C2);

[0034] Based on the clinical application, either keep the myocardium as a single region of interest or divide the myocardium into subregions of interest. The subregions of interest are selected from the group consisting of vascular territories, cardiac segments, and other combinations of voxels. For example, the myocardium is divided into 17 segments as defined by the American Heart Association [Cerqueira et al, Standardized Myocardial Segmentation and Nomenclature for Tomographic Imaging of the Heart. Circulation. 2002|Volume 105, Issue 4:539-542];

[0035] Calculate and record the average of the voxel values ​​of the region of interest and sub-regions segmented in steps C1) and C2) according to the following formula: Formula 5:

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[0036] Stage D: Calculating Myocardial Blood Flow Adjust the radiotracer input function (blood activity concentration vs. time) using equation 4:

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[0037] In particular, reference is made to minimizing the distance between the fitting function and the measured data, for example by the least squares method (minimization of the L2 norm) or by minimization of the L1 norm.

[0038] Using equation 4 from step D1), calculate the coefficient A of the input function using the following equation:

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[0039] formula 7a

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[0040] Formula 8:

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[0041] For example, values ​​of α and β for the radioactive tracers 13N-ammonia and 82Rb are published in [Yoshida K, Mullani N and Gould KL 1996 Coronary flow and flow reserve by PET simplified for clinical applications using rubidium-82 or nitrogen-13-ammonia J. Nucl.Med.37 1701-12]. Exemplary embodiments

[0042] The following exemplary embodiment of the method described in this invention has been implemented. This exemplary embodiment is contrasted with a conventional dynamic test to demonstrate its correct functioning:

[0043] Thirty-four dynamic resting myocardial perfusion studies were analyzed. The studies were performed using PET / CT techniques with 13N-ammonia as a radioactive tracer in individuals with cardiovascular disease. The studies were performed on a GE Healthcare brand PET / CT hybrid scanner, model Discovery 710. The administered radioactivity was 3.2 MBq / kg, using a contrast infusion pump with an injection flow rate of 0.3 ml / s and a total saline volume of 40 ml. Dynamic image acquisition began simultaneously with the start of the intravenous injection and used the following time sequence: 35 s x 1 image, 5 s x 30 images, 20 s x 3 images, 30 s x 3 images, and 5 min x 1 final image. Each dynamic sequence image was reconstructed using the VuePoint HD iterative algorithm with 2 iterations, 24 subsets, 2.73 mm voxel size, 3.27 mm slice thickness, and a Gaussian smoothing filter with 7.0 mm full width at half maximum. During reconstruction, attenuation correction, scatter radiation correction, random coincidence and dead time correction, detector sensitivity correction, and cross-calibration with a dose calibrator were performed using a CT scan of the same anatomical region.

[0044] For each dynamic study, values ​​of the transfer coefficient K1c [ml / min / g] and myocardial blood flow Fc [ml / min / g] were determined using the software Carimas v2.10 applying a validated method according to [DeGrado TR, Hanson MW, Turkington TG, Delong DM, Brezinski DA, Vallee JP, Hedlund LW, Zhang J, Cobb F, Sullivan MJ, Coleman RE. 13N-labeled ammonia and positron emission tomography. J Nucl Cardiol. 1996 Nov-Dec;3(6 Pt 1):494-507. doi: 10.1016 / s1071-3581(96)90059-8.pmid: 8989674]. Until t=T

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[0045] The values ​​of Ca (T) and Cm (T) were obtained by measuring the average values ​​of voxels of the left ventricle and myocardium, respectively, using resting PET / CT tomography images of the heart corresponding to a time T after administration of the radiotracer 13N-ammonia, as shown in steps C1) and C2) of the method of the present invention. Figure 6 shows the segmentation of the left ventricle (LV) and myocardium (M) in the individual of this example.

[0046] The arterial input function Ca(t) was modeled by the function expressed in Equation 4 after the maximum arterial concentration peak in the left ventricle to determine the mean output (b = 0.4523) for the test group. Ca(t) was determined using the value at t = T measured in the left ventricle on PET / CT dynamic tomography images.

[0047] The coefficient A was calculated for each test within the group using the coefficient b above and the Ca(T) value of each test, using the formula stated in step D2).

[0048] For each test, up to t=T

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[0049] For each test, a new relationship is obtained from the correlation coefficient m estimated above in this example and the new Ca(t) integral calculated in the previous paragraph, using equation 6 described in step D3) of the method of the invention.

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[0050] For the transfer coefficients, the mean absolute error of prediction of the proposed method was estimated with respect to the previously validated methods and defined as the average of the absolute differences between K1c and K1 (or MAE, mean absolute error). Figure 7A shows the results obtained from the comparison between the two methods.

[0051] The time T corresponding to 360 seconds was chosen to minimize the MAE and to determine the best coefficient of determination (R 2 ) was obtained by considering

[0052] Using the obtained K1 values, the value of myocardial blood flow, called F, was determined for each test using Equation 8, Equation 9 and the coefficients α=1.34, β=0.48 for 13N-ammonia mentioned in step D4) of the method of the invention. Figure 7B shows the results obtained from the comparison of the values ​​of F between both methods.

[0053] The present invention, as defined by the method for quantifying myocardial blood flow from nuclear medicine tomography images as disclosed in the appended claims, is embodied in a data processing system. [Brief description of the drawings]

[0054] [Figure 1] 1 shows a prior art two compartment model and the differential equations that represent the model. [Diagram 2] 1 is a diagram of the radioactivity concentration curves (Bq / ml) of the 13N-ammonia radiotracer in the left ventricle (Ca(t)) and in the myocardium (Cm(t)) as a function of time (t) according to the prior art. [Figure 3A] FIG. 14. Input curves of an exemplary embodiment of a radiotracer (13N-ammonia) in the left ventricle (Ca(t)) after the maximum concentration peak for different individuals. [Figure 3B] FIG. 14. Input curves of an exemplary embodiment of a radiotracer (13N-ammonia) in the left ventricle (Ca(t)) after the maximum concentration peak for different individuals. [Figure 4] 1 is a graphical representation of the object of the present invention. [Diagram 5] For 34 tests of the exemplary embodiment, K1c and

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Claims

1. A method for quantifying myocardial blood flow from nuclear medicine tomography images, comprising the preliminary step B of acquiring and reconstructing tomography images, the step C of processing said tomography images, and the step D of calculating said myocardial blood flow, The preliminary step B comprises the following steps: B1) obtaining a volumetric tomographic image of the heart; B2) recording the time T in seconds that elapses from the start of administration of the radiotracer in step A3) to the start of acquisition of the static tomographic images in step B1); B3) reconstructing the images acquired in step B1); which is a step excluded from the method; The method comprises: The step C of processing the tomographic images comprises the steps of: C1) depending on the clinical application, segmenting the left ventricle, the ascending aorta, or other regions of interest in the reconstructed image of step B3) where blood radioactivity concentration can be sampled with minimal interference from adjacent tissues, and segmenting said myocardium based on step C2); C2) depending on the clinical application, maintaining the myocardium as a single region of interest or dividing the myocardium into sub-regions of interest, the sub-regions of interest being selected from the group consisting of vascular regions, cardiac segments, and combinations of other voxels; C3) calculating and recording the mean value of the voxels of the region and sub-regions of interest divided in steps C1) and C2) according to the following formula: [0010] Where: V ｍ is the average value of N voxel values ​​belonging to the region of interest defined in steps C1) and C2); V ｉ is the value of a single voxel belonging to the region of interest; The calculating step D comprises the steps of: D1) Adjusting the input function (blood activity vs. time) of the radiotracer using the following formula: [0025] Where: Ca(t) is the average value of the concentration of radioactivity obtained in step C3) in the left ventricle, the ascending aorta, or in any other region of interest in which the blood radioactivity concentration can be sampled with minimal interference from adjacent tissues that show the concentration of arterial radioactivity at time t=T; A is the variable being adjusted; T is the time after administration of the radiotracer recorded in step B2); and b is a power factor, the value of which is greater than 0 and is based on the test conditions defined in step A1) which determine the radiotracer used and the conditions under which the myocardial perfusion test is performed; D2) using the equation of step D1) calculating the coefficients A of the input function using the following equation: [0030] where T is the time after administration of the radiotracer recorded in step B2); D3) The input constant of the radioactive tracer into the myocardium, called K1, is defined as [ml / min / g ｔｉｓｓｕｅ ] using the following formula: [0045] Where: m is a coefficient based on the radiotracer, the conditions of the preliminary phase A myocardial perfusion study, and the population being studied; Furthermore, Cm(T) is the average value of the radioactivity concentration for the myocardium obtained in step C2); D4) [ml / min / g ｔｉｓｓｕｅ ], referred to as F, is at least 1×10 －３ Iteratively calculating using the following formula until an acceptable value in ml / min / g is achieved: [0050] Where: α and β are coefficients based on the myocardial perfusion radiotracer; In addition, the term α + β · F is the surface transmittance product of the Rekin-Cron model adapted to multiple capillaries.

16. A method for quantifying myocardial blood flow, comprising:

2. The region of step C1) preferably includes the left ventricle; 2. The method of claim 1, wherein said region of step C2) preferably comprises the complete myocardium.

3. The region of step C1) includes the left ventricle, 2. The method of claim 1, wherein the regions in step C2) include three of the vascular regions.

4. The region of step C1) preferably includes the left ventricle; 2. The method of claim 1, wherein said region of step C2) preferably comprises 17 of said cardiac segments.

5. The region of step C1) preferably includes the left ventricle; 2. The method of claim 1, wherein said region of step C2) preferably includes each voxel of said myocardium.

6. The region of step C1) preferably includes the ascending aorta; 2. The method of claim 1, wherein said region of step C2) preferably comprises the complete myocardium.

7. The region of step C1) preferably includes the ascending aorta; 2. The method of claim 1, wherein said regions in step C2) preferably include three of said vascular regions.

8. The region of step C1) preferably includes the ascending aorta; 2. The method of claim 1, wherein said region of step C2) preferably comprises 17 of said cardiac segments.

9. The region of step C1) preferably includes the ascending aorta; 2. The method of claim 1, wherein said region of step C2) preferably includes each voxel of said myocardium.

10. A method for quantifying myocardial blood flow according to any of claims 1 to 9, characterized in that the method is implemented in a data processing system.

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