Wireless Measurement of Internal Body Dimensions for Patient Monitoring and Diagnosis

Abstract

A method is disclosed for continuous or intermittent wireless monitoring of cardiac ventricular volume with the ability to combine with pressure measurements for optimal remote monitoring of cardiac patients. A set of wireless position sensors or reflectors is placed within a cardiac ventricle (i.e., the left ventricle), the method including means for sensing pressure within one or more cardiac ventricles, and an external device configured to interrogate the wireless sensors to determine their relative and / or absolute positions with respect to each other and / or an external device, calculate the resulting ventricular volume, and create a pressure-volume loop.

Description

[Technical Field]

[0001] The present invention relates generally to the field of diagnostic medicine, and more particularly to in-body measurements using implantable medical devices, such as wireless sensors, that enable patient monitoring and diagnosis, as well as related systems, devices, methods, particularly computer-implemented methods, and software products. [Background technology]

[0002] Remote monitoring of cardiac patients, especially those suffering from congestive heart failure (CHF), is extremely challenging. Several methods exist for monitoring such patients, including monitoring symptoms, weight gain, ECG changes, thoracic impedance, and other parameters. However, these are of limited value due to suboptimal performance (e.g., in terms of sensitivity, specificity, and rapidity).

[0003] Currently, there are no optimal devices / methods to detect worsening heart disease at its early stages, so that further deterioration, hospitalization, and even death can be prevented.

[0004] This section is intended to introduce the reader to various aspects of art that may be related to various aspects of the present disclosure, which are described and / or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present disclosure. As such, it should be understood that these statements are to be read in this light, and not as admissions of prior art.

[0005] Recently, several devices have been introduced into clinical practice that allow for the measurement of left atrial pressure (LAP), with elevated LAP being considered a predictor of worsening CHF. This is achieved by placing a pressure sensor in either the pulmonary artery (indirect measurement) or the left atrium, which measures and transmits the results wirelessly. Although these devices have shown several advantages over traditional methods, their performance is still suboptimal and they rely on the measurement of a single parameter that is often not indicative of a particular person's condition.

[0006] The gold standard in research cardiology for the assessment of myocardial function is the measurement of ventricular volumes throughout the cardiac cycle (systole and diastole) and their correlation with simultaneous pressure measurements to produce pressure-volume loops (PVLs) in which each cardiac cycle is represented by a single loop (Sagawa, The End-systolic Pressure-Volume Relation of the Ventricle: Definition, Modifications, and Clinical Use, Circulation 63:6 pp. 1223-1227. 1981), the reference of which is incorporated herein by reference for all purposes. Analysis of these loops, whether of a single or a series of cardiac cycles, provides valuable information regarding important parameters of cardiac function, such as myocardial contractility during systole (inotropy), myocardial relaxation during diastole (lusotropy), preload, and afterload. This is currently possible only in experimental models or by performing continuous volume measurements using a conductance catheter, an invasive method that is not applicable to routine medical practice (Baan et al., Continuous measurement of left ventricular volume in animals and humans by conductance catheter, Circulation 70:5, pp 812-823 1984; and Burkhoff, Pressure-Volume Loops In Clinical Research, J. American College of Cardiology 62:13 pp 1173-1176 2013), the references of which are incorporated herein by reference for all purposes. Ventricular volumes can also be assessed by various testing methods, such as echocardiography, CT, or MRI. However, these are only available in hospitals or clinics and require specialized staff, making them unsuitable for remote ambulatory monitoring.

[0007] Echocardiographic measurements of ventricular volumes are also known to be prone to inter-examiner variability, and results may differ even between consecutive measurements by the same operator, as it is difficult to ensure accurate reproducibility of the plane or location measured.

[0008] Recently, automated methods for processing echocardiographic images have been used to measure ventricular dimensions. These include, among others, enhancing analysis by applying speckle tracking techniques or artificial intelligence (AI) algorithms (U.S. Patent No. 10,078,893, "Automated Left Ventricular Function Assessment," by Guterman et al.). However, these methods still require the acquisition of high-quality echocardiographic images, a task requiring a trained physician or technician, and are therefore not suitable for home monitoring of cardiac patients. Furthermore, the majority of patients with heart failure have a preserved ejection fraction (EF). These cases, generally caused by myocardial diastolic dysfunction, are referred to as "heart failure with preserved ejection fraction" (HFpEF). Therefore, their condition is often inaccurately assessed by relying solely on volumetric measurements without correlation with ventricular contour detection and simultaneous pressure measurements. Current practice for diagnosing HFpEF relies primarily on measurements of flow across the mitral valve and mitral annular velocity performed by Doppler echocardiography. However, these measurements are dependent on operator skill, have high inter-examiner variability, and are affected by a variety of other parameters. A consistent and reliable method for the diagnosis of HFpEF is still not available for routine clinical use.

[0009] Currently, no suitable devices or methods exist for reliable, user-friendly acquisition of cardiac pressure-volume loops, which are considered the gold standard for the assessment of ventricular function in routine cardiology practice. The ability to introduce measurement and monitoring of parameters derived from cardiac pressure-volume loops could significantly contribute to the management of heart failure and other cardiac diseases, improving patients' quality of life and reducing healthcare costs. Summary of the Invention

[0010] Accordingly, embodiments of the present invention preferably seek to mitigate, alleviate or eliminate one or more deficiencies, disadvantages or problems in the art such as those identified above, singly or in any combination, by providing devices / apparatus / systems, methods, computer readable media and software products, particularly in accordance with the appended claims.

[0011] The present disclosure includes methods, devices / apparatus / systems, computer-readable media, and software products suitable for or configured for continuous or intermittent wireless monitoring of bodily parameters, such as ventricular volume. As such, the present disclosure can provide important information regarding cardiac valve function as well as myocardium function. Optimal remote monitoring and / or diagnosis of cardiac patients can be achieved, particularly non-invasively, in combination with pressure measurements. Thus, in its aspects, the present invention provides a wireless sensing solution for monitoring PVL as well as ventricular volume, effectively providing the most important parameters of cardiac function without the need for trained medical professionals to acquire and analyze echocardiographic images. The method can be customized according to each patient's specific medical condition.

[0012] The present invention is designed as an easy-to-use device that can be operated by the patient, family members, or other non-professionals, and allows remote monitoring of CHF patients by wirelessly measuring intraventricular volume and pressure, either continuously or intermittently, to create a pressure-volume loop that provides the best estimate of cardiac function.

[0013] The main components of the main example include: A set of wireless position tracking sensors (preferably passive reflectors suitable for use with ultrasound signals). The tracking sensors are alternatively referred to in this disclosure as position sensors or position markers, all of which terms refer to the same type of wireless implantable element that can be tracked after implantation and the distance between them can be calculated. These are implanted in the body at relatively mobile locations, for example at various points on the walls of the ventricles. Once implanted, the positions of previously implanted sensors can be continuously tracked and the distance between them can be calculated. This allows for (for example) measurement of the volume of the ventricle (i.e., the left ventricle). · Means for sensing and transmitting pressure within one or more chambers (including atria and ventricles), ideally again using wireless means. An external device configured to track previously implanted wireless position sensors and determine their relative and / or absolute positions relative to each other and / or the external device, as well as take readings from the pressure sensor(s) and generate a series of ventricular PVLs for further analysis. The external device typically comprises one or more ultrasound transducers, which may take the form of a linear or matrix array.

[0014] As previously mentioned, the preferred embodiment for a position tracking sensor is to use a passive reflector for use with ultrasonic signals.

[0015] Pressure sensing can be achieved by an additional sensor, for example as a standalone sensor or alternatively integrated with some of the volume sensors of the present disclosure, but a third alternative is to not measure pressure and only track volume.

[0016] The present invention is intended for continuous or intermittent monitoring, primarily focused on the outpatient setting, which is useful for patients suffering from congestive heart failure (CHF), valvular heart disease, intracardiac shunts, etc., among other conditions.

[0017] The placement of the position sensor ensures that successive measurements over time are always taken in the exact same place or plane, thereby ensuring reliability and repeatability of the measurements. This allows the device to compare the results of each test with those of previous tests, thus providing the ability to not only determine whether results conform to generally accepted population-based normal values, but also to perform reliable trend analyses, with each patient as its own control. As such, the present disclosure can also be integrated into existing or future echocardiography devices used in clinics and hospitals to improve the diagnostic accuracy of routine echocardiography.

[0018] In one aspect of the present disclosure, a system for wireless cardiac diagnostics is described, the system comprising: a. a set of wireless location sensors configured to be placed within the ventricle (location sensors are alternatively referred to in this disclosure as location markers or tracking sensors, all of which terms refer to the same type of wireless implantable elements that can be tracked after implantation and distances between them can be calculated); b. pressure sensing means configured to sense pressure within the ventricle; c. An external device, i. once positioned, determining displacement between the wireless location sensors to provide displacement data; ii. determining pressure from the pressure sensing means to provide pressure data; iii. determining at least one pressure-volume loop (PVL) of ventricular pressure and volume based on the displacement data and the pressure data; and iv. an external device configured to determine a preferably real-time measure of cardiac health based on pressure-volume loop(s) (PVL); The system is thereby preferably configured to determine cardiac health wirelessly, non-invasively, continuously, and without the acquisition or analysis of high-quality echocardiographic images. Cardiac health preferably includes the presence and severity of heart failure, particularly in patients with diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF), but also relates to the function or dysfunction of one or more heart valves on the left and / or right side of the heart, and / or the measurements can be adjusted by external manipulation of the patient's body to generate a series of pressure-volume loops displaced relative to one another, for example, for calculation of end-systolic pressure-volume relationship (ESPVR), end-diastolic pressure-volume relationship (EDPVR), and other parameters of myocardial function related to cardiac health.

[0019] In some examples of the present disclosure, the wireless location sensor may be a solid or hollow shape selected from the group consisting of a sphere, a coil, a cylinder, a polyhedron, a corner cube, an ellipsoid, and a ring. In some examples of the present disclosure, the wireless location sensor may be a passive ultrasonic reflector with high ultrasonic reflectivity, where an external device uses an ultrasonic transmitter and receiver to cause reflections from the wireless location sensor.

[0020] In some examples of the present disclosure, the external device may be configured to determine the displacement of the wireless position sensor using true range multilateration or triangulation.

[0021] In some examples of the present disclosure, the external device may be configured to extract and process raw spatial data from the ultrasonic transducer(s) to determine the displacement of the wireless position sensor.

[0022] In some examples of the present disclosure, the pressure sensing means may be wireless.

[0023] In some examples of the present disclosure, the pressure sensing means may be incorporated into one or more of the wireless location sensors.

[0024] In a further aspect of the present disclosure, a method for determining cardiac health is described, comprising non-invasively determining a cardiac pressure-volume loop, the method comprising: a. continuously determining the displacement(s) between two or more position sensors pre-fixed in or to the ventricle, thus providing displacement data (position sensors are alternatively referred to in this disclosure as position markers or tracking sensors, all of which terms refer to the same type of wirelessly implantable element, which can be tracked after implantation and the distance between them can be calculated); b. continuously determining the pressure within the ventricle, preferably by a pressure sensor implanted within the ventricle or a non-invasive cardiac pressure sensor or method, thereby providing pressure data; c. forming at least one pressure-volume loop from the displacement and pressure measurement data; d. calculating at least one pressure-volume loop parameter configured to be indicative of cardiac health; whereby cardiac health is determined wirelessly, non-invasively, continuously, and without the need to acquire or analyze high quality echocardiographic images, the cardiac health preferably including the presence and severity of heart failure, particularly in patients with diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF); Such measurement information may be obtained, for example, regarding the function or dysfunction of one or more cardiac valves on the left side of the heart and / or the right side of the heart, and / or the measurements may be adjusted by external manipulation of the patient's body to generate a series of pressure-volume loops displaced relative to one another, for example, for calculation of the end-systolic pressure-volume relationship (ESPVR), the end-diastolic pressure-volume relationship (EDPVR), and other parameters of myocardial function related to cardiac health.

[0025] In some examples of the present disclosure, the wireless location sensor may be a solid or hollow shape selected from the group consisting of a sphere, a coil, a cylinder, a polyhedron, a corner cube, an ellipsoid, and a ring.

[0026] In some examples of the present disclosure, the wireless location sensor may be a passive ultrasonic reflector with high ultrasonic reflectivity, where an external device uses an ultrasonic transmitter and receiver to cause reflections from the wireless location sensor.

[0027] In some examples of the present disclosure, the external device may use multilateration or triangulation of real distances to determine the displacement of the wireless position sensor.

[0028] In some examples of the present disclosure, the external device may extract and process raw spatial data from the ultrasonic transducer(s) to determine the displacement of the wireless position sensor.

[0029] In some examples of the present disclosure, the pressure sensing means may be wireless.

[0030] In some examples of the present disclosure, the pressure sensing means may be incorporated into one or more of the wireless location sensors.

[0031] In another aspect of the present disclosure, a system is described that includes an implantable medical device for monitoring variable body geometry, the system comprising: a. one or more wireless location sensors configured to be placed at a set of body locations (location sensors are alternatively referred to in this disclosure as location markers or tracking sensors, all of which terms refer to the same type of wireless implantable element that can be tracked after implantation and distances between them can be calculated); c. An external device, i. once positioned, determining displacement between the wireless location sensors to provide displacement data; ii. an external device configured to determine an instantaneous measure of cardiac health based on a pressure-volume loop; This allows variable body geometry to be monitored, preferably continuously, non-invasively, and without the need to acquire or analyze high quality echocardiographic images.

[0032] In some examples of the present disclosure, the implantable medical device may further include at least one pressure sensor, preferably located in the same ventricle in which the position sensor is located, and the external device may further include means for determining pressure from the pressure sensor.

[0033] In some examples of the present disclosure, a wireless position sensor of the implantable medical device may preferably be placed within the ventricle so that left ventricular volume may be monitored and a pressure-volume loop may be determined. In yet another aspect of the present disclosure, software is described for determining cardiac health, including executable instructions for a processing unit of a device and performing the methods described herein. Cardiac health preferably includes the presence and severity of heart failure, including patients suffering from diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF). i. In yet a further aspect of the present disclosure, an external device for wireless cardiac diagnostics is described, the external device determining displacement data regarding displacement between a set of wireless position sensors (position sensors are alternatively referred to as position markers or tracking sensors in this disclosure, all of which terms refer to the same type of wireless implantable element, which can be tracked after implantation and distances between them can be calculated) placed within or in a cardiac chamber; ii. determining pressure data relating to pressure from a pressure sensing means configured to sense pressure within the ventricle; iii. determining a pressure-volume loop of ventricular pressure and volume based on the displacement data and pressure data; and iv. determining an instantaneous measure of cardiac health based on a pressure-volume loop; The device is thereby preferably configured to determine cardiac health wirelessly, non-invasively, continuously, and without the acquisition or analysis of high-quality echocardiographic images, where cardiac health preferably includes the presence and severity of heart failure, particularly in patients suffering from diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF), where such measurement information is obtained, for example, regarding the function or dysfunction of one or more heart valves on the left and / or right side of the heart, and / or where the measurements are adjusted by external manipulation of the patient's body to generate a series of pressure-volume loops displaced relative to one another, for example, for calculation of end-systolic pressure-volume relationship (ESPVR), end-diastolic pressure-volume relationship (EDPVR), and other parameters of myocardial function related to cardiac health.

[0034] While the foregoing examples have been described and illustrated in conjunction with systems and methods thereof, these are intended to be illustrative only and not limiting. Furthermore, as any specific reference may embody a particular method / system, although that does not yet require it, ultimately such teachings are intended to be all-encompassing, regardless of the use of a particular embodiment. [Brief explanation of the drawings]

[0035] Specific embodiments of the present invention will now be described with reference to the accompanying drawings. However, the present invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the disclosure to those skilled in the art. The terminology used in the detailed description of the embodiments illustrated in the accompanying drawings is not intended to be limiting of the invention. In the drawings, like numbers refer to like elements.

[0036] Embodiments and features of the present invention are described herein in conjunction with the following drawings.

[0037] [Figure 1] FIG. 1 is a block diagram illustrating system components. [Figure 2] 1 is a flowchart of one embodiment of system operation. [Figure 3] FIG. 1 is a schematic diagram showing location sensors / markers in place within the heart. [Figure 4A] 10A-10C show some possible embodiments of the external unit of the device. [Figure 4B] 10A-10C show some possible embodiments of the external unit of the device. [Figure 4C] 10A-10C show some possible embodiments of the external unit of the device. [Figure 4D] 10A-10C show some possible embodiments of the external unit of the device. [Figure 5] FIG. 1 shows a typical pressure-volume loop (PVL) of the left ventricle. [Figure 6] FIG. 1 shows a position sensor made up of several layers. [Figure 7A] 1A and 1B are diagrams illustrating examples of pressure-sensitive resonant devices. [Figure 7B] 1A and 1B are diagrams illustrating examples of pressure-sensitive resonant devices. [Figure 8A] FIG. 1 shows resonance curves for various pressures. [Figure 8B] 1 is a typical graph showing the relationship between resonance frequency and pressure. [Figure 9] FIG. 10 illustrates storage and analysis of pressure-volume results on a local external device and in a cloud-based database. DETAILED DESCRIPTION OF THE INVENTION

[0038] The present invention will be understood from the following detailed description of preferred embodiments, which are for purposes of illustration and not limitation. For purposes of brevity, some well-known features, methods, systems, procedures, components, circuits, etc. will not be described in detail.

[0039] The "gold standard" for assessing myocardial function and other important parameters of cardiac function is the pressure-volume relationship for the left ventricle, reflected in the "PVL" or pressure-volume loop for the left ventricle. To date, either invasive means, such as catheters, or ultrasound imaging and associated image processing have been employed to measure ventricular volumes. Invasive means have obvious drawbacks, while volumetric ultrasound requires the acquisition and analysis of high-quality images by echocardiographic experts, which are prone to inter-examiner variability. A representative PVL is shown in Figure 5.

[0040] The present disclosure describes a method for continuous or intermittent wireless monitoring of cardiac ventricular volumes with the ability to combine with pressure measurements for optimal remote monitoring of cardiac patients without the need to acquire or analyze high quality ultrasound images.

[0041] Monitoring of various body regions has been introduced, for example, in U.S. Patent No. 6,498,944 to Ben Haim, entitled "Intracorporeal Measurements," which discloses a catheter-based method for measuring the size of body regions and calculating the distance between them using a set of position sensors attached to the tips of one or more catheters. The position sensors include small coils that reflect electromagnetic waves that are produced and detected by appropriate equipment outside the body.

[0042] Similarly, U.S. Patent No. 10,918,858, entitled "Cardiac Volume Sensing with an Implantable Medical Device Supporting Cardiac Resynchronization Therapy," which is incorporated herein by reference for all purposes, discloses an implantable medical device having two electrodes coupled thereto and configured to identify a measure of impedance between the two electrodes.

[0043] Due to the obvious drawbacks of using either invasive means such as catheters or active electrical measurements, it is an object of the present disclosure to introduce a method that avoids both the use of catheters and active impedance measurements for determining time-varying body volumes.

[0044] The main components of the main examples of the present disclosure include one or more of the following: A set of wireless sensors placed within the ventricle (these sensors are referred to in this disclosure as position sensors, position markers, or tracking sensors, all of which terms refer to wireless implantable elements of the same type that can be tracked after implantation and the distance between them can be calculated). These are preferably passive devices configured to have high ultrasound reflectivity. Using spatial information obtainable from real-distance multilateration, triangulation, or similar means, or from ultrasound transducers per specific design, the positions of the sensors can be continuously tracked and the distance between the sensors can be calculated, allowing the volume of the ventricle (i.e., the left ventricle) to be determined. The wireless sensors can be passive reflectors that can be tracked using ultrasound signals. · Means for sensing pressure within one or more ventricles. An external device configured to track the wireless sensors and determine the relative and / or absolute positions of the wireless sensors relative to each other and / or the external device. The external device generally comprises one or more ultrasonic transducers, which may take the form of a linear array, a phased array, or a matrix array.

[0045] A block diagram of one embodiment of the system components of a wearable external unit is shown in Figure 1. On the left side is shown the external unit having a signal source and receiving module, preferably one or more ultrasound transducer elements, communication means, a processing module, relative position determining means, display means, and a power supply that powers all of these components. On the right side is shown the sensors embedded in the system, including two or more position sensors and at least one pressure sensor. As mentioned above, a pressure sensor may not be required, which may be the case when using the present disclosure for a particular clinical indication.

[0046] In another embodiment, the external unit of the present disclosure may also be integrated, in whole or in part, into existing or future echocardiography devices used in clinics and hospitals to improve the diagnostic accuracy of routine echocardiography.

[0047] The communication means of the external unit may include modules intended for communication with other devices such as PCs, smartphones, etc., as well as with other components of the system.

[0048] The display means of the external device allows operation of the device as well as providing user feedback regarding signal quality, analysis of results, etc.

[0049] An example of an embodiment of an implantable component of the present disclosure with one pressure sensor and two position sensors (position sensors may alternatively be referred to as position markers or tracking sensors) is shown in Figure 3. A left ventricle 301 is provided with position sensors 302a-c and a pressure sensor 303.

[0050] The position sensors are tracked by external means (in the preferred embodiment this is by using ultrasonic reflections from passive sensors, but could also be implemented by electromagnetic sensors or other means) to determine their relative displacement Δx and absolute distance.

[0051] Further shown in Figure 3 is an example of a specific location for a position sensor within the left ventricle. Figure 3 shows the heart in an apical 4-chamber view, one of the views commonly used during echocardiography. The distance (L1) between a position sensor placed on the endocardial surface of the ventricular apex and a position sensor placed on the endocardial surface of the ventricular lateral wall represents the longitudinal or axial dimension of the left ventricle, which is commonly used by experts in the field to assess global longitudinal shortening or strain (GLS), while the distance (L2) between two position sensors placed at opposite locations on the transverse plane of the ventricle represents the horizontal dimension of the ventricle at a specified level.

[0052] Based on the assumption that the left ventricle resembles an oval and that the distance L2 is similar to the distance perpendicular to it between the endocardial aspects of the ventricular wall at the same level, simultaneous measurement of the two distances (L1 and L2) allows the calculation of the left ventricular volume according to the following formula:

[0053]

number

[0054] Although the formula for calculating the volume of an ellipsoid to estimate ventricular volume is well established in cardiology practice, other formulas may be used to calculate ventricular volume from the distance between position sensors. These may be derived from actual measurements of ventricular volume using imaging modalities such as CT, MRI, and echocardiography by nonlinear regression or other mathematical techniques. However, other formulas may be used depending on the exact location where the position sensors are placed, as well as the data accumulated for particular patients and patient groups and populations.

[0055] In addition to estimating ventricular volume as described above, changes in the distance L1 between diastole and systole also allow for the measurement of global longitudinal shortening (GLS), a parameter of growing interest as an indicator of myocardial function. Specifically, the distance between a sensor placed at the apex and a sensor placed near the base of the lateral ventricular wall is measured at end-diastole and end-systole to calculate GLS.

[0056] In embodiments using passive ultrasound reflectors, the shape, size, design (solid or hollow), surface features, and material of the reflector affect the nature and strength of the reflection from the reflector. The difference between the acoustic impedance of the reflector and the acoustic impedance of the surrounding medium determines the strength of the reflection, or "reflection coefficient." The table below lists the acoustic impedance of several materials along with the predicted reflection coefficient at the blood-material interface. Therefore, the materials in the table all have predicted reflectivities near or above 80% and may be good candidates for reflectors depending on their biocompatibility. Non-biocompatible materials can be coated with or encapsulated within a biocompatible material. Such materials may include polyurethane, ceramic, medical-grade silicone, titanium, nitinol, and others, among others.

[0057] [Table 1]

[0058] While it is within the scope of the present invention to use any material for the reflector, formed into any shape, it may prove useful to use a regular polyhedron, a cylinder, a "corner cube," or a sphere for the reflector, since reflection depends on the orientation of the reflector (which may change with heart wall movement and cannot be controlled). Corner cubes have the useful property that the reflected wave is entirely in the direction of the incident wave. Whatever the shape, the reflector may be hollow, preferably filled with air, to take advantage of the nearly complete further reflection of the transmitted wave at the reflector's inner walls.

[0059] Smooth, hollow titanium or nitinol spheres with diameters of a few wavelengths are examples of simple, biocompatible, isotropic specular reflectors. Medical ultrasound systems often use frequencies of 3.5 MHz with wavelengths of 0.44 mm, necessitating the use of spheres with diameters of approximately 1 mm or larger. However, the reflector size can be such that it provides optimal reflection for any wavelength currently or in the future used in cardiac imaging.

[0060] In another possible embodiment, the passive reflector can be made from a porous material containing air or fluid bubbles or pores with sizes ranging from tens to hundreds of micrometers (μm). One such material that can be used for the reflector is hydroxyapatite, a biocompatible material that can be manufactured with various densities and porosities and is already used in various medical implants, primarily in the orthopedic and dental fields. Hydroxyapatite can be classified as a ceramic material and is just one example of this material group. There are also metallic biocompatible materials, such as nitinol and stainless steel, that can be produced with various porosities. Similarly, various biocompatible polymers, such as polyethylene, polyurethane, and poly(lactic-co-glycolic acid) (PLGA), can also be used to manufacture position sensors.

[0061] Porous materials have unique "ultrasound signatures," depending on factors such as the size and distribution of the pores. Such materials contain multiple air (or fluid)-solid interfaces, each with specific reflection, absorption, and scattering patterns. The presence of multiple interfaces between the solid matrix and the pores can lead to multiple reflections of ultrasound, creating complex patterns within the material such that the overall reflected signal from the porous reflector can be distinguished from reflections generated by surrounding tissue.

[0062] As will be understood by those skilled in the art, reflectors used for the purposes of the present invention may also include resonant devices, which have one or more resonances that can be easily detected by appropriate signal processing methods employed by an external interrogation device. It is within the scope of the present invention that the resonances of reflectors used for position detection can be made distinguishable by using objects with different resonance characteristics, such as the hollow spheres mentioned above, each with a different outer and / or inner radius; solid spheres of different radii; porous materials with different porosities, pore sizes, and void materials; or 2D or 3D arrays of spheres. As a simpler alternative to large arrays, several linked position sensors can be arranged in a known pattern to generate unique return signals. Because the resonances of the objects being used can be fully characterized before use, the process of detecting their reflections and triangulating their positions is somewhat simplified.

[0063] Another embodiment for a position sensor involves resonance. Resonant devices also use acoustic (ultrasonic) waves emitted from an external transducer toward the sensor element. However, in this case, instead of simply reflecting a portion of the input signal, the sensor element resonates when it absorbs an input signal close to the element's frequency. Each sensor's specific natural frequency results from its physical properties (e.g., stiffness, mass, and geometry), giving it unique characteristics that can be detected by analyzing the resulting (reflected) signal. The external acoustic wave is ideally emitted at a frequency that provides an optimal amplification-to-attenuation ratio, resulting in the best SNR. A resonant object vibrates easily at one of its resonant frequencies and less strongly at other frequencies. This "picks out" the resonant frequency from complex excitations, such as impulse or broadband noise excitations, effectively filtering out all frequencies other than the resonance. As discussed in the pressure sensing section below, this resonant frequency can depend on external pressure, and changes in this resonance can be sensed by the external device of the present invention, enabling position and pressure sensing with a single device.

[0064] Calibration allows the distance Δx between two (or more) sensors and the volume of the left ventricle V LV Since the relationship between distance and volume is highly dependent on the location of the sensor within the ventricle and the size, morphology, and function of the individual patient's heart, calibration is performed once during the procedure in which the sensor is placed, and then the relationship between distance Δx and volume V can be determined. LV is used to determine the pressure-distance relationship. If the patient undergoes cardiac catheterization for other indications, the calibration may be repeated. Furthermore, it may be the case that the exact shape or coefficient of the calibration is not important, but rather that changes in the pressure-distance relationship over time prove to be sufficiently clinically significant. In this case, the distance-pressure curve may be used as a surrogate for the volume-pressure curve. Also, a volume calculated from two distances (as described above for the volume of an ellipsoid) may be used to generate a pressure-volume loop without the need for calibration with absolute volume measurements.

[0065] In another example, illustrated in FIG. 6, the position sensor (501) may include several layers (502a-502d), each with a specific thickness and acoustic impedance. The reflected ultrasound beam travels back from each interface between the layers (502a-502d) in a time dependent on the thickness, but the signal strength is proportional to the reflection coefficient at the interface between the layers (502a-502d). In such a design, reflectors with specific "signatures" (503) are produced, allowing multiple reflectors (501) to be used and distinguished during tracking. The unique reflector signatures (503) can be displayed as a "bar code," where the width of each bar (504a-504d) corresponds to the thickness of the layer (502a-502d), and the color or gray scale corresponds to the acoustic impedance of each layer (502a-502d). The bars (504a-504d) can be arranged in an inside-out direction or vice versa. The display of the barcode (503) is not required for the actual implementation, but can serve other purposes of the system. For example, a user may scan the barcode (503) of a particular reflector (501) and request the system to locate only this particular reflector (501).

[0066] A simplified flowchart of one embodiment of the present invention is shown in Figure 2. First, the sensor of the present disclosure is implanted by the means described below. Once implantation is complete, the calibration steps described above are performed as needed. These steps are generally performed in a hospital. After discharge, the patient, family member, or other non-professional can activate the external device and repeatedly perform a sequence of distance and pressure measurements. This is done by moving the ultrasound transducer, or a belt holding a series of ultrasound-emitting and receiving elements, until feedback is received from the external device in the form of a color indicator, sound, or other form, confirming that good signal quality has been achieved and instructing the patient to maintain this position as steadily as possible. The device then repeatedly measures the distance between the position sensors and correlates them with pressure measurements until several pressure-volume loops (PVLs) can be generated. Upon completion, the user receives another "Complete" feedback, confirming a satisfactory testing session, and may power off and remove the device from the chest. The PVL allows for the calculation of several values, including cardiac preload, afterload, and measures of myocardial contractility and relaxation. A measurement validation step is performed, and if the measurement is valid, the results may be stored and transmitted to the network. The results may also be compared to predefined thresholds, and if exceeded, an alert may be issued. Results may also be compared to previous test results for the same patient, and deterioration or worsening may be detected even if the absolute values ​​are still within the normal range. This may take the form of a local alarm, or an alert sent to a healthcare provider, telephone contact, or the like. The frequency of measurements may be determined by the treating physician based on the type and severity of the patient's disease, and may range from once or several times per day to once or several times per week to enable useful predictions of cardiac behavior in time to intervene as needed.

[0067] As shown in FIG. 9 , the results of each test (parameters derived from pressure-volume data) can be stored on an external device 1102 for comparison with previous or subsequent tests. To enable comparisons across multiple patients, test results can preferably be sent to a cloud server 1104 associated with the present invention, for example, by a smartphone or other personal device 1103. These devices can communicate with the external device 1102, for example, by Bluetooth or other communication means, while the personal device 1103 can communicate with the Internet by Wi-Fi or other network means. This allows a physician and / or the system's algorithms to perform individual trend analyses 1101 to determine whether a patient's cardiac health remains stable, worsens, or improves, and also enables various types of cohort analyses of multiple patients.

[0068] Each test result may also be uploaded to the cloud database 1103 via the internet or other modes of communication using a smartphone, PC, etc. This allows for the creation of a large population-based database, increasingly accumulating test results from multiple patients, that allows users and / or algorithms of the present invention to perform trend analyses on individual patients as described above, as well as compare each patient's results to constantly updated normal and pathological pressure-volume data parameter ranges. This allows for the implementation of artificial intelligence (AI) tools and machine learning algorithms to analyze the pressure-volume data, recognize patterns in the data related to cohorts of patients as well as single patients, and make predictions or decisions based on that analysis.

[0069] The physician can be provided with test result updates directly from the external unit or via a cloud database and data processing system, and alerts can be issued when necessary, allowing appropriate pharmacological adjustments to be made accordingly.

[0070] While the present invention is intended for use in an outpatient or home setting, as depicted in Figure 2, the high-quality, operator-independent measurements provided by the technology and based on the present disclosure can be used in hospital or clinic settings where the technology can be integrated into existing or future ultrasound devices and transducers, providing clinicians with a reliable and consistent method for assessing the presence and severity of heart failure, particularly in the subset of patients with diastolic dysfunction or HFpEF.

[0071] The cloud database (or any equivalent) is used to store and analyze individual and population data for cardiac function parameters derived from analysis of pressure-volume loops, as well as other clinically significant parameters derived from ventricular dimensions alone. These include, among others, ejection fraction, end-diastolic volume, stroke volume, cardiac output, cardiac index, and global longitudinal shortening (GLS). Furthermore, the database also allows for correlation of any parameter of cardiac function generated by the present invention with all other clinically relevant information (i.e., age, sex, weight, blood pressure, medications, comorbidities, previous clinical signs, and hospitalizations, etc.).

[0072] In a preferred embodiment, the position sensor may be any kind of passive reflector configured to return any predetermined specific wavelength, preferably ultrasonic.

[0073] In another embodiment, the sensor may be active, for example receiving power from an external source such as radio frequency or ultrasound and transmitting data to an external receiver by RF or any other applicable wireless transmission method, or may be powered by an internal power means such as a battery or energy harvesting means. The sensor may be made of any material configured to interfere with, reflect, or transmit any particular wavelength or set of wavelengths of sound, ultrasound, electric field, magnetic field, or other type of energy.

[0074] In yet another embodiment, the sensor may be a piezoelectric ultrasound measurement crystal that receives power from an external source, such as radio frequency or ultrasound, emits ultrasound signals to and receives ultrasound signals from other piezoelectric ultrasound measurement crystals implanted at various locations within the ventricle, and transmits data by wireless means to an external device.

[0075] The ultrasound transducers are configured to function as a "medical radar" or data transmission system. To be able to determine the precise location of each sensor, the method requires a method for achieving true-range multilateration or triangulation (similar to applications such as surveying, navigation, etc.). This can be achieved by using a series of existing ultrasound transducers (i.e., a phased array) or by creating a series of custom arrays with angled ultrasound transmitting and receiving elements relative to each other, such as within a single probe or on a strip / belt, to allow for angular adjustment. Such an implementation is shown in FIG. 4, where the phased array is placed on a band around the chest and positioned directly over the heart for clear signals. An alternative embodiment of the method can be performed by using a matrix ultrasound probe that scans in two mutually perpendicular planes and extracting spatial information from the transducers, such that true-range multilateration or triangulation is not required.

[0076] An embodiment using a chest strap carrying an ultrasound probe is shown in FIG. 4A. Here, a belt or strap 401 is provided with a matrix ultrasound probe 402 utilizing a set of transducer elements. Alternatively, a set of several linear (or phased) arrays 403, as shown in FIG. 4B, may be used. The linear arrays are generally angled relative to one another. Each array may be linear 403 (FIG. 4C) or may itself be in the form of a matrix array 406 (FIG. 4D). The array generally has a set of (transmit and receive) transceiver elements 404 (FIG. 4C), although in some implementations separate elements may be used for transmit and receive. In FIG. 4D, the transceiver elements 407 are shown in a square matrix. FIG. 4C shows a relatively flat beam pattern 410 of a linear array scanning a "slice" of an organ, while FIG. 4D shows a more volumetric (pyramid-shaped) scan pattern 411 of a matrix array. The arrays and elements may be angled relative to one another. The belt carrying the array(s) is worn obliquely on the chest over the intercostal spaces, using an "acoustic window" between the ribs to allow ultrasound signals to reach the heart unobstructed by bone and cartilage. This approach is similar to the commonly used apical four-chamber and parasternal long axis views.

[0077] It is within the scope of this disclosure that suprasternal and substernal approaches may be applied using handheld transducers without the use of such belts. In the case of a matrix probe or matrix array, such as that shown in FIG. 4D, a single probe may be sufficient because the probe scans in two planes perpendicular to each other. It is within the scope of this disclosure to use any of the available acoustic windows, including the parasternal and apical windows mentioned above, as well as subcostal, suprasternal, and other windows that may be found useful in the practice of this invention.

[0078] It is within the provisions of this disclosure that various configurations of transducers or sets of transducers (including transceivers or separate transmitters and receivers) may be used to accommodate specific clinical needs.

[0079] For example, if it proves impossible to mount all the necessary electronics, power source, display means, communication means, etc. on the chest strap as in Figure 4, the external unit may be split into two physical parts. Thus, the chest strap of Figure 4 may carry ultrasound arrays, while a separate power / computation unit in communication with these arrays performs data analysis, cloud transmission, power supply, etc. This separate power / computation unit may be in wired or wireless communication with the chest strap transducers.

[0080] It is within the scope of the present disclosure for the ultrasound elements to include separate or unitized transmitting and receiving elements, with the array configured to be placed in contact with the skin, e.g., disposed on a flexible substrate configured to conform to the body to promote good contact with the skin. To ensure proper coupling of the ultrasound signal to the subject's skin, an encapsulated gel unit may be used between each transducer and the skin. Alternatively, the recess in the element holding the transducer opposite the skin may be filled with coupling gel before each test.

[0081] The position and angle of the ultrasound transducer are determined in a manner that ensures acquisition of good quality signals from passive reflectors according to their specific location within the heart, which may include the intercostal space, substernal, or suprasternal, among others.

[0082] As will be apparent to those skilled in the art, an advantage of a phased array is the ability to control the directionality of the main beam. This can be used, for example, by scanning the beam over an area to simultaneously detect and track at least two reflectors, and then using the angle at which the response is greatest to achieve a high SNR. The number of elements in each transducer and their drive order are adjusted to ensure optimal performance. Similarly, the drive delays of the elements are optimized to minimize interference between their signals. When implemented as a collection of arrays, the delay between the drive of each array can be adjusted to achieve optimal performance and avoid signal interference.

[0083] As known to those skilled in the art, multiple ranges (distances) between a moving object and multiple spatially separated known locations are used to determine the position of the moving object. In an ultrasound probe, each transmitter / receiver element acts as an independent reference. Combining multiple ultrasound probes with multiple transmitter / receiver elements, configured as a linear array (or phased array) or matrix probe, provides multiple measurements taken from different angles, ensuring high accuracy and spatial resolution.

[0084] As mentioned above, methods and apparatus for determining the distance between two or more sensors are also provided. The present invention may also be applied to the continuous or intermittent tracking of multiple sensors and the determination of their relative positions.

[0085] Specifically, the present disclosure enables measurement of the distance between two or more sensors within a cardiac chamber (i.e., the left ventricle). The position of each sensor relative to an external device can be determined using multilateration or triangulation of actual distances, or alternatively, the absolute position of the sensor can be determined and then the distance calculated by simple geometric means.

[0086] When using a matrix ultrasound probe, the inherent property of the transducer, which scans the target volume in two mutually perpendicular planes, allows for the calculation of the distance between sensors, possibly without the use of traditional real-distance multilateration or triangulation.

[0087] Magnetic field means may also be used (instead of or in addition to ultrasonic means) to sense the relative or absolute position of a wireless sensor, in which case the implantable sensor would have a special magnetic structure suitable for remote detection.

[0088] Sensors can also be placed in more than one ventricle (e.g., the left atrium and left ventricle, or the left and right ventricles). In some applications, sensors can be placed adjacent to a ventricle rather than within it (i.e., the coronary sinus, aorta, pulmonary artery or vein, inferior or superior vena cava). Sensors can be integrated into any existing or future implantable cardiac device, such as a prosthetic valve, PFO occluder, pacemaker, implantable cardioverter defibrillator (ICD), or left ventricular assist device (LVAD). Sensors are matched with specific geometries, materials, surfaces (smooth-rough), or echogenic coatings and engineered to respond to specific energies / signals to create specific reflective footprints ranging from "stealth" to noisy (corresponding to non-reflective or low-reflective to high-reflective, respectively).

[0089] The sensor (reflector) can be in the form of an encapsulated cluster of microbubbles.

[0090] In one embodiment of the present disclosure, sensors may be delivered to their target location by a transcatheter approach, via the arterial system to the left ventricle or via the venous system to the right ventricle. The left ventricle may also be reached by a venous route through a transseptal puncture in the right atrium to the left atrium.

[0091] It is expected that most sensor implantation procedures will be performed as an additional step during cardiac catheterization or cardiac surgery (e.g., open-chest surgery, minimally invasive surgery, transapical surgery, transmural surgery, etc.) performed for other purposes, such as coronary angiography, valve repair or replacement, etc. Alternatively, sensor placement may be performed in a stand-alone procedure. Another method for placing sensors at their target locations may employ an injection mechanism whereby the sensors are implanted into the myocardium and instantly covered by surrounding tissue, potentially eliminating the need for further fixation.

[0092] The sensors can be positioned at their targets on the ventricular wall by several methods, including, but not limited to, attachment via hook-like or spring-like mechanisms, self-expanding nitinol anchors, or other means that will be apparent to those skilled in the art. It is anticipated that the sensors will undergo endothelialization over a short period of time, eliminating the need for anticoagulation therapy because they are no longer exposed to blood within the heart. However, the functionality of the passive reflector is not affected by being covered by endothelium or implanted within the myocardium. Fixation of the sensor to the myocardium is not just a safety feature; it ensures that successive measurements over time are always taken at the exact same location or plane, ensuring reliability and reproducibility of the measurements.

[0093] As discussed above, the sensors are made of or coated with biocompatible materials, and the materials used need to be non-degradable to ensure a durable lifespan.

[0094] Measurements can be performed sporadically or continuously in real time. Assuming a heart rate of 60-120 bpm (cardiac cycle of 0.5-1.0 seconds), a sufficiently high sampling frequency is used to achieve the desired time resolution, particularly to avoid missing precise points of deflection in the PVL curve. By way of non-limiting example, a sampling frequency in the range of 20-100 Hz provides the desired time resolution.

[0095] In a preferred embodiment, where a passive ultrasound reflector is implanted within the heart to determine volume, the external device comprises an ultrasound transducer. For echocardiography, most transducers operate at frequencies between 2 and 4 MHz, allowing for the required depth of penetration within the chest.

[0096] Although the external devices described in this disclosure may be custom-made for remote monitoring applications, the high-quality, operator-independent measurements provided by the technology and based on this disclosure may be used in hospital or clinic settings where the technology may be integrated into existing or future ultrasound devices and transducers, providing clinicians with a reliable and consistent method for assessing the presence and severity of heart failure, particularly in the subset of patients with diastolic dysfunction or HFpEF.

[0097] It is within the provisions of this disclosure for an external device to scan a particular "slice" of an organ when using a linear (or phased) array, while the matrix arrangement of piezoelectric elements, by their phased firing, generates an ultrasound beam that can be steered vertically (axially), laterally (azimuth), and anterior-posteriorly (elevation) to acquire a volumetric (pyramidal) data set. These scanning characteristics ensure that at least two sensors are identified within that slice or volume and tracked for at least several cardiac cycles in each session.

[0098] It is within the provisions of this disclosure for the external device to provide feedback to the user to ensure that the signals reflected from the at least two sensors are of sufficient quality to allow reliable results. This may be achieved by various self-checking means, such as threshold settings for pressure and volume values, PVL area, time derivatives of volume and / or pressure, signal strength, signal-to-noise ratio, etc.

[0099] Unlike other imaging modalities, images do not need to be acquired to achieve the desired results, but images may be displayed as a by-product of the system as part of the feedback provided to the user, such as highlighting identified position sensors within the overall ultrasound scan.

[0100] The external device performs certain calculations on the measurements, including deriving ventricular volumes from one or more distance measurements and calculating the pressure-volume loop accumulated over time and functions of this loop, such as the end-systolic pressure-volume relationship (ESPVR), end-systolic elastance (EEs) (the slope of the ESPVR considered the best indicator of myocardial contractility), end-diastolic pressure-volume relationship (EDPVR), and arterial elastance (Ea) (a measure of afterload).

[0101] The results calculated by the external device can be stored, transmitted, and further analyzed by a mobile phone, the cloud, another computer, etc.

[0102] Although the present invention is primarily concerned with deriving parameters from ventricular pressure-volume data, several clinically significant parameters can also be derived from ventricular dimensions alone, including ejection fraction, end-diastolic volume, stroke volume, cardiac output, cardiac index, and global longitudinal shortening (GLS), among others.

[0103] As previously mentioned, the device's measurements can be correlated with measurements of other parameters, such as pressure within one or more ventricles. Pressure sensing can be accomplished by a separate wireless sensor or, alternatively, can be integrated with volume sensing means. A third alternative is to track volume only, without measuring pressure.

[0104] Pressure sensing can be accomplished by one of several means well known to those skilled in the art. For example, an active (powered) MEMS pressure sensor can be used, which is powered by an external power source, such as an RF or other wireless power source.

[0105] The second option is to use a resonant sensor. This is any device that has the ability to resonate at a defined resonant frequency upon excitation by energy / power from an external source, preferably ultrasound. This resonance can be altered as a result of a change in a physical variable, such as the pressure to which the device is exposed, for example, by geometric changes to the device resulting from the pressure change. As will be appreciated, the resonant sensor is completely passive in this case, which is a great advantage in this application. This implementation has the advantage of making it possible to combine position sensing and pressure sensing in a single device. The resonant sensor is used for both position sensing (by triangulation) and pressure sensing (by sensing the pressure-dependent shift in the resonant frequency).

[0106] For the purposes of this application, a resonant sensor is intended to encompass any device with a particular size, shape, stiffness, and elasticity, resulting in a defined natural resonant frequency, and having the ability to resonate at this defined frequency upon excitation by an external energy source, i.e., ultrasound, and further having the ability to change the resonant frequency in a predetermined manner by affecting its shape (e.g., causing deformation), density, or stiffness with a change in a physical variable, such as pressure.

[0107] To give a few simple examples, the spherical or rectangular devices in Figures 7A and 7B represent devices that can be used as resonators, enabling both position measurement by triangulation and pressure measurement by changing the resonant frequency with pressure. Figure 7A shows a sphere 10000 having an outer biocompatible coating 10001, a body 10002 made of a material, an inner coating 10003, and an interior volume 10004. The interior volume can be air, for example, at atmospheric pressure, allowing for high ultrasound reflectivity and high dependence on external pressure. Alternatively, the sphere can be solid, with only the outer biocompatible coating 10001, or it can be made of some biocompatible material, thus eliminating the need for a coating. In either case, the sphere's configuration is designed so that the frequency at which it resonates depends on the external pressure, allowing such a device to function as both a position sensor and a pressure sensor. This can be achieved, for example, if the sphere is compressible to some extent. The sphere compresses under higher external pressure, allowing it to resonate at a higher frequency due to its increased stiffness upon compression. FIG. 7B shows another possible rectangular embodiment, in which an outer biocompatible layer 10101 again surrounds the now rectangular object, and an upper membrane 10102 has properties that may differ from the "box" material 10103, such as being made more flexible and / or thinner. Again, the interior volume 10104 may be filled with air or another medium, or the device may be solid, not requiring the use of a separate interior volume; the device material itself may be inherently biocompatible. For all such devices, the desired characteristic is that the device have one or more distinct resonances that are measurably affected by changes in the pressure of the surrounding medium. Therefore, non-rigid or semi-rigid materials, such as polymers, gels, including rubbers and plastics, may be found to be used to form these objects.

[0108] As mentioned above, the resonant frequency of a pressure sensing device ideally changes in a predictable manner in response to changes in external pressure. A typical situation is shown in Figures 8A and 8B, where at an initial pressure p1 (leftmost curve), the resonant frequency of the pressure sensing device may be v1. The graph shows the amplitude (y-axis) of the reflected signal from the resonator in response to a drive signal of a given frequency (x-axis), with a peak for resonance at ω1. If the external pressure changes to p2, the resonant frequency of the pressure sensing device similarly changes to v2 (rightmost curve). Therefore, the change in resonant frequency in response to pressure may be determined as in Figure 8B. This curve is assumed to be determined during a calibration procedure.

[0109] The change in the resonance of such a device in response to changes in external pressure can be detected in several ways. The simplest method is to use the input signal at its original frequency, unaltered, and analyze the peak frequency of the return signal to calculate the pressure. As long as the resonant response curve (e.g., the curve in Figure 8A) is not too steep, the resonator will respond to signal frequencies outside its resonant frequency to some degree, even if the input signal frequency does not exactly match the resonant frequency. Thus, for a drive signal at frequency ω1, the response signal will still respond and exhibit a peak at ω2.

[0110] Another approach is to constantly sweep or otherwise vary the frequency of the input signal to find the frequency at which the maximum response occurs at the resonant frequency of the pressure-sensing body. A third approach is to use a broadband or impulse signal to excite resonance in the resonating body. Because the excitation signal contains a broadband of frequencies, the resonating body is driven into resonance to some degree.

[0111] A fourth approach is to use the Doppler shift of the echo from the input signal. Vibration of the pressure-sensing body causes a regular Doppler shift in the echo from the pressure-sensing body. In this approach, two input signals may prove more useful: one used to excite resonance in the pressure-sensing body, and another used to determine the Doppler shift of the echo from the now-vibrating pressure-sensing body.

[0112] In yet another embodiment, the pressure sensor, regardless of the method of fixation to the endocardial side of the ventricle, is covered with an antiproliferative drug, similar to the drugs used in drug-eluting stents. This inhibits endothelial cell growth over the sensor, ensuring long-term sensor functionality. Such drugs can be embedded in a polymer, ensuring sustained release over time. Drugs used for this purpose can include, among others, mTOR inhibitors such as sirolimus, cell proliferation inhibitors such as paclitaxel, immunosuppressants such as zotarolimus, or any other cell proliferation inhibitors.

[0113] In some embodiments, one of the position sensors may be integrated (eg, encapsulated together) with the pressure sensor so that the total number of sensors may be reduced.

[0114] As an example of the utility of the present invention, left ventricular volume measured throughout the cardiac cycle can be correlated with continuous pressure measurements to provide a pressure-volume loop indicative of myocardial function.

[0115] Furthermore, it is within the provisions of this disclosure to obtain information regarding the function or malfunction of heart valves on the left side of the heart (i.e., mitral or aortic stenosis or regurgitation). The same may apply to valves on the right side of the heart (i.e., tricuspid or pulmonary stenosis or regurgitation).

[0116] The measurements may be correlated with or linked to the heart's electrical activity (ECG).

[0117] The system may also integrate measurements obtained from one or more miniaturized triaxial (3D) accelerometers. When placed in the atrium, accelerometers can provide information about arrhythmias (i.e., atrial fibrillation) and allow for improved PV loops. Meanwhile, when placed in the ventricle, accelerometers can improve assessment of displacement and orientation between position sensors by identifying areas of dyskinesis.

[0118] The measurements can be adjusted by external manipulation (brachial or thigh cuff to increase afterload, Valsalva maneuver or repositioning to decrease preload), which can generate a series of pressure-volume loops displaced relative to one another, thus allowing the calculation of the end-systolic pressure-volume relationship (ESPVR), the end-diastolic pressure-volume relationship (EDPVR), and other parameters of myocardial function.

[0119] This disclosure is intended primarily for continuous or intermittent monitoring of patients with congestive heart failure (CHF), as well as valvular disease and intracardiac shunts, with an emphasis on outpatient settings. However, the high-quality, operator-independent measurements provided by the technology and based on this disclosure can be used in hospital or clinic settings where the technology can be integrated into existing or future ultrasound devices and transducers. This provides clinicians with a reliable and consistent method for assessing the presence and severity of heart failure, particularly in the subset of patients with diastolic dysfunction or HFpEF.

[0120] It is within the scope of this disclosure that this may be applied to any organ in the human body. As a further example of use, the present disclosure may be used to continuously monitor the range of motion of the diaphragm between the chest and abdominal cavity, indices of lung function, and other parameters in chronic lung diseases, some neurological diseases, and critical illnesses. As will be appreciated by those skilled in the art, position sensors may be attached or implanted to provide the necessary data as appropriate.

[0121] Ultrasound transducers used in this disclosure may include wireless handheld transducers, fingertip probes, wearable transducers such as a set of "belt-like" ultrasound transducers (a set of arrays), a combination of an array of transmitters angled relative to one another, ultrasound on a chip using capacitive micromachined US transducers as an alternative to piezoelectric transducers, or externally powered wireless implantable sonomicrometry crystals.

[0122] While the present invention is primarily intended for use by patients at home (after placement of the implantable element of the present disclosure), it can also be of great value in hospitals and point-of-care (POC) clinics. Current echocardiography often results in inter-examiner variability in determining important parameters such as ejection fraction (EF) due to measurement variability, such as measurements taken in slightly different planes by different operators. This problem is solved by examples of the present invention, as it relies on detection from an implantable sensor that always remains in the same place.

[0123] Another advantage of examples of the present invention over diagnostic ultrasound imaging is that it does not rely on the acquisition and analysis (by experts or AI) of high-resolution ultrasound images, a method that is subject to inevitable inaccuracies due to (for example) operator variability and / or inaccuracies due to the estimation of 3D volumes from 2D images. Passive ultrasound reflectors of examples of the present invention produce a high SNR, making them detectable with a high level of reliability and consistency.

[0124] The ability to generate and analyze ventricular pressure-volume loops as described in this disclosure provides a reliable means for monitoring a large group of patients suffering from heart failure with preserved ejection fraction (HFpEF), where volume measurements alone may not provide clinically relevant information and adequate assessment of disease severity.

[0125] The foregoing description and illustrations of embodiments and examples of the present invention or disclosure have been presented for illustrative purposes and are not intended to be exhaustive or to limit the invention in any manner to the above description.

[0126] All terms defined above and used in the claims should be construed in accordance with these definitions.

[0127] The reference numbers in the claims are not part of the claims, but rather are used to facilitate their reading, and shall not be construed as limiting the claims in any way.

Claims

1. 1. An external device for wireless cardiac diagnostics, the external device comprising: i. determining displacement data relating to displacements between wireless location markers of a set of wireless location markers placed within or in the cardiac chamber; ii. determining pressure data relating to pressure from a pressure sensing means configured to sense pressure within the ventricle; iii. determining one or more pressure-volume loops of pressure and volume of the ventricle based on the displacement data and the pressure data; and iv. determining cardiac health based on the pressure-volume loop; An external device whereby the device is configured to wirelessly, non-invasively, and continuously determine the health of said heart.

2. 2. The external device of claim 1, wherein the cardiac health status includes the presence and severity of heart failure, particularly in patients suffering from diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF), and such measurement information is obtained, for example, regarding the function or dysfunction of one or more heart valves on the left side of the heart and / or the right side of the heart.

3. 1. A system for wireless cardiac diagnostics, said system comprising: a. a set of wireless location markers configured to be placed within the ventricle; b. pressure sensing means configured to sense pressure within said ventricle; c. the external device of claim 1; A system whereby the system is configured to wirelessly, non-invasively, and continuously determine cardiac health.

4. The system of claim 3 , wherein the wireless location marker has a solid or hollow shape selected from the group consisting of a sphere, a coil, a cylinder, a polyhedron, a corner cube, an ellipsoid, and a ring.

5. 5. The system of claim 3 or 4, wherein the wireless location marker is a passive electromagnetic wave reflector or ultrasonic wave reflector with high ultrasonic reflectivity.

6. The system of claim 5 , wherein the external device uses an ultrasonic transmitter and receiver to generate reflections from the wireless location marker.

7. 7. The system of claim 3, wherein the wireless location marker has one or more distinct resonances at specific frequencies, and the external device uses electromagnetic or ultrasonic transmitters and receivers to induce and sense the resonances of the wireless location marker.

8. 8. The system of claim 3, wherein the wireless pressure sensor has a different resonant frequency that is affected by the external pressure surrounding the pressure sensor, whereby the pressure can be determined by correlating the measured value of the resonant frequency with a predetermined calibration curve relating external pressure to resonant frequency.

9. The system of any one of claims 3 to 7, wherein the external device is configured to determine the displacement of the wireless location marker using real-range multilateration or triangulation.

10. The system of any one of claims 3 to 9, wherein the external device is configured to extract and process raw spatial data from an ultrasound transducer to determine the displacement of the wireless location marker.

11. A system according to any one of claims 3 to 10, wherein the pressure sensing means is wireless.

12. A system according to any one of claims 3 to 11, wherein said pressure sensing means is incorporated into one or more of said wireless location markers.

13. The system of any one of claims 3 to 12, wherein the position marker is made up of multiple layers, each layer having a specific thickness and acoustic impedance.

14. The system of claim 13 , wherein the location marker is a reflector.

15. The system of claim 14 , wherein the reflector is made of a porous material.

16. 16. The system of claim 15, wherein the porous material comprises any one of air or fluid bubbles or pores having a size that can range from tens to hundreds of micrometers (μm).

17. The system of claim 16 , wherein the material is a biocompatible material.

18. The system of claim 17 , wherein the biocompatible material is a ceramic material, a metallic material, or a polymer.

19. A system according to any one of claims 3 to 21, wherein the pressure sensing means uses a passive sensor having a resonant frequency that is pressure dependent.

20. 23. The system of any one of claims 3 to 22, wherein parameters derived from a pressure-volume loop from a given test of a patient are used to compare with parameters derived from previous pressure-volume loops measured from the patient to determine changes in the cardiac health over time.

21. A system according to any one of claims 3 to 23, wherein the pressure sensing means is coated with an anti-proliferative drug.

22. 22. The system of claim 21, wherein the antiproliferative drug is embedded in a polymer to ensure sustained release over a long period of time.

23. 24. The system of any one of claims 3 to 23, wherein clinical parameters are derived from ventricular dimensions obtained from the location markers, such as ejection fraction, end-diastolic volume, stroke volume, cardiac output, cardiac index, and global longitudinal shortening (GLS).

24. 1. A method of cardiac health assessment comprising non-invasive determination of a cardiac pressure-volume loop, said method comprising: a. continuously determining the displacement between two or more location markers pre-fixed within or to the ventricle, thus providing displacement data; b. continuously determining the pressure within the ventricular volume, preferably by a pre-implanted pressure sensor within said ventricle or a non-invasive cardiac pressure sensor or method, thereby providing pressure data; c. forming at least one pressure-volume loop from said displacement and pressure measurement data; d. calculating a parameter of the at least one pressure-volume loop configured to be indicative of cardiac health; This method allows cardiac health to be determined wirelessly, non-invasively, and continuously.

25. 25. The method of claim 24, wherein the cardiac health status preferably includes the presence and severity of heart failure, particularly in patients suffering from diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF), and such measurement information is obtained, for example, regarding the function or dysfunction of one or more heart valves on the left side of the heart.

26. 26. The method of claim 24 or 25, wherein the measurements are adjusted by external manipulation of the patient's body to generate a series of pressure-volume loops displaced relative to one another, for example for calculation of end-systolic pressure-volume relationship (ESPVR), end-diastolic pressure-volume relationship (EDPVR), and other parameters of myocardial function related to said cardiac health.

27. 27. The method of any one of claims 24 to 26, wherein the wireless location marker is a solid or hollow shape selected from the group consisting of a sphere, a coil, a cylinder, a polyhedron, a corner cube, an ellipsoid, a ring, a shape configured to have a different resonance, a shape configured to have high reflectivity, and an array of any of these shapes.

28. A method according to any one of claims 24 to 27, wherein the wireless location marker is a passive electromagnetic wave reflector or an ultrasonic wave reflector.

29. 29. The method of any one of claims 24 to 28, wherein the wireless location marker has one or more distinct resonances at particular frequencies, and the external device uses electromagnetic or ultrasonic transmitters and receivers to induce and sense said resonances of the wireless location marker.

30. 30. A method according to any one of claims 24 to 29, wherein frequency is affected by external pressure surrounding the location marker, whereby said pressure can be determined by correlating measured values ​​of resonant frequency with a predetermined calibration curve relating external pressure to said resonant frequency.

31. A method according to any one of claims 24 to 30, wherein the external device uses real-distance multilateration or triangulation to determine the displacement of the wireless location marker.

32. A method according to any one of claims 24 to 31, wherein an external device extracts and processes raw spatial data from the ultrasound transducer to determine the displacement of the wireless location marker.

33. A method according to any one of claims 24 to 32, wherein the pressure sensing means is wireless.

34. A method according to any one of claims 24 to 33, wherein the pressure sensing means is incorporated into one or more of the wireless location markers.

35. A method according to any one of claims 24 to 34, wherein the pressure sensing means uses a passive sensor having a resonant frequency that is pressure dependent.

36. 36. The method of any one of claims 24 to 35, wherein parameters derived from the pressure-volume loop from a given test of a patient are used in comparison to parameters derived from previous pressure-volume loops measured from the patient to determine changes in the cardiac health over time.

37. 1. An implantable medical device for monitoring variable body geometry, said implantable medical device comprising: a. one or more wireless location markers positioned at a set of body locations; b. An external device, i. determining the displacement between the wireless location sensors; ii. determining an instantaneous measure of cardiac health based on said displacement; iii. an external device configured to communicate the cardiac health measurements with a cloud-based server configured to store and analyze the measurements; This allows an implantable medical device whereby variable body geometry may be monitored continuously, non-invasively, and without the need to acquire or analyze high quality echocardiographic images.

38. 38. The implantable medical device of claim 37, wherein the implantable medical device further comprises a set of pressure sensors positioned at a set of body locations, and the external device further comprises means for determining pressure from the pressure sensing means.

39. 39. An implantable medical device as described in claim 37 or 38, wherein the pressure sensing means is a location marker having a resonance that is pressure dependent.

40. 40. The implantable medical device of any one of claims 37 to 39, wherein the wireless location marker is placed within a ventricle so that left ventricular volumes can be monitored and pressure-volume loops determined.

41. 1. A system for wireless cardiac diagnostics, said system comprising: a. a set of wireless location markers placed within the ventricle; b. An external device, i. determining displacements between said wireless location markers, measured over time; ii. an external device configured to determine an instantaneous measure of cardiac health based on said displacement over time; This system determines cardiac health wirelessly, non-invasively, continuously, and without the need to acquire or analyze high-quality echocardiographic images.

42. Software for cardiac health determination, comprising executable instructions for a processing unit of a device for performing the method of any one of claims 24 to 36, said method comprising: a. continuously determining, based on the collected data, the displacement between two or more location markers pre-fixed in or to the ventricle, thus providing displacement data; b. continuously obtaining pressure data within the cardiac volume from a non-invasive cardiac pressure sensor; c. forming at least one pressure-volume loop from said displacement and pressure data; d. calculating a parameter of the at least one pressure-volume loop configured to be indicative of cardiac health; whereby said cardiac health status preferably comprises the presence and severity of heart failure, particularly in patients suffering from diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF).

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