Wireless measurement of in vivo dimensions for patient monitoring and diagnosis

Abstract

A method for continuously or intermittently wirelessly monitoring the volume of a heart chamber is disclosed that enables the volume to be combined with pressure measurements for optimal remote monitoring of a cardiac patient by a user. The present invention relates to a system comprising a set of wireless position sensors or reflectors placed within a heart chamber (i.e. Left ventricle), means for sensing pressure within one or more heart chambers, and external means adapted to query the wireless sensors to determine a relative and / or absolute position of the wireless sensors between each other and / or relative to the external means, and calculating a resulting volume within the heart chamber and creating a pressure-volume loop.

Description

Technical Field

[0001] The present invention generally relates to the field of diagnostic medicine, in particular to in-vivo measurement methods using implantable medical devices such as wireless sensors and capable of patient monitoring and diagnosis, as well as related systems, devices, methods, in particular computer-implemented methods and software products. Background Art

[0002] Remotely monitoring patients with heart disease, especially those with congestive heart failure (CHF), is very challenging. There are several ways to observe such patients, including monitoring symptoms, weight gain, electrocardiogram changes, thoracic impedance, and other parameters. However, due to poor performance (e.g., in terms of sensitivity, specificity, and rapidity), the value of these methods is limited.

[0003] Currently, there is no optimal device / method to detect cardiac deterioration at the initial stage, which can prevent further deterioration, hospitalization, and even death.

[0004] This section is intended to introduce to the reader various aspects of the field that may be related to various aspects of the present disclosure, which will be described and / or claimed below. This discussion is considered to help provide background information to the reader to better understand the various aspects of the present disclosure. Therefore, it should be understood that these statements should be construed accordingly and not as an admission of prior art.

[0005] Recently, several devices have been introduced into clinical practice that are capable of measuring left atrial pressure (LAP), and an increase in left atrial pressure is regarded as a predictor of CHF deterioration. This is achieved by deploying a pressure sensor in the pulmonary artery (indirect measurement) or the left atrium, which measures and transmits the results wirelessly. These devices have some advantages compared to previous methods, but their performance is still poor, relying on the measurement of a single parameter, which usually cannot account for the condition of a specific individual.

[0006] The gold standard for evaluating myocardial function in cardiology research is the measurement of the volumes of the cardiac chambers during the entire cardiac cycle (systole and diastole), and correlating this measurement with synchronous pressure measurements to produce a pressure-volume loop (PVL), where 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), (for all purposes, this reference document is incorporated herein by reference). Analysis of these loops, whether single or consecutive cardiac cycles, provides valuable information on important parameters of cardiac function, such as myocardial contraction (contractility) during cardiac systole, myocardial relaxation (lusitropy) during cardiac diastole, preload, and afterload. Currently, this is only feasible in experimental models or by using a conductance catheter for continuous volume measurements, which is an invasive method 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), (for all purposes, this reference document is incorporated herein by reference). Cardiac chamber volume can also be evaluated in different ways, such as echocardiography, CT, or MRI. However, these modalities are only available in hospitals or clinics, require professional personnel, and are thus not suitable for remote ambulatory monitoring.

[0007] It is well known that echocardiographic measurements of cardiac chamber volume are prone to inter-observer variation, and even consecutive measurements performed by the same operator may produce different results because it is difficult to ensure accurate reproducibility of the plane or position during measurement.

[0008] Recently, methods using automated processing of echocardiogram images have been employed to measure cardiac chamber dimensions. These methods include speckle tracking techniques or analysis enhancement by applying artificial intelligence (AI) algorithms (US10078893 to Guterman et al., "Automatic Left Ventricular Function Evaluation"). However, these methods still require acquisition of high-quality echocardiogram images, which is a task requiring trained physicians or technicians, and thus these methods are not suitable for home monitoring of heart disease patients. Additionally, a large proportion of heart failure patients have preserved ejection fraction (EF). These cases, often caused by myocardial diastolic dysfunction, are referred to as "heart failure with preserved ejection fraction" (HFpEF), and as such, the condition of these patients cannot usually be accurately evaluated by simply detecting cardiac chamber contours and volume measurements without correlation to synchronous pressure measurements. Currently, the practice of diagnosing HFpEF mainly relies on Doppler echocardiogram measurements of mitral valve blood flow and mitral annulus velocity. However, these are operator skill-dependent, have a high inter-observer variability, and are affected by various other parameters. Currently, there is no continuous, reliable method for diagnosing HFpEF that can be used in routine medical care.

[0009] Currently, in routine cardiology practice, there is no device or method suitable for reliably and user-friendly acquisition of cardiac pressure-volume loops, which are considered the gold standard for evaluating ventricular function. Introducing the ability to measure and monitor parameters from cardiac pressure-volume loops can significantly facilitate the management of heart failure and other heart diseases, improve the quality of life of patients, and reduce healthcare costs. Summary of the Invention

[0010] Accordingly, embodiments of the present invention preferably seek to alleviate, mitigate, or eliminate one or more deficiencies, drawbacks, or problems in the art, for example, by providing apparatus / devices / systems, methods, computer-readable media, and software products, particularly in accordance with the appended patent claims, either individually or in any combination, to alleviate, mitigate, or eliminate the above-mentioned deficiencies, drawbacks, or problems.

[0011] The present disclosure includes methods, apparatus / devices / systems, computer-readable media, and software products that are at least adapted or configured to wirelessly monitor physiological parameters, such as the volume of a heart chamber, continuously or intermittently. Thus, the present disclosure can provide important information regarding myocardial and heart valve function. When combined with pressure measurements, optimal remote monitoring and / or diagnosis of heart disease patients can be achieved, particularly non-invasively. Thus, the present invention provides in some aspects a wireless sensing scheme for monitoring heart chamber volume as well as PVL, effectively providing the most important parameters of heart function without the need for a trained medical professional to acquire and analyze echocardiogram images. The method can be customized according to the specific medical condition of each patient.

[0012] The present invention is designed as a comprehensive device that can be operated by a patient, a family member, or any other non-professional person, and is capable of remotely monitoring CHF patients by wirelessly measuring the volume of the heart chamber and the pressure within the heart chamber to generate a pressure-volume loop, which provides an optimal assessment of heart function in a continuous or intermittent manner.

[0013] The main components of a main example include:

[0014] · A set of wireless position tracking sensors (preferably passive reflectors adapted to work with ultrasonic signals). These tracking sensors are alternatively also referred to as position sensors or position markers in the present disclosure, and these terms all refer to the same type of wireless implantable elements that can be tracked after being implanted and the distance between them can be calculated. These sensors are implanted in parts of the body where relative movement is likely to occur, such as different positions on the wall of the heart chamber. Once implanted, the positions of the previously implanted sensors can be continuously tracked, and the distance between the sensors can be calculated. This enables, for example, the determination of the volume of the heart chamber (i.e., the left ventricle).

[0015] · A device for sensing and transmitting the pressure within one or more heart chambers (including atria and ventricles), also preferably using a wireless device.

[0016] · An external device adapted to track the previously implanted wireless position sensors to determine the relative and / or absolute positions of the wireless position sensors with respect to each other and / or with respect to the external device, and to read data from the pressure sensors and generate a series of PVLs of the heart chamber for further analysis. The external device typically includes one or more ultrasonic transducers, which can be in the form of a linear or matrix array.

[0017] As described above, a preferred embodiment for the position tracking sensor is to use a passive reflector that works with ultrasonic signals.

[0018] Pressure sensing can be achieved, for example, by additional sensors, which can be independent sensors or alternatively integrated with some of the volume sensors of the present disclosure. A third alternative is to not measure pressure and only track volume.

[0019] The present invention is mainly used for continuous or intermittent monitoring, with a focus on the outpatient setting. This is useful for patients with congestive heart failure (CHF), valvular heart disease, intracardiac shunts, etc.

[0020] The placement of the position sensors ensures that continuous measurements are always taken over time at exactly the same position or plane, ensuring the reliability and repeatability of the measurements. This will enable the device to compare the results of each examination with those of previous examinations, thus providing the ability to perform reliable trend analysis, where each patient is their own control, rather than just determining whether the results conform to generally accepted population-based normal values. Accordingly, 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 examinations.

[0021] In one aspect of the present disclosure, a system for wireless cardiac diagnosis is described. The system can include:

[0022] a. A set of wireless position sensors configured to be deployed in cardiac chambers (the position sensors may alternatively also be referred to in the present disclosure as position markers or tracking sensors, all terms referring to the same type of wireless implantable elements that can be tracked and the distance between which can be calculated after implantation);

[0023] b. A pressure sensing device adapted to sense the pressure within a cardiac chamber;

[0024] c. An external device adapted to:

[0025] i. Determine the displacement between the wireless position sensors in the deployed state to provide displacement data;

[0026] ii. Determine the pressure from the pressure sensing device to provide pressure data,

[0027] iii. Determine at least one pressure-volume loop (PVL) of the pressure and volume of the cardiac chamber based on the displacement data and the pressure data;

[0028] iv. And preferably determine an instantaneous measurement of cardiac health based on the pressure-volume loop (PVL),

[0029] Accordingly, the system is configured to preferably determine cardiac health in a wireless, non-invasive, and continuous manner and without acquiring or analyzing images of a high-quality echocardiogram, which 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 cardiac valves on the left side and / or the right side of the heart, and / or wherein the measurements can be adjusted by external manipulation of the patient's body to generate a series of pressure-volume loops that are displaced relative to each other, for example, for calculating the end-systolic pressure-volume relationship (ESPVR), the end-diastolic pressure-volume relationship (EDPVR), and other parameters of myocardial function related to cardiac health.

[0030] In some examples of the present disclosure, the wireless position sensor can be in the form of a solid or hollow body, selected from the group including: spheres, coils, cylinders, polyhedra, corner prisms, ellipsoids, rings.

[0031] In some examples of the present disclosure, the wireless position sensor can be a passive ultrasonic reflector having a high ultrasonic reflectivity, and wherein the external device uses an ultrasonic transmitter and receiver to cause reflections from the wireless position sensor.

[0032] In some examples of the present disclosure, the external device can be configured to determine the displacement of the wireless position sensor using true distance multilateration or triangulation.

[0033] In some examples of the present disclosure, wherein the external device can be configured to extract and process raw spatial data from an ultrasonic transducer to determine the displacement of the wireless position sensor.

[0034] In some examples of the present disclosure, the pressure sensing device can be wireless.

[0035] In some examples of the present disclosure, the pressure sensing device can be incorporated into one or more of the wireless position sensors.

[0036] In a further aspect of the present disclosure, a method for determining cardiac health is described, the cardiac health determination including non-invasive determination of cardiac pressure-volume loops. The method can include:

[0037] a. continuously determining the displacement between two or more position sensors previously fixed in or at cardiac chambers, thereby providing displacement data (the position sensors are alternatively also referred to in the present disclosure as position markers or tracking sensors, all terms referring to the same type of wireless implantable element that can be tracked after implantation and the distance between which can be calculated);

[0038] b. Continuously determine the pressure within the heart chamber, preferably by means of a pressure sensor implanted within the heart chamber or a non-invasive cardiac pressure sensor or method, so as to provide pressure data;

[0039] c. Form at least one pressure-volume loop based on the data of the displacement and pressure measurements;

[0040] d. Calculate the parameters of the at least one pressure-volume loop, which parameters are suitable for indicating heart health;

[0041] Thereby, heart health is determined wirelessly, non-invasively and continuously, and there is no need to acquire or analyze high-quality echocardiogram images. The heart health preferably includes the presence and severity of heart failure, especially in patients with diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF).

[0042] And such measurement information is obtained, for example, in relation to the function or dysfunction of one or more heart valves on the left side and / or the right side of the heart, and / or wherein the measured value can be adjusted by external manipulation of the patient's body to generate a series of pressure-volume loops that are displaced relative to each other, for example, for calculating the end-systolic pressure-volume relationship (ESPVR), the end-diastolic pressure-volume relationship (EDPVR), and other parameters of myocardial function related to heart health.

[0043] In some examples of the present disclosure, the wireless position sensor can be in a solid or hollow form and is selected from the group including: sphere, coil, cylinder, polyhedron, corner prism, ellipsoid, ring.

[0044] In some examples of the present disclosure, the wireless position sensor can be a passive ultrasonic reflector with high ultrasonic reflectivity, and wherein the external device uses an ultrasonic transmitter and receiver to cause reflection from the wireless position sensor.

[0045] In some examples of the present disclosure, the external device can use true distance multilateration or triangulation to determine the displacement of the wireless position sensor.

[0046] In some examples of the present disclosure, the external device can extract and process the original spatial data from the ultrasonic transducer to determine the displacement of the wireless position sensor.

[0047] In some examples of the present disclosure, the pressure sensing device can be wireless.

[0048] In some examples of the present disclosure, the pressure sensing device can be incorporated into one or more of the wireless position sensors.

[0049] In another aspect of the present disclosure, a system is described that includes an implantable medical device for monitoring variable body geometry. The system may include:

[0050] a. One or more wireless position sensors configured to be deployed at a set of body locations (the position sensors may alternatively also be referred to in the present disclosure as position markers or tracking sensors, all terms referring to the same type of wireless implantable element that can be tracked after implantation and the distance between which can be calculated);

[0051] b. An external device adapted to:

[0052] i. Determine the displacement between the wireless position sensors in the deployed state to provide displacement data;

[0053] ii. And determine an instantaneous measurement of cardiac health based on the pressure-volume loop;

[0054] Thereby, the variable human body geometry is preferably monitored in a continuous and non-invasive manner and without the need to acquire or analyze high-quality echocardiogram images.

[0055] In some examples of the present invention, the implantable medical device may further include at least one pressure sensor preferably deployed in the same heart chamber as the position sensor is deployed, wherein the external device may further include means for determining the pressure from the pressure sensor.

[0056] In some examples of the present disclosure, the wireless position sensors of the implantable medical device may preferably be placed within the heart chamber such that the left heart chamber volume can be monitored and the pressure-volume loop can be determined.

[0057] In yet another aspect of the present invention, a software for cardiac health determination is described, including executable instructions for a processing unit of a device to perform the methods described herein. Cardiac health preferably includes the presence and severity of heart failure, including patients with diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF).

[0058] i. In yet another aspect of the present invention, an external device for wireless cardiac diagnosis is described, the external device being adapted to: determine displacement data of the displacement between wireless position sensors for a set of wireless position sensors deployed within or at the heart chamber (the position sensors may alternatively also be referred to in the present disclosure as position markers or tracking sensors, these terms all referring to the same type of wireless implantable element that can be tracked after implantation and the distance between which can be calculated);

[0059] ii. Determine pressure data for a pressure from a pressure sensing device adapted to sense the pressure within the heart chamber;

[0060] iii. Determine a pressure - volume loop of the pressure and volume of the heart chamber based on the displacement data and the pressure data;

[0061] iv. And, determine an instantaneous measurement of cardiac health based on the pressure - volume loop;

[0062] Thereby, the device is configured to preferably determine cardiac health in a wireless, non - invasive and continuous manner and does not require acquisition or analysis of high - quality echocardiogram images. The cardiac health preferably includes the presence and severity of heart failure, especially in patients with diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF), and such measurement information is preferably derived as being related to the function or dysfunction of one or more heart valves on the left side and / or the right side of the heart, and / or wherein the measurement value can be adjusted by external manipulation of the patient's body to generate a series of pressure - volume loops shifted relative to each other, for example for calculating end - systolic pressure - volume relationship (ESPVR), end - diastolic pressure - volume relationship (EDPVR) and other parameters related to myocardial function associated with cardiac health.

[0063] The above examples have been described and illustrated in connection with their systems and methods. These examples are merely illustrative and not restrictive. In addition, just as each specific reference may include a specific method / system, but such a method / system is not necessary, ultimately, despite the use of specific embodiments, this teaching is applicable to all expressions. BRIEF DESCRIPTION OF THE DRAWINGS

[0064] Specific embodiments of the present invention will now be described with reference to the accompanying drawings. However, the present invention can be implemented in many different forms and should not be construed as limited to the embodiments described herein; rather, these embodiments are provided so that this disclosure is thorough and complete and fully conveys the scope of the invention to those of ordinary skill in the art. The terms used in the detailed description of the embodiments shown in the drawings are not intended to limit the present invention. In the drawings, the same numbers represent the same elements.

[0065] Embodiments and features of the present invention will be described in conjunction with the following drawings:

[0066] Figure 1 A block diagram of system components is shown.

[0067] Figure 2 A flowchart of one embodiment of system operation is shown.

[0068] Figure 3 A schematic diagram showing the placement of a position sensor / position marker in the heart is presented.

[0069] Figure 4A A, B, C, and D show several possible embodiments of the external unit of the device.

[0070] Figure 5 shows a typical pressure - volume loop (PVL) of the left ventricle.

[0071] Figure 6 A position sensor including several layers is shown.

[0072] Figure 7A A, B show examples of piezoresistive resonant devices.

[0073] Figure 8A Resonance curves at various pressures are shown, and Figure 8B A schematic diagram between the resonance frequency and pressure is shown.

[0074] Figure 9 The storage and analysis of pressure - volume results on a local external device and a cloud - based database are shown. Detailed Description of the Preferred Embodiment

[0075] The present invention will be understood through the following detailed description of preferred embodiments, which are intended to be descriptive rather than restrictive. For the sake of brevity, some well - known features, methods, systems, processes, components, circuits, etc. are not described in detail.

[0076] Another key parameter for evaluating cardiac function and the "gold standard" for myocardial function is the pressure - volume relationship of the left ventricle, which is reflected by the "PVL" or pressure - volume loop of the left ventricle. To determine ventricular volume, heretofore, invasive devices such as catheters have been used, or ultrasonic imaging and associated image processing have been used. Invasive devices have obvious drawbacks, and using ultrasound for volume determination requires experts to acquire and analyze high - quality images in echocardiograms, and even these images are prone to inter - observer variations. Figure 5 shows a representative PVL.

[0077] The present disclosure describes a method for continuously or intermittently wirelessly monitoring the volume of a cardiac chamber, which is capable of combining these measurements with pressure measurements for optimal remote monitoring of heart disease patients without the need to acquire or analyze high - quality ultrasound images.

[0078] For example, in US6498944 "Intrabody Measurement", Ben Haim proposed a method for monitoring various body parts, which is incorporated herein by reference, and the method discloses a catheter-based method that measures the size of a body part by using a set of position sensors mounted at the tip of one or more catheters and calculating the distance between the position sensors. The position sensors include microcoils that reflect electromagnetic waves, and the electromagnetic waves are generated and detected by a suitable device outside the body.

[0079] Similarly, US10918858 "Cardiac volume sensing via an implantable medical device in support of cardiac resynchronization therapy" is incorporated herein by reference, which discloses an implantable medical device having two electrodes and coupled to the electrodes, and the device is configured to identify a measured value of the impedance between the two electrodes.

[0080] Due to the obvious disadvantages of using invasive devices such as catheters or active electrical measurements, an object of the present disclosure is to introduce a method for determining the body volume that changes over time without using catheters and active impedance measurements.

[0081] The main components of the main examples of the present disclosure include one or more of the following:

[0082] · A set of wireless sensors deployed in the cardiac chamber (these position sensors are referred to as position sensors, position markers or tracking sensors in the present disclosure, and all terms refer to the same type of wireless implantable elements that can be tracked after implantation and the distance between them is calculated). These sensors are preferably passive devices adjusted to have high ultrasonic reflectivity. Using true range multilateration, triangulation or similar means, or spatial information obtained from an ultrasonic transducer according to its specific design, the positions of the sensors can be continuously tracked and the distance between the sensors can be calculated to be able to determine the volume of the cardiac chamber (i.e., the left ventricle). The wireless sensor can be a passive reflector, and the passive reflector can be tracked using ultrasonic signals.

[0083] · A device for sensing the pressure in one or more cardiac chambers.

[0084] · An external device adapted to track wireless sensors to determine the relative and / or absolute positions of the wireless sensors with respect to each other and / or with respect to the external device. The external device typically includes one or more ultrasonic transducers, which may be in the form of a linear array, a phased array, or a matrix array.

[0085] Figure 1 A block diagram of an embodiment of the system components of a wearable external unit is shown. On the left, the external unit is shown, which has a signal source and a receiving module, preferably having one or more ultrasonic transducer elements, a communication device, a processing module, a relative position determination device, a display device, and a power source for powering all these components. On the right, the sensors implanted in the system are shown, including two or more position sensors and at least one pressure sensor. As described above, when applying the present disclosure to certain clinical indications, the pressure sensor may not be required either.

[0086] In another embodiment, the whole or part of the external unit of the present disclosure may also be integrated into existing or future echocardiography devices used in clinical and hospital settings to improve the diagnostic accuracy of conventional echocardiography examinations.

[0087] The communication device of the external unit may include modules for communicating with other components of the system and with other devices, such as a PC, a smartphone, etc.

[0088] The display device of the external device enables the device to operate and provides user feedback regarding signal quality, result analysis, etc.

[0089] Figure 3 An example of an embodiment of the implanted portion of the present disclosure is shown, which includes a pressure sensor and two position sensors (the position sensors may alternatively also be referred to as position markers or tracking sensors). The left ventricle 301 is provided with position sensors 302a-c and a pressure sensor 303.

[0090] The position sensors are tracked by the external device (in a preferred embodiment, by using ultrasonic reflections from passive sensors, and it may also be achieved by electromagnetic sensors or other devices) to determine the relative displacement Δx and the absolute distance of the position sensors.

[0091] Figure 3An example of a specific location of a position sensor within the left ventricle is also shown. The figure shows the heart as seen in the apical four-chamber view, which is one of the views commonly used in echocardiography. The distance (L1) between the position sensor deployed in the endocardial direction of the apex of the ventricle and the position sensor deployed in the endocardial direction of the lateral ventricular wall represents the longitudinal or axial dimension of the left ventricle, which is commonly used by experts in the field to assess the global longitudinal shortening (GLS), while the distance (L2) between the two position sensors deployed at relative positions on the cross-section of the ventricle represents the horizontal dimension of the ventricle at a specific level.

[0092] Based on the assumption that the left ventricle is ellipsoidal and that the distance L2 is similar to the perpendicular distance between the endocardial direction of the ventricular wall at the same level, and that the two distances (L1 and L2) are measured simultaneously, the left ventricular volume can be calculated according to the following formula:

[0093]

[0094] In cardiology practice, although formulas for calculating the volume of the ellipsoid to estimate the ventricular volume are well known, other formulas can be used to calculate the ventricular volume based on the distance between the position sensors. These formulas can be derived by nonlinear regression or other mathematical methods from actual measurements of ventricular volume by imaging modalities such as CT, MRI, and echocardiography. However, other formulas can be used depending on the exact location where the position sensor will be deployed and the data accumulated on a specific patient, patient group, or population.

[0095] In addition to the estimation of ventricular volume as described above, the change in distance L1 between diastole and systole will enable measurement of global longitudinal shortening (GLS), a parameter that is gaining increasing attention as an indicator of myocardial function. Specifically, the distance between the sensor placed at the top and the sensor placed near the base in the transverse direction of the ventricular wall will be measured at end-diastole and end-systole to calculate GLS.

[0096] For embodiments using passive ultrasound reflectors, the shape, size, design (solid or hollow), surface features, and material of the reflector will affect the nature and intensity of the reflection from it. The difference between the acoustic impedance of the reflector and the acoustic impedance of the surrounding medium will determine the intensity of the reflection or "reflection coefficient". The following table shows the acoustic impedance of several materials, and the expected reflection coefficient at the interface between blood and the material in question; therefore, the expected reflection of the materials in the table is close to 80% or higher, and depending on their biocompatibility, these materials may be good candidates for reflectors. Non-biocompatible materials will be covered or encapsulated by biocompatible materials. Such materials may include polyurethane, ceramics, medical grade silicon, titanium, nitinol, etc.

[0097] Material Acoustic impedance [10^6 kg / m^2s] Reflection coefficient Air 0.0004 0.999 Aluminum oxide 9.7 0.51 Blood 1.6 0 Bone 4.7 .24 Copper 33.4 .83 Glass 11.6 .57 Silver 37.7 .84 Steel 40.3 .85 Titanium 27.6 .79 Tungsten 97.8 .93 Zirconium oxide 42 .86

[0098] Table 1 Reflectivity coefficients of several materials in blood

[0099] The use of any material to form any shape for the reflector is within the scope of the present disclosure; however, since the reflection depends on the orientation of the reflector (which can vary as the heart wall moves and cannot be controlled), it may be more advantageous to use regular polyhedra, cylinders, "corner cubes", or spheres for the reflector. The corner cube has the useful property that the reflected wave is exactly along the direction of the incident wave. Regardless of its form, the reflector can be hollow and preferably filled with air to utilize the inner wall of the reflector for almost complete reflection of the emitted wave.

[0100] A smooth hollow titanium or nitinol sphere with a diameter of several wavelengths is an example of a simple, biocompatible, isotropic specular reflector. Since medical ultrasound systems typically use a frequency of 3.5 MHz and a wavelength of 0.44 mm, spheres with a diameter of about 1 mm or larger are required. However, the size of the reflector provides optimal reflection for any wavelength currently or in the future used for cardiac imaging.

[0101] In another possible embodiment, the passive reflector can be made of a porous material that contains air or fluid bubbles or pores, the size of which can range from several tens of micrometers to several hundreds of micrometers (μm). Hydroxyapatite is one such material that can be used for the reflector, which is a biocompatible material for various medical implants that have been used mainly in the fields of orthopedics and dentistry, and the medical implants can be manufactured to have different densities and porosities. Hydroxyapatite can be classified in the family of ceramic materials and is just one example of such materials. Metal biocompatible materials, such as nitinol and stainless steel, can also be used, which can be manufactured to have different porosities. Similarly, various biocompatible polymers, polyethylene, polyurethane, and poly(lactic-co-glycolic acid) (PLGA), can also be used to manufacture the position sensor.

[0102] The porous material has unique "ultrasonic properties" that depend on the size and distribution of the pores. Such a material includes multiple air (or fluid)-to-solid interfaces, each with specific reflection, absorption, and scattering patterns. The presence of multiple interfaces between the solid matrix and the pores can cause multiple reflections of ultrasonic waves, generating complex patterns in the material so that the overall reflected signal of the porous reflector can be distinguished from the reflections generated by the surrounding tissue.

[0103] Those skilled in the art will understand that the reflector for the purposes of the present invention may also include a resonance device having one or more resonances that can be readily captured by suitable signal processing methods employed by an external interrogation device. Within the scope of the present invention, the resonance characteristics of the reflector for position detection should be distinguishable, for example, by using the above-described hollow spheres, each having a different outer diameter and / or inner diameter; using solid spheres of porous material with different radii, different porosities, pore sizes, and hollow materials; or objects having different resonance properties, such as 2D or 3D arrays of balls. As a simple alternative to large arrays, several coupled position sensors can be arranged in a known pattern to produce a unique return signal. Since the resonances of the objects used can be well characterized prior to use, the process of detecting the reflections of the position sensors and triangulating the positions of the sensors will be relatively straightforward.

[0104] Another embodiment of the position sensor relates to resonance. The resonance device also uses sound waves (ultrasound) emitted by an external transducer towards the sensor element. However, in this case, instead of simply reflecting a portion of the incident signal, the sensor element enters a resonance state when absorbing the incident signal near the frequency of the element. The specific natural frequency of each sensor is determined by its physical properties (such as stiffness, mass, and geometric structure), allowing each sensor to have a unique signature that can be detected by analyzing the resulting (reflected) signal. The external sound waves are ideally emitted at a frequency that will produce an optimal amplification-to-attenuation ratio to provide the best SNR. A resonant object vibrates easily at any of its resonant frequencies and with reduced intensity at other frequencies. The resonant frequency is "picked out" from a complex excitation, such as a pulsed or broadband noise excitation - effectively, filtering out all frequencies other than the resonance. As will be discussed in the section on pressure sensing below, the resonant frequency can depend on the external pressure, and the change in this resonance can be sensed by the external device of the present invention, enabling the sensing of both position and pressure in a single device.

[0105] Through calibration, the relationship between the distance Δx between two (or more) sensors and the volume V of the left ventricle can be determined. LV Since the relationship between distance and volume is highly dependent on the position of the sensors within the ventricle and the size, shape, and function of the heart of an individual patient, calibration will be performed once during the deployment of the sensors and then relied upon to determine the volume V based on the distance Δx. LVWhen a patient undergoes cardiac catheterization for other indications, recalibration can be repeated. There are also situations where the exact shape or coefficient of calibration may prove to be unimportant, while the pressure-distance relationship over time has sufficient clinical significance. In such cases, this distance-pressure curve can be used as a surrogate for the volume-pressure curve. There are also situations where the volume calculated from two distances (such as the ellipsoid volume described above) can be used to generate a pressure-volume loop without calibrating the absolute volume measurements.

[0106] In another example, as Figure 6 shown, the position sensor (501) can include a number of layers (502a-d), each layer having a specific thickness and acoustic impedance. This will cause the reflected ultrasonic beam to return from each interface between the layers (502a-d) at a time relative to the thickness of the respective layer, and the intensity of the signal will be proportional to the reflection coefficient at the interface between the respective layers (502a-d). This design will produce reflectors with a specific "signature" (503) such that multiple reflectors (501) can be used while being able to distinguish these reflectors when being tracked. The reflector-specific signature (503) can be presented as a "barcode", where the width of each bar (504a-d) is related to the thickness of the layer (502a-d), and the color or gray scale is related to the acoustic impedance of each layer (502a-d). These bars (504a-d) can be arranged in an in-out direction or the opposite direction. In a practical implementation, it is not necessary to present the barcode (503), but the barcode can be used for other purposes of the system. For example, a user can scan the barcode (503) of a certain reflector (501) and request the system to only locate this specific reflector (501).

[0107] Figure 2A simplified flowchart of an embodiment of the present invention is shown. First, the sensor of the present disclosure is implanted by the means described below. Once implanted, the above calibration steps are performed if necessary. These steps are typically carried out in a hospital environment. After discharge, the patient, family member, or any other non-professional can activate the external device to perform a series of repeated distance and pressure measurements. This is achieved by moving the ultrasonic transducer or the strap that fixes the array of ultrasonic transmitting and receiving elements until a color indication, sound, or other form of feedback is received from the external device, ensuring good signal quality and guiding the patient to maintain this position as stable as possible. Then, the device repeatedly measures the distance between the position sensors and correlates the measurement values with the pressure measurement values until several pressure-volume loops (PVLs) can be generated. When completed, the user receives another feedback "completed" to ensure that a satisfactory inspection session has been completed, and the device can be turned off and removed from the chest. The PVL allows the calculation of several values, including measurements of cardiac preload, afterload, myocardial contractility, and relaxation. Steps for performing the measurement validity are carried out, and if the measurement is valid, the results are stored and can be sent to a network. The results are also compared with predefined thresholds, and if these thresholds are exceeded, an alarm can be issued. The results can also be compared with previous examinations of the same patient so that even if the absolute values are still within the normal range, deterioration or aggravation can be detected. This can take the form of a local alarm and sending an alarm to healthcare providers, phone contacts, etc. The frequency of measurement can be determined by the attending physician based on the type and severity of the patient's disease, and the range can be from once or several times a day to once or several times a week to enable useful predictions of cardiac behavior in a timely manner for intervention if necessary.

[0108] As Figure 9 shown, the results of each examination (parameters derived from pressure-volume data) can be stored in the external device 1102 for comparison with previous or subsequent examinations. For performing comparisons involving multiple patients, the examination results can be sent, for example, via a smartphone or other personal device 1103, preferably to a cloud server 1104 associated with the present invention. These devices can communicate with the external device 1102 via, for example, Bluetooth or other communication means, while the personal device 1103 can communicate with the Internet via Wi-Fi or other network means. In addition to performing various types of cohort analyses involving more than one patient, this will enable doctors and / or the system's algorithms to perform individual trend analysis 1101 to determine whether the patient's cardiac health remains stable, deteriorates, or improves.

[0109] Each examination result can also be uploaded to the cloud database 1103 via the Internet or any other communication means using a smartphone, a PC, etc. This enables the creation of a database based on a large population, which will, as described above, enable trend analysis for each individual patient by the user and / or the algorithm of the present invention, and comparison of the results of each patient with the continuously updated normal and pathological pressure-volume data parameter ranges, while accumulating more and more examination results of multiple patients. This enables the implementation of artificial intelligence (AI) tools and machine learning algorithms to analyze the pressure-volume data and identify data patterns in the data relevant to an individual patient as well as a group of many patients, and make predictions or decisions based on the analysis.

[0110] The doctor can use the examination results directly from the external device or via the cloud database and the data processing system for updates. Alarms can be issued when needed, enabling appropriate drug adjustments accordingly.

[0111] Although, as Figure 2 described herein, the present invention is intended for outpatient or home environments, the high-quality, operator-independent measurements provided by this technology based on this disclosure can be used in hospital or clinic environments, where the technology can be integrated into existing or future ultrasound devices and transducers. This will provide clinicians with a reliable and continuous method to assess the presence and severity of heart failure, especially in subgroups of patients with diastolic dysfunction or HFpEF.

[0112] The cloud database (or any equivalent database) is used to store and analyze individual and population data, including not only cardiac function parameters derived from the analysis of the pressure-volume loop, but also any other clinically significant parameters derived solely from ventricular dimensions. These parameters include: ejection fraction, end-diastolic volume, stroke volume, cardiac output, cardiac index, and global longitudinal strain (GLS). In addition, the database is capable of correlating any parameter of cardiac function generated by the present invention with all other clinically relevant information (i.e., age, gender, weight, blood pressure, medications, complications, past clinical events, and hospitalizations, etc.).

[0113] In a preferred embodiment, the position sensor can be any type of passive reflector adapted to return any predetermined specific wavelength, which is preferably ultrasound.

[0114] In another embodiment, the sensor can be active, e.g., receiving energy such as radio frequency or ultrasound from an external source and transmitting data to an external receiver via RF or any other suitable wireless transmission method, or be provided with an internal power device such as a battery or an energy harvesting device. The sensor can be made of any material suitable for interfering with, reflecting, or emitting sound, ultrasound, electric fields, magnetic fields, or any particular wavelength or set of wavelengths of other types of energy.

[0115] In yet another embodiment, the sensor can be a piezoelectric acoustic micrometer crystal, receiving power from an external source such as radio frequency or ultrasound, emitting ultrasonic signals to other piezoelectric acoustic micrometer crystals at different locations implanted within a heart chamber, receiving ultrasonic signals from these crystals, and transmitting data to an external device via a wireless device.

[0116] The ultrasonic transducer is configured to function as a “medical radar” or data transmission system. To be able to determine the exact position of each sensor, the method requires a way to implement true distance multilateration or triangulation (similar to applications such as surveying, navigation, etc.). This can be achieved by using a series of existing ultrasonic transducers (i.e., phased arrays) or by creating an array of a series of custom-made ultrasonic transmitting and receiving elements angled with respect to each other, which can be within a single probe or in a strip / band, etc., such that angling is possible. Figure 4 shows such an implementation, where the phased array is placed on a band around the chest, where the phased array can be positioned above the heart such that the signal is clear. An alternative implementation of the method can be achieved by using a matrix ultrasonic probe that scans in two planes perpendicular to each other and extracting spatial information from the transducer such that true distance multilateration or triangulation is not required.

[0117] Figure 4A An embodiment using a chest band carrying an ultrasonic probe is shown, where the band or strip 401 is provided with a matrix ultrasonic probe 402 employing a set of transducer elements. Alternatively, a set of several linear (or phased) arrays 403 as shown in Figure 4B can be used. The linear arrays are typically angled with respect to each other. Each array can be linear 403( Figure 4C ) or in the form of a matrix array 406( Figure 4D ) itself. The arrays typically have multiple sets of transceiver elements (transmitting and receiving) 404( Figure 4C ), although in some embodiments, separate elements can also be used for transmission and reception. In Figure 4D , the transceiver elements 407 are shown as a square matrix. Figure 4C The relatively flat beam pattern 410 of a linear array scanning a “slice” of an organ is shown, Figure 4DShows a large-volume (pyramidal) scanning mode 411 of a matrix array. The array and elements can be angled. The belt carrying one or more arrays is worn obliquely over the intercostal space on the chest, and by using the "acoustic window" between the ribs, ultrasonic signals can reach the heart without being blocked by bones and cartilage. This method is similar to the commonly used apical four-chamber view and parasternal long-axis view.

[0118] Within the scope of the present disclosure, a hand-held sensor can be used for supra-sternal and infra-sternal paths without using such a belt. In the case of a matrix probe or matrix array as Figure 4D shown, since the probe scans in two mutually perpendicular planes, a single probe is sufficient. Within the scope of the present invention, any available acoustic window can be used, including the above-mentioned parasternal and apical windows, as well as subcostal, supra-sternal, and any other windows that may be found effective for practicing the present invention.

[0119] Within the scope of the present disclosure, various configurations of transducers or transducer groups (including transceivers or separate transmitters and receivers) can be used to adapt to specific clinical needs.

[0120] For example, if it is found impossible to arrange all necessary electronic components, power supply, display device, communication device, etc. on the chest belt as shown in FIG. 4, the external unit can be divided into two physical parts. Thus, the chest belt of FIG. 4 can carry the ultrasonic array, while a separate power / computation unit that communicates with these arrays performs data analysis, transmission to the cloud, power supply, etc. This independent power / computation unit can communicate with the chest belt transducer either wired or wirelessly.

[0121] Within the scope of the present disclosure, the ultrasonic element includes separate or unitized transmitting and receiving elements, and the array is adapted to be placed in contact with the skin. For example, it is arranged on a flexible substrate adapted to conform to the body to facilitate good contact with the skin. To ensure proper coupling of the ultrasonic signal with the subject's skin, an encapsulation gel unit can be used between each transducer and the skin. Alternatively, coupling gel can be used to fill the grooves in the element opposite the skin that house the transducer before each examination.

[0122] The position and angle of the ultrasonic transducer will be determined in the following manner, which depends on the specific position of the passive reflector within the heart to ensure obtaining a high-quality signal from the passive reflector. These positions can include the intercostal space, infra-sternal or supra-sternal, or other positions.

[0123] It is clear to those skilled in the art that the advantage of a phased array is the maneuverability of the main beam; for example, this can be used to synchronously detect and track at least two reflectors by scanning an area with a light beam and then using the angle with the maximum response to achieve a high SNR. The number of elements in each transducer and the order of their activation are adjusted to ensure optimal performance. Similarly, the delay of element activation can be optimized to minimize interference between the signals of the elements. When implemented through an array group, the delay between array activations can be adjusted to achieve optimal performance and avoid signal interference.

[0124] Furthermore, as is known to those skilled in the art, in order to use multiple ranges (distances) between a moving object and multiple known positions spatially separated to determine the position of the moving object, in an ultrasonic probe, each transceiver element is an independent reference. The combination of several ultrasonic probes provides multiple measurements from different angles, ensuring high accuracy and high spatial resolution, where each ultrasonic probe consists of multiple transceiver elements arranged in a linear (or phased array) or a single matrix probe.

[0125] As described above, a method and apparatus for determining the distance between two or more sensors from each other are also provided. The present invention can also be applied to continuously or intermittently track multiple sensors and determine the relative positions between the sensors.

[0126] Specifically, the present disclosure enables the measurement of the distance between two or more sensors within a cardiac chamber (i.e., the left ventricle). By using true distance multilateration or triangulation to determine the position of each sensor relative to an external device, or alternatively, the absolute position of the sensor can be determined and then the distance can be calculated by simple geometric means.

[0127] When using a matrix ultrasonic probe, the inherent property of such a transducer to scan a target volume in two mutually perpendicular planes can calculate the distance between sensors without using traditional true distance multilateration or triangulation methods.

[0128] Magnetic field devices can also be used (instead of or in addition to ultrasonic devices) to sense the relative or absolute position of wireless sensors. In this case, the implanted sensors will have a specific magnetic structure suitable for remote detection.

[0129] Sensors can also be deployed in more than one heart chamber (i.e., left atrium and left ventricle, left ventricle and right ventricle, etc.). For some applications, the sensor can be deployed at the location of the heart chamber rather than within the heart chamber, but close to the heart chamber (i.e., coronary sinus, aorta, pulmonary artery or vein, inferior vena cava or superior vena cava). The sensor can be integrated into any existing or future implanted cardiac device, such as an artificial valve, PFO occluder, pacemaker, implantable cardioverter defibrillator (ICD), left ventricular assist device (LVAD), etc. The sensor is adapted to have a specific geometry, material, surface (smooth - rough) or echo coating, with a designed response to a specific energy / signal to create a specific reflection footprint ranging from "invisible" to noisy (which respectively correspond to non - reflective or weakly reflective to highly reflective).

[0130] The sensor (reflector) can be in the form of a cluster of encapsulated microbubbles.

[0131] In one embodiment of the present disclosure, the sensor can be delivered to the target location via a transcatheter method, either via the arterial system to the left ventricle or via the venous system to the right ventricle. It can also be reached to the left atrium via a transseptal puncture in the right atrium towards the left atrium via the venous approach.

[0132] It is expected that the implantation process of most sensors will be carried out as an additional step during cardiac catheterization or cardiac surgery (such as open, minimally invasive, transapical, transmural, etc.) performed for other purposes, such as coronary angiography, valve repair or replacement. Alternatively, the placement of the sensor can also be an independent procedure. Another method for deploying the sensor at its target location can employ an injection mechanism, whereby the sensor is embedded in the myocardium and immediately covered by the surrounding tissue, such that further fixation may not be required.

[0133] The sensor can be deployed at the target location on the wall of the heart chamber by several methods, including but not limited to attachment by a hook - shaped or spring - shaped mechanism, self - expanding nitinol anchors or other means known to those skilled in the art. It is expected that the sensor will be endothelialized in a short time so that it is not exposed to the blood in the heart, thus eliminating the need for anticoagulation. However, the function of the passive reflector is not affected by being covered by endothelium or embedded in the myocardium. Fixing the sensor to the myocardium is not only a safety feature but also ensures continuous measurements over time at exactly the same location or plane, thus ensuring the reliability and reproducibility of the measurements.

[0134] As described above, the sensor is made of a biocompatible material or covered by a biocompatible material. The material used must be non - degradable to ensure the service life.

[0135] Measurements can be made intermittently or in a continuous, real-time fashion. 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 temporal resolution, especially important so as not to miss the precise deflection points of the PVL curve). Only as a non-limiting example, a sampling frequency in the range of 20 - 100 Hz will provide the desired temporal resolution.

[0136] In a preferred embodiment, wherein the passive ultrasound reflector is implanted in the heart to determine volume, the external device includes an ultrasound transducer. For echocardiography, most transducers operate at frequencies of 2 - 4 MHz, enabling penetration to the required depth in the chest.

[0137] While the external device described in the present disclosure can be customized for use in remote monitoring, the high-quality, operator-independent measurements provided by and based on the present disclosure can be used in a hospital or clinic environment, where the technology can be integrated into existing or future ultrasound devices and transducers. This will provide clinicians with a reliable, ongoing method to assess the presence and severity of heart failure, particularly in subgroups of patients with diastolic dysfunction or HFpEF.

[0138] Within the scope of the present disclosure, when using a linear (or phased) array, the external device scans a certain "slice" of the organ, and the matrix arrangement of the piezoelectric elements enables the piezoelectric elements to emit in phase to generate an ultrasonic beam that can be steered in the vertical (axial), lateral (azimuthal), and front-to-back (elevation) directions to acquire a volume (pyramid) dataset. These scanning attributes ensure that in each instance, at least two sensors are identified within the slice or volume and are tracked over at least several cardiac cycles.

[0139] Within the scope of the present disclosure, the external device provides feedback to the user to ensure that the signals reflected from at least two sensors have sufficient quality to achieve reliable results. This can be achieved by various self-check means, for example, setting thresholds for values of pressure and volume, area of PVL, time derivatives of volume and / or pressure, signal strength, and signal-to-noise ratio, etc.

[0140] Unlike other imaging modalities, no image needs to be acquired to produce the desired result. However, an image can be displayed as a byproduct of the system and provided to the user as part of the feedback, for example, highlighting the identified position sensors throughout the ultrasound scan.

[0141] The external device performs certain calculations on the measurements, including deriving the volume of a heart chamber based on one or more distance measurements, and accumulating over time to calculate a pressure-volume loop and the function of the loop, such as end-systolic pressure-volume relationship (ESPVR), end-systolic elastance (EEs) - the slope of ESPVR which is considered the best indicator of myocardial contractility, end-diastolic pressure-volume relationship (EDPVR), arterial elastance (Ea) - a measure of afterload, etc.

[0142] The results calculated by the external device can be stored, transmitted, and further analyzed via a mobile phone, cloud, other computers, etc.

[0143] Although the present invention is mainly concerned with parameters of ventricular pressure-volume data, a number of clinically significant parameters can be derived based solely on ventricular dimensions. These include ejection fraction, end-diastolic volume, stroke volume, cardiac output, cardiac index, and global longitudinal strain (GLS).

[0144] As described above, the measurements of the device can be correlated with measurements of other parameters, such as the pressure within one or more heart chambers. Pressure sensing can be achieved by a stand-alone wireless sensor or one integrated with the volume sensing device. A third alternative is to not measure pressure and only track volume.

[0145] Pressure sensing can be achieved by one of several means familiar to those skilled in the art. For example, an active (powered) MEMS pressure sensor can be used, powered by an external power source such as RF or other wireless power source.

[0146] A second option is to use a resonant sensor, which is any device that resonates at a defined resonant frequency when excited by energy / electricity from an external source such as ultrasound. This resonance can be altered due to changes in physical variables it is exposed to, such as pressure, for example, by pressure changes causing a change in the geometry of the device. As is to be understood, the resonant sensor can be completely passive in this case, which has significant advantages in this application. The advantage of this implementation is the ability to combine position sensing and pressure sensing into a single device - the resonant sensor is used for both position sensing (by triangulation) and pressure sensing (by sensing the drift of the resonant frequency with pressure changes).

[0147] For the purposes of the present application, a resonant sensor means any device including having a certain size, shape, stiffness and elasticity, which generates a defined natural resonance frequency and can resonate at that defined frequency under the excitation of an external energy source (i.e., ultrasonic waves). In addition, due to the change of physical variables, such as the pressure borne by the device will affect the shape (e.g., cause deformation), density or stiffness of the device, so the device can change its resonance frequency in a defined manner.

[0148] By way of some simple examples, Figure 7A the spherical or rectangular devices in B represent devices that can be used as resonators, which are capable of performing position measurements by triangulation and pressure measurements by the change of resonance frequency with pressure. Figure 7A The sphere 10000 is shown, which has an external biocompatible coating 10001, a body made of material 10002, an inner coating 10003 and an internal volume 10004. The internal volume can be, for example, air at atmospheric pressure, such that it has a high ultrasonic reflectivity and a high dependence on external pressure. Alternatively, the sphere can be solid, having only the external biocompatible coating 10001, or the sphere itself can be made of some biocompatible material, thus eliminating the need for a coating. In any case, the composition of the sphere is designed such that the frequency at which the sphere resonates depends on the external pressure, such that such a device serves as both a position and pressure sensor. For example, if the sphere has a certain compressibility such that it compresses under higher external pressure and thus resonates at a higher frequency due to greater stiffness upon compression, the above situation can be achieved. Figure 7B Another possible embodiment in the form of a rectangle is shown, where an external biocompatible layer 10101 surrounds the rectangular object, and the characteristics of the top membrane 10102 can be different from those of the "box" material 10103, for example, having better flexibility and / or being made thinner. Similarly, the internal volume 10104 can be filled with air or other medium, or the device can be solid and without the use of a separate internal volume, and the material of the device itself can be inherently biocompatible. For all such devices, the desired characteristic is that the device has one or more different resonances that are affected by the change of pressure in the surrounding medium. Therefore, it has been found that non-rigid or semi-rigid materials, such as polymers including rubber, plastic and gel, etc., can be used to form these objects.

[0149] As described above, the resonance frequency of the pressure sensing device changes in a predictable manner in response to changes in external pressure. Figure 8A, B shows a representative scenario; at an initial pressure p1 (the leftmost curve), the resonant frequency of the pressure sensing device can be ν1. The figure shows the amplitude (y-axis) of the signal reflected from the resonator for a drive signal corresponding to a given frequency (x-axis), and the resonant peak is at ω1. If the external pressure becomes p2, the resonant frequency of the pressure sensing device will similarly shift to ν2 (the rightmost curve). Thus, the variation of the resonant frequency with pressure can be determined as shown in Figure 8B . Assume that this curve is determined during the calibration step.

[0150] The shift of the resonance response of such a device in response to an external pressure change can be detected in several ways. Perhaps the simplest is that the input signal frequency can be kept constant, and the peak frequency of the returned signal is analyzed and used to determine the pressure. As long as the resonance response curve (e.g., Figure 8A 's curve) is not too steep, even if the input frequency is not exactly at the resonant frequency, the resonator will still respond to a non-resonant input signal frequency to some extent. Thus, even for a drive signal with a frequency of ω1, the response signal will still respond and show a peak at ω2.

[0151] Another method is to continuously scan or change the frequency of the input signal to try to find the frequency of the maximum response, which will occur at the resonant frequency of the pressure sensing body. A third method is to use a bandwidth or pulsed signal to excite the resonance in the resonator - due to the bandwidth of the frequencies contained in the excitation signal, the resonator will be driven into resonance.

[0152] A fourth method is to use the Doppler shift in the echo from the input signal; due to the vibration of the pressure sensing body, the Doppler shift in the echo of the pressure sensing body is regular. For this method, it may be found that two input signals are more useful; one for exciting the resonance in the pressure sensing body, and the other for determining the Doppler shift in the echo from the now vibrating pressure sensing body.

[0153] In yet another embodiment, regardless of the manner of attachment to the endocardial direction of the ventricle, the pressure sensor is coated with an anti-proliferative drug similar to the drugs used in drug-eluting stents. The anti-proliferative drug inhibits the growth of endothelial cells on the sensor and ensures the maintenance of the sensor function over a long period of time. Such a drug can be embedded in a polymer to ensure slow release over a longer period. Drugs for this purpose can include mTOR inhibitors such as sirolimus, cell growth inhibitors such as paclitaxel, immunosuppressants such as zotarolimus, or any other cell growth inhibitor.

[0154] In some embodiments, one of the position sensors can be integrated (e.g., encapsulated together) with the pressure sensor, such that the total number of sensors can be reduced.

[0155] As an example of the utility of the present invention, when associated with continuous pressure measurements, left ventricular volumes measured throughout the cardiac cycle can generate a pressure-volume loop indicative of myocardial function.

[0156] In addition, within the scope of the present disclosure, information regarding the function or dysfunction of cardiac valves on the left side of the heart (i.e., mitral or aortic stenosis or regurgitation) should be derived. The same applies to valves on the right side of the heart (i.e., tricuspid or pulmonary stenosis or regurgitation).

[0157] The measurements can also be correlated with or controlled using the electrical activity of the heart (ECG).

[0158] The system can also integrate measurements from one or more miniature three-dimensional (3D) accelerometers. When positioned in the atrium, the accelerometer can provide information about arrhythmias (i.e., atrial fibrillation), which improves the PV loop, while when positioned in the cardiac ventricle, the identification of the kinetic region can improve the assessment of displacements between position sensors and their orientation.

[0159] The measurements can be adjusted by external maneuvers (increasing afterload with a brachial or femoral cuff, decreasing preload with the Valsalva maneuver or a change in body position) to generate a series of pressure-volume loops with relative displacements, enabling the calculation of end-systolic pressure-volume relationship (ESPVR), end-diastolic pressure-volume relationship (EDPVR), and other parameters of myocardial function.

[0160] The present disclosure is primarily for continuously or intermittently monitoring patients with congestive heart failure (CHF) as well as valvular heart disease, intracardiac shunts, etc. in an outpatient setting. However, the high-quality, operator-independent measurements provided by this technology can be used in a hospital or clinic environment, where the technology can be integrated into existing or future ultrasound devices and transducers. This will provide clinicians with a reliable and continuous method to assess the presence and severity of heart failure, particularly in subgroups of patients with diastolic dysfunction or HFpEF.

[0161] Within the scope of the present disclosure, the present disclosure is suitable for any organ of the human body. As an example of an additional use, the present disclosure can be used to continuously monitor the movement offset of the diaphragm between the thoracic and abdominal cavities, which is an indicator of lung function and other parameters in chronic lung diseases, certain neurological diseases, and critically ill patients. Those skilled in the art will recognize that position sensors can be attached or implanted accordingly to provide the necessary data.

[0162] The ultrasonic transducers used in this disclosure may include wireless hand-held transducers, fingertip probes, wearable transducers such as "belt-type" ultrasonic transducer groups (array groups), combinations of emitter arrays angled to each other, on-chip ultrasonic waves, capacitive micromachined ultrasonic transducers that replace piezoelectric transducers, or externally powered wirelessly implanted acoustic crystals.

[0163] Although the present invention is primarily intended to be used by patients at home (after placing the implant element of this disclosure), it can also provide significant value in hospitals and point-of-care (POC) clinics. Current practices in echocardiography are often affected by inter-observer variability when determining key parameters such as ejection fraction (EF), due to variations in measurements, e.g., different operators making measurements in slightly different planes. This problem is solved by examples of the present invention because the present invention relies on detecting an implant sensor that always remains in the same position.

[0164] Another advantage of examples of the present invention compared to imaging ultrasound is that the present invention does not rely on the acquisition and analysis of high-resolution ultrasound images (by experts or artificial intelligence). Methods that rely on the acquisition and analysis of high-resolution ultrasound images are inevitably inaccurate due to, for example, operator variations and / or inaccuracies in estimating three-dimensional volumes from two-dimensional images. The passive ultrasonic reflectors in examples of the present invention produce a high signal-to-noise ratio and can therefore be detected with high reliability and consistency.

[0165] As described in this disclosure, the ability to generate and analyze pressure-volume loops of cardiac chambers provides a reliable device for monitoring a large number of heart failure with preserved ejection fraction (HFpEF) patients, where measurements of volume alone may not provide clinically relevant information and an appropriate assessment of disease severity.

[0166] For illustrative purposes, the above description and illustration of embodiments and examples of the present invention or disclosure have been given. It is not intended to be exhaustive, nor is it intended to limit the present invention in any form to the above description.

[0167] Any term defined above and used in the claims shall be interpreted according to that definition.

[0168] The reference numerals in the claims are not part of the claims but are used to facilitate reading of the claims. These reference numerals should not be construed as limiting the claims in any form.

Claims

1. An external device for wireless cardiac diagnosis, adapted to: i. Determine displacement data of displacements between wireless position markers for a set of wireless position markers deployed within or at a cardiac chamber; ii. Determine pressure data for pressure from a pressure sensing device adapted to sense pressure within the cardiac chamber; iii. Based on the displacement data and the pressure data, determine one or more pressure - volume loops of the pressure and volume of the cardiac chamber; iv. And based on the pressure - volume loop, determine cardiac health; Thereby, the device is configured to wirelessly, non - invasively and continuously determine the cardiac health.

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

3. A system for wireless cardiac diagnosis, comprising: a. A set of wireless position markers configured to be deployed within a cardiac chamber; b. A pressure sensing device adapted to sense pressure within the cardiac chamber; c. The external device according to claim 1, Thereby, the system is configured to wirelessly, non - invasively and continuously determine the cardiac health.

4. The system according to claim 3, wherein The wireless position markers are in solid or hollow form and are selected from the group including: spheres, coils, cylinders, polyhedra, corner prisms, ellipsoids, rings.

5. The system according to any one of claims 3 to 4, wherein, The wireless position markers are passive electromagnetic or ultrasonic reflectors with high ultrasonic reflectivity.

6. The system according to claim 5, wherein, The external device uses ultrasonic transmitters and receivers to cause reflections of the wireless position markers.

7. The system according to any one of claims 3 to 6, wherein The wireless position markers have one or more different resonances at a specific frequency, and wherein the external device uses electromagnetic or ultrasonic transmitters and receivers to induce and sense the resonances of the wireless position markers.

8. The system according to any one of claims 3 to 7, wherein The wireless pressure sensor has a distinct resonance frequency that is affected by the external pressure surrounding the pressure sensor, whereby the pressure can be determined by correlating a measured value of the resonance frequency with a predetermined calibration curve that correlates external pressure and resonance frequency.

9. The system according to any one of claims 3 to 7, wherein, The external device is configured to use true - range multilateration or triangulation to determine the displacement of the wireless position markers.

10. The system according to any one of claims 3 to 9, wherein The external device is configured to extract and process raw spatial data from ultrasonic transducers to determine the displacement of the wireless position markers.

11. The system according to any one of claims 3 to 10, wherein, The pressure sensing device is wireless.

12. The system according to any one of claims 3 to 11, wherein, The pressure sensing device is incorporated into one or more of the wireless position markers.

13. The system according to any one of claims 3 to 12, wherein The position marker includes a number of layers, each layer having a specific thickness and acoustic impedance.

14. The system according to claim 13, wherein, The position marker is a reflector.

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

16. The system according to claim 15, wherein The porous material includes any of air or fluid bubbles or pores sized in the range of tens to hundreds of micrometers (μm).

17. The system according to claim 16, wherein, The material is a biocompatible material.

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

19. The system according to any one of claims 3 to 21, wherein, The pressure sensing device employs a passive sensor having a resonance frequency that varies with pressure.

20. The system according to any one of claims 3 to 22, wherein, By comparing parameters derived from the pressure-volume loop obtained from a given examination of a patient with parameters derived from a previous pressure-volume loop measured from the patient, the change in the heart health over time is determined.

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

22. The system according to claim 21, wherein The anti-proliferative drug is embedded in a polymer to ensure slow release over an extended period of time.

23. The system according to any one of claims 3 to 23, wherein, Clinical parameters are derived from the ventricular dimensions obtained from the position markers, and the clinical parameters are, for example, ejection fraction, end-diastolic volume, stroke volume, cardiac output, cardiac index, and global longitudinal strain (GLS).

24. A method for determining heart health, the heart health determination including non-invasive determination of a cardiac pressure-volume loop, the method: a. Continuously determining the displacement between two or more position markers previously fixed within or at the cardiac chamber, thereby providing displacement data; b. Continuously determining the pressure within the cardiac volume, preferably by means of a pressure sensor previously implanted within the cardiac chamber or a non-invasive cardiac pressure sensor or method, thereby providing pressure data; c. Forming at least one pressure-volume loop based on the displacement and pressure measurement data; d. Calculating parameters of the at least one pressure-volume loop, the parameters being adapted to indicate heart health; Thereby, heart health is determined wirelessly, non-invasively, and continuously.

25. The method according to claim 24, wherein The heart health preferably includes the presence and severity of heart failure, particularly in patients with diastolic dysfunction or heart failure with preserved ejection fraction (HFpEF), and such measurement information is, for example, derived in relation to the function or dysfunction of one or more heart valves on the left side and / or the right side of the heart.

26. The method according to any one of claims 24 to 25, wherein The measured values are adjusted by external manipulation of the patient's body to generate a series of pressure-volume loops that are displaced relative to each other, for example, for calculating end-systolic pressure-volume relationship (ESPVR), end-diastolic pressure-volume relationship (EDPVR), and other parameters of myocardial function related to the heart health.

27. The method according to any one of claims 24 to 26, wherein, The wireless position marker is in solid or hollow form and is selected from the group including: spheres, coils, cylinders, polyhedra, corner prisms, ellipsoids, toroids, shapes adapted to have distinct resonances, shapes adapted to have high reflectivity, and arrays of any of these shapes.

28. The method according to any one of claims 24 to 27, wherein The wireless position marker is a passive electromagnetic or ultrasonic reflector.

29. The method according to any one of claims 24 to 28, wherein, The wireless position marker has one or more distinct resonances at a specific frequency, and wherein the external device uses an electromagnetic or ultrasonic transmitter and receiver to induce and sense the resonances of the wireless position marker.

30. The method according to any one of claims 24 to 29, wherein The frequency is affected by an external pressure around the position marker, whereby the pressure can be determined by correlating a measured value of the resonance frequency with a predetermined calibration curve that correlates external pressure with resonance frequency.

31. The method according to any one of claims 24 to 30, wherein, The external device uses true range multilateration or triangulation to determine the displacement of the wireless position marker.

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

33. The method according to any one of claims 24 to 32, wherein, The pressure sensing device is wireless.

34. The method according to any one of claims 24 to 33, wherein The pressure sensing device is incorporated into one or more of the wireless position markers.

35. The method according to any one of claims 24 to 34, wherein, The pressure sensing device employs a passive sensor having a resonance frequency that varies with pressure.

36. The method according to any one of claims 24 to 35, wherein, By comparing parameters derived from the pressure-volume loop obtained from a given examination of a patient with parameters derived from a previous pressure-volume loop measured from the patient, the change in heart health over time is determined.

37. An implantable medical device for monitoring variable human geometry, comprising: a. One or more wireless position markers deployed at a set of body positions; b. An external device adapted to: i. Determine the displacement between the wireless position sensors; ii. Determine an immediate measurement of heart health based on the displacement; iii. Transmit the measurement of heart health using a cloud-based server adapted to store and analyze the measurement; Thereby, variable human geometry can be continuously and non-invasively monitored and high-quality echocardiogram images do not need to be acquired or analyzed.

38. The implantable medical device according to claim 37, further comprising a set of pressure sensors deployed at a set of body locations, wherein, The external device further includes means for determining pressure from the pressure sensing device.

39. The implantable medical device according to any one of claims 37 to 38, wherein, The pressure sensing device is the position marker having a resonance that varies with pressure.

40. The implantable medical device according to any one of claims 37 to 39, wherein, The wireless position marker is placed within a heart chamber such that the left heart chamber volume can be monitored and a pressure-volume loop can be determined.

41. A system for wireless cardiac diagnosis, comprising: a. A set of wireless position markers deployed within a heart chamber; b. An external device adapted to: i. Determine the displacement measured over time between the wireless position markers; ii. Determine an immediate measurement of heart health based on the displacement over time; Thereby, heart health is determined wirelessly, non-invasively, and continuously and echocardiogram images do not need to be acquired or analyzed.

42. A software for heart health determination, comprising executable instructions for a processing unit of a device to perform the method according to any one of claims 24-36, comprising: a. Continuously determine the displacement between two or more position markers previously fixed within or at a heart chamber based on collected data, thereby providing displacement data; b. Continuously obtain pressure data in the heart volume from a non-invasive cardiac pressure sensor; c. Form at least one pressure-volume loop based on the displacement and pressure data; d. Calculate parameters of the at least one pressure-volume loop, the parameters being adapted to indicate heart health; Wherein, said 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).

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