Echocardiographic methods for early detection of cardiovascular deterioration, treatment optimization and screening

Abstract

The present invention relates to a method and system for monitoring cardiac functions and quantifying objective, operator-independent indices of cardiac functions. The invention quantifies both ventricle cavity and wall dynamics. It provides a picture with a comprehensive view of the six phases of cardiac contraction, relaxation and filling (isovolumic contraction, ejection, isovolumic relaxation, rapid filling, diastasis and atrial kick). It enables to quantify the effect of respiration and mechanical ventilation on cardiac chamber loadings and thereby to optimize mechanical ventilation in the general and cardiac intensive care units. It enables to assess the phase differences between the electrical activations and mechanical contractions of the various chambers and thus to adjust and optimize the parameters of cardiac synchronization therapies of ventricle chambers and chamber walls (as cardiac resynchronization therapy).

Description

ECHOCARDIOGRAPHIC METHODS FOR EARLY DETECTION OF CARDIOVASCULARDETERIORATION, TREATMENT OPTIMIZATION AND SCREENINGFIELD OF THE INVENTION

[0001] The present invention relates to a method and system for monitoring cardiac functions and quantifying objective, operator-independent indices of cardiac functions.BACKGROUND OF THE INVENTION

[0002] The unmet needs and existing solutions

[0003] There are three main unmeet clinical needs in the field of cardiac imaging: (1) Early detection of cardiac deterioration, especially in intensive care units and emergency rooms. (2) Treatment optimization of critically ill patients in the intensive care units and optimization of cardiac electrical resynchronization therapies in patients with heart failure, and (3) Precise screening of populations at risk of systolic or diastolic myocardial dysfunctions.

[0004] Early detection of progressing cardiac dysfunction is of immense clinical merit in intensive care units. Sepsis is one of the leading causes of mortality, making up 19.7% of the global death. The reported mortality rate of patients suffering from sepsis ranges between 22% and 41%, depending on patient characteristics. Myocardial involvement and development of myocardial dysfunction in the presence of a severe catabolic state increases the likelihood of severe deterioration and death. Organ failure due to cardiovascular collapse is a leading cause of mortality in all the intensive cardiac units (ICUs). The mechanisms underlying the development of myocardial injury are complex and not fully known. But proper management of myocardial injury require early detection.

[0005] There are only five vital signs that are continuously monitored in the ICUs: heart rate, blood-pressure, respiratory rate, blood oxygen saturation and temperature. Some advance monitors allow also continuous monitoring of the cardiac output. However, the brainstem cardiovascular and respiratory centres tightly control the blood pressure, cardiac output and blood oxygenation by modulating cardiac contractility, peripheral resistance and the respiration. Thus, decline in the blood pressure and cardiac output appear late, after the system collapses and all the adaptive control responses fail. Timely detection of cardiac function deterioration is crucial for managing critically ill patients.

[0006] The earlier signs of myocardial injury appear in cardiac function and myocardialwall dynamics, but currently, it is not continuously monitored in the ICU. Interestingly, the early sign of myocardial involvement and dysfunction during severe sepsis and inflammatory diseases is the development of diastolic dysfunction of the left ventricle, impairment in left ventricle filling.

[0007] Thus there is a need for easy to use and simple to understand imaging that can quickly assess cardiac function and detect early signs of deterioration. This would enable to initiate appropriate interventions promptly and improve patient outcomes. Early detection of myocardial injury can prevent ominous deterioration by relatively simple means, as early detection is better than cure of life-threatening conditions.

[0008] Treatment optimization of critically ill patients requires tight adjustment of the treatment to changes in the patient conditions. Determining the appropriate treatment approach can be challenging and require reasonable assessment of cardiac performances. Myocardial dysfunction can develop as a complication of various severe diseases, as sepsis and systemic inflammatory response syndrome (SIRS). The critically ill patients may be hemodynamically instable with low cardiac output and blood pressure. Improvement of cardiac output may require fluid challenge or administration of inotropic drugs to improve cardiac contractility. The appropriate treatment should be tailored to the patient’s myocardial function. Fluid overloading to patient with myocardial dysfunction, in an attempt to improve cardiac output, can accelerate further deterioration, leading to heart failure and pulmonary edema. Therefore, there is a need for bedside testing that provides rapid diagnostics and quantification of cardiac function for decision-making and treatment optimization.

[0009] Optimization of the electrical activation of the heart can improve the efficiency of cardiac contraction in patients that suffer from inappropriate synchronization of the ventricular wall contractions, or poor synchronization between the atrial and ventricular contractions, especially in the presence of heart failure. These issues often arise from inappropriate propagation of the electrical waves within the ventricular electrical conduction system or in the atria and ventricles.

[0010] To address these challenges, precise quantification of myocardial chamber contractions at high temporal rate, combined with precise identification of the six mechanical phases based on the novel technology, with simultaneous measurement of the electrical activity, is necessary. This approach enables to quantify the impacts of theelectrical wave propagation on cardiac mechanics and thus allows for fine-tuning of the various cardiac pacemaker paraments, such as the cardiac resynchronization device (CRT).

[0011] Key metrics in this optimization process include, for example:

[0012] Time delay between the R wave peak and Atrioventricular valve closure: The interval from the peak of the R wave on the ECG to the transition from the atrial filling phase to the isovolumic contraction phase (which marks the closure of the atrioventricular valves) is crucial. This delay informs the adjustment of the timing between atrial pacing and the ventricular pacing.

[0013] Time Delay between the End of the QRS Complex and Ventricular Outlet Valve Opening: The time from the end of the QRS complex to the transition from the isovolumic contraction phase to the ejection phase (indicating the opening of the ventricular outlet valves) is also vital. This delay helps synchronize the activation of various ventricular electrodes, aiming for a coordinated depolarization of the ventricle before ejection begins.

[0014] By optimizing these time delays, it is possible to enhance the synchronization of cardiac contractions, thereby improving overall heart function and patient outcomes.

[0015] Screening of the population at risk is important for preventive medicine. Heart failure is a leading case of severe morbidity and mortality in the western world. High ventricular filling pressure, the hallmark of heart failure, can occur at a wide range of left ventricle (LV) ejection fraction (EF). Interestingly, in the recent decades, heart failure with preserved EF (HFpEF) is the leading type (>50%) of heart failure and its prevalence is steadily growing. HFpEF is characterized by impaired diastolic filling, which is also denoted as diastolic dysfunction.

[0016] There are tight interactions between cardiac systolic and diastolic functions. Cardiac contraction is associated with a twist of the myocardium that occurs mainly during the isovolumic contraction phase, while untwist or recoil takes place mainly during the diastolic isovolumic relaxation and early rapid filling phases. The speed of the recoil affects the duration of the isovolumic relaxation and the magnitude of the decline in the intraventricular pressure and the ensuing atrioventricular pressure gradient that dictates the amplitude of the rapid diastolic filling phase. Thus, energy stored in the myocardial wall during systole and is associated with rotation (twist) and changes in theshape of the heart, turn into intramyocardial work (IMW) that drives the untwist during early diastole. This systolic to diastolic energy conversion is of great importance in the normal functioning of the heart. The IMW is essential for at least the following three purposes: (1) Rapid isovolumic relaxation of the heart and rapid filling toward its previous diastolic volume, what is known as early diastolic recoil and early diastolic filling. (2) Facilitating the coronary flow, and providing the energy to the intramyocardial pump of coronary flow. Interestingly, the coronary flow immediately accommodates to changes in the generated external work and myocardial oxygen consumption. (3) Propelling the myocardial lymphatic flow from the heart.

[0017] Echocardiography and stress tests play a vital role in diagnosing heart conditions. Although echocardiography is the most precise tool to assess the presence of diastolic function, the current techniques and measurements are cumbersome and not so precise. The most important parameter that determines the severity of the diastolic function is the filling pressure, but it requires invasive measurement. Echocardiography provides only indirect indices to severity of the elevated filling pressure. Echocardiography can identify structural abnormalities that cause diastolic dysfunction, as hypertrophy, or structural changes that result from elevated filling pressure as left atrial dilatation. Echocardiography is used to quantify the mitral flow and tissue dynamics, but still, these indices did not predict well the LV filling pressure.

[0018] Diastolic dysfunction is associated with variety of abnormalities as (1) an increase in the passive ventricular stiffness which is characterized by leftward and upward shift of the end-diastolic pressure-volume relationship (EDPVR). (2) Slowing down of the pressure decline rate during the isovolumic relaxation phase and prolongation of the isovolumic relaxation phase. This phenomenon is attributed also to changes in the active intracellular excitation-contraction coupling, specifically, slower rate of calcium sequestration from the cytosol and slower rate of actomyosin cross-bridge weakening.

[0019] These two indices (the EDPVR and isovolumic relaxation rate) require invasive measurements of the intraventricular pressure. Since ventricle filling pressure cannot be quantified noninvasively, other non-invasive echocardiographic surrogates were developed. Traditional comprehensive approach to diagnose diastolic dysfunction includes a thorough hemodynamic Doppler measurements of the mitral and tricuspid valve flows, tissue Doppler measurements of the mitral annulus velocity and two-dimensional echocardiographic measurements of the left-atrium volume. Diastolic dysfunction is commonly identified by measuring the amplitudes of the transmitral flows from the left atrium to the left ventricle during the early rapid filling phase (E wave) and during left-atrial contraction (A wave) and the ratio between them (E / A ratio). Since these measurements are not linearly proportional to the severity of diastolic dysfunction, there is a need also to measure the velocity of the mitral annulus, the early (e’) and atrial (a') annular velocities, as well as the E / e' ratio. The early trans-mitral flow velocity to early mitral annular tissue velocity (E / e’) is used to estimate LV filling pressure. Recent guidelines rely on four parameters: early diastolic tissue velocity (septal and lateral e’), the average E / e’ ratio (from septal and lateral e’), left atrial volume indexed to body surface area (LAVI), and tricuspid regurgitation velocity (TRV).

[0020] The limitations of the known solutions to the problem

[0021] Current diagnosis of myocardial dysfunction includes assessment of the hemodynamic indices, biomarkers and echocardiography.

[0022] The commonly used noninvasive hemodynamic indices as blood pressure and cardiac output can be continuously monitored, but do not provide early detection of myocardial injury. Although blood pressure and cardiac output measurements are the most cardinal indices for the severity of heart failure, they are under tight control of the autonomous nervous system that attempts to keep them within the normal range. Therefore, they cannot provide early detection of myocardial injury, as they decrease at late stages.

[0023] More advance hemodynamic indices as increased end-diastolic pressure (EDP) in the left ventricle, a hallmark of heart failure, can provide precise detection of myocardial injury. Measurement of the LV EDP requires insertion of pressure catheter into the LV. A Swan-Ganz catheter that is inserted into the pulmonary artery can be used to measure the pulmonary capillary wedge pressure, a surrogate of the left atrial pressure. However, these measurements are invasive and cannot be used for continuous monitoring, since the catheter should be replaced every few days, and the risks associated with these invasive techniques are high. Therefore, they are rarely used in the ICUs.

[0024] Collection of biomarkers such as cardiac troponin and BNP can provide high sensitivity for detection of cardiac injury. Elevated values can reflect heart failure severity but monitoring of biomarkers suffers from several limitations; it (1) requiresrepeated blood samples, which is inconvenient. (2) is a sporadic measurement and not a continuous monitoring, and the event of deterioration can be missed, (3) is not specific and does not disclose the nature of cardiac injury, and (4) it was not proven that biomarkers can differentiate between the group of survivors and the non-survivors in the ICUs, and their predictive and prognostic values are not high.

[0025] The available imaging modalities are limited mainly to echocardiography, since the patients in the ICUs are not mobile. Mobile X-ray provides poor information on cardiac function, while echocardiography provides real-time imaging of cardiac contraction. Detection of severe systolic dysfunction with decrease in the ejection fraction is relatively simple. Global longitudinal strain imaging might help with sub- clinical myocardial systolic evaluation, but its necessity in clinical decision making has not been proven yet. The earlier signs of left- ventricle injury are signs of diastolic dysfunction but the detection of progressive development of diastolic dysfunction is more cumbersome as described above.

[0026] The advantages of current echocardiographic studies

[0027] Echocardiography is a very powerful imaging modality that offers numerous advantages: (1) Ultrasound machines are portable, small and can be used in the ICUs, where the patients are not mobile (2) Noninvasive, safe, harmless, and does not expose patients to ionizing radiation, therefore it can be used for continuous monitoring. (3) Inexpensive compared to other imaging modalities like magnetic resonance imaging (MRI) or computed tomography (CT), easy to operate with minimal maintenance expenses, and finally, (4) Echocardiography provides high frame rate and enables acquisition of fast changes in cardiac dynamic and imaging of blood flow in various organs and vessels.

[0028] Advanced imaging modalities, such as cardiac magnetic resonance imaging (MRI) and computed tomography (CT) angiography provide detailed anatomical information about the heart and can even detect atherosclerotic coronary artery disease. However, they are cumbersome, require mobilization of the patient to these huge machines and it is quite impossible to manage a critical ill patient within these machines, which make it dangerous and in most of the cases impractical to utilize them. Echocardiography machines are compact and portable, allowing them to be easily transported to different locations. This portability enables the medical professionals toperform echocardiograms conveniently, even in intensive care units and emergency room at the patient’s bed-side. It also makes echocardiography particularly suitable for repeated or serial imaging studies, when there is a need for repeated follow-up. Emerging point-of- care ultrasound (POCUS) technology is being explored to meet these needs. POCUS allows healthcare providers to make bedside imaging and immediate diagnostic and treatment decisions, leading to timely and efficient patient care. It can be especially useful in the setting of ICUs and emergency rooms, where there is continuous monitoring of the mechanical ventilation and peripheral hemodynamic indices, but there is a crucial need to assess the cardiac function, optimize the treatment, to improve the outcomes and to reduce morbidity and mortality.

[0029] Another remarkable advantage of echocardiography is its ability to acquire images at a high acquisition rate, which allows for the visualization and analysis of the fast dynamics of cardiac contraction and relaxation. By capturing images at a high acquisition rate, echocardiography can accurately assess various aspects of cardiac function, including: (1) Visualization of the intricate movements of the heart's chambers and the rapid contraction and relaxation of the myocardium. (2) Assessment of valvular function and detection of abnormalities such as stenosis or regurgitation of the heart valves. (3) Quantification of blood flow patterns and velocities within the heart chambers, cardiac valves and major blood vessels, utilizing Doppler imaging. (4) Quantification of myocardial motion utilizing tissue Doppler Imaging or tissue spackle tracking. The latter provides insights into regional myocardial function and detects inhomogeneity in cardiac contraction and relaxation. Tissue Doppler imaging assists also in detection of diastolic dysfunction. The ability to acquire images at high acquisition rate enables to use it at different physiological condition and particularly useful in evaluating stress echocardiography, where the heart is subjected to physical or pharmacological stress, to assess its response and detect any underlying coronary artery disease.

[0030] The disadvantage of the current Echocardiographic studies

[0031] The main drawbacks of echocardiography are: (1) Echocardiography is a cumbersome procedure that requires a skilled operator to perform the various measurements from various positions and utilizing various modalities: M-mode, 2D echocardiogram, hemodynamic Doppler and tissue velocity imaging, and 3D echocardiography. The operator has to utilize various apical, parasternal and suprasternalviews, and to obtain various short axis, long axis, two chamber, four and five chamber views. (2) It is dependent on the operator and there are significant inter and intra-observer disagreements. Consequently (3) the derived measurements are not considered objective measurements, since the interobserver disagreements limit its precision and reliability.

[0032] Several factors influence the quality and accuracy of the echocardiographic images. Firstly, optimal positioning of the ultrasonic probe is essential. The correct orientation of the probe is crucial to capture the specific structures and areas of interest within the heart. Secondly, once the initial image is obtained, the operator needs to carefully examine it and make adjustments as necessary. The operator must have a good understanding of cardiac anatomy and pathology to identify the relevant structures and areas that need to be evaluated. Lastly, the operator has to select the object of interest and to use additional tools such as markers and measurements to assess various indices of interest. This includes measuring dimensions, blood flow velocities, and other parameters. The accurate placement of these points and markers is crucial to obtain reliable measurements and interpret the findings correctly. Assessment of diastolic dysfunction is particularly complex and requires different echocardiographic modalities and views, as described above. All the above can lead to interobserver disagreements, where different operators may select different images and perform different measurements, and obtain slightly different measurements. Proper training and adherence to standardized protocols are critical to overcome the user-dependent limitations and ensure the highest quality of echocardiographic assessments. However, there is a need for echocardiographic measurements in various settings, where specialists in echocardiography are not available.

[0033] Current echocardiographic measurements are cumbersome, time consuming, require highly trained staff but their availability is limited, and they suffer from interobserver disagreement. Therefore, there is a need for a more robust, real-time, reliable, simple to use, and operator independent method for the diagnosis and quantification of myocardial dysfunction.SUMMARY OF THE INVENTION

[0034] The present invention seeks to provide a method and a system for monitoring cardiac functions and quantifying objective, operator-independent indices of cardiac functions, as described in detail below.

[0035] The invention quantifies both ventricle cavity and wall dynamics. It provides a picture with a comprehensive view of the six phases of cardiac contraction, relaxation and filling (isovolumic contraction, ejection, isovolumic relaxation, rapid filling, diastasis and atrial kick). It enables to quantify the effect of respiration and mechanical ventilation on cardiac chamber loadings and thereby to optimize mechanical ventilation in the general and cardiac intensive care units. It enable to assess the phase differences between the electrical activations and mechanical contractions of the various chambers and provides information regarding synchronization of ventricular wall contractions, or synchronization between atrial and ventricular contractions, which information can be used to adjust and optimize the parameters of cardiac synchronization therapies (as cardiac resynchronization therapy).

[0036] Furthermore, the invention can accurately detect the opening and closure times of the mitral and aortic valves with high temporal resolution. The invention also works effectively with easily obtainable echocardiographic views. The method is particularly valuable, without limitation, for early bedside detection of myocardial deterioration, facilitating decision-making and treatment optimization for patients with suspected heart diseases in intensive care units or emergency rooms. Additionally, it is suitable for screening systolic and diastolic diseases, offering a wide range of applications.BRIEF DESCRIPTION OF DRAWINGS

[0037] The present invention will be understood and appreciated more fully from the following detailed description, taken in conjunction with the drawings in which

[0038] Fig. 1 is a simplified block diagram of non-limiting features of the invention.

[0039] Fig. 2A is a simplified graph of prior art description of cardiac function, which is based on plotting the pressure-volume relationship of the cardiac ventricle.

[0040] Fig. 2B is a simplified graph of the intramyocardial work (IMW), based on monitoring pressure and changes in the myocardial wall geometry (not just the cavity volume), the graph plotting the pressure against the wall-area.

[0041] Fig. 3 is a simplified graph of the differences between the temporal changes in the lumen area and wall area, particularly during the isovolumic contraction and relaxation phases.

[0042] Fig. 4 is a simplified graph of instantaneous measurements of the lumen area against the wall area, acquired from health adult sheep, wherein the myocardial work loop in Fig. 4 immediately reveals the six different phases of cardiac contraction.

[0043] Fig. 5 is a simplified illustration of maximal compliance of a heart with an ellipsoidal-spherical shape.

[0044] Fig. 6 is a simplified schematic diagram of left and right ventricles segmentation.

[0045] Fig. 7 is a simplified illustration of examples of the automated segmentation and tracking of cardiac contractions in two hearts.

[0046] Fig. 8 is a simplified graph of two lumen-area plots that were derived from the same sheep, under normal condition and after the induction of systolic heart failure.

[0047] Fig. 9 is a schematic presentation of three lumen-area plots that demonstrate the utility of the invention in characterizing various cardiac pathologies. The plot at the center represents the normal heart. Heart failure with systolic dysfunction is characterized by cardiac dilatation (upward shift) and reduced wall dynamics thickening. In contrast, heart failure with diastolic dysfunction is characterized by smaller lumen (downward shift) and reduced wall dynamic, especially during the rapid filling phase.

[0048] Fig. 10 is a simplified illustration of an experimental setup using a vertical Langendorff perfusion system with computer-controlled loading conditions and ultrasound acquisition.

[0049] Fig. 11 is a simplified illustration of the left-ventricle peak systolic pressure (green and purple) varied with the cyclical modulation of the end-diastolic pressure (blue and yellow), during baseline (green) and collagenase perfusion (purple).

[0050] Figs. 12A and 12B are simplified illustrations of an example of left-ventricle end- diastolic volume (Fig. 12A) and LV ventricular wall cross-section area (Fig. 12B) evolution at baseline (green) and during collagenase perfusion (red).

[0051] Fig. 13 is a simplified illustration of pressure-volume relationships in left and right ventricles, wherein left shift in end-diastolic pressure-volume relationship (EDPVR) is observed during collagenase perfusion (red) compared to baseline (green) without immediate decrease in the maximal elastance (end-systolic pressure-volume relationship) in both ventricles.

[0052] Fig. 14 is a simplified illustration of the effects of cardiac matrix degradation by collagenases (MMP8) on the Intramyocardial work (IMW) in an isolated rat heart.

[0053] Fig. 15 is a simplified illustration of Al assisted segmentation of the LV wall dynamics from echocardiographic studies in the same sheep, at normal baseline condition (left) and after the induction of systolic heart failure (right).DETAILED DESCRIPTION

[0054] Reference is now made to Fig. 1, which is a simplified block diagram of nonlimiting features of the invention.

[0055] Quantification of myocardial wall dynamics involves scanning the ventricle to obtain a cross-section that encompasses the entire width of the wall. The trans-thoracic short axis cross section at the mid- wall level is a simple to use one, as depicted in Figs 7 and 14 below. This short axis view is easily obtained in echocardiography to provide all the range of useful indices for assessing global heart function, as described below. Other views, such as trans -esophageal echo (TEE) or long axis views can also be utilized.

[0056] The ultrasound (US) cines are acquired at high temporal resolution of a few milliseconds (< 8 msec), to capture fast dynamics that cannot be observed with the naked eye, and to derive indices with high temporal resolution. The frame rate depends on the shortest phase in the cardiac cycle; e.g., to obtain at least 5 frames from the isovolumic contraction that lasts 40 msec, the frame rate should be above 125 Hz. The high temporal resolution can be achieved either by acquiring cines at high frame rate (above 125 frame per second, fps), or generating a fused cine from several heartbeats that contract under the same loading condition and without respiratory displacement, utilizing respiratory gating.

[0057] Another step in Fig. 1 is fast Al (artificial intelligence)-assisted segmentation of a large number of frames and measurements of the various radii and area indices (as depicted in Figs. 6 and 7 below).

[0058] Another step in Fig. 1 is transformation of the data to the Lumen-Wall area planes or alike and presentation of a single plot depicting the six phases of cardiac cycle (as depicted in Figs. 4 and 8 below).

[0059] Another step in Fig. 1 is measurements of objective indices from this unique six phase plot of the cardiac cycle that quantify the various phases of the myocardial contraction and relaxation and filling dynamics.

[0060] These steps are explained and detailed below.

[0061] Quantification of myocardial wall dynamics

[0062] Current description of cardiac function is based on plotting the pressure- volume relationship of the cardiac ventricle, as depicted in Fig. 2A. The area within the pressurevolume loop (PV loops) describes the external work (EW in Fig. 2A) done by the ventricle on the blood. Measurement of several PV loops at different preloads (initial end-diastolic volumes) provides different end-systolic points that construct the end- systolic pressure-volume relationship (Fig. 2A). The latter is used to define the cardiac maximal elastance and the potential energy (PE in Fig. 2A). The sum of the EW and PE is defined as the Pressure- Volume Area (PVA), and is equal to the total cardiac mechanical work. It is important to note that all these measurements (PV loops, maximal elastance, EW, PE, and PVA) are based on measurements of the changes in the ventricle volume, and are derived from multiple cardiac cycles at different loading conditions.

[0063] In the invention, instead of considering the cavity volume (Fig. 2A), geometrical changes in the myocardial wall, as depicted in Fig. 2B, are considered, which was never described or measured before in this manner.

[0064] During systole, part of the energy generated by the cardiomyocytes is used to generate the external work (EW) and part of it is stored within the myocardial wall and is used for at least three additional main goals: (1) Fast myocardial recoil at early diastole, for rapid filling of the heart, (2) facilitating coronary blood flow for the adjustment of the coronary blood flow and oxygen supply to meet the demands of the generated work and for oxygen consumption, and (3) squeezing out the lymphatic fluids out of the myocardium.

[0065] Plotting the pressure against the wall-area, as depicted in Fig. 2B provides novel finding. The area enclosed within this loop relates to additional work that is done by the heart, and is stored within the myocardial wall. We denote this energy, the area enclosed within this loop, as the intramyocardial work (IMW). The heart performs work not only on the blood within the cavity, as is commonly described by plotting the pressure against the volume of the heart cavity (Fig. 2A), but also an additional work on the myocardium, as described in the Fig. 2B. The latter cannot be adequately described from the currently used pressure-cavity volume loops (Fig. 2A).

[0066] Direct quantification of the intramyocardial work (IMW), based on monitoring the changes in the myocardial wall geometry (not just the cavity volume) can describe theenergy sources for normal diastolic function. Figure 2B represents the feasibility of quantifying the IMW, as described in the isolated heart study section below.

[0067] The IMW in Fig. 2B consists of three phases that constitute a triangle in the pressure-wall area plan: (1) A fast initial thickening of the myocardium at early systole, (from point 1 to 2) while there is only a small increase in the generated pressure, that creates the base of the triangle. This first phase relates to the fast isovolumic twist of the heart and is associated with large wall thickening, with 74+15% of the total wall thickening, while there is only 7.79+6.44% increase in the pressure out of the total systolic pressure. (2) The second phase describes a significant increase (94.7+8.0% of the total pressure upstroke) in the generated pressure (from point 2 to 3) with only minor changes in wall thickness. These two phases describe the amount of energy stored within the myocardium due to changes in both wall geometry (first phase) and intramyocardial pressure development (second phase). (3) The third phase describes the fast energy release during the isovolumic relaxation period, when moving over the hypotenuse in the triangle-like loop, from the end-systolic point, to the left lower corner that denote the end of the isovolumic relaxation (from point 3 to 4). Interestingly, the myocardium practically stays at that corner (points 4 and 1) along the rest of the diastole. Thus, the most striking changes in myocardial wall thickness occur during the early isovolumic contraction ( 1 to 2) and isovolumic relaxation (3 to 4), and the changes during the rest of the diastole are less significant.

[0068] Fig. 3 depicts the mark differences between the temporal changes in the lumen area and wall area, particularly during the isovolumic contraction and relaxation phases. These different dynamics of the lumen and wall areas explain the differences between the pressure-lumen area (Fig. 2A) and pressure- wall area (Fig. 2B).

[0069] The commonly used rectangular pressure-volume loops describe the work done on the blood from end-diastole to end-systole, but at the same time elastic energy is stored within the myocardium. At end-systole the aortic valve closes and the heart can no longer do work on the blood. However, precisely from this point the energy that was stored in the myocardium is converted into IMW by moving on the hypotenuse of the triangle, from the end-systole to the end of the isovolumic relaxation. The isolated rat heart study from which the IMW (intrinsic myocardial work) was derived lacked functional mitral and aortic valves, which are responsible for the rectangular shapeobserved in the cardiac pressure-volume loop. Consequently, the IMW in this study exhibits a triangular shape.

[0070] The pressure-wall area plot is based on measuring the LV cavity pressure, which is not available in the clinical practice. However, important dynamics of the myocardial wall can be derived from non-invasive echocardiography as depicted in Fig. 4. Fig. 4 presents instantaneous measurements of the lumen area against the wall area, acquired from health adult sheep. The myocardial work loop in Fig. 4 immediately reveals the six different phases of cardiac contraction: (1) isovolumic contraction (IVC, blue line), (2) ejection phase (Ejection, green line), (3) isovolumic relaxation (IVR, red line), (4) rapid filling (black line) (5) diastasis, and (6) atrial kick (black line). Clear separation between the phases is evident due to marked changes in the lumen area and wall area dynamics during the transitions between these phases. The work loop exhibits a parallelogram shape, where the corners correspond to the opening and closure of the mitral or aortic valves. Therefore, although the work loop is derived from the short axis view in this figure, it enables the detection of the six phases of the cardiac cycle and identification of the opening and closure times of the ventricle valves. The sharp corner between the IVR and the ejection phases corresponds to aortic valve opening (AO in Fig. 4), while the sharp corner between the ejection and IVR phases corresponds to aortic valve closure (AC in Fig. 4). Additionally, the sharp corner between the IVR and rapid filling phases corresponds to mitral valve opening (MO in Fig. 4), and finally, the sharp corner between the atrial kick and IVC phases corresponds to mitral valve closure (MC in Fig. 4). This distinct presentation of the cardiac cycle, which allows for the identification of the transitions between the different phases at a high temporal resolution, enables the derivation of objective temporal indices of cardiac contraction, relaxation and filling, as detailed below.

[0071] In Fig. 4, the lumen-wall area plot of the cardiac cycle reveals the six different phases of cardiac contraction: isovolumic contraction (IVC, blue line), ejection phase (green line), isovolumic relaxation (IVR, red line), rapid filling (black line), diastasis, and atrial kick (black line). The different corners of the parallelogram shape correspond to the opening and closure of LV valves: AO-aortic valve opening, AC-aortic valve closure, MO-mitral valve opening, MC-mitral valve closure

[0072] There are significant changes in the wall area during the isovolumic contraction and relaxation phases because ventricle shape undergoes significant changes during these phases. During diastole, the shape of the normal heart tends to resemble an ellipsoid, as the maximum volume at a given surface area is obtained in a spherical shape. The maximal compliance is obtained with an ellipsoidal-spherical shape, as depicted in Fig. 5. However, during isovolumic contraction, when the ventricle generates the maximum impact toward the aortic valve, the shape of the heart turns from ellipsoidal to conical. During the isovolumic relaxation and rapid filling the heart turns back from conical to ellipsoidal shape. These shape changes are associated with myocardial twist (during isovolumic contraction) and untwist (during isovolumic relaxation) of the various intramyocardial sheet layers one over the other, ultimately resulting in the observed changes in the wall area.

[0073] In Fig. 5 the changes in the wall area during the isovolumic contraction (left to right) and relaxation (right to left) phases are partially attributed to the changes in the vertical shape, from an ellipsoidal shape with large compliance during diastole to a conical shape with maximal impact toward the aortic valve during systole.

[0074] Image acquisition at high temporal resolution to present the fast wall dynamics that cannot be seen by the naked eye.

[0075] Fast dynamic changes in the myocardial wall occur during the isovolumic contraction and relaxation phases. The isovolumic contraction phase last about 40 msec in length and the normal isovolumic relaxation phase is about 100 msec. The high temporal resolution is essential for precise identification of these phases and the fast transition to and from these isovolumic phases to the other phases of the cardiac cycle. Acquiring images at a slow frame rate blurs these phases and smoothens the fast transitions between the different phases of the cardiac cycle. The ability to accurately detect the opening and closure time points of the aortic and mitral valves, as depicted in Fig. 4, depends on high temporal resolution. Identifying the opening and closure time points of the two valves is of great importance, since they are used to derive the various novel objective indices.

[0076] High temporal resolution is achieved by either cine acquisition at high frame rate (above 125 fps), or generating a fuses cine from several heartbeats that contract under the same loading conditions and without respiratory displacement, utilizing respiratorygating. Aligning several echo cines based on the ECG and respiration results in a fused cine of a single heartbeat with more data points and high temporal resolution. The temporal resolution of the fused cine is calculated as: 1 / (US frame-rate) / (number of fused heartbeats). For instance, utilizing a regular US machine with a frame-rate of 50 fps, and acquiring data from 4 heartbeats yields a temporal resolution of 5 msec.

[0077] The fused cine is achieved by adding respiratory gating capability to the US machine. This respiratory gating can work with spontaneous breathing and mechanical ventilation in anesthetized patients, in intensive care units. The respiratory dynamics is measured by wearable sensors such as respiratory belts (piezoelectric, impedance or inductance sensors), accelerometers, or by remote sensing utilizing optical sensors.

[0078] The novel device includes additional modality with: (1) An input for to respiratory sensor. (2) Amplification, sampling and filtering the respiratory signal. (3) Dedicated signal processing of the respiratory signal and to identify the inspiration and expiration phases. (4) Automatically detection of the longest quiescent time interval, with negligible respiratory motion. (5) Capability to present the respiratory signal and the detected intervals on the US screen, alongside with the US cine, with or without the ECG, (6) A real-time user interface that allows the user to approve or select time intervals of interest. The US cine is stored in temporary memory, and after the user selects the intervals of interest (e.g. quiescent time interval, end of inspiration), the selected time intervals and heartbeats are processed to generate the fused heartbeat.

[0079] At a frame rate slower than of 30 Hz it is impossible to detect the 40 msec isovolumic contraction (IVC) phase, since it will be sampled only once (single data point) in most (83%) cases. However, at a frame rate of 125Hz, the 40 msec IVC includes at least 5 points. The minimal acquisition rate is determined by the shortest phase of the cardiac cycle and the desired accuracy of the derived indices. The shortest interval is the IVC interval, and to measure this interval with a precision of about 10%, the data needs to be acquired at 250 Hz. Acquisition of several heartbeats can be used to achieve high temporal resolution even at a lower frame rate. Plotting the lumen-wall area or similar plots from multiple heartbeats, as depicted in Fig. 2B, provides more data points at the various phases and improves the segmentation of the different heart cycles.

[0080] The precise acquisition of the isovolumic phases is crucial because these phases are characterized by significant twist and untwist of the heart around itself and notablechanges in the ventricle shape, ranging from ellipsoidal to conical shapes, as shown in Fig. 5. These geometrical changes correspond to variations in the cross-section area of the myocardial wall and energy stored and release within the myocardium. The isovolumic relaxation is particularly important as it involves rapid untwist and recoil of the heart, which play pivotal roles in diastolic relaxation and swift filling of the heart. To accurately quantify these essential dynamics, it is necessary to shift the focus toward the rapid changes in the myocardial wall dynamics and effectively measure these dynamical changes that occur within the relative narrow time windows of the isovolumic contraction and relaxation phases.

[0081] Automatic ALassisted segmentation

[0082] An automatic tool for fully echocardiographic segmentation can improve monitoring of critically ill patients. A fully automated method for segmenting the left and right ventricles in ultrasound images in the short axis has been developed using the U-net algorithm. This method combines the use of artificial intelligence for myocardial segmentation with coding of a set of features based on an anatomical understanding of the heart's structure. Figs. 6 and 7 demonstrate the effectiveness of the method in identifying the borders of the endocardium and epicardium in both ventricles of a rat heart. A similar algorithm was employed to analyze the wall dynamics of the human heart. Artificial intelligence is utilized to perform myocardial segmentation and to generate binary masks from ultrasound images, as depicted in Figure 6. Subsequently, a ventricular geometrical segmentation method is employed to identify the epicardium, the endocardium of the left and right ventricles, and the septum.

[0083] The ALassisted segmentation identifies 5 regions in the isolated rat heart study presented in Fig. 7: LV lumen / cavity, LV wall, RV lumen / cavity, RV free wall and the region outside the heart. The algorithm identifies the endocardium of the left ventricle (red in Fig 7), the endocardium of the right ventricle (in blue in Fig. 7), the interventricular septum of the LV (green in Fig. 7) and the epicardium (in white in Fig. 7). The automatic segmentation enables to extract time varying parameters as the mean endocardial radius, mean epicardial radius, mean wall thickness, lumen / cavity area and wall area.

[0084] Precise detection of the endocardium and epicardium is based on algorithm for edge detection and edge-enhancement, as lateral inhibition, that work on each frameY1irrespectively of the preceding or successive frame. The detection of the endocardium and epicardium also utilized the information encompassed in the successive frame. The main difference in the successive frames is the motion of the borders, i.e., the endocardium and epicardium of the two ventricles. Thus, detection of the differences between successive frames assists in the segmentation and also provides additional information on myocardial dynamics.

[0085] The fast novel method efficiently and accurately quantifies not only the volume of the two ventricle cavities, but also the changes in the thickness of the walls of the heart chambers at any given moment, along the entire cardiac cycles.

[0086] Fig. 6 illustrates a schematic diagram of left and right ventricles segmentation. U- Net was utilized to create binary masks from ultrasound images, and ventricular geometrical segmentation method is employed to identify the epicardium, the left and right ventricle endocardium and septum.

[0087] Fig. 7 illustrates examples of the automated segmentation and tracking of cardiac contractions, in two hearts. The machine learning algorithm was used to identify five elements: Left ventricle cavity (red), left ventricle wall area, right ventricle cavity (blue - free wall, yellow- septum), right ventricle cross-section area, and the surrounding.

[0088] The Transformation of data into Lumen-Wall area or similar planes and the presentation of different phases of cardiac cycle in a single plot.

[0089] The novel transformations of cardiac function to lumen-wall area (Fig. 4) or similar planes offer a range of innovative features. The pressure-wall area plot in Fig. 2B illustrates the three phases of contraction in an isolated rat heart. The isolated heart lacks functional mitral and aortic valves and therefore includes only three phases. This plot presents the rapid changes in wall dynamics during the initial isovolumic contraction (from point 1 to 2 in Fig. 2B) and isovolumic relaxation (from point 3 to 4).

[0090] Fig. 4 showcases the clinically relevant dynamics of cardiac contraction, in vivo, captured from large animal (sheep) and obtained from human subjects. These images provide valuable insights into cardiac function.

[0091] The lumen-wall area plot is a unique and novel representation that reveals two often overlooked phases, the isovolumic contraction and isovolumic relaxation phases, which are typically omitted in commonly used axial views. Traditional 2D imaging tendsto focus on ventricle end-diastolic volume, end-systolic volume and on the uniformity of myocardial wall contraction.

[0092] The novel single plot presentation that can be derived from a single heartbeat yields crucial data:

[0093] The clear identification of all the six phases of the cardiac cycle is achieved (Fig. 4). The M-mode and Doppler imaging of the mitral flow also can be used to identify the six phases; they do not offer such a distinct identification of the transitions between the phases. When only one dimension, such as changes in the ventricle diameter (M mode) or flow (Doppler), is presented as a function of time, it is not clear when each cardiac phase begins and ends. However, by plotting two different dimensions with distinct dynamics, one against the other, such as the lumen area vs. wall area, the identification of the various phases is significantly facilitated. These different lumen and wall area dynamics yields the sharp transitions between the various phases in the lumen-wall plane

[0094] The clear identification of the opening and closure times of the ventricle valves. This feature allows for measuring the duration of each phase and examining the relationship between the durations of the various phases.

[0095] Visualization of the complex relationships between the changes in lumen volume and wall dynamics reveals interesting patterns. During the IVC (Isovolumic Contraction) and IVR (Isovolumic Relaxation) phases, relatively rapid changes occur in the wall crosssection area due to shape changes in the left ventricle geometry, while the cavity volume remains constant. In contrast, smaller changes occur in the wall area during the systolic ejection and diastolic rapid-filling phases. The wall area is determined by the cavity radius and wall thickness. During the systolic ejection and rapid-filling phases, there are opposite changes in cavity radius and wall thickness, resulting in only minor changes in the wall area. During the systolic ejection phase, the cavity lumen decreases while the wall thickness increases, and vice versa during the rapid-filling phase. As a result, the lumen- wall area plot takes on a parallelogram shape: the lines representing the IVC and IVR phases are parallel to each other, and the lines representing the systolic ejection and diastolic rapid- filling phases are also parallel to each other.

[0096] Assessment of the intramyocardial work involves assessing the energy stored in the ventricle wall during systole and its release during the early diastolic phases, including the isovolumic relaxation (IVR) and rapid filling. The area enclosed within thepressure-wall area loop (Fig. 2B) directly correlates to the intramyocardial work. Similarly, the area within the lumen-wall area loop serves as a surrogate index for this intramyocardial work. The lumen-wall area loop provides a representative of the changes in the wall area during the isovolumic contraction, when energy is stored within the myocardium. Additionally, the lumen-wall area reveals the changes in wall area during the isovolumic relaxation and rapid filling phases, corresponding to the rapid recoil of the ventricle. When the ventricle contracts and the cavity radius decreases, the wall thickness increases. However, the overall area should remain relatively constant due to conservation of the mass. Therefore, the primary factor causing changes in the wall area is the alteration in ventricle shape, as depicted in Fig. 5. The lumen-wall area loop effectively captures these changes in ventricle shape, which reflect the energy stored in the wall during systole and subsequently released during the diastolic isovolumic relaxation and rapid filling phases.

[0097] This approach offers novel quantification of the interplay between the cardiac systolic and diastolic functions. The decrease in the lumen area relative to the maximum lumen area relates to the systolic ejection fraction. Changes in the IVR and rapid filling phase provide insights into diastolic function.

[0098] Objective echocardiographic indices can be derived from this unique representation, enabling a more precise assessment of cardiac function.

[0099] Quantification of objective indices representing cardiac dynamic and the six phases of cardiac cycle.

[0100] The novel presentation in the lumen-wall area plane enables to derive various objective indices of cardiac systolic (contraction) and diastolic (relaxation and filling) functions, as:

[0101] The durations of the different six phases and changes in the durations of the various phases with the development of myocardial dysfunction. The accurate identification of the precise opening and closure time points of ventricle valves enables the calculation of the durations of the six cardiac phases; duration of the IVC, Ejection phase, IVR, Rapid filling, diastasis and atrial kick. Changes in the duration of each phase correspond to significant alterations in ventricle systolic or diastolic function. For instance, a prolongation of the isovolumic contraction phase (IVC) is associated with the development of systolic dysfunction, heart failure and even atrial fibrillation. It issensitive to the development of heart failure as depicted in Fig. 8 below. Similarly, prolongation of the isovolumic relaxation (IVR) phase indicates the development of diastolic dysfunction.

[0102] The ratio between the durations of different phases. For example, systolic dysfunction is characterized by a shortened ejection phase, and a prolongation of the IVC phase, leading to a significant decrease in the ratio of the ejection to IVC time duration. Similarly, Diastolic dysfunction with prolonged active relaxation is associated with prolongation of the IVR relative to the ejection phase duration.

[0103] The absolute value of the change in the luminal area at the various phases and the ratios between the changes in the lumen area at the various phases. For example, the low lumen area systolic fractional change represents a small decrease in the luminal area relative to the end-diastolic area. This index can be related to commonly used metrics such fractional shortening and ejection fraction.

[0104] The absolute values of the changes in the wall area at the various phases and the ratio between the changes in the wall area at the various phases. The fractional increase in wall area during the isovolumic contraction phase, for instance, is indicative of both systolic contractility and diastolic function. An increase in the systolic contractility is associated with larger twist and changes in LV shape and larger energy store in the myocardium during the IVC phase. Consequently, more energy is available for diastolic recoil. Thus, the relative increase in the wall area in relation to the end-diastolic area is linked to cardiac contractility.

[0105] The ratios between the changes in the wall area and the lumen area, at different phases (slopes of the phases in Fig. 4), as well as between the various phases (the relationships between the slopes of the different phases of cardiac cycle, in the lumenwall area parallelogram). The ratio of the increase in wall area during the isovolumic contraction phase and the decrease in the lumen area during the ejection phase corresponds also to the afterload experienced by the LV. In conditions such as hypertension or aortic stenosis, where afterload increases, there is a prolongation of the isovolumic phase, an increase in generated isovolumic stress, and a decrease in LV stroke volume. Examining the relative changes in the wall and lumen areas can be used for early detection of diastolic dysfunction, as depicted below in Fig. 14. The development of diastolic dysfunction is characterized by a shift toward smaller lumen and larger wallarea, as depicted in Fig. 12 below. Therefore, a decrease in the ratio of lumen to wall area can serve as an early indicator of diastolic dysfunction.

[0106] The rate of changes in the luminal or wall area during the various phases, and the ratios between the rates at the different phases. The rates of changes in the different areas are calculated as the ratio between the changes in area and the duration of each specific phase. For example, the rate of change in the lumen are during the rapid filling phase is related to the LV mean filling rate.

[0107] The absolute area within the lumen-wall area loop and the changes during the follow-up. The area within the pressure-wall area loop represents the intramyocardial work (IMW). The IMW (Fig. 2B) allows for assessment of systolic-to-diastolic energy conversion that is crucial for myocardial recoil and rapid ventricular filling. The quantification of diastolic work has not been previously described. The development of myocardial diastolic dysfunction is associated with a marked decrease in the IMW, as depicted in Fig. 14. The area within the lumen-wall area loop can serve as a surrogate for the IMW, providing insights into cardiac function and the conversion of the energy between systole and diastole.

[0108] Fig. 8 presents the strength of the novel method, by presenting two lumen-area plots that were derived from the same sheep, under normal condition and after the induction of systolic heart failure. The two plots present very distinct indices, to mention a few of them:

[0109] The normal lumen-wall area loop has normal lumen area (about 10 cm ) while HF loop presents significant myocardial dilatation (about 22 cm , a marked upward shift in the lumen area).

[0110] The normal loop presents significant change of lumen area, of 60%, while the HF loop presents markedly reduced changes of only 30%.

[0111] The normal loop presents significant wall area broadening during contraction of -50% (from 18 to 27 cm ), while the HF loop presents significantly smaller wall area broadening of only 41%.

[0112] The normal heart has short IVC of 58.11 msec while failing heart suffers from prolongation of the IVC to 76.84 msec.

[0113] Fig. 8 illustrates lumen- wall area plots that clearly illustrate notable differences between a normal heart and a failing heart. These plots were obtained from the same sheep under normal conditions and after the induction of systolic heart failure.

[0114] Some non-limiting advantages of the invention

[0115] The advantages of the innovation are derived from the novel approach, method and novel indices. The innovation provides:

[0116] New insight on cardiac mechanics is derived by focusing on wall dynamics and particularly on the radial direction. The pressure- wall area and lumen-wall area shed new lights on the isovolumic contraction and relaxation phases. These phases are associated with fast shape changes (twist and untwist) and energy storage in the myocardium during isovolumic contraction and release at early diastole during the isovolumic relaxation and the rapid filling phases. It is impossible to identify these phases by the naked eyes, even when the acquired echocardiographic cine is presented at slow motion. The naked eye cannot observe feature at a frame rate faster than 25 fps. Even when a video is played at a slow frame rate, it is impossible to remember and follow all the changes in the various features in hundreds of frames.

[0117] The novel presentation clearly identifies the beginnings and ends of these phases and the dynamics of wall and lumen changes during these phases. The magnitude and duration of wall-area changes during the isovolumic contraction provide novel afterload independent indices of cardiac systolic function.

[0118] The changes in wall-area in the short axis results from changes in the endocardial radius and wall thickness, and thus relate to changes in the radial directions. The direction of the pressure is also in the radial direction. Thus, the pressure-wall area loops provide new insight on the intramyocardial work.

[0119] A simple, single plot presentation of myocardial dynamics that clearly presents the different six phases of the cardiac cycle and thereby quantify both cardiac systolic and diastolic dysfunctions, as depicted schematically in Fig. 9. The presentation depicts the large changes in both wall and lumen dynamics, and changes between the two in the various phases of cardiac contraction in the normal heart. During the isovolumic contraction there are significant changes in the wall dynamic and smaller changes in the lumen. The opposite occurs in the normal heart during ejection, rapid filling and atrial kick phases. Thus, the isovolumic to ejection phase, for example, have different slope inthe lumen-wall area plan, and the transition between the two, due to the opening of the aortic valve, appears as sharp corner with fast transition between two lines with different slopes.

[0120] Quantify significant indices that were hitherto unmeasurable and can assist in quantifying cardiac systolic and diastolic functions, as depicted schematically in Fig. 9. Each point in the figure is associated with three values: time, lumen area and wall area. The six time points where the suffix 'i' denotes the MC, AO, AC, MO or Dia points depicted in the lumen-wall area plane in Fig. 9, where MC is mitral valve closure point, AO is aortic valve opening point, AC is aortic valve closure point, MO is mitral valve opening point and Dia represents the diastasis point, respectively. Similarly, LAi represents the lumen areas, and WAi represents the wall areas, at the time point points MC, AO, AC, MO or Dia, respectively.

[0121] Some Characteristics of systolic heart failure include (a partial, non-limiting list):

[0122] Cardiac dilatation, i.e., larger lumen areas: Larger LAMC, LAAO, and LAAC

[0123] Decrease in luminal area shortening fraction: Smaller (LAAO-LAAC) LAAO

[0124] Decrease in ejection rate: Smaller (LAAO-LAAC) / ( IAC-IAO)

[0125] Prolongation of the I VC duration: Larger IAO-IMC

[0126] Shortening of EJE duration: Shorter IAC-IAO

[0127] Low systolic efficacy (relative shorter ejection phase): Smaller (tAc-tAo) / ( IMO- tMc)

[0128] Smaller loop area: Smaller (WAAO-WAMC)* (LAAO-LA)

[0129] Decrease in wall area thickening fraction: Smaller (WAAC-WAMC) WAMC

[0130] Some Characteristics of Diastolic heart failure include (a partial, non-limiting list):

[0131] Decrease in lumen areas: Smaller LAMC, LAAO, and LAAC

[0132] Larger Wall areas: Larger WAMC, WAAO, and WAAC

[0133] Prolongation of the I VR duration: Larger tMO-tAc

[0134] Smaller wall recoil during IVR: Smaller WAMO-WAAC

[0135] Smaller energy storage during IVC: Smaller WAAO-WAMC

[0136] Prolongation of the Rapid Filling duration: Larger toia-tMO

[0137] Smaller luminal rapid filling: Smaller LA^H-LAMO

[0138] Larger luminal atrial kick: Larger LAMO-LADIH

[0139] Decrease in the lumen rapid filling rate: Smaller (LAoia-LAMo) / ( tDia-tMo)

[0140] Smaller loop area: Smaller (WAAC-WAMC)* (LAAO-LAAC)

[0141] Smaller suction during rapid filling: Smaller (WAMo-WADia)*(LADia- 2LAMo) / (tDia-tMo)

[0142] The last index, “suction during rapid filling”, is proportional to the product of the rates of lumen expansion and wall thinning. During this phase, some recoil of the wall occurs while the lumen rapidly fills. The recoil is depicted by wall thinning, resulting from shape changes, transitioning from a conical to an ellipsoidal shape with maximum compliance (as depicted in Fig. 5). A faster recoil indicates stronger suction and filling.

[0143] These indices can improve the early and accurate diagnosis of cardiac injury and can serve for monitoring patients at risk, for example patients with severe sepsis in the intensive care units.

[0144] Objective and operator independent indices that are based on precise monitoring of the duration of the different cardiac phases, and the relative changes in the lumen and wall dynamics at the various phases and between cardiac phases. The user-dependency and interobserver disagreement is a major limitation of current echocardiography. The Al-assisted segmentation and automated image analysis algorithms, frame by frame, aid in reducing user-dependency. The user does select regions of interest or performs any manual measurement, but receives the parallelogram with the six phases of the cardiac cycle and all indices derived from it.

[0145] High temporal resolution. The high frame rate acquisition or the fused cines utilizing the respiratory gating as well as the frame-by-frame analysis of the entire echocardiographic cine provide a high temporal resolution for all the indices.

[0146] Quantification of indices of cardiac energetics from a single heartbeat or several fused beats, without the need to change the cardiac loading conditions. Cardiac energetic is commonly evaluated based on the elastance model, where cardiac energy consumption is determined by pressure-volume area, the sum of the external work and the potential energy. However, quantification of the maximal systolic elastance and the potential energy require the acquisition of several pressure-volume loops at different loading conditions, which is not practical in the clinics. The suggested pressure-wall area plot and lumen-wall area plot overcome this limitation of the elastance model, as they aremeasured from a single cardiac cycle. A single cardiac cycle can provide both the external-work and the intramyocardial work.

[0147] Relating to the changes in the most important radial direction. Quantification of the changes in the radial direction surpasses the detailed measurements of the myocardial longitudinal and circumferential strain and strain rate. Measurements of the longitudinal and circumferential strain and strain rate are of great importance for assessment of the inhomogeneity in cardiac contraction. However, the longitudinal and circumferential strains are perpendicular to the radial strain and to the tensor of the pressure, thus their contribution to the assessment of the intramyocardial work are negligible. The work is a scalar product of the pressure and volume changes only in the direction of the pressure tensor, i.e., in the radial direction.

[0148] Provide detailed description of cardiac diastolic function. The suggested quantification of myocardial wall dynamic is novel. The parallelogram of cardiac systolic and diastolic function present how energy that is generated during systole is utilized to expedite cardiac relaxation and the early phase of cardiac filling. This concept is not new and was generally mentioned in the literature, but without suggesting any reasonable means to quantify it. The elastance model is of great importance for quantifying cardiac systolic function; the maximal elastance and the generated external work. However, the ability of the elastance model to describe the diastolic function is limited. The suggested pressure-wall area and lumen-wall area loops may overcome this limitation of the elastance model and better relate to the cardiac diastolic function and provide novel indices that relate to the cardiac diastolic function.

[0149] The echocardiographic e’ index for the diagnosis is based on measurement the velocity of a single or two particular points (septal and lateral) on the mitral annulus. Our method quantifies the dynamics of the entire cross-section of the wall. The measured dynamics of a large mass is more accurate and robust than the dynamics of a single point within that mass.

[0150] Simple to use since it can utilize easy to obtain short axis view of the heart. The short axis view is the simplest 2D image of the heart. The suggested method can derive important information and indices on cardiac contraction, relaxation and filling from this simple 2D image of the heart. It is a great advantage in the setting of intensive care units, where there is a need for fast decision making, and there is a need for continuousmonitoring for early detection of deterioration, and it is impractical to do repeated measurements with a cumbersome and time-consuming modality.

[0151] A simple and fast automated analysis can facilitate early and fast diagnosis of cardiac function and loading conditions. It can significantly improve the management of patients in intensive care units, where continuous monitoring and fast diagnosis are required.

[0152] The US can present several six -phase plots obtained at different physiological conditions and time points to facilitate the correct diagnosis. For example: (1) At admission and after detecting significant hemodynamic changes, (2) Before and after some treatments, such as fluid challenge or administration of inotropic drugs (3) During inspiration and expiration to check potential adverse effects of mechanical ventilation. These different six -phase plots can be presented on the same lumen-wall plane or in cascade.

[0153] These advantages make this invention effective in various applications:

[0154] Early detection of myocardial injury in the setting of intensive care units and emergency rooms and other departments.

[0155] Treatment optimization and decision making in patients at risk with some myocardial dysfunction, where there is a need to tailor the appropriate treatment to changes in cardiac functions, e.g., fluid management and inotropic drug administration in patients under intensive care. The currently available framework provides analyses of the patient condition based on the respirator outputs and the hemodynamic monitoring, but there is lack of crucial knowledge relating to heart function. The product provides the needed crucial assessment of cardiac systolic and diastolic functions.

[0156] Simple screening, follow-up and management of the population at risk. About 2% of the population suffer for various degrees of heart failure. More than 50% of the heart failure patients suffer from diastolic heart failure with preserved (EF>50%) ejection fraction, and the diagnosis of diastolic dysfunction is cumbersome. Simple and objective indices can improve the diagnosis and follow-up.

[0157] VERIFICATION STUDIES

[0158] The innovation was tested and validated in isolated rat heart and, in vivo, in sheep with normal heart and after the induction of heart failure.

[0159] Verification in isolated rat hearts

[0160] This study highlights the importance of monitoring myocardial wall dynamics frame by frame, as suggested in this innovation, and the ability to quantify: ( 1 ) the energy stored within the myocardium and its dependence on the loading conditions (preload), as depicted above in Fig. 2B (2) the fast isovolumic contraction phase, (3) The significant changes in the myocardial wall cross-section area that occur during the isovolumic phase, as depicted in Fig.2 (first phase in Fig. 2B), (4) early signs of myocardial dysfunction due to matrix degradation by collagenases, as occurs in myocarditis and inflammatory storms (Figs. 12-14 below).

[0161] Male Sprague Dawley rats (body weight about 350 gr) were anaesthetized with isoflurane. The hearts were quickly excised and transferred to a horizontal Langendorff setup. A cannula was inserted into the ascending aorta and the isolated hearts were perfused through the aorta with Krebs-Henseleit solution at room temperature. Two ventricle cannulas were inserted into the two ventricles through the atria and fixed with purse string sutures above the ventriculoatrial valves. After the cannulation, the isolated hearts were transferred to the experimental setup that is described in Fig. 10, and were immersed in a large saline bath at temperature of about 19°C. The cannulas were connected to two pressure transducers (right and left ventricular pressures) and through shutters to a vertical glass column that determined the EDP of both ventricles, as depicted in Fig. 10. The shutters disconnected the ventricles from the preload during the systolic contractions and were opened during the diastolic filling phase. The EDP (saline level in the cannula) swung in a sinusoidal manner between the target values of 2 and 22 mmHg by a computer-controlled peristaltic pump (Heidolph, Schwabach, Germany).

[0162] Ultrasound transducer (linear array, 128 elements, 15 MHz frequency, Philips Ultrasound, Bothell, Washington) was positioned on the side of the water tank to allow short axis view of the heart.

[0163] Fig. 10 illustrates an experimental setup using a vertical Langendorff perfusion system with computer-controlled loading conditions and ultrasound acquisition. Two ventricle cannulas, from the right and left ventricles, were connected to two pressure transducers and though shutters to a column that determined the preload. A computer- controlled peristaltic pump controlled the filling pressure in a sinusoidal manner between 2 and 22 mmHg. The simultaneous measurements of the pressures and the myocardial wall dynamics enable to measure the intramyocardial work.

[0164] Ultrasound images and ventricular pressures were continuously recorded. The pressures were acquired using custom NI LabView software. Pressure and ultrasound recordings were synchronized by connecting computer controlled electrical stimulator to ECG module of ultrasound scanner.

[0165] Echocardiographic images segmentation was performed using proprietary Python and Matlab software. The number of pixels in each quantified area was multiplied by the resolution of the acquired cine.

[0166] Severe inflammatory diseases, and severe myocarditis, sepsis and Systemic inflammatory response syndrome (SIRS) as Covid- 19 are associated with severe infiltration of myocardium by neutrophil cells and macrophages, and a huge increase (about 30 folds) in the levels of matrix-metalloproteases (MMPs) in the blood. The MMPs dismantle the cardiac extracellular matrix. The effects of the severe inflammatory diseases on the matrix and cardiac function were emulated by adding collagenases to the perfusion of isolated rat hearts.

[0167] After a period of baseline measurements with Krebs-Henseleit solution, collagenase-2 (or MMP8) (Worthington, NJ, USA, at concentration of lOOmcg / ml) was added to the Krebs-Henseleit solution. MMP8 is the same enzyme that is released from inflammatory cells during an inflammatory storm. The rate of matrix degradation is affected by the collagenase concentration, the temperature and calcium concentration.

[0168] Results

[0169] The study included seven isolated rat hearts. Under normal baseline condition the ventricles presented the well-known Frank- Starling Law of the heart, where an increase in the preload (end-diastolic pressure) yields a significant increase in the peak systolic pressure, as depicted in Fig. 11. The addition of collagenase-2 (or MMP8) to the perfusion caused progressive deterioration of cardiac contraction, which was manifested by a gradual decrease in the maximum systolic pressures produced by the ventricles as depicted in Fig 11. The gradual decrease in the peak systolic pressures during collagenase perfusion was associated with a decrease in the rate of pressure generation and a prolongation of the time to peak pressure, which represent the progressive systolic dysfunction.

[0170] Fig. 11 illustrates the left-ventricle peak systolic pressure (green and purple) varied with the cyclical modulation of the end-diastolic pressure (blue and yellow),during baseline (green) and collagenase perfusion (purple). Collagenase perfusion caused progressive decline in the peak systolic pressure.

[0171] Interestingly, dismantling the extracellular matrix by collagenases did not lead to cardiac dilatation, as expected from destruction of the cardiac matrix. On the opposite, collagenase perfusion produced progressive decrease in the end-diastolic volume, as depicted in Fig. 12A, and thickening of the myocardial walls, as depicted in Fig. 12B. The thickening of the ventricles was concentric i.e., thickening towards the center of the heart with narrowing of the cavity lumen.

[0172] The thickening of the ventricle wall was caused by the edema created from the breakdown of the collagen in the matrix, which elevated the oncotic pressure and attracted fluids into the interstitium. The gradual decrease in the EDV suggests that there was a gradual decrease in the cardiac ability to restore the EDV during diastole. Thickening of the wall in a concentric rather than eccentric direction resulted from development of diastolic dysfunction; at same given filling pressure the end-diastolic volume decreased in the presence of MMP. In a normal heart, part of the energy generated during systole is invested in the wall, in collagenous perimysium that is stretched when the ventricle wall thickness increases during systolic contraction. During diastole, the elastic fibers that were stretched during systole provide the energy that assists the heart to rotate back around its axis (untwist, recoil) and rapidly return to towards the original end-diastolic volume. This recoil occurs mainly during the first phase of diastole (isovolumic relaxation in vivo). Dismantling the extracellular matrix diminished the ability to store energy in the ECM during the systole and consequently decreased the ability of the heart to rapidly restore its previous end-diastolic volume. Consequently, there was a gradual decrease in the end-diastolic volume of the heart chambers after each contraction, as depicted in Fig. 12A.

[0173] Figs. 12A and 12B illustrate an example of left-ventricle end-diastolic volume (Fig. 12A) and LV ventricular wall cross-section area (Fig. 12B) evolution at baseline (green) and during collagenase perfusion (red). Note the marked decrease in the EDV and increase in the LV wall area after initiation of collagenase perfusion.

[0174] Fig. 13 presents the end-diastolic pressure volume relationships (EDPVR) and the end-systolic pressure volume relationships (EDPVR) at baseline (green) and during collagenase perfusions (red). The pressure-volume plots reveal that the decrease in thepeak systolic pressure and the related “systolic dysfunction” depicted in Fig. 11 was mainly due to the development of diastolic dysfunction and the associated decrease in the end-diastolic volume. A decrease in the end-diastolic volume had a dominant role in the development of systolic dysfunction. This postulation is based on three findings: (1) The changes in the cardiac maximal elastance appeared relatively late. Although the end- systolic pressure gradually decreased during the collagenase perfusion, all the end- systolic points in the successive cycles fell on the same ESPVR, i.e., on the same baseline maximum elastance, as depicted in Fig 13 (green lines). The maximal elastance during the initial phase of the collagenase perfusion (cycles 1 to 3) was identical to the baseline (control) maximal elastance. (2) When the end-diastolic volume was elevated to the volume at baseline (by increasing the filling pressure), the ensuing end-systolic pressure was the same as at baseline contraction from the same end-diastolic volume. At the same diastolic filling pressure, the ability of the heart to generate maximum pressure decreased due to the decrease in the EDV, but at the same EDV the isolated heart was able to reach the same end-systolic pressure. (3) When muscle fibers were isolated from the heart after being treated with collagenase, the isolated fiber generated identical stresses and sarcomere shortening as normal fibers from shame hearts. Therefore, the observed contractile dysfunction does not result from a direct damage to the cardiomyocytes, but mainly due to the decrease in the sarcomere length at the cellular level, or decrease in the EDV at the whole heart level.

[0175] Fig. 13 illustrates pressure-volume relationships in left and right ventricles. Left shift in end-diastolic pressure-volume relationship (EDPVR) is observed during collagenase perfusion (red) compared to baseline (green) without immediate decrease in the maximal elastance (end-systolic pressure-volume relationship) in both ventricles. The numbers denote successive cycles of preload cyclical changes.

[0176] Fully automatic segmentation for all the ultrasound films revealed an interesting phenomenon that has not been quantified so far and is of great importance in the functioning of the healthy and diseased heart. The fully automatic segmentation enables to precisely analysis of thousands of US images. Approximately 120,000 ultrasound images of the heart, at different states and with different filling volumes were analyzed. The huge number of images was required for precise description of the instantaneous pressure-wall thickness relationship along the entire cardiac cycle. Each heart wasmonitored for several minutes, but with a frame rate of about 70 frames per second. About 4,200 images were grabbed per minute and analyzed. The novel software automatically identifies the endocardium and epicardium of both ventricles and the changes in the ventricle wall volumes.

[0177] Plotting the pressure against the wall cross-section area, as depicted in Fig. 2B and Fig. 14, instead of the cavity volume as us commonly done (Fig. 2 A) revealed novel finding: the left ventricle pressure-myocardial wall area relationship generated a pressurearea loops in the pressure-wall area plane. The area enclosed within these loops related to additional work that was done by the heart and affect the myocardial wall. We denote this energy, the area enclosed within these loops as the intramyocardial work (IMW). Thus, the heart generated work not only on the blood within the cavity, as is commonly described by plotting the pressure against the cavity volume (Fig. 2A), but also additional work on the myocardium, as described in the Figs 2B and 14.

[0178] Interestingly, the IMW is strongly affected by matrix degradation. The large loop in Fig. 14 depicts the IMW under normal baseline condition. With the instillation of the collagenase, the volume of the wall increased but there is a conspicuous reduction in the area of the loops, i.e., in the energy stored during systole and the IMW.

[0179] The loops of the IMW in Figs. 2B and 14 consist of three phases that constitutes a triangle in the pressure-wall area plane. A fast initial thickening of the myocardium at early systole, while there was only a mild increase in the generated pressure, that creates the base of the triangle (from point 1 to 2 in Fig. 14). This first phase relates to the fast isovolumic twits of the heart. The second phase describes a significant increase in the generated pressure while the wall area was apparently constant (from point 2 to 3 in Fig. 14). These two phases describe the amount of energy stored within the myocardium due to changes in both the wall-area (first phase) and intramyocardial pressure (second phase). The third phase describes the fast energy release during the isovolumic relaxation period, when moving over the hypotenuse in the triangle-like loop, from the peak that denotes the end-systolic point, to the left lower corner that denotes the end of the isovolumic relaxation (from point 3 to 4 in Fig. 14). Thus, the most striking changes in myocardial wall area occur during the early isovolumic contraction (the fast increase in the wall area) and isovolumic relaxation. It was possible to quantify these phenomena, the changes in the pressure wall-area during the isovolumic contraction and relaxationphases, due to (1) the high frame rate (2) the precise Al segmentation of wall area from all the frames and (3) transformation of the wall dynamics to the pressure- wall area plane, where each point is derived from a single frame, and the assembly of all the points from a large number of frames generates the pressure-wall area plot. These three cardinal steps are at the core of the present innovation.

[0180] The commonly used pressure-volume loop, based on monitoring the cavity volume, describes the external work done on the blood. However, at the same time elastic energy is stored within the myocardium. The systolic to diastolic energy conversion, from energy that is stored in the wall during systole, to energy that is converted to diastolic work during diastole, can be measured by monitoring the changes in wall dynamics. At end-systole the aortic valve closes and the heart can no longer do external work on the blood, but exactly from this point the energy that was stored in the myocardium is converted into IMW by moving on the hypotenuse of the triangle, from the end-systole to the end of the isovolumic relaxation (Figs. 2B and 14). The IMW has a triangular shape in this study since there were no valves in this isolated heart study, like the aortic and mitral valves which are responsible for the rectangular shape of the cardiac pressurevolume loop. Thus, all the energy that was stored in the myocardium turned into mechanical work that was used for fast diastolic recoil.

[0181] The effect on collagenase on the IMW presents the strength of this innovation. Mild destruction of extracellular matrix by collagenases created edema and concentric thickening of the heart. The heart developed diastolic dysfunction as higher filling pressure was required to reach the same end-diastolic volume (Figs. 13 and 14). Although the collagenases increased the myocardial wall volumes, it conspicuously decreased the IMW (Fig. 14). This means that less energy was stored during systole and was available during the isovolumic relaxation to produce the required diastolic recoil and to restore the baseline EDV. The decrease in end-diastolic volume, a hallmark of diastolic dysfunction, was accompanied with conspicuous drop in the IMW (-60.82+19.44%, p=0.03). The large (blue) loop in Fig. 14 depicts the IMW under normal baseline condition. Interestingly, the IMW decreased by -60% when the end diastolic volume decreased by only -20% and the myocardial mass increased by less than 5%. Thus, the changes in IMW could be used as early and sensitive mechanical sign of myocardial injury.

[0182] Fig. 14 illustrates the effects of cardiac matrix degradation by collagenases(MMP8) on the Intramyocardial work (IMW) in an isolated rat heart. The normal IMW at baseline (blue) shifted to higher area due to edema and marked progressive declined in the IMW developed (orange and yellow loops) with the deterioration of cardiac diastolic recoil.

[0183] Verification In-vivo, in sheep with normal and failing hearts.

[0184] The isolated heart study reveals the ability to see and quantify important features that cannot be seen in the current method of echocardiography. This ability is derived from three major changes: acquiring cardiac dynamics at high temporal resolution, focusing on the myocardial wall dynamics and transformation of the data points to a single pressure- wall area plane.

[0185] However, the isolated rat heart study suffered from some limitation: (1) It was performed on isolated heart without functional valves, (2) The small rodent heart dose not resemble the geometry the human heart, (3) The study was performed at low temperature and with KH perfusion, (4) We have measured the pressure to quantify the IWM, but this is an invasive measurement.

[0186] Thus, the suggested method was validated in sheep, in-vivo, to test the feasibility and utility in human, since the adult sheep heart structure and dynamics resemble the normal adult human heart structure and function. We have utilized high fidelity echocardiographic studies to quantify myocardial wall dynamics under normal condition and after we have generated systolic heart failure with low ejection fraction.

[0187] Chronic heart failure was achieved by performing several (up to 3) catheterizations in which microsphere beads (100pm) were injected into the main coronary arteries. The sheep received amiodarone to prevent arrhythmias, and fentanyl during the procedure to alleviate angina (chest pain). The intracoronary bead injection was performed once every week, unless cardiac deterioration was too fast or the ejection fraction (EF) was smaller than 40%. The cardiac function and the homogeneity of contraction were assessed before each intracoronary bead injection, utilizing either echocardiography or / and measurement of the pressure -volume loops by inserting an impedance catheter into the LV cavity. The sheep were continuously monitored for: (1) General physical examination: weight, appetite, and physical activity (2) hemodynamic and ECG changes in the heart rate, blood-pressure, breath rate, QRS and ST segments (3) Echocardiographic evaluation of myocardial wall motion, Ejection fraction, mitral flowindices and mitral regurgitation, left atrial size, Pulmonary pressure and tricuspid regurgitation. (4) Blood tests for hemoglobin level, BNP, Troponin and CRP.

[0188] The method used for the analysis of the data from sheep was similar to the method used for the analysis of the isolated rat hearts. It includes: (1) imaging of the cardiac short axis in a high frame rate of above 110 frames per second. (2) Al assisted segmentation of the LV endocardium and epicardium, for high temporal and spatial resolution of the myocardial wall dynamics. (3) Transformation to the Lumen - wall area plane, instead of the pressure-wall area plane, where each data point represents the lumen area and wall area in each frame. (4) Measurements of objective indices that were derived from the myocardial work loop that was obtained in the lumen- wall area plane.

[0189] Results

[0190] Fig. 15 presents an example of Al assisted segmentation of the LV wall dynamics. From this segmentation various indices were derived from each frame, e.g., mean endocardial radius, mean epicardial radius, mean wall thickness, lumen area, and myocardial wall area.

[0191] Fig. 15 illustrates Al assisted segmentation of the LV wall dynamics from echocardiographic studies in the same sheep, at normal baseline condition (left) and after the induction of systolic heart failure (right). Note that the segmentations were performed on all the frames.

Claims

CLAIMSWhat is claimed is:

1. A method for monitoring cardiac functions comprising: acquiring images of a ventricle of a heart, said ventricle having a wall and a lumen, said images comprising a cross-sectional plane that encompasses an entire width of the wall of the ventricle, said images being acquired at a temporal resolution that cannot be observed with a human eye; deriving from said images a lumen area and a wall area at said cross-sectional plane; generating a presentation of the lumen area versus the wall area derived from a set of said images over time, said presentation showing at least one of following phases of cardiac movement: (1) isovolumic contraction, (2) ejection phase, (3) isovolumic relaxation, (4) rapid filling phase, (5) diastasis, and (6) atrial kick.

2. The method according to claim 1, wherein echocardiography is used to acquire said images.

3. The method according to claim 1, wherein said cross-sectional plane comprises a transthoracic short axis cross section of the ventricle.

4. The method according to claim 1, wherein said cross-sectional plane comprises a transesophageal echo (TEE) plane of the ventricle.

5. The method according to claim 1, wherein said cross-sectional plane comprises a transthoracic long axis cross section of the ventricle.

6. The method according to claim 1, wherein said temporal resolution is less than 8 milliseconds and comprises acquiring cines at a frame rate above 125 frames per second, or by generating a fused ultrasound cine from several heartbeats that contract under same loading conditions without respiratory displacement, utilizing respiratory gating.

7. The method according to claim 1, wherein said presentation of the left ventricle pressure or a surrogate of the left ventricle pressure against the wall area depicts intramyocardial work (IMW) of the heart including three dominant phases: (1) a first phase of initial thickening of ventricular wall thickness, (2) a second phase of increased intramyocardial pressure with smaller changes in the ventricular wall thickness, and (3) a phase of fast energy release during the isovolumic relaxation.

8. The method according to claim 1, wherein said presentation shows relations between cardiac systolic and diastolic functions.

9. The method according to claim 1, wherein said presentation shows ventricle suction power during diastolic rapid filling as a product of a rate of lumen-area expansion and wall-area thinning.

10. The method according to claim 1, wherein a decrease in the lumen area relative to a maximum lumen area is related to systolic ejection fraction.

11. The method according to claim 1 , wherein changes in the isovolumic relaxation and the rapid filling phase are related to diastolic function.

12. The method according to claim 1, further comprising using ventricular geometrical segmentation to identify regions in the heart.

13. The method according to claim 1, wherein said regions in the heart comprise an epicardium, an endocardium of left and right ventricles, and a septum.

14. The method according to claim 1, wherein the ventricular geometrical segmentation is expedited by using an artificial intelligence method.

15. A system for monitoring cardiac functions comprising: an ultrasound imaging device configured to acquire images of a ventricle of a heart, said ventricle having a wall and a lumen, said images comprising a cross-sectional plane that encompasses an entire width of the wall of the ventricle, said images being acquired at a temporal resolution that cannot be observed with a human eye; and said ultrasound imaging device comprising a processor configured to derive from said images a lumen area and a wall area at said cross-sectional plane, and to generate a presentation of the lumen area versus the wall area derived from a set of said images over time, said presentation showing at least one of following phases of cardiac movement: (1) isovolumic contraction, (2) ejection phase, (3) isovolumic relaxation, (4) rapid filling phase, (5) diastasis, and (6) atrial kick.

16. The system according to claim 15, further comprising a respiratory gating system configured to cooperate with spontaneous respiration or mechanical ventilation.

17. The system according to claim 16, wherein said respiratory gating system comprises at least one of a wearable sensor, a piezoelectric sensor, an impedance sensor, an inductance sensor, an accelerometer, an optical sensor and a remote sensor.

18. The system according to claim 15, wherein said ultrasound imaging device is configured to: (1) process a respiratory signal into a processed respiratory signal, (2) present said processed respiratory signal on a screen with or without ECG, (3) allow a user to select time intervals onsaid processed respiratory signal, (4) automatically detect an interval with negligible respiratory motion, and (5) automatically detect inspiration and expiration intervals.

19. The system according to claim 15, wherein said ultrasound imaging device is configured to acquire cines from several heartbeats, which represent only inspiration intervals or expiration intervals, or intervals without respiratory motion, said cines being aligned based on an ECG, resulting in a fused cine with higher temporal resolution.

20. The system according to claim 15, wherein said ultrasound imaging device is configured to present lumen area versus wall area plots based on fused cines, said plots being done on same lumen-wall planes or in cascade.

21. The system according to claim 20, wherein said plots of the lumen area versus the wall area, at the different phases of cardiac contraction, include time labels corresponding to time points of interest in the cardiac electrical activation such as: the beginning of the QRS, the peak of the R wave, the end of the QRS complex and the end of the T wave.

22. The system according to claim 21 , wherein delays between the time points of interest in the cardiac electrical activation and the corresponding time points of transition between mechanical phases of cardiac contraction, relaxation and filling are monitored and reported.

23. The system according to claim 22, wherein said delays are monitored and reported for adjustment and optimization of cardiac pacing devices, and include a Time delay between R wave peak and Atrioventricular valve closure, and / or a Time Delay between End of QRS Complex and Ventricular Outlet Valve Opening.

24. The method according to claim 1, wherein said presentation provides information regarding synchronization of ventricular wall contractions, or synchronization between atrial and ventricular contractions.

25. The system according to claim 15, wherein said presentation provides information regarding synchronization of ventricular wall contractions, or synchronization between atrial and ventricular contractions.

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