System and method for controlling a heart pump to minimize myocardial oxygen consumption

Abstract

Systems, devices, and methods are disclosed for curing patients with acute myocardial infarction (AMI) using a cardiac pump controlled in a manner that maximizes left ventricular mechanical unloading in the presence of cardiovascular instability, minimizes myocardial oxygen consumption (MVO2) and consequently infarct size, and prevents the subsequent development of heart failure. In a closed feedback system, the system can include a sensor configured to generate an output used to measure or calculate left ventricular systolic pressure (LVSP) in a left ventricle of the heart, and a controller coupled to the heart pump. The controller can be configured to measure or calculate the LVSP based on the output of the sensor, and to control operation of the heart pump to maximize mechanical unloading of the left ventricle based on the measured or calculated LVSP.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the priority and benefit of U.S. Patent Application No. 16 / 050,542, entitled "Systems and Methods for Controlling a Heart Pump to Minimize Myocardial Oxygen Consumption," filed on July 31, 2018. The entire content of the above application is incorporated herein by reference.

[0002] Field The present disclosure relates to systems for controlling a heart pump and related methods for treating patients with acute myocardial infarction (AMI), and more particularly, to maximizing mechanical unloading of the left ventricle (LV) during treatment of AMI patients and controlling the operation of the heart pump to minimize myocardial oxygen consumption (MVO 2 ) and, as a result, infarct size, and to a closed - feedback control system for preventing the development of long - term heart failure.

Background Art

[0003] Background AMI, generally known as a heart attack, can be described as a life - threatening condition that occurs when blood flow to the myocardium is suddenly blocked, causing tissue damage. Due to insufficient blood supply to the affected area, necrotic tissue, i.e., infarcts, can form in the heart. AMI is usually the result of occlusion in one or more of the coronary arteries. The coronary arteries carry oxygen - rich blood to the myocardium. When these arteries become occluded or stenosed, blood flow to the heart is significantly reduced or completely stopped.

[0004] AMI may require urgent medical treatment (also called reperfusion therapy) to restore blood flow through the occluded artery. Reperfusion therapy can include surgical procedures to remove or avoid occlusion, such as percutaneous coronary intervention (PCI), coronary angioplasty, and bypass surgery. Reperfusion therapy can alternatively or additionally include administration of various drugs, including thrombolytics, fibrinolytic agents, beta blockers, and nitroglycerin.

[0005] In some AMI patients, it is possible to perform a safe and effective reperfusion therapy that stabilizes hemodynamics using a heart pump and salvages the ischemic myocardial layer of the affected area. For example, recent clinical trials and basic research have demonstrated that the left ventricle (LV) can be mechanically unloaded by withdrawing blood from the LV and injecting the withdrawn blood into the aorta using a left ventricular assist device (LVAD). Mechanical unloading significantly reduces the workload performed by the LV, and thus 2 can reduce MVO. Reduction of MV0 2 has been recognized to be able to reduce infarct size, that is, the area of necrotic tissue resulting from a heart attack. The degree of infarct size reduction generally parallels the reduction of MVO 2 .

[0006] Despite such beneficial effects of mechanical unloading of the LV on AMI, its clinical application has not yet been established. In patients with chronic heart failure, manual control of the LVAD flow rate (e.g., liters per minute) can achieve stable hemodynamics. However, in AMI patients, the cardiac and hemodynamic state is inherently unstable because AMI can cause significant changes in myocardial contractility, vascular resistance, blood pressure, effective blood volume, heart rate, and / or the activity of the sympathetic and parasympathetic autonomic nervous systems on a second-by-second, minute-by-minute, or hourly basis. These fluctuations are known to have a significant impact on hemodynamics. Therapeutic interventions such as drug therapy and reperfusion can further result in complex dynamic modulation of these fluctuating factors, leading to complex hemodynamics.

[0007] In the presence of such cardiovascular instability in AMI, preventing excessive or insufficient mechanical unloading of the LV, even with continuous monitoring of LVAD flow or continuous manual fine-tuning, is difficult if not unrealistic. Mechanical unloading of the LV at a flow rate slightly higher than the volume coming from the pulmonary venous system gradually reduces the LV volume, ultimately inducing suction, which can cause arrhythmias that crush the heart and endanger life, and may severely damage the myocardium. Conversely, mechanical unloading of the LV at a flow rate slightly lower than the volume increases the LV volume and MVO 2 and makes it difficult to reduce the infarct size of the LV. Therefore, manual control of the heart pump to optimally unload the LV is unrealistic, ineffective, and potentially life-threatening.

[0008] Therefore, there is a need for an improved system and related methods for treating AMI patients using a heart pump that is controlled in a manner that optimizes mechanical unloading of the LV despite the presence of cardiovascular instability, thereby optimally reducing MVO 2 and infarct size. SUMMARY OF THE INVENTION

[0009] Summary The present disclosure relates to various systems, devices, and methods for treating AMI patients using a heart pump that is controlled in a manner that maximizes mechanical unloading of the LV, minimizes MVO 2 and consequently infarct size, and prevents the onset of subsequent heart failure, in the presence of cardiovascular instability.

[0010] In one exemplary aspect of a system for controlling a heart pump, the system includes a sensor configured to generate an output used to measure or calculate the left ventricular systolic pressure (LVSP) in the left ventricle of the heart, and a control device coupled to the heart pump, configured to measure or calculate the LVSP based on the output of the sensor and to control the operation of the heart pump to maximize mechanical unloading of the left ventricle based on the measured or calculated LVSP.

[0011] In some embodiments, the control device can be configured to control one or more of the pump speed and flow rate of the heart pump such that the LVSP in the left ventricle is maintained at a target reference pressure. The target reference pressure can be set to a ratio of the end-systolic pressure during normal ejection, and the ratio can be from about 0.2 to about 0.4. The target reference pressure can be set to a ratio of the mean aortic pressure, and the ratio can be from about 0.2 to about 0.4. The target reference pressure can be set to minimize the pressure-volume area (PVA) of the left ventricle. For example, in some embodiments, the target reference pressure can be set to minimize the PVA of the left ventricle by about 90% to about 97%. The target reference pressure can be set to minimize the myocardial oxygen consumption (MVO 2 ) of the left ventricle. For example, in some embodiments, the target reference pressure can be set to minimize the MVO 2 of the left ventricle by about 45% to about 48.5%.

[0012] In some embodiments, the control device can be configured to control the pump speed and / or flow rate of the heart pump to maintain the LVSP at the target reference pressure based on a plant transfer function that models the change in LVSP in response to a change in pump speed. For example, in some embodiments, the plant transfer function is TIFF0007691404000001.tif13128 (where K is the gain, ζ is the damping coefficient, f N is the natural frequency, and L is the time lag) and can be a second-order lag system with a time lag. In some embodiments, the gain K can be equal to about 0.013 mmHg / rpm, the damping coefficient ζ can be equal to about 1.9, the natural frequency f N can be equal to about 0.41 Hz, and the time lag L can be equal to about 0.03 seconds.

[0013] In some embodiments, the control device can be configured to control the pump speed and / or flow rate of the heart pump such that the LVSP reaches the target reference pressure in less than a clinically determined response time and with an overshoot of less than 10% of the target reference pressure. The control device can be configured to control the pump speed and / or flow rate of the heart pump to maintain the LVSP at the target reference pressure when the open-loop loop gain of the plant transfer function changes by 16 times or less. In some embodiments, the control device can include a proportional-integral controller configured with a proportional gain equal to about 40, an integral gain equal to about 20, and a derivative gain equal to about 0. In some embodiments, the control device can include an adaptive control mechanism configured to update the plant transfer function and reconfigure the control device to control the pump speed and / or flow rate of the heart pump in response to changes in the plant transfer function.

[0014] In one exemplary embodiment of a method for treating a patient with acute myocardial infarction (AMI), the method includes measuring or calculating the LVSP within the LV of the patient's heart and controlling the operation of the heart pump to maximize mechanical unloading of the LV based on the measured or calculated LVSP. The heart pump is implanted in the heart to perform mechanical unloading of blood from the LV to the aorta.

[0015] In some embodiments, controlling the operation of the heart pump can include controlling one or more of the pump speed and flow rate of the heart pump such that the LVSP within the left ventricle is maintained at the target reference pressure. The target reference pressure can be set to a ratio of the end-systolic pressure during normal ejection, and the ratio can be from about 0.2 to about 0.4. The target reference pressure can be set to a ratio of the mean aortic pressure, and the ratio can be from about 0.2 to about 0.4. The target reference pressure can be set to minimize the pressure-volume area (PVA) of the left ventricle by about 90% to about 97%. The target reference pressure can be set to minimize the myocardial oxygen consumption (MVO 2 ) of the left ventricle by about 45% to about 48.5%. [Invention 1001] A sensor configured to generate an output for use in measuring or calculating a left ventricular systolic pressure (LVSP) in a left ventricle of a heart; A control device coupled to the heart pump, configured to measure or calculate the LVSP based on the output of the sensor, and to control the operation of the heart pump to maximize mechanical unloading of the left ventricle based on the measured or calculated LVSP; A system for controlling a heart pump, comprising the above. [Invention 1002] The system of Invention 1001, wherein the control device is configured to control one or more of a pump speed and a flow rate of the heart pump such that the LVSP in the left ventricle is maintained at a target reference pressure. [Invention 1003] The system of Invention 1002, wherein the target reference pressure is set to a ratio of an end-systolic pressure in a normal ejection, and the ratio is about 0.2 to about 0.4. [Invention 1004] The system of Invention 1002, wherein the target reference pressure is set to a ratio of an average aortic pressure, and the ratio is about 0.2 to about 0.4. [Invention 1005] The system of Invention 1002, wherein the target reference pressure is set to minimize a pressure-volume area (PVA) of the left ventricle. [Invention 1006] The system of Invention 1005, wherein the target reference pressure is set to minimize the PVA of the left ventricle by about 90% to about 97%. [Invention 1007] The system of Invention 1002, wherein the target reference pressure is set to minimize a myocardial oxygen consumption (MVO 2 ) of the left ventricle. [Invention 1008] The system of Invention 1007, wherein the target reference pressure is set to minimize the MVO 2 of the left ventricle by about 45% to about 48.5%. [Invention 1009] A system according to any one of the present inventions 1002 to 1008, wherein the control device is configured to control one or more of the pump speed and the flow rate of the heart pump so as to maintain the LVSP at a target reference pressure based on a plant transfer function that models the change in the LVSP in response to a change in the pump speed. [The present invention 1010] The plant transfer function is TIFF0007691404000002.tif13128(where K is the gain, ζ is the damping coefficient, and f N is the natural frequency, and L is the time lag) A system according to the present invention 1009, which is a second-order lag system with a time lag, defined as [The present invention 1011] The gain K is equal to about 0.013 mmHg / rpm, the damping coefficient ζ is equal to about 1.9, the natural frequency f N is equal to about 0.41 Hz, and the time lag L is equal to about 0.03 seconds. A system according to the present invention 1010. [The present invention 1012] A system according to the present invention 1011, wherein the control device is configured to control one or more of the pump speed and the flow rate of the heart pump so that the LVSP reaches the target reference pressure within less than the clinically determined response time and with an overshoot of less than 10% of the target reference pressure. [The present invention 1013] A system according to the present invention 1011, wherein the control device is configured to control one or more of the pump speed and the flow rate of the heart pump so as to maintain the LVSP at the target reference pressure when the open-loop gain of the plant transfer function changes by 16 times or less. [The present invention 1014] The control device A proportional-integral controller composed of a proportional gain equal to about 40, an integral gain equal to about 20, and a derivative gain equal to about 0 A system according to the present invention 1011, including [The present invention 1015] The control device An adaptive control mechanism configured to update a plant transfer function and reconfigure the control device to control one or more of the pump speed and flow rate of the heart pump in response to a change in the plant transfer function The system of the present invention 1011 including the same. [The present invention 1016] A method for treating a patient with acute myocardial infarction (AMI) using any one of the systems of the present invention 1001 to 1015. [The present invention 1017] A step of measuring or calculating a left ventricular systolic pressure (LVSP) in the left ventricle (LV) of a patient's heart, wherein the heart pump is implanted in the heart to perform mechanical unloading of blood from the LV to the aorta, the step of measuring or calculating A step of controlling the operation of the heart pump to maximize the mechanical unloading of the LV based on the measured or calculated LVSP A method for treating a patient with acute myocardial infarction (AMI) including the same. [The present invention 1018] The method of the present invention 1016, wherein the step of controlling the operation of the heart pump includes controlling one or more of the pump speed and flow rate of the heart pump such that the LVSP in the LV is maintained at a target reference pressure. [The present invention 1019] The method of the present invention 1017, wherein the target reference pressure is set to a ratio of the end-systolic pressure in normal ejection, and the ratio is about 0.2 to about 0.4. [The present invention 1020] The method of the present invention 1017, wherein the target reference pressure is set to a ratio of the mean aortic pressure, and the ratio is about 0.2 to about 0.4. [The present invention 1021] The method of the present invention 1017, wherein the target reference pressure is set to minimize the pressure-volume area (PVA) of the left ventricle by about 90% to about 97%. [The present invention 1022] The target reference pressure is set to minimize the myocardial oxygen consumption (MVO 2 ) of the LV by about 45% to about 48.5%, the method of the present invention 1017.

[0016] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate exemplary embodiments and, together with the above general description and the following detailed description, serve to explain the features of the various embodiments.

Brief Description of the Drawings

[0017]

Figure 1

Figure 2

Figure 3-1

Figure 3-2

Figure 4

Figure 5

Figure 6

Figure 7A

Figure 7B

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Figure 9

Best Mode for Carrying Out the Invention

[0018] Detailed Description In the following, to provide an overall understanding of the structure, function, manufacture, and principles of use of the systems, devices, and methods disclosed in this specification, specific exemplary embodiments will be described. One or more examples of these embodiments are shown in the accompanying drawings. Those skilled in the art will understand that the systems, devices, and methods specifically described in this specification and shown in the accompanying drawings are exemplary and non-limiting embodiments, and that the scope of the present disclosure is defined only by the claims. Features illustrated or described in connection with one exemplary embodiment may be combined with features of other embodiments. Such modifications and changes are considered to be within the scope of the present disclosure. In the present disclosure, components with similar numbers in various embodiments generally have similar features when those components have similar properties and / or serve similar purposes. Those skilled in the art will understand, in view of the present disclosure, various examples in which components with similar numbers between different drawings are of the same kind.

[0019] The present disclosure relates to various systems, devices, and methods for treating AMI patients using a heart pump that is controlled in a manner that maximizes LV mechanical unloading, MVO 2 and consequently minimizes infarct size, to prevent the onset of subsequent heart failure, in the presence of cardiovascular instability.

[0020] Figure 1A shows the pressure-volume relationship of the LV during the cardiac cycle. Each of the pressure-volume loops 110 and 120 represents approximate LV pressure and LV volume measurements during one complete cardiac cycle. The cardiac cycle, i.e., the heartbeat, can be divided into four basic phases: ventricular filling 110a, isovolumetric contraction 110b, systolic ejection 110c, and isovolumetric relaxation 110d. It is well established that the end-systolic pressure correlates linearly with the end-systolic volume, and is shown as the end-systolic pressure-volume relationship (ESPVR, line 130). The ESPVR is substantially non-responsive to changes in loading conditions, and its slope well represents ventricular contractility.

[0021] Figure 1B shows an exemplary pressure-volume area (PVA) of the LV and represents the total mechanical work of the LV in one contraction. PVA is the specific surface area defined by the ESPVR and the end-diastolic pressure-volume curve (EDPVR) as well as the systolic segment (SS) of the pressure-volume trajectory during contraction. Geometrically, in the pressure-volume plane, PVA is the sum of the external work (EW) and the potential energy (PE), i.e., PVA = PE + EW. As shown in Figure 1A, the PVA of the cardiac cycle, and thus the total mechanical work of the ventricle, can be reduced by reducing the LV systolic pressure (LVSP). For example, when the LVSP is reduced from LVSP 112 to LVSP 122, the PVA decreases (e.g., from PVA 115 to PVA 125). As detailed herein, the LVSP can be reduced by using a heart pump to reduce the LV volume.

[0022] Figure 2 shows the linear relationship between PVA (e.g., per beat) and MV02 in one contraction. It is well established that PVA correlates linearly with MVO 2 (line 210). Thus, a decrease in PVA (e.g., from PVA 220 to PVA 222) reduces MV02 (e.g., from MVO 2 230 to MVO 2 232). It has been recognized that a decrease in MVO 2 can reduce the infarct size, i.e., the area of necrotic tissue resulting from a heart attack.

[0023] Figures 3A - 3F show the effects of mechanical unloading of the LV by a heart pump on hemodynamics, pressure - volume loops, PVA, and LVSP. For example, FIGS. 3A, 3B, and 3C show exemplary changes in left ventricular pressure (LVP) and aortic pressure (AP) over time for different levels of LV mechanical unloading. FIG. 3D shows exemplary pressure - volume loops Lo (without mechanical unloading), Lp (partial mechanical unloading), and LMAX (maximum mechanical unloading) corresponding to each change in LVP. FIG. 3A shows exemplary LV pressure (LVP) and aortic pressure (AP) without mechanical unloading by the heart pump. As shown in FIG. 3B, partial mechanical unloading can reduce the aortic pulse pressure, and as demonstrated by the pressure - volume loop Lp in FIG. 3D, the LV continues to eject. As shown by the pressure - volume loop Lmax in FIG. 3D, when mechanical unloading is maximized, the LV no longer ejects, and as shown in FIG. 3C, the LV pressure LVP becomes lower than the aortic pressure AP. FIG. 3E shows that maximum unloading can make PVA (PVAMAX), and thus MV02, very small. In AMI, maximum unloading is the state where the infarct size is minimized. However, mechanical unloading can cause the LVSP to decrease almost suddenly and rapidly, even under a relatively stable hemodynamic state, as shown for normal and AMI dog models with respect to LVSPo and LVSP AMI in FIG. 3F. In the AMI state, the cardiac and hemodynamic states are extremely dynamic and can change greatly, so it can be said that maintaining maximum unloading by manually controlling the heart pump is unrealistic if not impossible. Accordingly, aspects of a closed - feedback control system for a heart pump that can be configured to maintain a predetermined target LVSP in the presence of the hemodynamic instability inherent in the AMI state during mechanical unloading are disclosed herein.

[0024] Figures 4A and 4B are illustrations of exemplary aspects of a heart pump 400 suitable for mechanical unloading of the LV. In the illustrated aspects, the heart pump 400 can include an impeller pump 410, a pump motor 412, a blood inlet 414, and a blood outlet 416. In some aspects, the pump 400 can be disposed within a catheter 420 so as to be insertable by standard catheter insertion procedures. For example, the heart pump 400 can be inserted into the femoral artery, into the ascending aorta 10, passed through the aortic valve 15, and into the left ventricle 20. A pressure sensor 430 can be disposed within the catheter 420 to measure LVSP during operation of the pump. In some aspects, another pressure sensor 432 can also be disposed within the catheter 420 to measure aortic pressure. In some aspects, the pressure sensor 432 used to measure aortic pressure and / or differential pressure can also be used to calculate LVSP during operation of the pump in the absence of the pressure sensor 430 in the left ventricle. The catheter 420 can also serve as a conduit to facilitate a wired connection from a remote control device or console (e.g., the pump control device 510 of FIG. 5) to the pump motor 412 and one or both of the pressure sensors 430, 432.

[0025] As shown, pump 400 can draw blood from LV 20 through blood inlet 414 into impeller pump 410 and expel it into ascending aorta 10 through blood outlet 416. The flow rate of heart pump 400 can be controlled based on the speed of pump motor 412. As will be described in more detail below, the speed of pump motor 412 can be controlled based on measurements obtained from LVSP sensor 430 and optionally aortic pressure sensor 432. In some embodiments, heart pump 400 can pump blood from the LV to the aorta at up to 5.0 liters per minute. In some embodiments, heart pump 400 can also pump at a flow rate greater than or less than 5.0 liters per minute. Examples of heart pumps suitable for use in various embodiments can include the family of Impella® heart pumps from Abiomed, Inc., based in Danvers, Massachusetts, USA, such as Impella 5.0®, Impella LD®, Impella CP® and Impella 2.5®. Those skilled in the art will readily understand that other left ventricular assist devices or heart pumps can also be used.

[0026] Although various heart pumps can unload the LV, it can be said that pumps that can generate a cardiac output sufficient to support (i.e., perfuse) the entire body of an AMI patient are useful. The reason is that in order to minimize PVA, the LV needs to regularly stop ejecting. This state can be achieved when a heart pump for mechanical unloading generates a flow rate for perfusing the entire body. If the LV regularly stops ejecting, PVA, and thus MVO 2 can be minimized by controlling the heart pump flow rate. Various aspects of the heart pump control system disclosed herein can be used with a heart pump that can generate a cardiac output sufficient to support the entire body.

[0027] FIG. 5 is a schematic diagram of one exemplary aspect of a closed feedback heart pump control system 4500 for controlling a heart pump to maximize mechanical unloading of the left ventricle regardless of the presence of cardiovascular instability. In the illustrated aspect, system 500 can include a heart pump 400, a pump control device 510, an LVSP pressure sensor 430, and optionally an aortic pressure sensor 432. As described above with respect to FIG. 4B, heart pump 400 can be disposed within the heart to mechanically unload blood from the left ventricle to the aorta.

[0028] Pump control device 510 can be configured to control the flow rate of pump 410 by adjusting the speed (e.g., revolutions per minute, or RPM) of pump motor 412. Pump control device 510 can send a command or signal via a wired or wireless connection to adjust the speed of pump motor 412 such that pump 410 mechanically unloads the left ventricle at a target flow rate (e.g., liters per minute) set by a target pressure.

[0029] In some aspects, pressure sensors 430 and / or 432 can be configured to generate an output for use by pump control device 510 to measure or calculate LVSP within the LV of the heart. For example, in some aspects, pressure sensor 430 can be configured to measure LVSP and output it to pump control device 510 as a feedback signal. Pump control device 510 can use the LVSP as feedback information to apply a speed adjustment to pump motor 412 such that the flow rate of the pump can be maintained at or near a target reference pressure that is lower than the normal LVSP and thus much lower than the mean aortic pressure. In some aspects, the target reference pressure can be set by a manual input to pump control device 510. In some aspects, the target reference pressure can be set to a calculated value obtained or determined by pump control device 510.

[0030] PVA and thus MVO 2To automatically control the heart pump to minimize it, a pump control device 510, sometimes referred to herein as a feedback control device, can be configured to control the speed, flow rate, or other operating characteristics of the heart pump so as to maintain the LVSP at a low reference pressure level regardless of large changes in the heart or hemodynamic state. This can be achieved when the open-loop gain of the feedback control device is large enough to stabilize the LVSP fluctuations resulting from large heart and hemodynamic instabilities related to AMI. In some embodiments, the feedback control device of the heart pump is stable and has no (or substantially no) fluctuations even in the presence of large heart and hemodynamic instabilities. Control theory shows that the higher the open-loop gain, the lower the stability of the closed-loop feedback system. Thus, in some embodiments, the pump control device 510 can be configured to balance the open-loop gain with system stability.

[0031] In order to develop a high open-loop gain feedback control device without compromising stability, the open-loop transfer function can be determined for the plant to be controlled. The plant can represent a heart augmented with a heart pump. For example, in some embodiments, the plant can model the dynamic changes in LVSP in response to changes in the pump speed of the heart pump used for mechanical unloading. For example, the plant can be defined as a single-input single-output (SISO) system where the input is the pump speed control command (e.g., rpm) and the output is LVSP (e.g., mmHg). In cardiovascular physiology, the transfer function of how changes in pump speed dynamically affect LVSP has not been studied. In some embodiments, the transfer function of the plant can also be determined using other inputs, such as the flow rate of the heart pump (e.g., milliliters per second) or other operating characteristics. In some embodiments, the transfer function of the plant can also be determined using other outputs, such as the LV diastolic pressure, aortic pressure, or other properties of the cardiovascular system (e.g., the heart) that can be measured or estimated using sensors (e.g., sensors 430, 432).

[0032] In some embodiments, an approximate transfer function from pump speed to LVSP can also be estimated using computer modeling of the cardiovascular system. In some embodiments, the transfer function can be approximated and reduced to the following second-order lag system. TIFF0007691404000003.tif13128where the four parameters are the gain K, the damping coefficient ζ, the natural frequency f N and the delay time L. The term j represents the imaginary unit (j 2 = -1). Since the second-order transfer function H(f) arises from the anatomical basic structure of the cardiovascular system, the transfer function can be applied to many species that have an anatomical structure similar to the human cardiovascular system. The transfer function H(f) can also be used as a plant for modeling a heart augmented with a heart pump under diseased conditions. The reason is that such conditions are unlikely to be accompanied by large anatomical changes in the cardiovascular system.

[0033] In some embodiments, the four parameters of the plant transfer function H(f) can include a gain K equal to approximately 0.013 mmHg / rpm, a damping coefficient ζ equal to approximately 1.9, a natural frequency f equal to approximately 0.41 Hz N and a delay time L equal to approximately 0.03 seconds. As will be described in detail with respect to FIG. 9 below, in some embodiments, the value of one or more parameters of the plant transfer function H(f) can be varied in response to changes in the AMI and volume load conditions. The approximate values of the parameters are based on animal experiments and a canine model of the AMI state, but those skilled in the art will understand that these parameters can be adjusted to accommodate any variations associated with the human cardiovascular system.

[0034] Based on the specified plant transfer function H(f), the pump control device 510 can be configured to maintain the LVSP at a constant value regardless of changes in the heart and hemodynamic states. For example, as shown in FIG. 5, in some embodiments, the pump control device 510 can include a comparator 512 and a proportional-integral (PI) controller or a proportional-integral-derivative (PID) controller 514. The comparator 512 can be coupled to the pressure sensor 430 and configured to receive the measured value of the LVSP output from the pressure sensor. The comparator 512 can be configured to compare the target reference pressure to the LVSP measured in the left ventricle and output a pressure difference or error signal e(t) to the PID controller 514.

[0035] The PID controller can be configured to implement the following equation. TIFF0007691404000004.tif10128where K p is the proportional gain, K i is the integral gain, K d is the derivative gain, t is time or instant, and τ is the variable of integration that takes values from time 0 to the current time t. The integral term can be configured to make the de gain of the controller substantially equal to infinity. The equation u(t) is U(s)=Kp+K in the Laplace domain.i / s and K d can be rewritten as s.

[0036] K p 、K i and K d The values of, K, and K can be selected to tune system 500 so that the time or frequency response of the closed-loop system's LVSP can be optimized with respect to a step change in pump speed or the corresponding flow rate. For example, in some embodiments, K, K, and K p 、K i and K d can be selected such that the measured LVSP can reach the target reference pressure with minimal overshoot and time delay in response to a corresponding adjustment of the pump speed. For example, in some embodiments, (i) the overshoot of the step response of the LVSP under closed-loop conditions can be less than about 10%, (ii) the time to reach the steady-state response of the LVSP can be shorter than a predetermined clinically relevant response time (e.g., about 60 seconds), and / or (iii) the steady-state deviation from the target pressure can be zero on average. In some embodiments, the PID controller 514 can be implemented such that the feedback control system 500 is stable and can meet one or more of such constraints in the presence of changes in the open-loop gain of the plant (e.g., up to 16 times, or more than 16 times).

[0037] In some embodiments, based on the transfer function H(f) of the specified plant, the minimum realization of the controller can be a proportional-integral (PI) controller having a proportional gain K equal to about 40, p an integral gain K equal to about 20, i and a derivative gain KJ equal to about 0. The gains K p and K iCombinations of these values for the system to allow the system to maintain the LVSP at a constant value in the presence of significant instability of the AMI-induced cardiac and hemodynamic states, including changes in the open-loop gain of the plant (e.g., up to about 16-fold or more than 16-fold). In some embodiments, one or more of each gain parameter K p , K i and K d can be adjusted according to the design requirements of the plant and / or changes in the open-loop gain.

[0038] FIG. 6 shows an exemplary step response of the LVSP under the control of the closed-loop heart pump control system 500 of FIG. 5 using the above control device parameters. For example, as shown, the control system 500 can provide a step response 610 that shows no overshoot with respect to the LVSP and reaches a steady state in about 20 seconds under the AMI condition. When the plant exhibits an open-loop gain that is four times its normal magnitude, the control system 500 can provide a step response 620 that shows less than about 5% overshoot with respect to the LVSP and reaches a steady state in less than about 20 seconds. When the plant exhibits an open-loop gain that is one-fourth less than normal, the control system can provide a step response 630 that shows no overshoot with respect to the LVSP and reaches a steady state in about 40 seconds.

[0039] Based on numerous animal experiments thoroughly conducted under extreme AMI conditions, it was found that the open-loop gain of the plant varies within a range of 4 to 1 / 4 times. In clinical applications, the open-loop gain associated with human patients should not change by more than 16-fold. A step response that takes about 20 seconds to about 40 seconds to reach a steady state should be sufficient to avoid adverse effects in the outcomes related to ventricular unloading therapy. However, those skilled in the art will understand that the control system may be configured to reach a steady state with other clinically relevant response times.

[0040] Figures 7A and 7B show exemplary performance of the closed feedback heart pump control system of FIG. 5 that uses pump speed to control LVSP. For example, FIG. 7A shows that when the input target reference pressure LVSP IN changes stepwise to 40, 70, and 40 mmHg, the control system 500 can adjust the commanded pump speed S to follow the target pressure with an output LVSP out . FIG. 7A also shows the controlled output LVSP and the corresponding output aortic pressure AP OUT and output LV volume LVV OUT .

[0041] FIG. 7B shows the stabilization of relevant metrics (e.g., LVSP and PVA) representing the MVO 2 consumption of the LV in the presence of large LV volume fluctuations (e.g., increases and decreases in left ventricular volume). Volume fluctuations are hemodynamic instabilities inherent to AMI. As shown in FIG. 7B, despite large changes in volume (e.g., ±8 ml / kg), by controlling the pump speed of the heart pump (e.g., 400) using the feedback control system 500 of the present aspect to maintain the target LVSP, LVSP and PVA can remain substantially constant. In contrast, using a fixed-speed heart pump, LVSP and PVA can vary significantly in response to large volume fluctuations of the LV.

[0042] In some aspects, when a faster response or a more stable response is desired depending on the purpose, one of ordinary skill in the art will understand that one or more of the gain parameters K p , K i and K d of the PID controller 514 can be adjusted. Accordingly, although specific gain parameter values for the PID controller are disclosed herein, such values are exemplary and are not intended to be limiting.

[0043] As described above, the heart pump control system 500 of the present aspect controls LVSP based on the MVO of the LV 2configured to maintain at a target reference pressure determined to minimize, for example, as shown in FIGS. 1 and 2, MVO 2 can be minimized by minimizing the PVA of the LV. Theoretically, zero PVA can minimize MVO 2 . However, it is very difficult to achieve safely and stably maintaining the PVA at zero (which means the LVSP is zero mmHg). The reason is that even a slight decrease in LVSP below zero can cause a large suction by the pump in the LV, which may damage the heart. Therefore, in some embodiments, the closed-loop heart pump control system 500 of FIG. 5 can be configured to maintain the LVSP at a target LVSP that can be safely and stably controlled by the feedback system while providing approximately minimal MV02. For example, in some embodiments, the target LVSP can be determined based on the relationship between the LVSP rate and the recruited PVA rate as shown in FIGS. 8A and 8B.

[0044] FIG. 8A shows the relationship between the LVSP rate and the LV volume rate. As shown, the pressure and volume are normalized to 1 at the end of systole of a normal ejection contraction. The LVSP rate "α" is the ratio of the LVSP during unloading to the end-systolic pressure during normal ejection, which defines the operating state of LV unloading. The lower the LVSP rate α, the stronger the unloading. For a given LVSP rate α, since the LV volume is normalized by the end-systolic volume, the LV volume rate is also α. The end-diastolic volume of LV expansion is obtained by 1 / (1 - β) (where β is the LV ejection rate, that is, the stroke volume divided by the end-diastolic volume).

[0045] The recruited PVA is the PVA recruited by the LV unloading in the operating state of α. The residual PVA is the PVA remaining due to the unloading in the operating state of α. The PVA recruitment rate is defined by the ratio of the residual PVA to the sum of the recruited PVA and the residual PVA, indicating what proportion of the total PVA is recruited by the LV unloading. Mechanical unloading reduces the LVSP rate α, increases the recruited PVA, and consequently leads to a decrease in the residual PVA of the LV.

[0046] Figure 8B shows the PVA recruitment rate as a function of the LVSP rate "α" under various ejection rates "β". As shown, the PVA recruitment rate decreases with the LVSP rate α. For example, when α = 1 (i.e., LV volume ratio = 1), the PVA recruitment rates 806, 804, and 802 are equal to 0.75, 0.57, and 0.33, respectively, for ejection rates β of 0.6, 0.4, and 0.2. This means that an LV with insufficient contraction may require a greater unloading to reduce the PVA. When α = 0.4, the PVA recruitment rates 806', 804', 802' can be 0.9 or more regardless of the ejection rate β. When α = 0.2, the PVA recruitment rates 806", 804", 802" can be 0.97 or more regardless of the ejection rate β.

[0047] Therefore, in some embodiments, to minimize the LV PVA by about 90% - 97%, the target LVSP can be set equal to the product of the end - systolic pressure during normal ejection and the LVSP rate α (α is a value from about 0.2 to about 0.4). The end - systolic pressure during normal ejection is typically 70 - 110 mmHg. The target LVSP within such a range can be safely and stably achieved by mechanical unloading using a heart pump under the control of the feedback system 500 of the present embodiment in FIG. 5. A reduction of about 90% - 97% of the PVA, assuming that 50% of the MVO 2 is PVA - independent, respectively, corresponding MVO 2can be converted to a reduction of about 45% to 48.5%. In the presence of significant noise when evaluating infarct size, small differences in MVO 2 are unlikely to affect infarct size. Such a reduction in MVO 2 achieves significant oxygen savings, thereby reducing infarct size and subsequent heart failure.

[0048] In some embodiments, to minimize LV PVA by about 90% to 97%, the target LVSP can be set equal to the product of the mean aortic pressure and the LVSP rate a (where a is a value from about 0.2 to about 0.4). As described above, a reduction of about 90% to 97% in PVA, assuming that about 50% of MVO 2 is PVA-independent, can correspond to a reduction of about 45 to about 48.5% in MVO 2 . Such a reduction in MVO 2 achieves significant oxygen savings, thereby reducing infarct size and subsequent heart failure.

[0049] In some embodiments, when the hemodynamics of an AMI patient are relatively stable, including the aortic pressure, the target reference pressure (e.g., target LVSP) can be set to a fixed ratio of the mean aortic pressure, e.g., non-limitingly, a ratio from about 0.2 to about 0.4. In some embodiments, the target reference pressure can be set to a fixed ratio of other hemodynamic parameters that can be measured or estimated. Once the target pressure is set, it is not changed until a clinical need arises. This simplifies the setting of target pressures that depend on the patient's hemodynamic state.

[0050] FIG. 9 is a schematic diagram of one exemplary embodiment of an adaptive feedback heart pump control system 900. As shown, the control system 900 can include a comparator 905, an adaptive pump control device 910, a heart pump actuator 920, a plant model 930, one or more sensors 940, a system identification module 950, and a control device design module 960. Except as described below, or as would be readily understood by one of ordinary skill in the art, the control system 900 can be substantially similar to the control system 500 described previously with respect to FIGS. 4 and 5. Accordingly, for the sake of brevity, a detailed description of its structure and function is omitted here. The control system 900 can include any one or more of the features of the control system 500 described above.

[0051] In some embodiments, the adaptive feedback heart pump control system 900 can be used to control the heart pump to maintain a target LVSP or AP in AMI patients who may require the application of more complex mechanical unloading. For example, the application of more complex mechanical unloading can be expected in patients with right ventricular failure, life-threatening arrhythmias, and other mechanical circulatory devices. Accordingly, a feedback heart pump control system configured to control a plant associated with a certain transfer function may not be able to guarantee maintaining LVSP and PVA constant. Thus, the system identification module 950 and the control device design module 960 can be used to adaptively configure the control system 900 to control the heart pump 920 based on the continuous and / or periodic identification and update of the plant model 930 representing the heart augmented by the heart pump (e.g., 400). In this way, the adaptive pump control device 910 can be adaptively configured to minimize PVA and MOV2 in AMI patients under a variety of pathological conditions.

[0052] In some embodiments, the system identification module 950 can be configured to periodically or continuously monitor and update the plant transfer function, and the control device design module 960 can be configured to update one or more parameters of the adaptive pump control device 910 in response to determined changes in the plant transfer function. For example, in some embodiments, the system identification module 950, in response to a change in the correlation between the pump speed and the LVSP, can adjust one or more of the parameters of the secondary transfer function H(f) of the plant, such as the gain K, the damping coefficient ζ, the natural frequency f N and / or the delay time L. In some embodiments, the system identification module 940 can also be configured to model the plant using a transfer function other than the secondary transfer function H(f). In some embodiments, the system identification module 950 can be configured to change the plant transfer function based on sensor measurements of the LVSP in response to a change in the pump speed.

[0053] Based on the determined change in the plant transfer function, the control device design module 960 can adjust one or more parameters of the adaptive pump control device 910. For example, if the adaptive pump control device is a PI or PID control device, the control device design module 960 can adjust the proportional gain K p , the integral gain K i and the derivative gain K d of the control device. One or more of K p , K i and K d can be adjusted such that the measured LVSP can reach the target reference pressure with minimal overshoot and time delay in response to the corresponding adjustment of the pump speed.

[0054] The various illustrative logical blocks, modules, circuits, and algorithmic operations described in connection with the aspects disclosed in this specification can be implemented as electronic hardware, computer software, or a combination of both. To clearly illustrate this interchangeability of hardware and software, various illustrative components, blocks, modules, circuits, and operations are generally described above in terms of their functionality. Whether such functionality is implemented as hardware or software depends upon the particular application and design constraints imposed on the overall system. Skilled artisans may implement the described functionality in varying ways for each particular application, but such implementation decisions should not be interpreted as causing a departure from the scope of the claims.

[0055] The hardware used to implement the various illustrative logics, logical blocks, modules, and circuits described in connection with the aspects disclosed in this specification can be implemented or executed with a general-purpose processor, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. The general-purpose processor may be a microprocessor, but in the alternative, any conventional processor, controller, microcontroller, or state machine may be used. The processor may also be implemented as a combination of receiver smart objects, such as a combination of a DSP and a microprocessor, two or more microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration. Alternatively, some operations or methods may be performed by circuitry that is dedicated to a given function.

[0056] In one or more aspects, the functions described may be implemented in hardware, software, firmware, or any combination thereof. When implemented in software, the functions may be stored as one or more instructions or code on a non-transitory computer-readable storage medium or a non-transitory processor-readable storage medium. The operations of the methods or algorithms disclosed herein may be embodied in processor-executable software modules or processor-executable instructions present on a non-transitory computer-readable or processor-readable storage medium. A non-transitory computer-readable or processor-readable storage medium can be any storage medium that can be accessed by a computer or a processor. By way of example and not limitation, such a non-transitory computer-readable or processor-readable storage medium can include RAM, ROM, EEPROM, FLASH memory, CD-ROM or other optical disk storage, magnetic disk storage or other magnetic storage devices, smart objects, or any other medium that can be used to store the desired program code in the form of instructions or data structures and that can be accessed by a computer. As used herein, disk and disc include compact disc (CD), laser disc, optical disc, digital versatile disc (DVD), floppy disk, and Blu-ray disc (disk typically reproduces data magnetically, while disc reproduces data optically using a laser). The above combinations are also included within the scope of non-transitory computer-readable and processor-readable media. Additionally, the operations of a method or algorithm may be present on a non-transitory processor-readable storage medium and / or a computer-readable storage medium that can be incorporated into a computer program product as one or any combination or set of codes and / or instructions.

[0057] The foregoing description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the claimed invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be applied to other embodiments without departing from the scope of the claimed invention. Accordingly, the disclosure is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the appended claims and the principles and novel features disclosed herein.

Claims

1. A system for cardiac support, comprising a heart pump, wherein the heart pump has a first portion configured to be disposed within the left ventricle of a patient, a second portion coupled to the first portion and configured to extend into the aorta of the patient across the aortic valve of the patient when the first portion is disposed within the left ventricle of the patient, a first sensor disposed within the first portion of the heart pump and configured to generate an output for use in measuring or calculating the left ventricular systolic pressure (LVSP) within the left ventricle of the patient, a control device coupled to the heart pump, configured to measure or calculate the LVSP based on the output of the first sensor, and configured to control the operation of the heart pump to mechanically unload the left ventricle of the patient based on the measured or calculated LVSP, and the heart pump has a pump speed and a flow rate, and the control device is configured to control the pump speed or the flow rate of the heart pump such that the LVSP within the left ventricle is maintained at a target reference pressure, wherein the target reference pressure is set to reduce the pressure-volume area (PVA) of the left ventricle by about 90% to about 97%, system.

2. The system according to claim 1, wherein the first sensor is a pressure sensor that directly measures the LVSP.

3. The left ventricle is mechanically unloaded to a level corresponding to a maximum mechanical unloading (L ＭＡＸ ), the system according to claim 1.

4. The system according to claim 1, wherein the patient is a patient with acute myocardial infarction (AMI).

5. The system according to claim 4, wherein the heart pump is capable of generating a cardiac output for perfusing the whole body of the AMI patient.

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