Methods for providing ventricular support for patients

Abstract

A method of providing ventricular support for patients experiencing an acute myocardial infarction (AMI) by performing a coronary intervention procedure. The method including inserting a mechanical circulatory support device into the vasculature of a patient; delivering the mechanical circulatory support device within the vasculature into a heart of the patient; operating the mechanical circulatory support device for a support period; and measuring a sympathetic nerve activity (CSNA) of the patient during the mechanical circulatory support. A reduction in the recorded CSNA levels during the mechanical circulatory support device is reduced after 60 minutes of the mechanical circulatory support by between about 40.8% to about 54.2% as compared to the CSNA levels at the initiation of the mechanical circulatory support.

Description

ABD0440WOPCT1_266489.036METHODS FOR PROVIDING VENTRICULAR SUPPORT FOR PATIENTSCROSS REFERENCE TO RELATED APPLICATIONSThis application claims the benefit of priority under 35 U.S.C. § 119 to prior filed U.S. Provisional Patent Application No. 63 / 724,052, filed November 22, 2024 (Attorney Docket No.: 266489.000011 (ABD0440USPSP1)), the entire contents of which is hereby incorporated by reference in its entirety as if set forth in full herein.TECHNICAL FIELD

[0001] Disclosed herein are methods for providing ventricular support for patients.BACKGROUND

[0002] Mechanical circulatory support devices, such as intracardiac or intravascular blood pumps may be introduced in the heart to deliver blood from the heart into an artery. Such devices are often introduced to support the function of the heart after a patient suffers a cardiac episode. One such class of devices is the Impella® line of blood pumps. Some blood pump assemblies may be introduced percutaneously through the vascular system during a cardiac procedure. Specifically, blood pump assemblies can be inserted via a catheterization procedure through the femoral artery or the axillary / subclavian artery, into the ascending aorta, across the aortic valve and into the left ventricle. The inserted blood pump assembly may be configured to pull blood from the left ventricle of the heart through a cannula and expels the blood into the aorta. A blood pump assembly may also be configured to pull blood from the inferior vena cava and to expel blood into the pulmonary artery. Some mechanical circulatory support devices are powered by an on-board motor, while others are powered by an external motor and a drive cable.

[0003] Acute myocardial infarction (AMI) of the left ventricle activates cardiac sympathetic nerve activity (CSNA) as a compensatory mechanism to improve tissue perfusion. An elevation in CSNA increases heart rate and myocardial contractility, both of which operate to improve cardiac output. While this may be beneficial in the short term, continued activation of CSNA is detrimental to cardiac recovery as increases in CSNA can result in fatal cardiac arrhythmias and sudden cardiac death. This elevation in CSNA can propel AMI into incipient cardiogenic shock, and once established, the cardiogenic shock typically continues in a downward cascade, if there is no intervention. Thus, there is a need to321989582 1ABD0440WOPCT1_266489.036 understand the effects of CSNA during an AMI to reduce the increase in CSNA during an AMI.BRIEF SUMMARY

[0004] The present disclosure describes systems, devices, and methods of providing ventricular support during a high-risk percutaneous coronary intervention procedure.

[0005] One aspect of the present disclosure relates to a method of providing ventricular support for patients during a high-risk percutaneous coronary intervention procedure. The method including providing ventricular support for patients experiencing an acute myocardial infarction (AMI) by performing a coronary intervention procedure. The method including inserting a mechanical circulatory support device into the vasculature of a patient; delivering the mechanical circulatory support device within the vasculature into a heart of the patient; operating the mechanical circulatory support device for a support period; and measuring a sympathetic nerve activity (CSNA) of the patient during the mechanical circulatory support. A reduction in the recorded CSNA levels during the mechanical circulatory support device is reduced after 60 minutes of the mechanical circulatory support by between about 40.8% to about 54.2% as compared to the CSNA levels at the initiation of the mechanical circulatory support.

[0006] Another aspect of the present disclosure relates to a significant reduction in CSNA with mechanical circulatory support. This reduction in CSNA may offset the pro- arrhythmogenic state and may underlie the decreased incidence of arrhythmias observed with MCS in some studies. Increased CSNA can also cause intense coronary vasoconstriction. This coronary vasoconstriction may be associated with an improvement in directly recorded coronary blood flow. A beneficial effect of mechanical circulatory support by an Impella® blood pump may be mediated in part by the inhibition of cardiac sympathetic drive as will be described in further detail below.BRIEF DESCRIPTION OF DRAWINGS

[0007] The foregoing and other objects and advantages will be apparent upon consideration of the following detailed description, taken in conjunction with the321989582 2ABD0440WOPCT1_266489.036 accompanying drawings, in which like reference characters refer to like parts throughout, and in which:

[0008] FIG. 1 illustrates an exemplary intravascular blood pump positioned within a left ventricle of a heart in accordance with aspects of the present technology;

[0009] FIG. 2 illustrates a chart outlining the Study of the present technology;

[0010] FIGs. 3A and 3B illustrate a baseline of blood pressure (BP) and cardiac sympathetic nerve activity (CSNA) of Fig. 2 in accordance with aspects of the present technology;

[0011] FIGs. 4A and 4B illustrate BP and CSNA over 60 minutes after coronary artery embolization and during Impella pump at level P8;

[0012] FIGs. 5A and 5B illustrate raw data traces of BP and CSNA in one animal post embolization over a 5-second interval.;

[0013] FIGs. 6A and 6B illustrate BP and CSNA at each pump flow rate level from P0 to P8 post embolization; and

[0014] FIGs. 7A and 7B illustrate raw data traces of BP and CSNA in one animal post embolization and during Impella CP® mechanical circulatory support at Pmax over a 5- second interval.DETAILED DESCRIPTION

[0015] Aspects of the present disclosure are described in detail with reference to the drawing figures wherein like reference numerals identify similar or identical elements. It is to be understood that the disclosed aspects are merely examples of the disclosure, which may be embodied in various forms. Well-known functions or constructions are not described in detail to avoid obscuring the present disclosure in unnecessary detail. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art to variously employ the present disclosure in virtually any appropriately detailed structure.

[0016] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements321989582 3ABD0440WOPCT1_266489.036 and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.

[0017] The phrase “and / or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and / or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and / or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and / or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.

[0018] The phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including”, “comprising”, or “having”, “containing”, “involving”, and variations thereof herein, is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including”, “carrying”, “having”, “containing”, “involving”, “holding”, “composed of”, and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of’ and “consisting essentially of’ shall be closed or semiclosed transitional phrases, respectively.321989582 4ABD0440WOPCT1_266489.036

[0019] As used herein, the terms “proximal” and “distal” refer to positions relative to a physician or operator of the intravascular blood pump. Thus, “proximal” indicates a position that is closer to the physician or operator or a direction that points towards the physician or operator, and “distal” indicates a position that is farther from the physician or operator or a direction that points away from the physician or operator.

[0020] As used herein, “operator” can include a doctor, surgeon, or any other individual or instrumentation associated with delivery and operation of a mechanical circulatory support device in a patient.

[0021] As used herein, the term “percutaneous coronary intervention” (PCI) refers to a non-surgical procedure used to treat the blockages in a coronary artery. PCI opens up narrowed or blocked sections of the artery, restoring blood flow to the heart.

[0022] As used herein, sustained arrhythmia refers to ventricular fibrillation, ventricular tachycardia, higher degree conductive disorder or newly developed atrial fibrillation lasting >60 seconds and requiring cardioversion / defibrillation and / or IV amiodarone_during placement of support with or removal of the device.

[0023] As used herein, temporary ventricular support refers to ventricular support to patients during high-risk PCI for 6 hours or less (< 6 hours).

[0024] As described herein, PCI is a nonsurgical procedure used to treat the blockages in a coronary artery. PCI opens up narrowed or blocked sections of the artery, restoring blood flow to the heart. It is performed in the catheterization lab by an interventional cardiologist. The purpose of the procedure is to open up narrowed arteries using either a stent and / or balloon angioplasty. PCI techniques have evolved over the past two decades as a result of advances in available technology and greater operator expertise. As a result, the indication for PCI has evolved from simple, discrete lesions in patients with single- vessel disease and well- preserved left ventricular function to multiple, complex lesions in sicker patients with complex coronary anatomy, depressed left ventricular function and advanced comorbidities. Coronary artery bypass grafting (CABG) is a procedure to improve blood flow to the heart by opening up narrowed arteries and / or blocked arteries. Both PCI and / or CABG are used during revascularization procedures.

[0025] Patients in need of revascularization procedures often present with very high-risk features, including but not limited to complex pathologic multivessel coronary anatomy,321989582 5ABD0440WOPCT1_266489.036 depressed left ventricular function and advanced comorbidities. Historically, CABG has been the recommended approach for revascularization procedures for patients with multi vessel disease and depressed left ventricular function, especially in patients who may also have angina or heart failure symptoms. However, patients exhibiting these symptoms may be very sick and thus, CABG may increase the risk of mortality and / or morbidity. In such instances, PCI may be the only viable alternative to executing a revascularization procedure for high- risk patients.

[0026] During such PCI procedures, many techniques are used to transiently interrupt blood flow within the target coronary artery. Such techniques may include repetitive contract dye injections, balloon inflations, atherectomy passes and stents. By using these techniques, the patient may experience ischemic and diastolic dysfunction. The patient may also later experience myocardial ischemia, which may result in decreased cardiac output and thus decreased coronary flow. Furthermore, in patients with poor cardiac reserve, the risk of immediate or delayed hemodynamic compromise or collapse is the highest. Thus, it may be necessary to hemodynamically support the patient’s heart during a PCI procedure.

[0027] One way of providing such hemodynamic support during a PCI procedure is by using a suitable mechanical circulatory support device. An example of a suitable mechanical circulatory support device is a transvalvular microaxial pump (e.g., Impella® line of blood pumps, or similar devices), where the pump is inserted percutaneously or surgically into the aorta and across the aortic valve, and pumps blood out of the left ventricle and into the aorta. Examples of such suitable mechanical circulatory support devices include both the Impella 2.5® blood pump and the Impella CP® blood pump (Abiomed, Danvers, Mass.) In both such examples, blood may be drawn through the cannula situated in the left ventricle and expelled into the aorta. Both the Impella 2.5 and the Impella CP have continuous pump flows up to 2.5 and 3.8 liters per minute, respectively.

[0028] In some embodiments, a suitable mechanical circulatory support device may be a transvalvular microaxial pump, where the pump may include an expandable portion. In such embodiments, the pump motor may be located extracorporeally. An example of a suitable mechanical circulatory support device may include the Impella ECP™ blood pump (Abiomed, Danvers, Mass.)321989582 6ABD0440WOPCT1_266489.036

[0029] Tmpella is incorporated into eight medical guidelines for multiple indications, including acute myocardial infarction (AMI) and PCI procedures. Specifically, there is support for the use of Impella in patients with reduced or normal left ventricular function and severe coronary artery disease for treatment of anticipated technically challenging or prolonged AMI or PCI procedures. The Impella 2.5 and Impella CP ventricular support systems are approved by the FDA for providing temporary (< 6 hours) ventricular support to patients during high risk percutaneous coronary interventions.

[0030] The Impella 2.5®, Impella CP®, Impella CP® with SmartAssist®, Impella 5.0®, Impella 5.5® with SmartAssist® and Impella LD® Catheters, in conjunction with the Automated Impella Controller™ (collectively, "Impella® System Therapy"), are temporary ventricular support devices intended for short term use (< 4 days for the Impella 2.5, Impella CP, and the Impella CP with SmartAssist, and < 14 days for the Impella 5.0, Impella 5.5 with SmartAssist and Impella LD) and indicated for the treatment of ongoing cardiogenic shock that occurs immediately (< 48 hours) following acute myocardial infarction or open heart surgery or in the setting of cardiomyopathy, including peripartum cardiomyopathy, or myocarditis as a result of isolated left ventricular failure that is not responsive to optimal medical management and conventional treatment measures (including volume loading and use of pressors and inotropes, with or without IABP). The intent of Impella System Therapy is to reduce ventricular work and to provide the circulatory support necessary to allow heart recovery and early assessment of residual myocardial function.

[0031] Existing transvalvular microaxial pumps, such as Impella 2.5 and Impella CP, require a relatively large bore (at least a 12 French) femoral access site for device placement. As used herein, a measurement of 1 French (Fr) is equivalent to 1 / 3 millimeter (mm). The bore access site size is primarily limited by the motor body size of the device. In some instances, a relatively large bore access site may be more susceptible to bleeding, vascular dissection or ischemia during access and / or closure of the access site than a comparatively smaller bore access site. A mechanical circulatory support device with a flow rate that is comparable to currently available mechanical circulatory support devices, but with a smaller bore access site may be advantageous, especially for short-term procedures such as a PCI. An example of such a mechanical circulatory support device is the Impella CP®. Disclosed herein is a method of using such a mechanical circulatory support device for providing ventricular321989582 7ABD0440WOPCT1_266489.036 support to patients during an acute myocardial infarction (AMI), resulting in a reduction in the recorded CSNA levels during the mechanical circulatory support device is reduced after 60 minutes of the mechanical circulatory support by between about 40.8% to about 54.2% as compared to the CSNA levels at the initiation of the mechanical circulatory support. More specifically, and as discussed in greater detail below, incremental pump support resulted in a significant decrease in CSNA (n=7) with a 47.3 ± 6.9 % reduction at P8 compared to P0 (oneway ANOVA; <0.001).

[0032] For example, FIG. 1 illustrates a mechanical circulatory support device that is an intravascular blood pump 1 for mechanically supporting a left ventricle of a heart according to some aspects of the present technology. It is to be appreciated that the intravascular blood pump 1 may include at least some of the features of the Impella CP® blood pump and pump1 may be used in any of the systems, methods, and procedures described herein.

[0033] As shown in FIG. 1, in some aspects, the intravascular blood pump 1 may include a catheter 5 and a pump section 4 mounted at a distal end region of the catheter 5. The pump section 4 may comprise a housing having a motor, a rotor, and an impeller. Alternatively, the motor may be exterior to the housing and the rotor can be driven by a flexible drive shaft. The intravascular blood pump 1 may be placed inside the heart 3 using a percutaneous, transluminal technique. As described in greater detail below, the pump section 4 of the intravascular blood pump 1 may be inserted percutaneously through an introducer sheath and placed in an access site. For example, the intravascular blood pump 1 may be introduced through, for example, a femoral artery or radially (wrist). Likewise, the intravascular blood pump 1 may be introduced through other vessels, such as through the subclavian artery. As shown in FIG. 1, the catheter 5 may be advanced into the aorta such that the pump section 4 reaches through the aortic valve into the left ventricle 2 of the heart 3.

[0034] The pump section 4 may further comprise a rotor to cause blood to flow from a blood flow inlet 6 at a distal end of the pump section 4 to a blood flow outlet 7 located proximally of the blood flow inlet 6. By placing the blood flow inlet 6 inside the left ventricle2 and the blood flow outlet 7 inside the aorta, the intravascular blood pump 1 may support the patient’s systemic blood circulation. It is to be appreciated that, if the intravascular blood pump 1 is configured and placed differently, it may be used, e.g., to support the patient’s pulmonary blood circulation instead.321989582 8ABD0440WOPCT1_266489.036

[0035] The catheter 5 may further house a drive shaft configured to be driven by an electric motor 8, which may be positioned outside the patient’s body. The drive shaft may be configured to drive the rotor contained inside the pump section 4.

[0036] As shown in FIG. 1, the pump section 4 may also have a flexible atraumatic tip 9, which is sometimes called a pig tail. The flexible tip 9 may be located at the distal end of the pump section 4. In some aspects, the proximal end of tip 4 is coupled to and extends from the distal end of the housing. The flexible atraumatic tip 9 may have any suitable shape, such as a pigtail or a J-form, and may be configured to facilitate placement of the intravascular blood pump 1 by aiding navigation inside the patient’s vascular system. In some embodiments, the flexible tip 9 may form a closeddoop shape. Furthermore, the softness of the flexible atraumatic tip 9 may be configured to allow the pump section 4 to support itself atraumatically against a wall of the left ventricle 2. In some aspects, the atraumatic tip 9 may have variable stiffness. In some aspects, the intravascular blood pump 1 may not include a flexible tip 9.

[0037] US Patent Nos. 8.439,859, 9,974,893, 10,709,828. 10,478.538, 8,721.516, 9,771,801, 10,478,540, 11,219,755, 11,793,997, and US Patent Publication Nos. 2022 / 0288381, 2023 / 0063196, 2020 / 0197585, 2022 / 0203084, 2020 / 0390953, 2022 / 0032037 disclose examples of the blood pump that may be used with the present disclosure, the entireties of each of which are incorporated herein by reference.

[0038] A study is described in “Mechanical Circulatory Support reduces directly recorded Cardiac Sympathetic Nerve Activity in an Ovine Model of Acute Myocardial Infarction.” the entirety of which is incorporated herein by reference and included in Appendix A attached hereto (also referred to as “the Study”).

[0039] Percutaneous insertion of the pump 1 into the patient may be performed under fluoroscopy to permit observation of the position of the pump 1 within the patient and aid appropriate positioning of the pump 1. In some aspects, a delivery assist device (or several delivery assist devices) may be used to aid in delivering the pump 1 to a desired location within the patient. For example, the delivery assist device may be used to aid in delivering the pump 1 to a location as shown in FIG. 1 with the outflow tube 20 across the aortic valve and the inlet 6 in the left ventricle 2 of the heart 3 and the outlet 7 in the aorta. The delivery assist device may be any device (or devices) configured to be inserted into the patient and to aid in the delivery of the pump 1 to a desired location within the patient. In some embodiments, the321989582 9ABD0440WOPCT1_266489.036 delivery assist device(s) may be configured to hold open an aortic valve leaflet of the patient as the pump 1 crosses the aortic valve. The delivery assist device may be inserted through the same introducer sheath as the pump 1 or through a separate access site or device. The delivery assist device may be inserted together (e.g., in parallel) or separately from the pump 1 through the introducer sheath. In some aspects, the delivery assist device may be inserted adjacent the pump 1 through the introducer sheath. In some aspects, the delivery assist device may be configured to aid in the delivery of the pump 1 to the desired location within the patient such that the pump 1 may not advance over the delivery assist device when inserting the pump 1 and the delivery assist device into the patient. The delivery assist device(s) may comprise any of one or more of guidewires, a secondary or companion catheter (separate from catheter 5) that may be steerable, or any other type of delivery assist device. In some aspects, where the delivery assist device comprises one or more of guidewires, the pump 1 may not advance over the one or more of guidewires, but rather, the pump 1 may be adjacent to the one or more of guidewires during the delivery of the pump 1 to the desired location in the patient. In some aspects, where the delivery assist device comprises a secondary or companion catheter, the distal end of the secondary catheter may be formed as an atraumatic tip having a predetermined shape and stiffness to aid delivery and positioning of pump 1. For example, the distal end of the secondary catheter may be formed in a pigtail shape (or other shape). Alternatively, where the delivery assist devices comprise a secondary catheter, the atraumatic tip (e.g., a pigtail shaped distal extension) may be coupled to and extend from a distal end of the secondary catheter. In any case, the secondary catheter may be referred to as a “pigtail catheter”. In some aspects, the delivery assist device may have an outer diameter of 9 Fr. In other aspects, the delivery assist device may have an outer diameter of less than 9 Fr, preferably, 7 Fr.

[0040] When pump I is inserted into the patient and positioned in the desired position to provide support, e.g., within the left ventricle 2 and aorta, as shown in FIG. 1, motor 8 may be controlled by a control unit to selectively drive rotation of a drive shaft and rotor to cause blood from left ventricle 2 to be drawn into pump 1 through inlet 6 and to be expelled from pump 1 through outlet 7. It is to be appreciated that rotor 10 may be rotated by motor 8 in the reverse direction to convey blood in an opposite direction from opening(s) 7 to opening(s) 6. In any case, a user may control operation of motor 8 and other aspects of pump 1 via user321989582 10ABD0440WOPCT1_266489.036 input to control unit. Moreover, the control unit may include one or more algorithms for automatically controlling operation of motor 8. The control unit may be configured to display operation data associated with the blood pump 1 (e.g., motor speed), the patient (e.g., blood flow rate, pressure, heart signal, etc.), or other relevant data and settings. The control unit may be configured to output notifications (e.g., displayed notifications and / or sounds) to alert the user(s) when operational data values fall beyond predetermined values or ranges, for example if a leak or loss of suction is detected, or when other conditions are detected.

[0041] The intravascular blood pump 1 described herein may be used to administer therapy to a patient in accordance with some aspects of the present disclosure. Such therapy includes, for example, support during a high-risk PCI. For example, the blood pump 1 described herein may be intended for temporary ventricular support during elective or urgent high-risk PCI performed in hemodynamically stable patients.

[0042] One aspect of the present disclosure as described in the Study provides a method of providing ventricular support for a predetermined patient population during a high-risk percutaneous coronary intervention procedure, the method includes: providing ventricular support for patients who are experiencing an acute myocardial infarction (AMI) by performing a coronary intervention procedure, the method including the steps of: a. inserting a mechanical circulatory support device into the vasculature of a patient; b. delivering the mechanical circulatory support device within the vasculature into a heart of the patient; c. operating the mechanical circulatory support device for a support period; d. measuring a sympathetic nerve activity (CSNA) of the patient during the mechanical circulatory support; and e. wherein a reduction in the recorded CSNA levels during the mechanical circulatory support device is reduced after 60 minutes of the mechanical circulatory support by between about 40.8% to about 54.2% as compared to the CSNA levels at the initiation of the mechanical circulatory support.

[0043] The Study was conducted on adult female Romney sheep (n=13 total) with a mean weight of 57 ± 5.7 Kg (range 50-71 kg). The sheep were fasted for 24 hours before induction of anaesthesia. Following anaesthesia, surgical instrumentation was carried out to measure321989582 11ABD0440WOPCT1_266489.036 arterial pressure (solid-state catheter in femoral artery), coronary blood flow (Transonic flow probes; 6PS) and CSNA (custom electrodes were placed in the inferior cardiac nerve). Following a baseline period, the left coronary artery was embolized under fluoroscopy guidance. Following 60 minutes post the embolization, the mechanical circulatory support device pump was inserted (Figure 1).

[0044] The implantation of Impella CP® pump was carried out through access of one carotid artery. Using echocardiography, the pump inlet position was adjusted to be in the midleft ventricular cavity, with the outlet in the ascending aorta. The Impella controller recorded the pressure waveform, and the pressure wave was confirmed to be aortic in origin. The pump was started at level 1 (Pl). Color Doppler was used to verify the inflow and outflow areas, and the position was adjusted as required. Once the positioning was satisfactory, the pump flow rate was increased every 2 minutes until level 8 or the highest level at which suction was noted. P0 was recorded when the pump was placed in the ventricle. Two minutes of continuous data were averaged at each stage of cardiac pump support. Adequate continuous CoBF waveforms in 7 sheep and clear CSNA recordings in 6 animals could not be recorded. Data are presented as the mean ± standard error of the mean. Statistical tests were conducted in SPSS (IBM, version 28).

[0045] Referring now to FIGs. 2-6B, some of the Study data is illustrated. The preparation and instrumentation were achieved over a 60-minute time period. A baseline was established over a 20-minute period. Then coronary artery embolization of the animal was initiated. Sixty (60) minutes post embolization, the Impella CP® pump was placed in the heart as described above with the inlet to the pump placed in the left ventricle and the pump 7 was placed in the aortic arch. Thereafter, the pump was turned on and operated at Pl for two (2) minutes. The pumps flow rate was increased in two-minute intervals from Pl to P8. In some animals the maximum flow rate was below P8. The pump support was maintained for thirty (30) minutes after reaching the maximum flow rate of Pmax.

[0046] FIGs. 3A and 3B illustrate raw data traces of blood pressure (BP) and cardiac sympathetic nerve activity (CSNA) in one animal during baseline over a 5-second interval. FIGs. 4A and 4B illustrate BP and CSNA from baseline over 60 minutes after coronary artery embolization. The changes to systolic, diastolic and mean arterial pressure (BP) and % change in cardiac sympathetic nerve activity (CSNA) is shown from baseline (n=7) before and serially321989582 12ABD0440WOPCT1_266489.036 after embolization of the left coronary artery. *p<0.05 (One-way ANOVA). The red arrow indicates the time point when embolization of the left coronary artery occurred.

[0047] FIGs. 5A and 5B illustrate raw data traces of blood pressure (BP) and cardiac sympathetic nerve activity (CSNA) in one animal post embolization over a 5-second interval.

[0048] FIGs. 6A and 6B illustrate BP and CSNA at each pump flow rate level from P0 to P8 post embolization in all of the animals post embolization and includes standard deviation bars at each P level. The chart shows the changes to systolic, diastolic and mean arterial pressure (BP) and % change in cardiac sympathetic nerve activity (CSNA). As can be seen, iincremental pump support resulted in a significant decrease in CSNA (n=7) with a 47.3 ± 6.9 % reduction at P8 compared to P0 (one-way ANOVA; <0.001).

[0049] FIGs. 7A and 7B illustrate raw data traces of blood pressure (BP) and cardiac sympathetic nerve activity (CSNA) in one animal post embolization and during Impella CP® mechanical circulatory support at Pmax over a 5-second interval.

[0050] 60 minutes after coronary artery embolization and during Impella pump at levelP8. The changes to systolic, diastolic and mean arterial pressure (BP) and % change in cardiac sympathetic nerve activity (CSNA) is shown from baseline (n=7) before and serially after embolization of the left coronary artery. *p<0.05 (One-way ANOVA).Results

[0051] The following was the effect of left coronary artery embolization. Injection of microspheres into the coronary artery decreased mean arterial pressure (MAP) by 28.6 ± 4.1 mmHg at 60 mins post embolization (n=13; Figure 4A). The ejection fraction decreased from 73.7 ± 1.8% to 30.1 ± 2.3% (One-way ANOVA; p <0.001; Figure 4A). The decrease in arterial pressure was associated with a significant increase in CSNA such that at the 60-minute time point, CSNA was increased by 164.6 ± 39.8 % (One-way ANOVA; j><0.05, Figures 4B).

[0052] The following was the effect of left ventricular support. Impella CP® mechanical circulatory support increased the MAP from 54.3 ± 3.1 mmHg to 63.5 ± 3.1 mmHg (n- 13; compare Figure 4A and 6A) at pump level P8 (one-way ANOVA P0-P8, <0.001). Incremental pump support resulted in a significant decrease in CSNA (n=7) with a 47.3 ± 6.9 % reduction at P8 compared to P0 (Figure 6B; one-way ANOVA; <0.001). Consistent with the reduction in CSNA, CoBF (n=7) was improved by 22.7 ± 6.8 mL / min at P8 compared to P0 (compare Figure 4A and 6A; one-way ANOVA; p= 0.041).321989582 13ABD0440WOPCT1_266489.036

[0053] The Study is the first to directly record cardiac sympathetic nerve activity (CSNA) during mechanical circulatory support. A significant reduction in directly recorded CSNA levels with mechanical circulatory support from the Impella CP® circulatory support was observed. Microembolisation of the coronary arteries results in a substantial elevation of CSNA consistent with other reports. It is known that this elevation in cardiac sympathetic drive increases myocardial oxygen consumption and can elevate arrhythmogenic risk. This significant reduction in CSNA with mechanical circulatory support may offset the pro- arrhythmogenic state and may underlie the decreased incidence of arrhythmias observed with MCS in some studies. Increased CSNA can also cause intense coronary vasoconstriction and our data indicates that this is associated with an improvement in directly recorded coronary blood flow consistent with other reports. Taken together, the data indicates that the beneficial effects of Impella CP® may be mediated in part by the inhibition of cardiac sympathetic drive as we have now shown with direct recordings.

[0054] The following are exemplary aspects of the disclosure.

[0055] Aspect 1. A method of providing ventricular support for patients who are experiencing an acute myocardial infarction (AMI) by performing a coronary intervention procedure, the method comprising: inserting a mechanical circulatory support device into the vasculature of a patient; delivering the mechanical circulatory support device within the vasculature into a heart of the patient; operating the mechanical circulatory support device for a support period; measuring a sympathetic nerve activity (CSNA) of the patient during the mechanical circulatory support; and wherein a reduction in the recorded CSNA levels during the mechanical circulatory support device is reduced after 60 minutes of the mechanical circulatory support by between about 40.8% to about 54.2% as compared to the CSNA levels at the initiation of the mechanical circulatory support.

[0056] Aspect 2. The method of claim 1, wherein the reduction in the recorded CSNA levels during the mechanical circulatory support device is reduced after 60 minutes of the mechanical circulatory support by about 47.3%.321989582 14ABD0440WOPCT1_266489.036

[0057] Aspect 3. The method of claim 1 , wherein the mechanical circulatory support device is a pump having a pump inlet and a pump outlet, wherein the pump inlet is placed in the left ventricle and the pump outlet is placed in the aorta.

[0058] Aspect 4. The method of claim 1, wherein the patients are adult female Romney sheep.

[0059] Aspect 5. The method of claim 4, wherein mean weight of the sheep ranges from about 50 kg to about 71 kg.

[0060] Aspect 6. The method of claim 5, wherein mean weight of the sheep is 57 kg.

[0061] Aspect 7. The method of claim 1, wherein the support period was 30 minutes.

[0062] Aspect 8. The method of claim 1, wherein the CSNA before operating the mechanical circulatory support device was increased by 164.6 ± 39.8 %.

[0063] Aspect 9. The method of claim 1, wherein the the mean arterial pressure (MAP) decreased from 54.3 ± 3.1 mmHg before AMI to 63.5 ± 3.1 mmHg (n=13; Figure 1) after AMI and with the mechanical circulatory support at a maximum pump flow rate (P8).

[0064] Aspect 10. A medical monitoring system for evaluating cardiac sympathetic nerve activity (CSNA) in patients experiencing an acute myocardial infarction (AMI), the system comprising:(a) a mechanical circulatory support device configured to provide ventricular unloading to a patient experiencing an AMI;(b) one or more sensors configured to measure cardiac sympathetic nerve activity (CSNA) levels in real-time; and(c) a controller configured to:(i) collect and store CSNA data at an initiation of the mechanical circulatory support;(ii) collect and store CSNA data at a time point 60 minutes after initiation; and(iii) calculate a reduction ratio in CSNA level between the initiation and the 60 minute time point; wherein the system is configured to determine whether the CSNA level is reduced by a range of approximately 40.8% to 54.2% at the 60 minute time point after the initiation of mechanical circulatory support.321989582 15ABD0440WOPCT1_266489.036

[0065] Aspect 11. The medical monitoring system of claim 10, wherein the system is configured to determine whether the CSNA level is reduced by approximately 47.3% at 60 minutes after the initiation of mechanical circulatory support reduction.

[0066] Aspect 12. The medical monitoring system of any of claims 10-11, wherein the mechanical circulatory support device is a pump having a pump inlet and a pump outlet, wherein the pump inlet is placed in the left ventricle and the pump outlet is placed in the aorta.

[0067] Aspect 13. The medical monitoring system of any of claims 10-12, wherein the patients are adult female Romney sheep.

[0068] Aspect 14. The medical monitoring system of claim 13, wherein mean weight of the sheep ranges from about 50 kg to about 71 kg.

[0069] Aspect 15. The medical monitoring system of claim 14, wherein mean weight of the sheep is 57 kg.

[0070] Aspect 16. The medical monitoring system of any of claims 10-15, wherein the one or more sensors are electrodes.

[0071] Aspect 17. The medical monitoring system any of claims 10-16, wherein the CSNA at the initiation of the support by the mechanical circulatory support device was increased by 164.6 ± 39.8 %.

[0072] Aspect 18. The medical monitoring system of any of claims 10-17, wherein a mean arterial pressure (MAP) of the patient increased from 54.3 ± 3.1 mmHg before AMI to 63.5 ± 3.1 mmHg (n=13; Figure 1) after AMI and with the mechanical circulatory support at a maximum pump flow rate.

[0073] Aspect 19. The medical monitoring system of any of claims 10-18, further comprising a user interface configured to display the CSNA reduction ratio.

[0074] Aspect 20. A system for supporting a cardiac function of a patient experiencing an acute myocardial infarction (AMI) by providing a coronary intervention, the system comprising:(a) a catheter-based ventricular unloading device configured to be deployed in the patient undergoing the coronary intervention for acute myocardial infarction (AMI) for a predetermined support duration;(b) a data acquisition module configured to monitor physiological parameters of the patient, including cardiac sympathetic nerve activity (CSNA);321989582 16ABD0440WOPCT1_266489.036(c) a comparator module configured to compare physiological data before and after the predetermined support duration; and(d) a storage medium storing patient data and clinical thresholds for assessment; wherein the system is operable to determine a functional change in cardiac sympathetic nerve activity (CSNA) which is indicative of improved autonomic regulation based on a percentage decrease in CSNA levels.

[0075] Aspect 21. The system for supporting a cardiac function of claim 20, wherein the system is configured to determine whether the CSNA level is reduced by a range of approximately 40.8% to 54.2% at 60 minutes after initiation of the catheter-based ventricular unloading device.

[0076] Aspect 22. The system for supporting a cardiac function of claim 21, wherein the system is configured to determine whether the CSNA level is reduced by approximately 47.3% at 60 minutes after initiation of the catheter-based ventricular unloading device.

[0077] Aspect 23. The system for supporting a cardiac function of any of claims 20-22, wherein the catheter-based ventricular unloading device is a pump having a pump inlet and a pump outlet, wherein the pump inlet is placed in the left ventricle and the pump outlet is placed in the aorta.

[0078] Aspect 24. The system for supporting a cardiac function of any of claims 20-23, wherein the patients are adult female Romney sheep.

[0079] Aspect 25. The system for supporting a cardiac function of claim 24, wherein mean weight of the sheep ranges from about 50 kg to about 71 kg.

[0080] Aspect 26. The system for supporting a cardiac function of claim 25, wherein mean weight of the sheep is 57 kg.

[0081] Aspect 27. The system for supporting a cardiac function any of claims 20-26, wherein predetermined support duration is approximately 60 minutes.

[0082] Aspect 28. The system for supporting a cardiac function any of claims 20-27, wherein the CSNA at the initiation of the predetermined support duration was increased by 164.6 + 39.8 %.

[0083] Aspect 29. The system for supporting a cardiac function any of claims 20-28, wherein the data acquisition module is configured to monitor a mean arterial pressure (MAP) of the patient, the MAP of the patient increased from 54.3 + 3.1 mmHg before AMI to 63.5 +321989582 17ABD0440WOPCT1_266489.0363.1 mmHg (n=13; Figure 1 ) after AMI and with the catheter-based ventricular unloading device at a maximum pump flow rate.321989582 18

Claims

ABD0440WOPCT1_266489.036CLAIMS1. A medical monitoring system for evaluating cardiac sympathetic nerve activity (CSNA) in patients experiencing an acute myocardial infarction (AMI), the system comprising:(a) a mechanical circulatory support device configured to provide ventricular unloading to a patient experiencing an AMI;(b) one or more sensors configured to measure cardiac sympathetic nerve activity (CSNA) levels in real-time; and(c) a controller configured to;(i) collect and store CSNA data at an initiation of the mechanical circulatory support;(ii) collect and store CSNA data at a time point 60 minutes after initiation; and(iii) calculate a reduction ratio in CSNA level between the initiation and the 60- minute time point; wherein the system is configured to determine whether the CSNA level is reduced by a range of approximately 40.8% to 54.2% at the 60 minute time point after the initiation of mechanical circulatory support.

2. The medical monitoring system of claim 1, wherein the system is configured to determine whether the CSNA level is reduced by approximately 47.3% at 60 minutes after the initiation of mechanical circulatory support reduction.

3. The medical monitoring system of any of claims 1-2, wherein the mechanical circulatory support device is a pump having a pump inlet and a pump outlet, wherein the pump inlet is placed in the left ventricle and the pump outlet is placed in the aorta.

4. The medical monitoring system of any of claims 1-3, wherein the patients are adult female Romney sheep.

5. The medical monitoring system of claim 4, wherein mean weight of the sheep ranges from about 50 kg to about 71 kg.321989582 19ABD0440WOPCT1_266489.0366. The medical monitoring system of claim 5, wherein mean weight of the sheep is 57 kg-7. The medical monitoring system of any of claims 1-6, wherein the one or more sensors are electrodes.

8. The medical monitoring system any of claims 1-7, wherein the CSNA at the initiation of the support by the mechanical circulatory support device was increased by 164.6 ± 39.8 %.

9. The medical monitoring system of any of claims 1-8, wherein a mean arterial pressure (MAP) of the patient increased from 54.3 ± 3.1 mmHg before AMI to 63.5 ± 3.1 mmHg (n=13; Figure 1) after AMI and with the mechanical circulatory support at a maximum pump flow rate.

10. The medical monitoring system of any of claims 1-9, further comprising a user interface configured to display the CSNA reduction ratio.

11. A system for supporting a cardiac function of a patient experiencing an acute myocardial infarction (AMI) by providing a coronary intervention, the system comprising:(a) a catheter-based ventricular unloading device configured to be deployed in the patient undergoing the coronary intervention for acute myocardial infarction (AMI) for a predetermined support duration;(b) a data acquisition module configured to monitor physiological parameters of the patient, including cardiac sympathetic nerve activity (CSNA);(c) a comparator module configured to compare physiological data before and after the predetermined support duration; and(d) a storage medium storing patient data and clinical thresholds for assessment; wherein the system is operable to determine a functional change in cardiac sympathetic nerve activity (CSNA) which is indicative of improved autonomic regulation based on a percentage decrease in CSNA levels.

12. The system for supporting a cardiac function of claim 11, wherein the system is configured to determine whether the CSNA level is reduced by a range of approximately321989582 20ABD0440WOPCT1_266489.03640.8% to 54.2% at 60 minutes after initiation of the catheter-based ventricular unloading device.

13. The system for supporting a cardiac function of claim 12, wherein the system is configured to determine whether the CSNA level is reduced by approximately 47.3% at 60 minutes after initiation of the catheter-based ventricular unloading device.

14. The system for supporting a cardiac function of any of claims 11-13. wherein the catheter-based ventricular unloading device is a pump having a pump inlet and a pump outlet, wherein the pump inlet is placed in the left ventricle and the pump outlet is placed in the aorta.

15. The system for supporting a cardiac function of any of claims 11-14, wherein the patients are adult female Romney sheep.

16. The system for supporting a cardiac function of claim 15, wherein mean weight of the sheep ranges from about 50 kg to about 71 kg.

17. The system for supporting a cardiac function of claim 16, wherein mean weight of the sheep is 57 kg.

18. The system for supporting a cardiac function any of claims 11- 17, wherein predetermined support duration is approximately 60 minutes.

19. The system for supporting a cardiac function any of claims 11-18, wherein the CSNA at the initiation of the predetermined support duration was increased by 164.6 ± 39.8%.

20. The system for supporting a cardiac function any of claims 11-19, wherein the data acquisition module is configured to monitor a mean arterial pressure (MAP) of the patient, the MAP of the patient increased from 54.3 ± 3.1 mmHg before AMI to 63.5 ± 3.1 mmHg (n=13: Figure 1) after AMI and with the catheter-based ventricular unloading device at a maximum pump flow rate.321989582 21

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