Systems and methods for left ventricular unloading in the treatment of myocardial infarction

Abstract

Provided herein is a method for preventing or limiting the effects of heart failure in a human patient with a sustained myocardial infarction by reducing maladaptive cardiac remodeling. The method includes percutaneously inserting a transvalve blood pump comprising a rotor and a cannula into the patient's vascular system and positioning the cannula across the aortic valve of the heart with the distal end of the cannula positioned in the left ventricle of the patient's heart and the proximal end of the pump positioned within the aorta. The method then includes operating the positioned pump to unload the left ventricle for an assist period of at least 30 minutes but not more than 60 minutes with a pump flow rate of at least 2.5 L / min of blood flow before reperfusing the heart. The method then includes applying coronary reperfusion therapy to the heart after the assist period.

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit under 35 U.S.C. § 119(e) from U.S. Provisional Patent Application No. 62 / 615,462, filed on January 10, 2018, U.S. Provisional Patent Application No. 62 / 732,936, filed on September 18, 2018, and U.S. Provisional Patent Application No. 62 / 758,164, filed on November 9, 2018, the contents of which are hereby incorporated by reference in their entirety.

Background Art

[0002] Background Acute myocardial infarction (AMI) due to coronary artery occlusion is a major cause of morbidity and mortality worldwide in humans. The current paradigm of AMI therapy focuses on primary reperfusion to rapidly restore coronary blood flow as soon as possible after AMI to re-establish myocardial oxygen supply. However, despite timely reperfusion, up to 25% of patients who experience a first AMI develop heart failure (HF) within one year. The in-hospital management of modern ST-segment elevation AMI (STEMI) focuses on reducing the door-to-balloon (DTB) time to reduce infarct size. However, despite strong resource allocation to achieve a DTB time of less than 90 minutes, the incidence of heart failure after AMI remains high. For every 5% increase in infarct size, the all-cause mortality and HF-related hospitalizations increase by 20% over one year, which places a significant burden on healthcare resources. For these reasons, new approaches to limit myocardial injury and subsequent ischemic HF remain an important unmet need for AMI patients.

[0003] Regarding these poor prognoses, one explanation is that primary reperfusion can paradoxically exacerbate myocardial injury known as ischemia-reperfusion injury (IRI). Previous attempts to limit IRI have included vascular conditioning approaches and pharmacological approaches to activate reperfusion injury salvage kinase (RISK) pathway activity, but the clinical effects of these approaches have not always been optimal. A critically important barrier to these cardioprotective strategies is the requirement for rapid coronary reperfusion, i.e., they may not leave sufficient time for a therapeutic effect on myocardial injury. Therefore, there is a need for improved strategies to limit myocardial injury by promoting cardioprotective mechanisms that reduce or eliminate IRI.

[0004] Over the past decade, there has been an increasing reliance on mechanical assist devices in daily clinical practice. Assist devices include transvalvular axial flow pumps (TV pumps) delivered percutaneously, intra-aortic balloon pumps, in-body axial flow catheters, and extracorporeal membrane oxygenation (ECMO) pumps, and have become widespread in the treatment of myocardial injury. In the case of TV pumps, such devices mechanically pump blood out of the left ventricle of the heart, thereby rapidly reducing the wall stress, stroke work, and myocardial oxygen demand of the left ventricle (LV), while increasing the mean arterial pressure of the whole body without the need for surgery, helping to unload the heart. However, even using only TV pumps, the 30-day mortality rate of patients with cardiogenic shock does not significantly decrease, and on the contrary, it has been reported that acute myocardial infarction worsened in certain patients (H. Thiele, “Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock”, New England Journal of Medicine, October 4, 2012, vol. 367, No. 14, pp. 1287-1296 (Non-Patent Document 1)).

[0005] It has been proposed that the combination of mechanical assistance and primary reperfusion can limit myocardial injury in AMI patients. By initially unloading the LV using a TV pump while delaying coronary reperfusion (Primary Unloading), the size of the myocardial infarction is reported to be reduced by 40 - 50% and the myocardial level of the cardioprotective chemokine stromal cell-derived factor 1α (SDF-1α) is increased (N. Kapur, “Mechanical Pre-Conditioning with Acute Circulatory Support Before Reperfusion Limits Infarct Size in Acute Myocardial Infarction,” JACC: Heart Failure, vol. 3 no. 11, November 2015 (Non-Patent Document 2)).

[0006] A preliminary porcine model of the AMI model has been studied to compare primary reperfusion therapy with a therapy that delays reperfusion therapy until the left atrium is unloaded using a percutaneously delivered extracorporeal centrifugal pump, with an initial suggestion that delaying coronary reperfusion (P-Unloading) may reduce myocardial injury. In another study, the effect of unloading was observed when a percutaneously delivered transvalvular pump was applied directly to the left ventricle of an animal to delay coronary reperfusion for 60 minutes. The impact on the treatment of MI in humans is not well understood.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Summary of the Invention

[0008] Summary The present disclosure relates to an improved method of assisting the heart of a human patient having a sustained myocardial infarction, with the surprising result that the order and timing of applying assistance to the heart before reperfusion improves the heart and can reduce the impact of the infarction. This technique can be further applied to prevent or limit the impact of heart failure in human patients. This can be done, for example, by reducing maladaptive cardiac remodeling in the patient. This method (and the system configured for application) stabilizes or reduces the size of the infarction; this is beneficial to the patient's heart. Certain applications include applying a mechanical circulatory assist device to reduce the size of the infarction; some applications include applying reperfusion therapy after a delay period, where the heart is assisted by a mechanical circulatory device. Generally, this method is applied by taking an approach contrary to conventional methods and theories in the art - not immediately applying reperfusion therapy to a patient who has had a heart attack - and this method (and system) first assists the heart by reducing myocardial oxygen demand for a period of time (e.g., unloading the heart), and then, after that period of assistance, restores the oxygen supply to the affected part of the heart (e.g., by reperfusion). Thus, this method seeks to shorten the time between AMI and the start of mechanical circulatory assistance, such a period being referred to for convenience as "door to unload". It has been found that taking such an approach can increase myocardial salvage in the human heart and reduce the size of the infarction in the human heart. Furthermore, such an approach has the surprising effect of preventing or limiting the impact of heart failure in human patients, for example by reducing maladaptive cardiac remodeling in the patient.

[0009] According to one aspect of the present disclosure, a method for assisting the heart of a human patient is provided. The method includes: (i) inserting a mechanical circulatory support device into a human patient after myocardial infarction; (ii) operating the mechanical circulatory support device for a certain assistance time (assistance period) before reperfusing the heart; and (iii) applying reperfusion therapy to the heart (e.g., inserting a stent or applying drug therapy to release stenosis or occlusion in the coronary vascular system) after the assistance period. The assistance period is preferably more than 15 minutes. For example, the assistance period can be at least 30 minutes and less than 60 minutes. The mechanical circulatory support device is a heart support device that operates to pump blood at a blood flow rate of at least 2.5 L / min.

[0010] According to another aspect of the present disclosure, a method for assisting the heart of a patient with persistent myocardial infarction is provided. The method includes percutaneously inserting a transvalvular blood pump into the patient such that the distal end of the pump is positioned in the left ventricle of the patient's heart, and disposing the pump across the aortic valve of the heart. Thereafter, before reperfusing the heart, the method continues with operating the disposed pump to unload the left ventricle for a pump operation period of more than 15 minutes at a pump flow rate of at least 2.5 L / min of blood flow. After the pump operation period, the method then includes treating the heart by reperfusion therapy.

[0011] According to a further aspect of the present disclosure, a method for reducing the size of a myocardial infarction scar in a patient's heart is provided. The method includes percutaneously inserting a transvalvular microaxial blood pump into the patient such that the distal end of the pump is positioned in the left ventricle of the patient's heart, and disposing the pump across the aortic valve of the heart. The method then includes, before reperfusing the heart, operating the disposed pump to unload the left ventricle for a pump operation period of more than 15 minutes at a pump flow rate of at least 2.5 L / min of blood flow. After the pump operation period, the method includes applying reperfusion therapy to the heart.

[0012] According to another aspect of the present disclosure, a method for assisting a heart that has suffered a myocardial infarction is provided. The method includes, after myocardial infarction in a patient's heart and before reperfusing the heart, percutaneously inserting a mechanical circulatory assist device into the patient; operating the device to unload the left ventricle over an unloading period of more than 15 minutes at a blood flow rate of at least 2.5 L / min (e.g., 3.5 L / min); and after the unloading period, applying reperfusion therapy to the heart.

[0013] According to another aspect of the present disclosure, a method for assisting the heart of a patient having a myocardial infarction is provided. The method includes (i) reducing the levels of BAX protein and active caspase 3 antibody in the patient's heart tissue in the myocardial infarction region (risk region); and (ii) increasing the levels of BCL-2 and BCL-XL proteins in the patient's heart tissue in the myocardial infarction region.

[0014] According to another aspect of the present disclosure, a method for assisting the heart of a patient having a myocardial infarction is provided, the method including (i) reducing the levels of BAX protein and active caspase 3 antibody in the patient's heart tissue near the myocardial infarction; (ii) increasing the levels of BCL-2 and BCL-XL proteins in the patient's heart tissue in the myocardial infarction region; (iii) increasing the level of stromal cell-derived factor 1α (SDF-1α) protein in the patient's heart tissue in the myocardial infarction region; (iv) maintaining the activity levels of MMP-2 and MMP-9 enzymes in the patient's heart tissue in the myocardial infarction region; (v) restricting the upregulation of the expression and activity of DPP-4 protein in the patient's heart tissue near the myocardial infarction; (vi) reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood; (vii) increasing the mRNA level of SERCA expression in the patient's heart cells near the myocardial infarction; and (viii) reducing the levels of calcineurin activity and type I collagen in the myocardial infarction region while maintaining the level of b-MHC in the non-infarcted region of the patient's heart, including at least one of the steps.

[0015] According to another aspect of the present disclosure, there is provided a method of assisting the heart of a patient having myocardial infarction, comprising the step of increasing the level of stromal cell-derived factor 1α (SDF-1α) protein in the patient's heart tissue near the myocardial infarction. The method may include the step of maintaining the activity levels of MMP-2 and MMP-9 enzymes in the patient's heart tissue in the myocardial infarction region. The method may also include the step of restricting the upregulation of DPP-4 protein expression and activity in the patient's heart tissue in the myocardial infarction region. Such a method can be performed using a mechanical circulatory assist device such as a transvalvular pump or an extracorporeal pump.

[0016] According to a further aspect of the present disclosure, there is provided a method of assisting the heart of a patient having myocardial infarction, comprising the step of reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood. The method also includes the step of increasing the mRNA level of SERCA expression in the patient's heart tissue in the myocardial infarction region. The method further includes the step of reducing the levels of calcineurin activity and type I collagen in the patient's heart tissue near the myocardial infarction while maintaining the level of b-MHC in the non-infarcted region of the patient's heart.

[0017] According to another aspect of the present disclosure, a method for assisting the heart of a patient having myocardial infarction is provided, the method comprising: (i) reducing the levels of BAX protein and active caspase 3 antibody in the patient's heart tissue in the myocardial infarction region; (ii) increasing the levels of BCL-2 and BCL-XL proteins in the patient's heart tissue in the myocardial infarction region; (iii) increasing the level of stromal cell-derived factor 1α (SDF-1α) protein in the patient's heart tissue in the myocardial infarction region; (iv) maintaining the active levels of MMP-2 and MMP-9 enzymes in the patient's heart tissue in the myocardial infarction region; (v) restricting the upregulation of DPP-4 protein expression and activity in the patient's heart tissue in the myocardial infarction region; (vi) reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood; (vii) increasing the mRNA level of SERCA expression in the patient's heart cells in the myocardial infarction region; and (viii) reducing the levels of calcineurin activity and type I collagen in the patient's heart tissue in the myocardial infarction region while maintaining the level of b-MHC in the non-infarcted region of the patient's heart.

[0018] According to one aspect of the present disclosure, a heart protection system for assisting the heart of a patient having persistent myocardial infarction is provided. The system comprises a mechanical circulatory assist device configured to be inserted into the patient and a reperfusion therapy device. The system is configured such that the mechanical circulatory assist device operates for an assist period of more than 15 minutes at a blood flow rate of at least 2.5 L / min before the operation of the reperfusion therapy device.

[0019] According to another aspect of the present disclosure, a heart protection system for assisting the heart of a patient with a persistent myocardial infarction is provided. The system includes a blood pump configured to be percutaneously inserted into the patient after myocardial infarction, the pump being sized and shaped to be disposed across the aortic valve of the patient's heart, and a distal end of the pump being configured to be located in the left ventricle of the heart. The system also includes a reperfusion therapy device. The system is configured such that the blood pump is programmed to operate before the reperfusion therapy device and pump blood for a pump operation period of more than 15 minutes at a blood flow rate of at least 2.5 L / min.

[0020] According to a further aspect of the present disclosure, a method of treating a human heart with a persistent myocardial infarction is provided, the myocardial infarction having an infarct size and being located within a portion of the heart, the method including the step of reducing the infarct size.

[0021] According to another aspect of the present disclosure, a method of preventing or limiting the effects of heart failure in a patient by reducing maladaptive cardiac remodeling in a human patient with a persistent myocardial infarction is provided. An adaptive form of the method includes percutaneously inserting a transvalvular blood pump having a rotor and a cannula into the patient's vasculature such that a distal end of the cannula is located in the left ventricle of the patient's heart and a proximal end of the pump is located in the aorta, and disposing the cannula across the aortic valve of the heart. Prior to reperfusion of the heart, the method then includes operating the disposed pump to unload the left ventricle for an assist period of at least 30 minutes to less than 60 minutes at a pump flow rate of a blood flow of at least 2.5 L / min. After the assist period, the method includes applying coronary artery reperfusion therapy to the heart. Maladaptive cardiac remodeling includes, but is not limited to, one or more of changes in the size, shape, structure, and function of the heart.

[0022] According to a further aspect of the present disclosure, there is provided a system for preventing or limiting the effects of heart failure in a patient by reducing maladaptive cardiac remodeling in a human patient having a persistent myocardial infarction. The system comprises a blood pump having a rotor and a cannula, the cannula being disposed across the aortic valve of the heart such that the distal end of the cannula is positioned in the left ventricle of the patient's heart and the proximal end of the pump is positioned in the aorta, the blood pump being configured to be percutaneously inserted into the patient's vasculature. The system may further comprise a controller coupled to the pump to control the operation of the pump. The system also comprises a coronary reperfusion therapy device. In this aspect, the controller programs the blood pump to unload the left ventricle for an assist period of at least 30 minutes to less than 60 minutes at a pump flow rate of at least 2.5 L / min prior to activation of the coronary reperfusion therapy device.

[0023] In certain embodiments, the assist period is about 30 minutes or can be between 15 and 30 minutes. In some embodiments, the assist period is greater than 30 minutes or greater than 45 minutes. In some embodiments, the mechanical circulatory assist device pumps at a blood flow rate of at least 3.5 L / min. In certain embodiments, the device provides a cannula that is placed within the patient's heart and pumps blood through the cannula. In some embodiments, the device is a microaxial blood pump comprising a motor and an onboard rotor-stator that mechanically operates to pump blood from the heart; in some embodiments, the device is operated by an external motor, the pump motor can be deployed outside the patient, and relies on a long cannula that extends through the patient's vasculature to the heart. Examples of suitable mechanical circulatory assist devices are transvalvular microaxial pumps (e.g., Impella (registered trademark) blood pumps such as Impella CP, or similar devices); the pump is inserted percutaneously or surgically into the aorta, across the aortic valve, and the pump is capable of pumping blood out of the left ventricle, thereby "unloading" the left ventricle. In some adaptations, the method includes percutaneously inserting a transvalvular microaxial blood pump (TV pump) comprising a rotor and a cannula into the patient's vasculature such that the distal end of the cannula is positioned in the patient's left ventricle and the proximal end of the pump is positioned within the aorta, and disposing the cannula across the aortic valve of the heart. Also, an extracorporeal pump (e.g., Tandem Heart) can be used to unload a cardiac chamber (e.g., atrium or ventricle) according to the methods disclosed herein. Unloading of the left atrium or right atrium is possible, and the same applies to the right ventricle.

[0024] In certain embodiments, the heart is unloaded by a mechanical circulatory support device simultaneously with reperfusion (e.g., after unloading the heart). The period of this unloading can be at least 30 minutes, at least 3 hours, or more. In the methods of the present disclosure, various mechanical circulatory support devices can be used alone or in combination. For example, an intra-aortic balloon pump can be used to provide assistance to the heart after a delay period. In certain embodiments, a combination of devices is used. For example, a TV pump can be used to unload the left ventricle, and at the same time, an extracorporeal membrane oxygenation (ECMO) pump, an intra-aortic balloon pump, or other mechanical circulatory support systems can be used in combination. In certain embodiments, the reperfusion therapy in the methods of the present disclosure includes at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis.

[0025] In some embodiments, these methods include one or more of: (i) reducing the levels of BAX protein and active caspase 3 antibody in a patient's heart tissue near the myocardial infarction; (ii) increasing the levels of BCL-2 and BCL-XL proteins in a patient's heart tissue near the myocardial infarction; (iii) increasing the levels of stromal cell-derived factor 1α (SDF-1α) protein in a patient's heart tissue near the myocardial infarction; (iv) maintaining the activity levels of MMP-2 and MMP-9 enzymes in a patient's heart tissue near the myocardial infarction; (v) restricting the upregulation of DPP-4 protein expression and activity in a patient's heart tissue near the myocardial infarction; (vi) reducing the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; (vii) increasing the mRNA levels of SERCA expression in a patient's heart cells near the myocardial infarction; and (viii) reducing the levels of calcineurin activity and type I collagen in a patient's heart tissue near the myocardial infarction while maintaining the level of b-MHC in the non-infarcted region of the patient's heart. These methods can be applied such that any combination (or all) of the foregoing steps are performed. The performance of one or more of steps (i)-(viii) in any of the methods of the foregoing aspects results in the surprising outcome of preventing or limiting the effects of heart failure in a human patient. This can be done, for example, by reducing maladaptive cardiac remodeling in the patient.

[0026] In some embodiments, these methods can be applied to reduce infarct size in patients with rising ΣSTE levels. For example, this method can be applied by unloading the left ventricle of a patient having MI and at least 4 (e.g., 5, or 6, or more than 6) ΣSTE levels to reduce the infarct size of that patient. In certain embodiments, this method can be applied to reduce infarct size and left ventricular scar size. In one embodiment, this method also includes increasing blood flow from the left ventricle of the patient's heart by applying mechanical circulatory support to the patient. In certain embodiments, the increased blood flow is provided over an unloading period of more than 15 minutes at a blood flow rate of at least 2.5 L / min. In certain embodiments, this method also includes applying reperfusion therapy to the patient's heart tissue near the myocardial infarction after applying mechanical circulatory support. In a further embodiment, the system comprises one or more of the following devices that are activated after or during the operation of the mechanical circulatory support device: an intra-aortic balloon pump, and an extracorporeal membrane oxygenation (ECMO) pump.

[0027] In some embodiments, reducing infarct size is done by reducing the myocardial oxygen demand of the heart in a portion of the heart containing the infarct and subsequently restoring the oxygen supply to that portion of the heart containing the infarct. In certain embodiments, this method includes reducing the level of at least one of BAX protein and active caspase 3 in the heart tissue. In other embodiments, this method includes increasing the level of at least one of BCL-2 and BCL-XL. In a further embodiment, this method includes increasing the myocardial salvage index (MSI) of the heart.

[0028] In certain embodiments, the method also includes: (i) inserting a blood pump into a patient's vasculature; (ii) driving the pump during an assist period to adjust blood flow within the vasculature prior to applying reperfusion therapy to the heart; and (iii) applying reperfusion therapy to the heart after the assist period. In some embodiments, the assist period is at least 15 minutes. In other embodiments, the assist period is at least 30 minutes, from about 20 minutes to about 40 minutes, or at least 45 minutes.

[0029] In further embodiments, the method also includes unloading the left ventricle of the heart at a pump flow rate of at least 2.5 L / min during the assist period. In some embodiments, the blood pump is a microaxial blood pump, and unloading the left ventricle includes inserting the distal end of the pump into the left ventricle and the proximal end of the pump into the aorta, and driving the pump to pump blood from the left ventricle to the aorta. In certain embodiments, the method includes: (i) inserting a balloon pump into the aorta of the heart, and (ii) expanding and contracting the balloon to adjust blood flow within the aorta. In other embodiments, the pump is a catheter-based intravascular blood pump.

[0030] In some embodiments, the method includes at least one of: (i) increasing the left ventricular ejection rate of the heart; (ii) reducing microvascular obstruction of the heart; (iii) reducing the left ventricular end-systolic volume of the heart; and (iv) reducing the left ventricular end-diastolic volume of the heart. In other embodiments, the method includes reducing the myocardial oxygen demand of the heart in a portion of the heart including an infarct over at least 15 minutes and then restoring the oxygen supply to the portion of the heart including the infarct. In certain embodiments, the heart is unloaded by a mechanical circulatory assist device simultaneously with performing reperfusion therapy on the heart. In some embodiments, the reperfusion therapy includes at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis.

[0031] In further embodiments, the method also includes: (i) reducing the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; (ii) increasing the mRNA levels of SERCA expression in the patient's heart cells near the myocardial infarction; and (iii) reducing the levels of calcineurin activity and type I collagen in the patient's heart tissue near the myocardial infarction while maintaining the level of b-MHC in the non-infarcted regions of the patient's heart. In certain embodiments, the method also includes removing the blood pump from the patient's heart after applying reperfusion therapy. In other embodiments, the method also includes increasing the blood flow to the patient's heart tissue near the myocardial infarction.

[0032] In some embodiments, these methods according to any of the foregoing aspects may include continuing the operation of the pump in parallel with the application of coronary reperfusion. In certain embodiments, the pump is operated in parallel with the application of coronary reperfusion for a total assist period of at least 3 hours. In other embodiments, these methods may include operating the pump to sufficiently unload the heart in order to alter gene expression in the cells within the myocardial infarction region. Unloading the heart is a method that has the advantage of preventing or limiting the effects of heart failure in a human patient. This can be done, for example, by reducing maladaptive cardiac remodeling in the patient. In further embodiments, these methods may include providing drug therapy to the patient in combination with the operation of the pump. In certain embodiments, the drug therapy may include providing the patient with a medicament comprising at least one of a beta blocker, a preload reducing agent, a neurohormonal agent, and an ACE inhibitor.

[0033] Even more advantageous embodiments of the present disclosure are provided in the examples and claims aspects described below.

[0034] After reviewing the present disclosure, those skilled in the art will conceive of various variations and modifications. The disclosed features can be implemented in any combination and sub - combination (including multiple dependent combinations and sub - combinations) with one or more other features described herein. The various features described or exemplified, including any of its components, can be incorporated or integrated into other systems. Further, certain features may be omitted or not implemented. [Invention 1001] A method for assisting the heart of a human patient having a persistent myocardial infarction, comprising: inserting a mechanical circulatory assist device into the patient after myocardial infarction; operating the mechanical circulatory assist device for an assist period of more than 15 minutes at a blood flow rate of at least 2.5 L / min before reperfusing the heart; and applying reperfusion therapy to the heart after the assist period The method comprising the above steps. [Invention 1002] The assist period is more than 20 minutes; more than 25 minutes; more than 30 minutes; more than 35 minutes; more than 40 minutes; more than 45 minutes; more than 15 minutes and up to about 30 minutes; about 20 minutes to about 45 minutes; and about 30 minutes to about 40 minutes The method of Invention 1001, wherein the assist period is any one of the above. [Invention 1003] The method of Invention 1001 or 1002, wherein the mechanical circulatory assist device is operated at a rate that provides a cardiac output of a blood flow of at least 3.5 L / min. [Invention 1004] The method of Invention 1003, wherein the inserted assist device comprises a blood pump. [Invention 1005] The method according to any of the above inventions, wherein the heart is unloaded by the mechanical circulatory assist device simultaneously with reperfusion. [Invention 1006] The method according to any of the above inventions, wherein the mechanical circulatory assist device comprises a cannula inserted into the heart. [Invention 1007] The method of Invention 1006, wherein the blood pump comprises a microaxial transvalvular pump. [Invention 1008] Assisting the heart by an intra - aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump The method according to any of the above inventions, comprising the above step. [Invention 1009] The method according to any of the above inventions, wherein the reperfusion therapy comprises at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis. [Invention 1010] Reducing the levels of BAX protein and active caspase - 3 antibody in the patient's heart tissue near the myocardial infarction; and Increasing the levels of BCL - 2 and BCL - XL proteins in the patient's heart tissue near the myocardial infarction The method according to any of the above inventions, comprising the above steps. [Invention 1011] Increasing the level of stromal cell - derived factor 1α (SDF - 1α) protein in the patient's heart tissue near the myocardial infarction; Maintaining the activity levels of MMP - 2 and MMP - 9 enzymes in the patient's heart tissue near the myocardial infarction; and A step of restricting the up-regulation of the expression and activity of DPP-4 protein in the heart tissue of a patient near myocardial infarction Any method of the present invention including the above step [Invention 1012] A step of reducing the circulating level of brain natriuretic peptide (BNP) in the blood of the patient; A step of increasing the mRNA level of SERCA expression in heart cells of a patient near myocardial infarction; and A step of reducing the levels of calcineurin activity and type I collagen in heart cells of a patient near myocardial infarction while maintaining the level of b-MHC in the non-infarcted region of the heart of the patient Any method of the present invention including the above steps [Invention 1013] Any method of the present invention, wherein the heart has a total ST segment elevation value (ΣSTE) of 4+ or 5+ or 6+ [Invention 1014] The method of Invention 1013, wherein the heart has a ΣSTE of 6+ [Invention 1015] A method for assisting the heart of a patient with persistent myocardial infarction, comprising: Percutaneously inserting a transvalvular blood pump into the patient, and arranging the pump across the aortic valve of the heart with the distal end of the pump located in the left ventricle of the patient's heart; Before reperfusing the heart, operating the arranged pump to unload the left ventricle over a pump operation period of more than 15 minutes at a pump flow rate of at least 2.5 L / min; and After the pump operation period, treating the heart by reperfusion therapy The method including the above steps [Invention 1016] The assistance period is More than 20 minutes; more than 25 minutes; more than 30 minutes; more than 35 minutes; more than 40 minutes; more than 45 minutes; about 20 minutes to about 45 minutes; more than 15 minutes and up to about 30 minutes; and about 30 minutes to about 40 minutes The method of Invention 1015 including any one of the above [Invention 1017] The method of Invention 1015 or 1016, wherein the pump is operated at a pump flow rate of at least 3.5 L / min [Invention 1018] Any method of Invention 1015 - 1017, wherein the heart is unloaded by a mechanical circulatory assist device simultaneously with reperfusion [Invention 1019] A step of removing the blood pump from the patient's heart after applying the reperfusion therapy Any method of Invention 1015 - 1018 including the above step [Invention 1020] A reperfusion therapy, which is any of the methods of the present invention 1015-1019 and includes at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis. [The present invention 1021] Reducing the levels of BAX protein and active caspase-3 antibody in the heart tissue of a patient near myocardial infarction; and Increasing the levels of BCL-2 and BCL-XL proteins in the heart tissue of a patient near myocardial infarction Any of the methods of the present invention 1015-1020, including. [The present invention 1022] Increasing the level of stromal cell-derived factor 1α (SDF-1α) protein in the heart tissue of a patient near myocardial infarction; Maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of a patient near myocardial infarction; and Restricting the upregulation of the expression and activity of DPP-4 protein in the heart tissue of a patient near myocardial infarction Any of the methods of the present invention 1015-1021, including. [The present invention 1023] Reducing the circulating level of brain natriuretic peptide (BNP) in the blood of the patient; Increasing the mRNA level of SERCA expression in the heart cells of a patient near myocardial infarction; and Reducing the levels of calcineurin activity and type I collagen in the heart cells of a patient near myocardial infarction while maintaining the level of b-MHC in the non-infarcted region of the patient's heart Any of the methods of the present invention 1015-1022, including. [The present invention 1024] A method for reducing the size of a myocardial infarction scar in a patient's heart, comprising Percutaneously inserting a transvalvular microaxial blood pump into the patient such that the distal end of the pump is positioned in the left ventricle of the patient's heart and arranging the pump across the aortic valve of the heart; Before reperfusing the heart, operating the arranged pump to unload the left ventricle over a pump operation period of more than 15 minutes at a pump flow rate of at least 2.5 L / min; and After the pump operation period, applying reperfusion therapy to the heart Including, the method. [The present invention 1025] The pump operation period is More than 20 minutes; more than 25 minutes; more than 30 minutes; more than 35 minutes; more than 40 minutes; more than 45 minutes; about 20 minutes to about 45 minutes; more than 15 minutes and at most about 30 minutes; and about 30 minutes to about 40 minutes Any one of which is the method of the present invention 1024. [The present invention 1026] The method of the invention 1024 or 1025, wherein the pump is operated at a pump flow rate of at least 3.5 L / min of blood flow. [Invention 1027] The method according to any one of inventions 1024 to 1026, wherein the heart is unloaded by the blood pump simultaneously with reperfusion. [Invention 1028] The step of removing the blood pump from the patient's heart after applying the reperfusion therapy The method according to any one of inventions 1024 to 1027, comprising. [Invention 1029] The method according to any one of inventions 1024 to 1028, wherein the reperfusion therapy includes at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis. [Invention 1030] The step of reducing the levels of BAX protein and active caspase-3 antibody in the patient's heart tissue near the myocardial infarction; and The step of increasing the levels of BCL-2 and BCL-XL proteins in the patient's heart tissue near the myocardial infarction The method according to any one of inventions 1024 to 1029, comprising. [Invention 1031] The step of increasing the level of stromal cell-derived factor 1α (SDF-1α) protein in the patient's heart tissue near the myocardial infarction; The step of maintaining the activity levels of MMP-2 and MMP-9 enzymes in the patient's heart tissue near the myocardial infarction; and The step of restricting the upregulation of the expression and activity of DPP-4 protein in the patient's heart tissue near the myocardial infarction The method according to any one of inventions 1024 to 1030, comprising. [Invention 1032] The step of reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood; The step of increasing the mRNA level of SERCA expression in the patient's heart cells near the myocardial infarction; and The step of reducing the levels of calcineurin activity and type I collagen in the patient's heart cells near the myocardial infarction while maintaining the level of b-MHC in the non-infarcted area of the patient's heart The method according to any one of inventions 1024 to 1031, comprising. [Invention 1033] A method for assisting a heart in which a myocardial infarction has occurred, comprising After myocardial infarction of the patient's heart, the step of percutaneously inserting a mechanical circulatory assist device into the patient; Before reperfusing the heart, operating the device to unload the left ventricle over an unloading period of more than 15 minutes at a blood flow rate of at least 2.5 L / min; and After the unloading period, the step of applying reperfusion therapy to the heart The method, comprising. [Invention 1034] The method of the present invention 1033, wherein the unloading period is at least 30 minutes. [The present invention 1035] The method of the present invention 1033 or 1034, wherein the mechanical circulatory assist device is operated at a blood flow rate of at least 3.5 L / min. [The present invention 1036] The method according to any one of the present inventions 1033 to 1035, wherein the unloading of the heart by the mechanical circulatory assist device is applied simultaneously with reperfusion therapy. [The present invention 1037] The method according to any one of the present inventions 1033 to 1036, wherein the mechanical circulatory assist device comprises a blood pump, such as a TV pump. [The present invention 1038] The step of assisting the heart with an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump The method according to any one of the present inventions 1033 to 1037, comprising: [The present invention 1039] The method according to any one of the present inventions 1033 to 1038, wherein the reperfusion therapy includes direct percutaneous coronary intervention (PCI) or fibrinolysis. [The present invention 1040] The step of reducing the levels of BAX protein and active caspase-3 antibody in the heart tissue of a patient near myocardial infarction; and The step of increasing the levels of BCL-2 and BCL-XL proteins in the heart tissue of a patient near myocardial infarction The method according to any one of the present inventions 1033 to 1039, comprising: [The present invention 1041] The step of increasing the level of stromal cell-derived factor 1α (SDF-1α) protein in the heart tissue of a patient near myocardial infarction; The step of maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of a patient near myocardial infarction; and The step of restricting the upregulation of the expression and activity of DPP-4 protein in the heart tissue of a patient near myocardial infarction The method according to any one of the present inventions 1033 to 1040, comprising: [The present invention 1042] The step of reducing the circulating level of brain natriuretic peptide (BNP) in the blood of the patient; The step of increasing the mRNA level of SERCA expression in the heart cells of a patient near myocardial infarction; and The step of reducing the levels of calcineurin activity and type I collagen in the heart cells of a patient near myocardial infarction while maintaining the level of b-MHC in the non-infarcted region of the heart of the patient The method according to any one of the present inventions 1033 to 1041, comprising: [The present invention 1043] A method for assisting the heart of a patient having myocardial infarction, comprising Reducing the levels of BAX protein and active caspase 3 antibody in the heart tissue of a patient near myocardial infarction; and Increasing the levels of BCL-2 and BCL-XL proteins in the heart tissue of a patient near myocardial infarction The method comprising the above. [The present invention 1044] Increasing the blood flow from the left ventricle of the heart of the patient by applying mechanical circulatory support to the patient The method of the present invention 1043 comprising the above. [The present invention 1045] The method of the present invention 1044, wherein the increased blood flow is provided over an unloading period of more than 15 minutes at a blood flow rate of at least 2.5 L / min. [The present invention 1046] The unloading period is More than 20 minutes; more than 25 minutes; more than 30 minutes; more than 35 minutes; more than 40 minutes; more than 45 minutes; about 20 minutes to about 45 minutes; about 15 minutes to about 30 minutes; and about 30 minutes to about 40 minutes The method of the present invention 1045, which is any one of the above. [The present invention 1047] The method according to any one of the present inventions 1043 to 1046, wherein the increased blood flow is provided at a blood flow rate of at least 3.5 L / min. [The present invention 1048] Applying reperfusion therapy to the heart tissue of the patient near myocardial infarction after applying mechanical circulatory support The method according to any one of the present inventions 1043 to 1047 comprising the above. [The present invention 1049] Applying mechanical circulatory support to the patient simultaneously with reperfusion The method according to any one of the present inventions 1043 to 1048 comprising the above. [The present invention 1050] The method of the present invention 1049, wherein the mechanical circulatory support device comprises a blood pump, such as a TV pump. [The present invention 1051] Assisting the heart by one or more of an intra-aortic balloon pump and an extracorporeal membrane oxygenation (ECMO) pump after or during the operation of a transvalvular microaxial pump The method of the present invention 1050 comprising the above. [The present invention 1052] The method according to any one of the present inventions 1048 to 1051, wherein the reperfusion comprises at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis. [The present invention 1053] A method for assisting the heart of a patient with myocardial infarction, comprising Reducing the levels of BAX protein and active caspase 3 antibody in the heart tissue of a patient near myocardial infarction; Increasing the levels of BCL-2 and BCL-XL proteins in the heart tissue of a patient near myocardial infarction; Increasing the level of stromal cell-derived factor 1α (SDF-1α) protein in the heart tissue of a patient near myocardial infarction; A step of maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of a patient near myocardial infarction; A step of restricting the up-regulation of the expression and activity of DPP-4 protein in the heart tissue of a patient near myocardial infarction; A step of reducing the circulating levels of brain natriuretic peptide (BNP) in the blood of the patient; A step of increasing the mRNA level of SERCA expression in the heart cells of a patient near myocardial infarction; and A step of reducing the levels of calcineurin activity and type I collagen in the heart tissue of a patient near myocardial infarction while maintaining the level of b-MHC in the non-infarcted area of the heart of the patient The method comprising at least one of the above. [The present invention 1054] A method for assisting the heart of a patient having myocardial infarction, comprising A step of increasing the level of stromal cell-derived factor 1α (SDF-1α) protein in the heart tissue of a patient near myocardial infarction; A step of maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of a patient near myocardial infarction; and A step of restricting the up-regulation of the expression and activity of DPP-4 protein in the heart tissue of a patient near myocardial infarction The method comprising the above. [The present invention 1055] A step of increasing the blood flow to the heart tissue of a patient near myocardial infarction The method of the present invention 1053 or 1054 comprising the above. [The present invention 1056] A step of applying mechanical circulatory support to the heart of the patient The method of the present invention 1055 comprising the above. [The present invention 1057] The method of the present invention 1056, wherein the mechanical circulatory support comprises applying a device equipped with a blood pump, such as a TV pump. [The present invention 1058] A step of assisting the heart by a TV pump and one or more of an intra-aortic balloon pump and an extracorporeal membrane oxygenation (ECMO) pump The method of the present invention 1057 comprising the above. [The present invention 1059] A step of unloading the left ventricle of the heart of the patient using a transvascular pump The method according to any one of the present inventions 1054 to 1058 comprising the above. [The present invention 1060] The method of the present invention 1059, wherein the left ventricle is unloaded over an unloading period of more than 15 minutes at a blood flow rate of at least 2.5 L / min. [The present invention 1061] The unloading period is More than 20 minutes; more than 25 minutes; more than 30 minutes; more than 35 minutes; more than 40 minutes; more than 45 minutes; about 20 minutes to about 45 minutes; about 15 minutes to about 30 minutes; and about 30 minutes to about 40 minutes The method of the present invention 1060, wherein it is any one of the above. [The present invention 1062] The method according to any one of the present inventions 1059 to 1061, wherein the left ventricle is unloaded at a blood flow rate of at least 3.5 L / min. [The present invention 1063] A step of applying reperfusion therapy after applying mechanical circulatory support to the patient's heart The method according to any one of the present inventions 1059 to 1062, comprising: [The present invention 1064] A step of applying mechanical circulatory support to the patient simultaneously with reperfusion The method according to the present invention 1063, comprising: [The present invention 1065] The method according to any one of the present inventions 1056 to 1064, wherein the mechanical circulatory support is provided by a TV pump or other blood pump. [The present invention 1066] The method according to any one of the present inventions 1063 to 1065, wherein the reperfusion includes at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis. [The present invention 1067] A method for assisting the heart of a patient having a myocardial infarction, comprising: Reducing the circulating level of brain natriuretic peptide (BNP) in the blood of the patient; Increasing the mRNA level of SERCA expression in the patient's heart tissue near the myocardial infarction; and Reducing the levels of calcineurin activity and type I collagen in the patient's heart tissue near the myocardial infarction while maintaining the level of b-MHC in the non-infarcted region of the patient's heart The method, comprising at least one of: [The present invention 1068] Increasing the blood flow to the patient's heart tissue near the myocardial infarction The method according to the present invention 1067, comprising: [The present invention 1069] Applying mechanical circulatory support to the patient's heart over an unloading period or other support period The method according to the present invention 1068, comprising: [The present invention 1070] The method according to the present invention 1069, wherein the increased blood flow is provided over an unloading period of more than 15 minutes at a flow rate of at least 2.5 L / min. [The present invention 1071] The unloading period is More than 20 minutes; more than 25 minutes; more than 30 minutes; more than 35 minutes; more than 40 minutes; more than 45 minutes; from about 15 minutes to about 30 minutes; from about 20 minutes to about 45 minutes; and from about 30 minutes to about 40 minutes The method according to the present invention 1070, wherein the unloading period is any one of the above. [The present invention 1072] The method according to any one of the present inventions 1068 to 1071, wherein the increased blood flow is provided at a flow rate of at least 3.5 L / min. [The present invention 1073] A step of applying reperfusion therapy after applying mechanical circulatory support to the patient's heart over the support period The method according to any one of the present inventions 1069 to 1072, comprising: [The present invention 1074] Applying mechanical circulatory support to the heart of the patient simultaneously with reperfusion therapy The method according to any one of the present inventions 1069 to 1073, comprising: [The present invention 1075] The method according to any one of the present inventions 1069 to 1074, wherein the mechanical circulatory support comprises applying a device equipped with a TV pump or other blood pump [The present invention 1076] Assisting the heart by an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump The method according to any one of the present inventions 1067 to 1075, comprising: [The present invention 1077] The method according to any one of the present inventions 1073 to 1076, wherein the reperfusion comprises at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis [The present invention 1078] A method for assisting the heart of a patient having a myocardial infarction, comprising: Reducing the levels of BAX protein and active caspase 3 antibody in the patient's heart tissue near the myocardial infarction; Increasing the levels of BCL-2 and BCL-XL proteins in the patient's heart tissue near the myocardial infarction; Increasing the level of stromal cell-derived factor 1α (SDF-1α) protein in the patient's heart tissue near the myocardial infarction; Maintaining the activity levels of MMP-2 and MMP-9 enzymes in the patient's heart tissue near the myocardial infarction; Restricting the upregulation of the expression and activity of DPP-4 protein in the patient's heart tissue near the myocardial infarction; Reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood; Increasing the mRNA level of SERCA expression in the patient's heart cells near the myocardial infarction; and Reducing the levels of calcineurin activity and type I collagen in the patient's heart tissue near the myocardial infarction while maintaining the level of b-MHC in the non-infarcted region of the patient's heart The method comprising: [The present invention 1079] A heart protection system for assisting the heart of a patient having a persistent myocardial infarction, the system comprising: The system comprising: A mechanical circulatory support device configured to be inserted into the patient; and A reperfusion therapy device Comprising: The mechanical circulatory support device is configured to operate for an assistance period of more than 15 minutes at a blood flow rate of at least 2.5 L / min before the operation of the reperfusion therapy device The system [The present invention 1080] The assistance period is Greater than 20 minutes; greater than 25 minutes; greater than 30 minutes; greater than 35 minutes; greater than 40 minutes; greater than 45 minutes; approximately 20 minutes to approximately 45 minutes; greater than 15 minutes and up to approximately 30 minutes; and approximately 30 minutes to approximately 40 minutes The system of the 1079th invention of the present invention, which is any one of them. [The 1081st invention of the present invention] The system of the 1079th or 1080th invention of the present invention, wherein the mechanical circulatory assist device is configured to operate at a blood flow rate of at least 3.5 L / min. [The 1082nd invention of the present invention] The system of any one of the 1079th to 1081st inventions of the present invention, wherein the mechanical circulatory assist device is configured to operate simultaneously with the reperfusion therapy device. [The 1083rd invention of the present invention] The system of any one of the 1079th to 1082nd inventions of the present invention, wherein the mechanical circulatory assist device includes a TV pump or other blood pump. [The 1084th invention of the present invention] The system of the 1083rd invention of the present invention, which includes one or more of the following devices that are operated after or during the operation of the mechanical circulatory assist device: an intra-aortic balloon pump and an extracorporeal membrane oxygenation (ECMO) pump. [The 1085th invention of the present invention] A heart protection system for assisting the heart of a patient with persistent myocardial infarction, wherein the system is configured to be percutaneously inserted into the patient after myocardial infarction, has a size and shape such that it is disposed across the aortic valve of the patient's heart, and is configured such that the distal end of the blood pump is located in the left ventricle of the heart; and a reperfusion therapy device and is provided with the blood pump is programmed to operate before the operation of the reperfusion therapy device and then pump blood for a pump operation period of more than 15 minutes at a blood flow rate of at least 2.5 L / min. the system. [The 1086th invention of the present invention] The pump operation period is Greater than 20 minutes; greater than 25 minutes; greater than 30 minutes; greater than 35 minutes; greater than 40 minutes; greater than 45 minutes; approximately 20 minutes to approximately 45 minutes; greater than 15 minutes and up to approximately 30 minutes; and approximately 30 minutes to approximately 40 minutes The system of the 1085th invention of the present invention, which is any one of them. [The 1087th invention of the present invention] The system of the 1085th or 1086th invention of the present invention, wherein the mechanical circulatory assist device is operated at a blood flow rate of at least 3.5 L / min. [The 1088th invention of the present invention] The system of any one of the 1085th to 1087th inventions of the present invention, wherein the blood pump is operated simultaneously with the reperfusion therapy device. [The 1089th invention of the present invention] A method for treating a human heart with persistent myocardial infarction, The method, wherein the myocardial infarction has an infarct size and is located within a portion of the heart, and the method includes a step of reducing the infarct size. [Inventive Concept 1090] The method of Inventive Concept 1089, wherein the step of reducing the infarct size is performed by reducing the myocardial oxygen demand of the heart in the portion of the heart including the infarct and subsequently restoring the oxygen supply to the portion of the heart including the infarct. [Inventive Concept 1091] A step of reducing the level of at least one of BAX protein and active caspase-3 in heart tissue The method of Inventive Concept 1089 or 1090, including the step. [Inventive Concept 1092] A step of increasing the level of at least one of BCL-2 and BCL-XL The method of any one of Inventive Concepts 1089 to 1091, including the step. [Inventive Concept 1093] A step of increasing the myocardial salvage index (MSI) of the heart The method of any one of Inventive Concepts 1089 to 1092, including the step. [Inventive Concept 1094] The method of Inventive Concept 1093, wherein the heart has a total ST elevation value (ΣSTE) of 6 or more. [Inventive Concept 1095] A step of inserting a blood pump into a patient's vascular system; A step of driving the pump during an auxiliary period to adjust the blood flow in the vascular system before applying reperfusion therapy to the heart; and A step of applying reperfusion therapy to the heart after the auxiliary period The method of any one of Inventive Concepts 1089 to 1094, including the steps. [Inventive Concept 1096] The method of Inventive Concept 1095, wherein the auxiliary period is at least 15 minutes. [Inventive Concept 1097] The method of Inventive Concept 1096, wherein the auxiliary period is at least 20 minutes. [Inventive Concept 1098] The method of Inventive Concept 1096, wherein the auxiliary period is at least 30 minutes. [Inventive Concept 1099] The method of Inventive Concept 1096, wherein the auxiliary period is at least 30 minutes, about 20 minutes to about 40 minutes, or at least 45 minutes. [Inventive Concept 1100] A step of unloading the left ventricle of the heart at a pump flow rate of at least 2.5 L / min during the auxiliary period The method of any one of Inventive Concepts 1095 to 1099, including the step. [Inventive Concept 1101] The method of Inventive Concept 1100, wherein the blood pump is a microaxial blood pump, and the step of unloading the left ventricle of the heart includes inserting the distal end of the pump into the left ventricle and inserting the proximal end of the pump into the aorta, and driving the pump to pump blood from the left ventricle to the aorta. [Inventive Concept 1102] Inserting a balloon pump into the aorta of the heart; and Expanding and contracting the balloon to adjust blood flow within the aorta A method according to any one of the inventions 1095 to 1099, including the above steps. [Invention 1103] Applying an extracorporeal membrane oxygenation system to the patient A method according to any one of the inventions 1095 to 1102, including the above step. [Invention 1104] A method according to any one of the inventions 1095 to 1103, wherein the pump is an intravascular blood pump by catheter. [Invention 1105] Increasing the left ventricular ejection fraction of the heart; Reducing microvascular obstruction of the heart; Reducing the left ventricular end-systolic volume of the heart; and Reducing the left ventricular end-diastolic volume of the heart A method according to any one of the inventions 1089 to 1104, including at least one of the above steps. [Invention 1106] Reducing the myocardial oxygen demand of the heart in a part of the heart including an infarction for at least 15 minutes, and then restoring the oxygen supply to the part of the heart including the infarction A method according to any one of the inventions 1089 to 1105, including the above step. [Invention 1107] A method according to any one of the inventions 1089 to 1106, wherein the heart is unloaded by a mechanical circulatory support device while reperfusion therapy is performed on the heart. [Invention 1108] A method according to any one of the inventions 1089 to 1107, wherein the reperfusion therapy includes at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis. [Invention 1109] Reducing the circulating level of brain natriuretic peptide (BNP) in the blood of the patient; Increasing the mRNA level of SERCA expression in patient heart cells near the myocardial infarction; and Reducing the levels of calcineurin activity and type I collagen in patient heart tissue near the myocardial infarction while maintaining the level of b-MHC in the non-infarcted area of the patient's heart A method according to any one of the inventions 1089 to 1108, including the above steps. [Invention 1110] Removing the blood pump from the patient's heart after applying the reperfusion therapy A method according to any one of the inventions 1089 to 1109, including the above step. [Invention 1111] Increasing blood flow to patient heart tissue near the myocardial infarction A method according to any one of the inventions 1089 to 1110, including the above step. [Invention 1112] A method for preventing or limiting the impact of heart failure in a human patient having a persistent myocardial infarction by reducing maladaptive cardiac remodeling in the patient, percutaneously inserting a transvalvular blood pump comprising a rotor and a cannula into the patient's vascular system such that the distal end of the cannula is positioned in the left ventricle of the patient's heart and the proximal end of the pump is positioned in the aorta, and disposing the cannula across the aortic valve of the heart; before reperfusing the heart, operating the disposed pump to unload the left ventricle over an assist period of at least 30 minutes to less than 60 minutes at a pump flow rate of at least 2.5 L / min; and after the assist period, applying coronary artery reperfusion therapy to the heart The method comprising [Invention 1113] The method of Invention 1112, wherein the pump is operated for an assist period of 30 minutes. [Invention 1114] The method of Invention 1112, wherein the pump is operated at a pump flow rate of at least 3.5 L / min of blood flow. [Invention 1115] continuing operation of the pump in parallel with the application of coronary artery reperfusion The method of Invention 1112, comprising [Invention 1116] continuing operation of the pump in parallel with the application of coronary artery reperfusion over a total assist period of at least 3 hours The method of Invention 1112, comprising [Invention 1117] reducing at least one of infarct size and left ventricular scar size The method of Invention 1112, comprising [Invention 1118] operating the pump to sufficiently unload the heart to alter gene expression in cells within the myocardial infarction region The method of Invention 1112, comprising [Invention 1119] reducing the levels of BAX protein and active caspase 3 antibody in the patient's heart tissue near the myocardial infarction; increasing the levels of BCL-2 and BCL-XL proteins in the patient's heart tissue near the myocardial infarction; increasing the level of stromal cell-derived factor 1α (SDF-1α) protein in the patient's heart tissue near the myocardial infarction; maintaining the activity levels of MMP-2 and MMP-9 enzymes in the patient's heart tissue near the myocardial infarction; limiting the upregulation of the expression and activity of DPP-4 protein in the patient's heart tissue near the myocardial infarction; reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood increasing the mRNA level of SERCA expression in cardiac cells of a patient near myocardial infarction; and reducing the levels of calcineurin activity and type I collagen in the heart tissue of a patient near myocardial infarction while maintaining the level of b-MHC in the non-infarcted area of the heart of the patient The method of the present invention 1118, comprising at least one of them. [The present invention 1120] The method of the present invention 1112, wherein the heart has a total ST segment elevation value (ΣSTE) of 4 or more. [The present invention 1121] The method of the present invention 1120, wherein the heart has a ΣSTE of 6 or more. [The present invention 1122] The method of the present invention 1112, wherein the patient is not in a state of cardiogenic shock. [The present invention 1123] assisting the heart with an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump The method of the present invention 1112, comprising this. [The present invention 1124] providing drug therapy to the patient in combination with the operation of the pump The method of the present invention 1112, comprising this. [The present invention 1125] The method of the present invention 1124, wherein the drug therapy comprises providing the patient with a medicament comprising at least one of a β-blocker, a preload-reducing agent, a neurohormonal agent, and an ACE inhibitor. [The present invention 1126] The method of the present invention 1112, wherein the reperfusion therapy comprises at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis. [The present invention 1127] The method of the present invention 1126, wherein PCI comprises implanting a stent in the patient. [The present invention 1128] A heart protection system for preventing or limiting the effects of heart failure in a patient by reducing maladaptive cardiac remodeling in a human patient with persistent myocardial infarction, a blood pump comprising a rotor and a cannula, the cannula being configured to be percutaneously inserted into the patient's vascular system such that the distal end of the cannula is positioned in the left ventricle of the patient's heart and the proximal end of the pump is positioned in the aorta, with the cannula being disposed across the aortic valve of the heart; a coronary reperfusion therapy device; and a controller coupled to the pump, programming the blood pump to unload the left ventricle over an assist period of at least 30 minutes to less than 60 minutes at a pump flow rate of at least 2.5 L / min before operation of the coronary reperfusion therapy device The system comprising this. [The present invention 1129] The system of the present invention 1128 that operates the pump over an auxiliary period of 30 minutes. [The present invention 1130] The system of the present invention 1128, wherein the pump is configured to operate in parallel with the application of a coronary reperfusion device. [The present invention 1131] The system of the present invention 1130, wherein the pump is configured to operate over a total auxiliary period of 3 hours.

Brief Description of the Drawings

[0035] The above and other objects and advantages will become apparent by considering the following detailed description in conjunction with the accompanying drawings, in which like reference characters refer to like parts throughout.

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DETAILED DESCRIPTION OF THE INVENTION

[0036] Detailed description To provide an overall understanding of the systems and methods, several exemplary embodiments will be described. The embodiments and features described herein are specifically described for use in connection with systems for circulatory and reperfusion therapies, but it will be understood that the components and other features outlined below can be combined with each other in suitable ways and can be adapted and applied to other types of circulatory and reperfusion therapy devices. Further, while specific embodiments are described herein with respect to specific devices for circulatory and reperfusion therapies, it should be noted that these various embodiments can be used in various combinations to enhance the therapeutic effect and maintain the life of patients after AMI.

[0037] Figure 1 shows a system 100 for providing a combination of mechanical assistance and primary reperfusion according to an embodiment of the present disclosure. The system 100 is aimed at limiting myocardial damage in a human patient 110 who has experienced an AMI in the heart 120. This system 100 includes a circulation unit 130 and a device 140 (or other source) for providing reperfusion therapy. The circulation unit 130 is in communication with a control unit 150. The control unit 150 can monitor signals emitted by the circulation unit 130 and, in response, control the operation of the device (or other source) comprising the circulation unit 130. These signals can indicate any one of the following: the operating state of the circulation unit 130, the position and state of the device 140 for reperfusion therapy, and the state of the patient's heart. Samples from an AMI patient, such as blood or heart tissue, can be obtained from either the circulation unit 130 or the device 140 for reperfusion therapy, or from a biopsy or other source, for characterization and further testing. This can be done via a test kit or a laboratory to extract various signs from these samples and make them observable by a clinician. Such signs include, for example, myocardial infarction scar size, and related parameters detailed in the following sections.

[0038] The circulation unit 130 includes a mechanical circulatory assist device that can be inserted, for example, into the left ventricle of a patient's heart. Such a mechanical circulatory assist device can change blood flow far beyond the actual cardiac output of the heart. For example, the mechanical circulatory assist device is inserted into the left ventricle of the heart of an AMI patient and is driven to unload the heart by pumping blood out of the ventricle. This can assist the heart in several possible ways. For example, the stress on the myocardial wall is reduced. This is beneficial because the unloading mechanism helps with myocardial salvage and repair. According to one embodiment of the present disclosure, the mechanical circulatory assist device may include a transvalvular microaxial blood pump. Examples of such blood pumps include, but are not limited to, Impella 2.5 (trademark) and Impella CP (registered trademark) by Abiomed, Inc., Danvers, MA. Other types of mechanical circulatory assist devices, such as extracorporeal pumps, can also be used to assist the heart. For example, an extracorporeal membrane oxygenation (ECMO) pump or an intra-aortic balloon pump can be used. In certain applications, the transvalvular pump is used in combination with another such device.

[0039] In addition to the mechanical circulatory assist device, the circulation unit 130 may also include an additional pump device that aids in unloading the heart. Examples of such pump assist devices include, but are not limited to, either an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump. For example, while the transvalvular pump is unloading the heart, a balloon pump or an ECMO device is applied to further assist the patient. Further, the circulation device can include a cannula portion in fluid communication with the pump, the distal end of the cannula may be located within the patient's heart, and the pump may be located in any one of (a) within the heart with the cannula, (b) outside the heart but within the patient, and (c) outside the patient.

[0040] In one embodiment of the present disclosure, device 140 is used to perform reperfusion therapy on a patient suffering from AMI. Such reperfusion therapy includes, for example, direct percutaneous coronary intervention (PCI). Such procedures can include the use of a coronary stent delivered to the distal left anterior descending artery (LAD). Examples of such coronary stents include, but are not limited to, the Promus PREMIER™ and REBEL™ bare metal platinum chromium coronary stents, and the SYNERGY™ bioabsorbable polymer stent, all of which are by Boston Scientific (Marlborough, MA). In certain aspects, reperfusion therapy 140 may include a drug or medicament that can assist in fibrinolysis, thereby providing reperfusion therapy in combination with or as an alternative to a stent or other device.

[0041] A kit or laboratory can provide the following clinical signs associated with myocardial infarction: protein levels of BAX, BCL-2, BCL-XL, DPP-4 and stromal cell-derived factor 1α (SDF-1α), active caspase-3 antibody levels, MMP-2 and MMP-9 enzyme levels in the patient's heart tissue near or in the region of the myocardial infarction site; mRNA levels of SERCA expression in the patient's heart cells near or in the region of the myocardial infarction area; calcineurin activity and levels of type I collagen in or near the myocardial infarction area; brain natriuretic peptide (BNP) levels in blood collected from the patient's left ventricle; myocardial salvage index; and the total ST elevation from an electrocardiogram map.

[0042] Figure 2 shows a flowchart of an exemplary method 200 for unloading the left ventricle of the heart of an AMI patient. The method starts at step S210, where a circulatory device, such as the mechanical circulatory device of the circulatory unit 130 of FIG. 1, is inserted into the patient after myocardial infarction. Such insertion can be achieved by using vascular access sheaths deployed in the patient's right internal jugular vein, left carotid artery, and one or more femoral arteries and veins. Further clinical details of such insertion procedures, and representative support data related to method 200, are detailed in Examples 1 and 2 of the following section.

[0043] Next, method 200 proceeds to step S220, where the circulatory device is operated in step S230 to assist the heart, for example, by unloading the patient's heart after myocardial infarction. Here, the circulatory device is operated to achieve a pump flow rate of at least 2.5 L / min of blood flow from the left ventricle of the heart. In certain embodiments, the circulatory device is operated to achieve a blood flow rate of at least 3.5 L / min from the left ventricle of the heart per cardiac output. The unloading is performed over a sufficiently long period (assist period t_sp) to promote reduction of infarct size. In one embodiment, the operation of the circulatory device is terminated after the assist period t_sp has elapsed. In other embodiments, the assist period is simply used as a marker indicating that time t_sp has elapsed since the circulatory device started operating, and there is no need to stop the operation of the circulatory device after t_sp has elapsed. Example 1 detailed in the following section provides support data for the step of unloading the patient's heart after myocardial infarction using the method 200 of the present disclosure. According to one embodiment, the assist period t_sp is greater than 15 minutes. According to other embodiments, the assist period t_sp is greater than 30 minutes.

[0044] After the heart has been unloaded over the assist period in step S230, the method proceeds to step S240 where reperfusion therapy is applied to the patient's heart. The reperfusion therapy is performed using a reperfusion device, drugs, or other techniques, and in FIG. 1, the reperfusion device 140 is applied. Clinical details of such reperfusion therapy procedures, and representative supporting data for method 200, are provided in Examples 1 and 2 below. According to certain embodiments of the present disclosure, the reperfusion therapy can be applied to the patient's heart after unloading the left ventricle of the heart. In other embodiments, the reperfusion therapy may be applied to the patient's heart while the left ventricle is still being unloaded by the circulation unit. In this embodiment, the parallel use of the reperfusion device and the circulation device is implemented only after the heart has been unloaded by the circulation device over the length of the assist period t_sp.

[0045] Currently, assisting the post-MI heart by mechanical circulatory support prior to applying reperfusion therapy is thought to have a beneficial effect on the patient's heart. One or more advantages may be detected in tissue or blood samples taken from the patient. Such advantages include one or more of the following outcomes: a decrease in the levels of BAX protein and active caspase-3 antibody in the patient's heart tissue near the myocardial infarction; an increase in the levels of BCL-2 and BCL-XL proteins in the patient's heart tissue near the myocardial infarction; an increase in the level of stromal cell-derived factor 1α (SDF-1α) protein in the patient's heart tissue near the myocardial infarction; maintenance of the active levels of MMP-2 and MMP-9 enzymes in the patient's heart tissue near the myocardial infarction; limitation of the upregulation of DPP-4 protein expression and activity in the patient's heart tissue near the myocardial infarction; a decrease in the circulating level of brain natriuretic peptide (BNP) in the blood taken from the patient's left ventricle; an increase in the mRNA level of SERCA expression in the patient's heart cells near the myocardial infarction; a decrease in the levels of calcineurin activity and type I collagen in the patient's heart tissue near the myocardial infarction while maintaining the level of b-MHC in the non-infarcted region of the patient's heart; a reduction in infarct size; an increase in the myocardial salvage index of the heart; and a total ST elevation of the heart exceeding 6. These results can be achieved using the systems and methods identified in the present disclosure.

[0046] Examples 1 and 2, detailed below, show the results of tests conducted by applying the method of the present invention to patients who had a heart attack. These tests were conducted by inserting a blood pump into the patient's vasculature after the patient had an AMI but before applying reperfusion therapy to the heart, driving the pump throughout the assistance period to regulate blood flow within the vasculature, and then applying reperfusion therapy to the heart after the assistance period. The results show a reduction in infarct size and an increase in the myocardial salvage index compared to the conventional method of applying reperfusion therapy immediately (or as soon as possible) after the infarction. Further results show that this method increases the left ventricular ejection fraction of the heart, decreases microvascular obstruction of the heart, reduces the left ventricular end-systolic volume of the heart, and reduces the left ventricular end-diastolic volume of the heart.

Example

[0047] Example 1: DTU-STEMI Pilot Study Under unload conditions, to initiate an investigation of whether delaying reperfusion improves myocardial salvage in human patients, the safety and feasibility of operating an unloading device with or without delaying coronary reperfusion were tested. The Door-To-Unload in STEMI (DTU-STEMI) pilot study was the first exploratory study to test the feasibility and safety of performing left ventricular (LV) unloading prior to reperfusion in STEMI without cardiogenic shock.

[0048] A. Method This DTU-STEMI trial was a prospective, multi-center, randomized pilot trial involving 14 facilities in the United States to examine the feasibility, safety, and potential benefits of mechanical unloading prior to coronary reperfusion in patients presenting with anterior wall STEMI. All patients received acute mechanical unloading with the Impella CP system (Abiomed Inc., Danvers, MA) and were randomly assigned to one of two arms: LV unloading followed by immediate reperfusion (U-IR) or LV unloading with a 30-minute delay in reperfusion (U-DR). The process flow of the U-IR and U-DR methodologies is shown in Figure 3. This comparison was specifically designed to precondition the myocardium for 30 minutes prior to reperfusion and was done by comparing infarct sizes between the U-DR and U-IR arms. Patients aged 21 to 80 years who presented to the hospital between 1 and 6 hours after the onset of chest pain and had a ST-segment elevation of 2 mm or more in two or more consecutive anterior wall leads, or a total ST-segment deviation of 4 mm or more in all anterior wall leads, were eligible for enrollment.

[0049] The patients were randomly assigned to either the U-IR arm or the U-DR arm immediately after femoral vascular access was obtained. The operator was instructed to place the Impella CP before diagnostic coronary angiography and to perform percutaneous coronary intervention (PCI) using second-generation drug-eluting stents, and to follow the guideline-based post-AMI care. In the U-DR group, the operator was permitted to shorten the time between unloading and reperfusion if clinically necessary. The Impella CP was removed after at least 3 hours of LV support after PCI.

[0050] The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events (MACCE), including cardiovascular mortality, reinfarction, stroke, or major vascular events, within 30 days. Table 1 includes the definitions used to adjudicate each element of MACCE. Additional safety parameters included all-cause mortality, hemolysis, acute kidney injury, hospitalization for heart failure, ventricular arrhythmia, LV thrombus, bleeding, and minor vascular events. The primary efficacy outcome was the assessment of infarct size as a percentage of total LV mass at 30 days using CMR. Secondary efficacy outcomes included infarct size by CMR at 3-5 days and 30 days. Exploratory assessments included comparison between groups of infarct size normalized to the area of the risk region at 3-5 days. The CMR protocol used in this trial has been described previously. A qualified 12-lead electrocardiogram was evaluated to quantify the sum of ST-segment elevation (ΣSTE), a well-established clinical marker of the risk region in STEMI. Specifically, ΣSTE was quantified by measuring the magnitude of ST-segment elevation 0.08 seconds after the J point in the precordial leads, compared with the isoelectric segment in an independent core laboratory blinded to the assignment of the study groups.

[0051] (Table 1) Baseline Characteristics TIFF0007684045000001.tif190128

[0052] Baseline demographic and clinical variables were summarized for the two treatment groups. This trial had the power to detect a large difference in infarct size, assuming a large standard deviation that could be expected in a small STEMI trial. Specifically, assuming a 10% standard deviation, a power of 0.88 and an α of 0.05 were used to detect an absolute difference in infarct size of 10%. All continuous variables were summarized as mean values with standard deviation, as well as median and interquartile range, and compared between treatment groups using appropriate parametric or nonparametric tests. Categorical variables were summarized as frequencies and percentages and compared between treatment groups using Pearson's chi-square test or Fisher's exact test of a contingency table, as appropriate. All statistical tests and / or confidence intervals were performed at α = 0.05 (two-sided), as needed. All p-values reported as greater than 0.01 were rounded to the second decimal place and p-values between 0.01 and 0.001 were rounded to the third decimal place. The comparability between treatment groups was evaluated for all clinically significant demographic and baseline characteristic variables.

[0053] B. Results From April 2017 to May 2018, a total of 50 patients with anterior wall STEMI were enrolled and randomly assigned to either the U-IR arm or the U-DR arm (n = 25 / group). As shown in Table 1, baseline characteristics were not statistically different between groups. The mean age of the trial participants was 59.7 years, and 38 patients (76%) were male. These patients had symptoms of hypertension at the time of examination, and the time from onset of chest pain to LV unloading was not statistically different between groups (176.2 ± 73.4 minutes vs. 200.2 ± 151.8 minutes, U-DR vs. U-IR, p = 0.48). ΣSTE was >4 in 90% (n = 45 / 50) of the patients. Before the placement of Impella CP, LV end-diastolic pressure increased in both groups (25.0 ± 9.6 and 24.0 ± 8.1 mmHg, U-DR vs. U-IR, p = 0.73). Baseline LVEF was obtained by left ventriculography before randomization in 90% (n = 45 / 50) of the patients using the necessary PCI arterial access (either femoral artery access or radial artery access at the discretion of the responsible physician). Baseline LVEF was 37.4% (13.2) in the entire population and was lower in the U-DR group (41.9% (12.3) vs. 32.7% (12.7), U-IR vs. U-DR, p = 0.02). Impella CP was successfully implanted in all 50 patients, and the mean power (P level) during the entire 3-hour assist period required by this trial protocol was 7.6 ± 1.0, and the mean device flow rate was 2.8 ± 0.4 L / min, indicating successful LV unloading. The mean time from the start of this procedure to the implantation and initiation of Impella CP was 15.4 (8.4) minutes in the entire population. All timing elements are shown in Table 2. Radial artery access was used for PCI in 60% (n = 30 / 50) of the patients. The use of vascular occlusion devices was left to the discretion of the responsible physician. A femoral artery occlusion device was used in 29 of 50 patients (14 / 25, 56% vs. 15 / 25, 60%, U-DR vs. U-IR, p = 0.99). As shown in Table 2, the left anterior descending artery was confirmed to be the culprit coronary artery, and 98% (n = 49 / 50) of the patients were treated with stent implantation. One patient randomly assigned to the U-DR arm had no coronary artery lesion requiring PCI.All patients who received PCI were administered a P2Y12 inhibitor before PCI. 8% of the patients were administered bivalirudin, and 94% received unfractionated heparin. Of these patients, 1 patient was administered both bivalirudin and unfractionated heparin. 8% of the patients were administered a glycoprotein 2b / 3a receptor inhibitor in addition to dual antiplatelet therapy before PCI. Coronary angiography was performed after LV unloading was initiated.

[0054] (Table 2) Timing elements TIFF0007684045000002.tif110161 T Based on the source document. Y One patient in the U-DR arm did not receive PCI.

[0055] Thrombolysis in Myocardial Infarction (TIMI) 0 - 1 flow was observed in 52% (n = 26 / 50) of the patients before PCI. After PCI, TIMI 3 flow was observed in 100% (n = 49 / 49) of the patients who received PCI.

[0056] All patients assigned to the U-DR arm completed 30 minutes of LV unloading before reperfusion without the need for emergency rescue PCI, as shown in Figure 4. The timing elements, including from device implantation to balloon reperfusion, are shown in Table 2. The mean DTB time was longer in the U-DR arm (96.7 ± 26 minutes vs. 72.6 ± 24 minutes, U-DR vs. U-IR, p = 0.002) due to the extended unloading-to-balloon time in the U-DR group (34.1 ± 3 minutes vs. 10.5 ± 7 minutes, U-DR vs. U-IR, p < 0.001).

[0057] For the combined cohort of 50 patients, the composite 30-day MACCE event rate was 10% (n = 5 / 50), as shown in Table 3. The prolonged DTB time in the U-DR group did not increase the 30-day MACCE (12% [3 events] vs. 8% [2 events], U-DR vs. U-IR, p = 1.00). The overall cardiovascular mortality was 4% (n = 2 / 50) with 1 death per group. No non-cardiovascular mortality was observed. One patient had a stroke 1 day after enrollment (2%; n = 1 / 50), and 2 patients had major vascular events related to the release of femoral artery blood flow restriction during device removal (4%; n = 2 / 50).

[0058] (Table 3) MACCE rate at 30 days TIFF0007684045000003.tif45149

[0059] Bleeding according to the Bleeding Academic Research Consortium (BARC) ε2 was observed in 14% of patients (n = 7 / 50). No BARC 3C (intracranial), 4 (CABG-related), or 5 (fatal) events were observed. 6% of patients (n = 3 / 50) were transfused, and each patient required only a single unit of packed red blood cells. Tables 3 and 4 provide details of all additional clinical events.

[0060] (Table 4) Cardiac magnetic resonance test, all patients TIFF0007684045000004.tif186170 Δ One patient in the U-DR arm underwent a contrast-free examination, and the core lab was only able to read the LVEF. T MVO: Microvascular obstruction. Y Myocardial salvage index (MSI) = 1 - infarct size / risk area (AAR).

[0061] CMR was performed in 82% (n = 41 / 50) of the patients on days 3 to 5 and in 80% (n = 40 / 50) of the patients during the 30-day follow-up. The primary efficacy endpoint of infarct size normalized to total LV mass at 30 days was 14.1% (n = 40 / 50) across the group. No difference between groups was observed (13.1 ± 11.3% vs. 15.3 ± 11.5%, U-DR vs. U-IR, p = 0.53). Among the secondary and exploratory endpoints at 3 to 5 days, mean infarct size normalized to total LV mass of 17.9 ± 13.5% and infarct size normalized to the risk area of 47.9 ± 21.4% were observed across the group (n = 40; Table 4). Infarct size normalized to the risk area was not statistically different between groups (44.2 ± 18.9 vs. 51.6 ± 23.6, U-DR vs. U-IR, p = 0.28). Mean microvascular obstruction was 1.3% vs. 2.7% in the U-DR and U-IR groups, respectively (p = 0.22). LV ejection fraction and LV volume were not statistically different between groups at 3 to 5 days and 30 days. TIMI blood flow was not correlated with infarct size in the U-IR and U-DR groups.

[0062] In patients in whom CMR data were available at 3 to 5 days, ΣSTE > 4, ΣSTE > 5, and ΣSTE > 6 were observed in 88% (n = 35 / 40), 83% (n = 33 / 40), and 75% (n = 30 / 40) of the patients, respectively. Compared with the U-IR group, infarct size normalized to the risk area was significantly reduced in the U-DR group with ΣSTE > 6 (44.1% vs. 59.9%, U-DR vs. U-IR, p = 0.04, as shown in Figure 5).

[0063] C. Analysis of Results The DTU-STEMI safety and feasibility pilot trial represents the first human experience of mechanically unloading the LV and intentionally delaying coronary reperfusion (primary unloading) in anterior wall STEMI using the method 200 of the present disclosure. These findings suggest for the first time that it is feasible to change the STEMI therapy by first focusing on reducing myocardial oxygen consumption (unloading) and then restoring coronary reperfusion.

[0064] Multiple attempts to limit infarct size have been tested, but previous clinical trials have not intentionally prolonged the delay to reperfusion after initiation of a cardiac protection treatment strategy. Based on the disruptive concept of first unloading the LV and delaying reperfusion, 30-day MACCE was selected as the primary safety endpoint to provide a rigorous and sensitive analysis of any potential risks associated with the DTU-STEMI strategy. In both the U-IR arm and the U-DR arm, the overall MACCE incidence was relatively low, and there were no safety signals prohibiting reinfarction. Among the individual MACCE components, CV mortality was observed in one patient per arm of this trial, comparable to the national benchmark for 30-day STEMI mortality. One patient was diagnosed with an acute exacerbation of pulmonary fibrosis on the third day after the procedure and died of respiratory failure 10 days later. The second death was in a patient who presented with cardiogenic shock detected only after enrollment. The major vascular event incidence in the DTU-STEMI trial was comparable to that in the pump arm of the Intra-aortic Balloon Counterpulsation and Infarct Size in Patients with Acute Anterior Myocardial Infarction Without Shock: CRISP-AMI trial. Overall BARC bleeding >2 in DTU-STEMI was lower than that reported in a recent analysis of bleeding events requiring percutaneous ventricular assist devices and higher than that reported in other STEMI trials involving drug therapy or devices of lower French size, as expected. An important aspect of testing the concept of feasibility was to better understand the time required to establish LV unloading prior to PCI and its impact on door-to-balloon and overall ischemia time. As shown in Table 2, in a trial of a total of 50 patients, an average of 15.4 minutes was required from the start of the procedure to the insertion and initiation of the Impella CP. This time included preparation, draping, vascular access, left ventricular angiography, and insertion of the Impella device.This observation highlights important insights from this pilot trial, including: 1) it is feasible to implant and activate this unloading device in a timely manner during anterior wall STEMI; 2) despite this inherent delay, the operators were able to achieve a door-to-balloon time of 84.4 (27.6) minutes on average in all 50 patients; and 3) despite this inherent delay, the infarct size was low compared to recent reports including CRISP-AMI and was not correlated with DTB time. These findings support that the DTU-STEMI strategy can be safely tested in a larger pivotal trial.

[0065] By providing 30 minutes of LV unloading prior to reperfusion, the inventors hypothesized that a cardioprotective shift in myocardial signaling and coronary perfusion limits myocardial injury. For this reason, patients with a larger at-risk myocardial area may derive more benefit from mechanical preconditioning prior to reperfusion. This is consistent with the observation that compared to unloading and immediate reperfusion alone, when 30 minutes of unloading is performed prior to reperfusion, the ΣSTE, a well-established marker of the at-risk myocardial area in STEMI, is higher in patients, the infarct size is smaller, and the myocardial salvage index is higher. Multiple studies have confirmed that infarct size and myocardial salvage quantified by single-photon emission computed tomography (SPECT) or CMR directly correlate with clinical outcomes including MACE 6 months after STEMI. The infarct size normalized to the risk area in both arms of the DTU-STEMI trial is lower than the values reported in recent STEMI trials including IABP or β-blocker therapy. Patients in the U-DR group showed a lower EF and a higher incidence of ST elevation of 6 or more, which was seen in a small number of patients despite randomization of the patients, but this did not lead to a larger infarct or lower EF at the 30-day time point. These findings suggest that the DTU-STEMI strategy does not increase infarct size and further suggest that in patients with high ST elevation, delaying the delay until reperfusion may improve myocardial salvage.

[0066] This DTU-STEMI pilot trial has overcome a major barrier to progress in the fields of cardioprotection and myocardial recovery by demonstrating for the first time that it is possible to delay coronary reperfusion, thereby giving LV unloading sufficient time to precondition the myocardium and reduce ischemia-reperfusion injury and overall myocardial damage in AMI.

[0067] Example 2 In the context of myocardial ischemia-reperfusion injury, increased expression of proteases such as matrix metalloproteinase (MMP)-2 and MMP-9, and dipeptidyl peptidase-4 (DPP-4) cleaves the N-terminus of stromal cell-derived factor (SDF)-1α, thereby inactivating the cytokine. The remaining SDF-1α can bind to CXCR4, which promotes phosphorylation of the RISK pathway such as extracellular signal-regulated kinase (Erk), protein kinase b (Akt), and glycogen synthase kinase 3b (GSK3b). Activation of RISK promotes cell survival by limiting apoptosis of cardiomyocytes and maintains mitochondrial integrity by preventing the opening of the mitochondrial permeability transition pore. Here, we further explain the mechanism underlying the cardioprotective effect of P-unloading and whether the rapid reduction in infarct size results in a permanent reduction in left ventricular (LV) scar and improvement in cardiac function. In this study, we tested the importance of delayed myocardial reperfusion, examined the cardioprotective mechanism, and investigated the late effects on myocardial function associated with P-unloading.

[0068] A. Methods The experiments were performed in adult male Yorkshire pigs. The Institutional Animal Care and Use Committee of Tufts Medical Center approved the experimental protocol. All experiments were conducted in accordance with the Committee's guidelines. Animals were pre-treated with terazolium (0.8 ml / kg, intramuscular; Zoetis Services LLC, Parsippany, NJ). General anesthesia was induced and maintained with isoflurane (1% - 2%). All animals were intubated and mechanically ventilated with room air (Harvard Apparatus, Holliston, MA) and supplemented with oxygen to maintain physiological pH and oxygen saturation. Surface electrocardiogram leads, an orogastric tube, a peripheral 18G intravenous catheter, and a rectal thermistor were placed in all animals. Heating pads were used as needed to maintain a core body temperature > 99°F. Next, vascular access sheaths were deployed into the right internal jugular vein (10-F), left carotid artery (7-F), and both the femoral artery (7-F) and femoral vein (10-F). A bolus of unfractionated heparin to target an activated clotting time of 300 - 400 seconds, a continuous lidocaine infusion (1 mg / kg), and norepinephrine (0.16 mg / min) were initiated in all animals.

[0069] A 6-F Judkins right coronary artery catheter (Boston Scientific, Marlborough, Massachusetts) was engaged from the right femoral artery to the left coronary artery, and a baseline angiogram was recorded. A 0.014-inch guidewire was delivered to the distal left anterior descending (LAD) branch, and a 3.0×8 mm bare metal stent (Boston Scientific) for the acute test or a 3.0×8 mm angioplasty balloon (Boston Scientific) for the chronic test was placed at the mid-LAD after the first diagonal branch where LAD occlusion was confirmed angiographically. Coronary angiography was performed immediately after reperfusion and again after the end of the test protocol when the patency of the LAD was confirmed. The LAD stent was used in acute animal experiments to mark the exact location of repeated balloon occlusion during Evans blue contrast staining. After 120 minutes of reperfusion, the animals were euthanized with pentobarbital and phenytoin.

[0070] As shown in Figure 6A, pigs were divided into four groups (n = 4 / group). All groups underwent 90 minutes of LAD occlusion. In Group 1, LAD occlusion and subsequent 120 minutes of reperfusion served as the control group. In Groups 2 and 3, after LAD occlusion, a TV pump (Impella CP, Abiomed, Danvers, Massachusetts) was inserted via a 14-F sheath into the left femoral artery and activated to maintain maximum assistance (achieving 44,000 revolutions per minute and 3.5 l / min). After this activity, an additional 15 minutes (Group 2) or 30 minutes (Group 3) of occlusion followed, and then 120 minutes of reperfusion with LV unloading ensued. In Group 4, reperfusion continued after LAD occlusion, and after 30 minutes of reperfusion, the TV pump was inserted and activated during the remaining 90 minutes of reperfusion.

[0071] At the end of each test, the animals were euthanized to measure the myocardial infarction size. Three sham-operated animals were intubated, anesthetized, and mechanically ventilated without myocardial infarction or mechanical unloading. LV tissue samples obtained from the sham control were used for histological analysis.

[0072] To evaluate the functional role of SDF-1α / CXCR4 signaling or the cardioprotective effect of LV unloading, a pharmacological inhibitor of CXCR4, the SDF-1α receptor (also known as AMD3100), was delivered to the risk area using an over-the-wire type balloon for coronary angioplasty while maintaining occlusion of the LAD in a closed-chest animal model of AMI. Adult male pigs were treated with intracoronary infusion of either vehicle or AMD3100 (3 mg / kg / min, intracoronary for 10 minutes; n = 4 / group) starting at the initiation of LV unloading for 30 minutes before reperfusion. The dose of AMD3100 was selected based on previous reports (Hu X, Dai S, Wu WJ, et al. Stromal cell derived factor-1 alpha confers protection against myocardial ischemia / reperfusion injury: role of the cardiac stromal cell derived factor-1 alpha CXCR4 axis. Circ 2007;116:654-63).

[0073] To study the long-term effects of LV unloading on infarct size, 19 adult male Yorkshire pigs were subjected to 90 minutes of mid-LAD occlusion followed by either immediate reperfusion (P-reperfusion) or 30 minutes of unloading prior to reperfusion (P-unloading). Five animals died of ventricular arrhythmias during LAD occlusion before randomization or pump implantation. Of the remaining 14 animals that successfully completed this protocol, two animals in the P-reperfusion group died within 6 hours after reperfusion due to refractory ventricular fibrillation. No animals died in the P-unloading group. In total, 7 out of 19 animals (37%) died during the test protocol. The 12 surviving animals were used for analysis in the chronic test in either the P-reperfusion group (n = 6) or the P-unloading group (n = 6) as shown in Figure 6A. The animal weights were 76.7 ± 6.9 kg in the P-unloading group and 76.2 ± 2.4 kg in the P-reperfusion group (p = 0.84). After reperfusion, all animals were allowed to recover and monitored for 28 days. After 28 days, the animals were anesthetized again and underwent repeated catheterization to evaluate infarct size according to cardiac magnetic resonance imaging (MRI) and LV hemodynamics.

[0074] The changes in LV pressure and volume were evaluated using a 5-F conductance catheter system (Sigma M, CD Leycom, Hengelo, the Netherlands) deployed from the left carotid artery to the left ventricle. Ventricular pressure and volume were measured at 28 days after the first infarction in the chronic phase test, using a solid-state pressure transducer and dual-field excitation mode, respectively, as previously described. Time-varying electrical conductance was measured across 5 - 7 ventricular blood segments delineated by the selected catheter electrodes. The correct positioning of the conductance catheter along the long axis of the left ventricle was confirmed by fluoroscopy. Parallel conductance was evaluated by injecting 20 ml of hypertonic (6%) saline into the right internal jugular vein. Absolute LV volume was measured by subtracting parallel conductance from the total conductance volume. Stroke volume was calculated as the difference in conductance volume at +dP / dtmax and -P / dtmin. The LV stroke work was calculated as the product of peak LV peak systolic blood pressure and stroke volume.

[0075] A-1. Measurement of Infarct Size At the end of the acute test protocol, balloon occlusion was performed within the mid-LAD stent, and Evans blue was injected into both coronary vessels to delineate the contour of the risk region, followed by excision and slicing of the left ventricle. Biopsy specimens were obtained from the antero-apical left ventricle (infarct area) distal to the stent deployment site and from the postero-basal wall (non-infarct area) for molecular analysis; next, as previously described, LV slices were incubated in 1% triphenyltetrazolium chloride. To quantify the LV scar size at 28 days after MI, the left ventricle was divided into 5 1-cm slices and incubated in triphenyltetrazolium chloride without Evans blue. Subsequently, the LV slices were photographed, and three blinded reviewers used digital planimetry to quantify the total myocardial area, risk region, and infarct area.

[0076] Animals in the chronic phase study underwent cardiac MRI with late-gadolinium enhancement (LGE) 28 days after the first infarction using a Philips Achieva 1.5-T scanner (Philips Healthcare, Best, the Netherlands). Breathhold cine images by steady-state free precession were acquired in three long-axis planes and in consecutive short-axis slices from the atrioventricular ring to the apex. Left ventricular (LV) and right ventricular volumes, weights, and ejection fractions were measured using standard volumetric methods and analyzed with commercially available software (QMASS version 7.4, Medis Medical Imaging Systems, Leiden, the Netherlands) by blinded observers experienced in cardiac magnetic resonance (CMR) analysis. LGE images were acquired 10 - 15 minutes after intravenous administration of 0.2 mmol / kg gadolinium-diethylenetriaminepentaacetic acid in the same location as the cine images with a breathhold two-dimensional phase-sensitive inversion recovery sequence. The LGE area was defined using the full width at half maximum (above 50% of the maximum myocardial signal intensity), with manual adjustment as needed. Areas with LGE were summed to obtain the total LGE volume and expressed as the percentage of the total LV myocardium (LGE%).

[0077] Whole transcriptome expression analysis was performed on ribonucleic acid (RNA) isolated from the infarcted area after the acute phase protocol using a Porcine 1.0 ST microarray. (The online appendix explains the details.) All raw and processed data from this microarray analysis are accessible with the Gene Expression Omnibus accession number GSE108644. Quantitative polymerase chain reaction (PCR) and western blot analysis confirmed the expression of significantly regulated genes and their activation in altered pathways.

[0078] LV tissue samples were obtained from the center of the infarct area, washed and fixed with 3% glutaraldehyde in phosphate buffer, and embedded in epoxy resin. Electron micrographs were taken to analyze myocardial cell damage, such as mitochondrial swelling and integrity.

[0079] A-2. Quantification of SDF-1α and CXCR4 levels Total proteins were extracted and separated from tissue homogenates as previously described (22-24). SDF-1α protein levels were quantified in sham-operated animals and LV tissue isolated from the infarct area using Western blot analysis and enzyme-linked immunosorbent assay. Circulating serum levels of SDF-1α were quantified by using an enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, Minnesota). CXCR4 levels in sham-operated animals and LV tissue isolated from the infarct area were quantified by Western blot analysis (Abcam, Cambridge, UK). Thereafter, immunoblot analysis was performed as previously described.

[0080] A-3. Quantification of MMP-2, MMP-9, and DPP-4 levels and activities The activities of MMP-2 and MMP-9 in the homogenate of cardiac tissue were quantified by zymography as previously described. Briefly, gelatin zymography was performed using a sodium dodecyl sulfate polyacrylamide gel electrophoresis gel containing 1 mg / ml of porcine gelatin. Samples were prepared under non-reducing conditions. Gel electrophoresis was carried out at 150 V for 1 hour. After electrophoresis, the gel was washed at room temperature for 6 hours with gentle agitation in 2.5% Triton X-100 solution and then exchanged into a developing buffer containing 50 mM Tris-HCl (pH 7.5), 0.2 M NaCl, 5 mM CaCl2 and 0.2% Brij-35. The gel was agitated at room temperature for 30 minutes, placed in fresh developing buffer and incubated overnight at 37°C. The next morning, the gel was stained with 0.5% Coomassie Brilliant Blue R-250 in 40% methanol and 10% acetic acid for 2 - 4 hours and destained at room temperature in 40% methanol and 10% acetic acid. Gelatinolytic bands were quantified by scanning densitometry using ImageJ software (National Institutes of Health, Bethesda, Maryland). DPP-4 protein levels were quantified by immunoassay and the activity levels were measured using a commercially available activity assay kit (MilliporeSigma, Burlington, Massachusetts).

[0081] A-4. Quantification of the Apoptosis Signaling Pathway Immunoblot analysis was performed using antibodies against porcine B-cell lymphoma (BCL)-2 (Cell Signaling Technology, Danvers, Massachusetts), BAX (Cell Signaling Technology), B-cell lymphoma-extra-large (BCL-XL) (Cell Signaling Technology), caspase-3 (Cell Signaling Technology), and glyceraldehyde-3-phosphate dehydrogenase. The expression levels of apoptosis regulatory proteins were normalized to both total protein levels and glyceraldehyde-3-phosphate dehydrogenase. TUNEL staining was performed using 10-mm-thick sections obtained from around the infarct area fixed with 4% paraformaldehyde / phosphate-buffered saline for 20 minutes. The slides were permeabilized with 0.1% Triton X-100 in 0.1% sodium citrate on ice, and the sections were labeled at 37°C for 60 minutes in the dark. The slides were rinsed with phosphate-buffered saline and labeled with ProLong Gold antifade reagent containing DAPI (Life Technologies, Grand Island, New York). Images were acquired using an Eclipse E800 fluorescence microscope (Nikon Corporation, Tokyo, Japan) and Openlab version 5 software (Perkin Elmer, Waltham, Massachusetts). TUNEL-positive cells were counted by an expert blinded to the experimental group at a magnification of 10× and expressed as a percentage of all nuclei.

[0082] A-5. Others In all cell-based real-time PCR experiments, total RNA was directly extracted with Trizol (Thermo Fisher Scientific, Waltham, Massachusetts) and converted to complementary deoxyribonucleic acid with the High Capacity cDNA Reverse Transcription Kit (Thermo Fisher Scientific). In all real-time PCR experiments, samples were run in triplicate and quantified using 40 cycles of 30 seconds at 94°C, 45 seconds at 60°C, and 45 seconds at 72°C with the ABI Prism 7900 Sequence Detection System (Thermo Fisher Scientific) using appropriate primers.

[0083] Results are shown as mean ± SD. Unpaired Student's t-test or one-way analysis of variance was used to compare continuous variables between groups. All data within groups over time were analyzed using nonparametric two-way repeated measures analysis of variance. Simple linear regression analysis was used to evaluate the correlation between two parameters. All statistical analyses were performed using GraphPad Prism (GraphPad Software, La Jolla, California). An α level of P < 0.05 was considered to indicate a significant effect or difference between groups.

[0084] B. Results B-1. LV unloading for 30 minutes before reperfusion reduces acute infarct size compared with reperfusion alone LV unloading for 30 minutes before reperfusion reduced myocardial infarct size compared with reperfusion alone (33.3 ± 5% vs. 62.2 ± 1.7% infarct / risk area, group 3 vs. group 1, respectively; p < 0.01) (see Fig. 6B). Rapid reperfusion within 15 minutes following LV unloading (group 2) or LV unloading after reperfusion (group 4) did not reduce myocardial infarct size compared with reperfusion alone.

[0085] B-2. LV unloading induces comprehensive changes in gene expression associated with a reduction in injury within the infarct area after AMI To initiate an examination of the cardioprotective mechanism associated with LV unloading before reperfusion, the inventors analyzed the whole transcriptome from within the infarct area between sham control group 1 and group 3 to identify genes that were differentially expressed between the treatment groups. A heatmap of all differentially regulated genes showed that 30 minutes of LV unloading before reperfusion attenuated changes in gene expression associated with reperfusion only, as compared to sham control (see Figure 7A).

[0086] Compared to reperfusion only, 30 minutes of LV unloading before reperfusion restricted the downregulation of genes associated with mitochondrial function and cellular respiration (see Table 5 below). Consistent with these observations, real-time PCR of LV tissue samples from the infarct area showed that group 3 had an increase in messenger ribonucleic acid (mRNA) levels of major genes associated with cellular respiration, as shown in Figure 7B, as compared to group 1. Electron microscopy further showed a loss of mitochondrial integrity within the infarct area from group 1 (but not group 3), as shown in Figure 7C. From these findings, it is clear that 30 minutes of LV unloading before reperfusion causes extensive changes in gene expression within the infarct area, along with significant protection of genes associated with mitochondrial function, as compared to reperfusion only.

[0087] B-3. LV unloading restricts SDF-1α degradation in AMI Considering the importance of SDF-1α / CXCR4 signaling in cardiac protection during ischemic reperfusion injury, the SDF-1α and CXCR4 protein levels were quantified within the infarct area. The inventors observed that reperfusion only (group 1), 15 minutes of LV unloading (group 2), or LV unloading after reperfusion (group 4) were associated with a decrease in the protein level of SDF-1α within the infarct area compared to sham controls (see Figures 8A and 8B). In contrast, only 30 minutes of LV unloading before reperfusion (group 3) maintained the SDF-1α protein level within the infarct area compared to sham controls. CXCR4 levels remained unchanged in all four test groups compared to sham controls.

[0088] To determine whether the increase in SDF-1α level is transcriptionally regulated, mRNA expression was quantified using real-time PCR among the groups, and no difference was observed in SDF-1α or CXCR4 gene expression (see Figures 8C and 8D). Since SDF-1α is highly regulated by proteolysis, next, the expression of the major proteases known to degrade SDF-1α was examined. Compared to sham controls, the activity levels of MMP-2 and MMP-9 increased with reperfusion only, but not with 30 minutes of LV unloading before reperfusion (see Figures 8E and 8F). With reperfusion only, the expression and activity levels of DPP-4 within the infarct area increased compared to sham controls (see Figures 8G and 8H). With 30 minutes of LV unloading before reperfusion, the upregulation of DPP-4 expression and activity was restricted. These data suggest that 30 minutes of LV unloading before reperfusion can maintain the SDF-1α protein level by restricting the activity of proteases known to degrade SDF-1α.

[0089] B-4. Loss of SDF-1α / CXCR4 activity attenuates the cardioprotective effect of LV unloading To examine whether SDF-1α / CXCR4 signaling is required for the cardioprotective effect of LV unloading, CXCR4 activity was blocked using intracoronary delivery of AMD3100 in a separate group of animals. Loss of CXCR4 activity increased infarct size and decreased cardioprotective signaling via the RISK pathway, including Akt, extracellular signal-regulated kinase, and glycogen synthase kinase 3b, compared with vehicle-treated controls that received LV unloading for 30 minutes before reperfusion (see Figures 8I and 8J). These findings suggest that SDF-1α / CXCR4 signaling is required for the cardioprotective effect of LV unloading before reperfusion.

[0090] B-5. LV unloading limits apoptosis-promoting signaling To further examine whether 30 minutes of LV unloading decreases the levels of apoptosis-related proteins in the infarct area, the inventors observed that reperfusion alone (group 1) increased the levels of apoptosis-promoting proteins, such as BAX and active caspase-3, and further decreased the levels of anti-apoptosis proteins, such as BCL-2 and BCLXL, compared with sham controls (see Figures 9A-9C). Compared with group 1, group 3 showed a decrease in the levels of BAX and active caspase-3 and an increase in the levels of anti-apoptosis BCL-2 and BCL-XL proteins. Compared with P-reperfusion, P unloading decreased the number of TUNEL-positive cells in the infarct area (see Figures 9D and 9E).

[0091] B-6. Compared with primary reperfusion, primary unloading reduces infarct size and maintains cardiac function 28 days after AMI To confer clinically meaningful cardiac protection, the P-unloading effect observed on infarct size reduction must be maintained beyond the acute treatment period. To test this theory, adult male pigs were treated with either P-reperfusion or P-unloading, and LV scar size, LV function, and molecular changes associated with heart failure were quantified 28 days after MI. Fourteen animals completed the ischemia-reperfusion period of this protocol. Two animals in the P-reperfusion group died within 6 hours after reperfusion, and 12 animals survived until 28 days (6 animals per group).

[0092] Compared with P-reperfusion, P-unloading reduced the LV scar size quantified using LGE (3.9 ± 3.2% vs. 9 ± 3.7%; p = 0.03) and decreased the anatomical pathology (7.2 ± 4.9% vs. 14.9 ± 4.1%; p = 0.02) (Figure 5A). Histological planimetry of infarct size was directly correlated with the percentage of LGE from CMR (R2 = 0.85) (see Figures 10B - 10D). Using CMR-derived volumes, end-diastolic volume and end-systolic volume were similar between groups (end-diastolic volume: 152 ± 29 ml vs. 142 ± 14 ml; P-reperfusion vs. P-unloading [p = NS]; end-systolic volume: 86 ± 26 ml vs. 74 ± 6 ml; P-reperfusion vs. P-unloading [p = NS]). CMR-derived LV weight did not differ between groups (90.4 ± 10.6 g vs. 84.4 ± 8.6 g; P-reperfusion vs. P-unloading [p = NS]). Hemodynamic analysis using an LV conductance catheter showed that P-unloading was associated with higher stroke volume (54 ± 7 ml vs. 40 ± 6 ml; p = 0.02), cardiac output (3.9 ± 0.6 l / min vs. 2.5 ± 0.2 l / min; p = 0.006), and stroke work (3,075 ± 339 ml×mmHg vs. 2,195 ± 307 ml×mmHg; p = 0.008) compared with P-reperfusion (see Table 5 below).

[0093] (Table 5) Hemodynamic variables 28 days after acute myocardial infarction Values are mean ± SD for TIFF0007684045000005.tif68128 EDV = end - diastolic volume; ESV = end - systolic volume; LV = left ventricle; NS = not significant.

[0094] B - 7. Primary unloading increases circulating and tissue levels of SDF - 1α at acute phase and 28 days after AMI Compared with P - reperfusion, P - unloading increased circulating SDF - 1α levels for 28 days after AMI and showed peak SDF - 1α levels 1 week after AMI (see Figure 10E). In contrast, P - reperfusion could not increase circulating SDF - 1α levels at any time point after AMI. Compared with sham control, P - reperfusion decreased SDF - 1α protein levels in the infarcted area of the left ventricle, while P - unloading did not. Circulating SDF - 1α levels on day 28 after AMI were inversely correlated with LV scar size (see Figures 10F and 10G).

[0095] B - 8. Primary unloading limits maladaptive cardiac remodeling Compared with P - reperfusion, P - unloading decreased circulating levels of B - type natriuretic peptide (BNP) at 28 days after AMI (see Figure 11A). Compared with sham control, P - reperfusion increased mRNA and protein levels of BNP in the non - infarcted area (see Figures 11B and 11C). In contrast, P - unloading attenuated the increase in tissue levels of BNP in the non - infarcted area of the left ventricle. Compared with P - reperfusion, P - unloading increased the mRNA level of sarcoplasmic / endoplasmic reticulum calcium ATPase and decreased the levels of calcineurin and type I collagen, but did not affect the levels from the non - infarcted area of the left ventricle (see Figures 11D - 11F).

[0096] C. Discussion The central finding of this example is that 30 minutes of P-unloading before reperfusion alters several important biological pathways, including post-translational regulation of cell respiration and SDF-1α levels, thereby reducing acute infarct size, as shown in Figure 12. Furthermore, P-unloading reduced LV scar size and improved cardiac function 28 days after AMI. Specifically, the inventors report the following: 1) 30 minutes of P-unloading is necessary and sufficient before reperfusion to limit infarct size. 2) P-unloading induces a comprehensive change in gene expression associated with protection of mitochondrial integrity within the infarct area. 3) Compared to P-reperfusion, 30 minutes of P-unloading maintains SDF-1α protein levels without altering SDF-1α mRNA levels within the infarct area and further promotes a shift towards anti-apoptotic signaling within the infarct area. 4) P-unloading reduces the activity levels of proteases known to degrade SDF-1α. And 5) P-unloading reduces LV scar size, maintains cardiac output, decreases BNP expression, and limits the expression of genes and proteins associated with maladaptive remodeling within the non-infarcted area 28 days after AMI. From these data, P-unloading is identified as a novel approach for enhancing cardiac protection mechanisms capable of maintaining cardiac function after AMI.

[0097] It was confirmed that 30 minutes of mechanical LV unloading by a TV pump before reperfusion, rather than after reperfusion, limits acute infarct size. This observation suggests for the first time that LV unloading itself can be a therapy, as opposed to merely an adjunctive support approach for a dysfunctional left ventricle. Regarding the beneficial effect of 30 minutes of mechanical LV unloading before reperfusion, there is one potential explanation that LV unloading biologically primes the myocardium towards reperfusion. Regarding the effect of LV unloading, there is a potential explanation that it can reduce infarct size and increase the protein level of SDF-1α within the infarct area.

[0098] Using a genomic approach, it was confirmed that 30 minutes of P-unloading altered the expression of over 600 genes within the infarct area differently compared to P-reperfusion. Pathway analysis revealed that P-unloading maintained the expression of genes related to cellular respiration and mitochondrial integrity. These observations were confirmed by direct quantification of selected genes from each component of the electron transport chain involved in cellular respiration. The findings of this study indicate that the initiation of LV unloading prior to reperfusion may limit the impact of ischemia-reperfusion injury on mitochondrial integrity and thereby promote cardiomyocyte survival.

[0099] In this study, it was observed that P-unloading did not increase the SDF-1α mRNA levels within the infarct area compared to P-reperfusion. However, compared to sham controls, P-reperfusion was observed to decrease the SDF-1α protein levels within the infarct area. In contrast, 30 minutes of LV unloading prior to reperfusion maintained the SDF-1α protein levels.

[0100] Since SDF-1α levels are highly regulated by proteases related to inflammation, the inventors next examined whether the protein and activity levels of major regulatory proteases such as MMP-2, MMP-9, and DPP-4 were altered by P-reperfusion and P-unloading. Compared to sham controls, P-reperfusion was observed to increase the activity of these proteases, while P-unloading weakened it. To further establish the downstream effects of P-unloading, the inventors also observed a decreased expression of apoptosis-related proteins within the infarct area. These findings suggest for the first time that 30 minutes of P-unloading limits protease activity within the infarct area, thereby restricting SDF-1α degradation in the state of AMI.

[0101] Preclinical trials were designed in which animals were assigned to P-reperfusion or P-unloading and LV scar was quantified using cardiac MRI 28 days later. P-unloading was observed to reduce infarct scar size blindly quantified by LGE-CMR for the first time, which was highly correlated with anatomical measurements of myocardial scar size. Subsequently, well-established molecular markers of maladaptive remodeling in the non-infarcted area were quantified; most of the compensatory remodeling would occur in the non-infarcted area in response to extensive anterior wall MI. Compared with P-reperfusion, P-unloading was observed to decrease calcineurin, β-myosin heavy chain, and BNP levels while maintaining sarcoplasmic reticulum / sarcoplasmic reticulum calcium ATPase levels at 28 days after AMI. Furthermore, the circulating and LV tissue levels of BNP, a clinically significant biomarker of heart failure, decreased after P-unloading but not after P-reperfusion. These findings are the first to demonstrate that the use of a transvalvular pump at the time of AMI has a permanent effect on both LV scar size and markers of maladaptive remodeling 28 days later. For decades, immediate reperfusion has been the main focus in AMI; however, these data suggest for the first time that the "pre-reperfusion time period" is a critical phase that may allow interventions such as LV unloading and delayed reperfusion to have a permanent effect on late cardiac remodeling.

[0102] Finally, quantification of SDF-1α levels after AMI revealed an increase in circulating and LV tissue levels of SDF-1α 28 days after P-unloading, but not after P-reperfusion. Circulating SDF-1α levels were inversely correlated with LV scar size. These findings indicate that, in addition to causing a rapid reduction in infarct size after MI, P-unloading promotes a more persistent reduction in LV scar size, improves cardiac function, and limits maladaptive remodeling after AMI. By using clinically meaningful biomarkers of myocardial injury such as CMR and circulating BNP levels, the results of this trial suggest the strong translational potential of P-unloading as an approach to limit ischemic heart failure after AMI.

[0103] D. Findings The findings of this trial indicate that operation of the transvalvular microaxial flow pump for 30 minutes before reperfusion, as in method 200 of FIG. 2 described above, limits both acute infarct size and subsequent scar size compared to P-reperfusion alone. The results of this trial provide new mechanistic insights into the biological effects of myocardial unloading and the activation of cardioprotective pathways within the infarct region.

[0104] The foregoing serves only to illustrate the principles of the disclosure, and the apparatus may be implemented in ways other than those described embodiments, which are presented for purposes of illustration and not limitation.

[0105] After reviewing the disclosure, those skilled in the art will envision various modifications and variations. The disclosed features may be implemented in any combination and sub-combination (including multiple dependent combinations and sub-combinations) with one or more of the other features described herein. The various features, including any of their components, described above or exemplified above can be incorporated or integrated into other systems. Additionally, certain features may be omitted or not implemented.

[0106] Examples of changes, substitutions, and modifications are ascertainable by one of ordinary skill in the art and can be made without departing from the scope of the information disclosed herein. All references cited herein are hereby incorporated by reference in their entirety and form a part of this application.

Claims

**Claim 1** A system for assisting the heart of a human patient having a sustained myocardial infarction, wherein the total ST segment elevation value (ΣSTE) of the heart of the human patient is greater than 6 mm, the system comprising: a microaxial blood pump having a mounted motor and stator that mechanically operates to pump blood from the heart of the human patient, further comprising a cannula configured to be percutaneously inserted into the vascular system of the human patient such that the cannula is disposed across the aortic valve of the heart of the human patient, the mechanical circulatory assist device configured to be inserted into the human patient after myocardial infarction; a coronary reperfusion therapy device; and a controller coupled to the microaxial blood pump, the system comprising: continuously operating the mechanical circulatory assist device such that the microaxial blood pump unloads the left ventricle at a blood flow rate of at least 2.5 L / min over an initial assist period of from 30 minutes to less than 60 minutes; and after the initial assist period, performing a step of applying coronary reperfusion therapy to the heart of the human patient, wherein the step of continuously operating the mechanical circulatory assist device over the initial assist period is performed prior to the step of applying the coronary reperfusion therapy, the system. **Claim 2** The system according to claim 1, wherein the mechanical circulatory assist device is configured to operate at a blood flow rate of at least 3.5 L / min. **Claim 3** The system according to claim 1, further configured to perform a step of unloading the heart of the human patient by the mechanical circulatory assist device simultaneously with the application of the coronary reperfusion therapy after the initial assist period. **Claim 4** The system according to claim 1, further comprising an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump configured to operate in combination with the mechanical circulatory assist device to assist the heart of the human patient. **Claim 5** The system according to claim 1, wherein the coronary reperfusion therapy includes at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis. **Claim 6** A system for preventing or limiting the impact of heart failure in a human patient by reducing maladaptive cardiac remodeling in a human patient having a persistent myocardial infarction, wherein the total ST segment elevation (ΣSTE) of the heart of the human patient is greater than 6 mm, the system comprising: a microaxial blood pump configured to be percutaneously inserted into the vascular system of the human patient, the microaxial blood pump including a mounted motor having a rotor and a stator; and a cannula configured to be disposed across the aortic valve of the heart of the human patient, the system further comprising: continuously operating the microaxial blood pump such that the microaxial blood pump unloads the left ventricle at a pump flow rate of at least 2.5 L / min over an initial assist period of from 30 minutes to less than 60 minutes; and performing a coronary reperfusion therapy on the heart of the human patient after the initial assist period, the system wherein the step of continuously operating the microaxial blood pump over the initial assist period is performed prior to the step of applying the coronary reperfusion therapy. **Claim 7** The system according to claim 6, wherein the microaxial blood pump is configured to operate at a pump flow rate of at least 3.5 L / min of blood flow. **Claim 8** The system according to claim 6, further configured to perform a step of continuing the operation of the microaxial blood pump in parallel with the application of the coronary reperfusion therapy after the initial assist period. **Claim 9** The system according to claim 6, further configured to perform a step of continuing the operation of the microaxial blood pump in parallel with the application of the coronary reperfusion therapy over a total assist period of at least 3 hours after the initial assist period. **Claim 10** The system according to claim 6, wherein the coronary reperfusion therapy includes at least one of direct percutaneous coronary intervention (PCI) and fibrinolysis. **Claim 11** The system according to claim 6, further comprising an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump configured to operate in combination with the microaxial blood pump to assist the heart of the human patient. **Claim 12** The system according to any one of claims 1 to 11, wherein the infarct size normalized by the area of the risk region measured between 3 and 5 days after coronary reperfusion therapy is about 44.1%.

13. The system according to claim 12, wherein the infarct size is measured using cardiac magnetic resonance imaging (CMR).

14. The total ST segment elevation value (ΣSTE) is measured by measuring the magnitude of the ST segment elevation 0.08 seconds after the J point in the precordial leads The system according to any one of claims 1 to 11, which is measured by.

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