Systems and methods for left ventricular unloading in treating myocardial infarction

Abstract

To provide a method of preventing or limiting the effects of heart failure in a human patient that has sustained myocardial infarction by reducing maladaptive cardiac remodeling in the patient.SOLUTION: A method 200 comprises a step S210 of percutaneously inserting a transvalvular blood pump, comprising a rotor and a cannula, into the patient's vasculature, and positioning the cannula across the aortic valve of the patient's heart, with a distal end of the cannula located in the left ventricle of the heart and a proximal end of the pump located in the aorta. The method then comprises a step of, prior to reperfusing the heart, operating the positioned pump to unload the left ventricle at a pumping rate of at least 2.5 L / min of blood flow for a support period between at least 30 minutes and less than 60 minutes. Then, after the support period, the method comprises a step of applying coronary reperfusion therapy to the heart.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 615,462, filed January 10, 2018, and U.S. Provisional Patent Application No. 62 / 615,462, filed September 18, 2018. U.S. Provisional Patent Application No. 62 / 732,936, and U.S. Provisional Patent Application No. 62 / 758,16, filed November 9, 2018 4, the contents of which are incorporated by reference in their entirety. No. 60 / 699,493, filed on Oct. 1, 2003, which is incorporated herein by reference. [Background technology]

[0002] background Acute myocardial infarction (AMI) caused by coronary artery occlusion is the leading cause of morbidity and mortality in humans worldwide. The current paradigm for AMI therapy is to use A to re-establish myocardial oxygen supply. Primary reperfusion is the process of rapidly restoring coronary blood flow as soon as possible after MI. However, despite timely reperfusion, many patients who have undergone a first AMI Up to 25% of patients who undergo this procedure will develop heart failure (HF) within one year. In-hospital management of ST-segment elevation AMI (STEMI) is aimed at reducing infarct size. Focused on reducing door-to-balloon (DTB) times However, there is a strong resource allocation requirement to achieve a DTB time of 90 minutes or less. Despite this, the incidence of heart failure after AMI remains high. Every 5% increase in risk is associated with a 20% increase in 1-year all-cause mortality and HF hospitalization. This places a heavy burden on medical resources. For these reasons, myocardial damage and subsequent Novel approaches to limit ischemic HF remain an important fulfillment point for patients with AMI. This is an unmet need.

[0003] These poor outcomes are due in part to the paradoxical effects of primary reperfusion, known as ischemia-reperfusion injury (IRI). One explanation is that it may exacerbate the myocardial damage that occurs before IRI is limited. Attempts include vascular contact to activate reperfusion injury salvage kinase (RISK) pathway activity. These include conditioning approaches and pharmacological approaches, but the clinical The floor effect was not always optimal, a critical barrier to these cardioprotective strategies. are prerequisites for rapid coronary reperfusion, i.e., they are important for the therapeutic impact on myocardial injury. Therefore, cardiac interventions that reduce or eliminate IRI may not be possible. There is a need for improved strategies to limit myocardial injury by promoting protective mechanisms. There is a need for

[0004] Over the past decade, there has been an increasing reliance on mechanical assist devices in everyday clinical practice. The auxiliary device is a transvalvular axial flow pump (TV pump) delivered percutaneously. It is equipped with an intra-aortic balloon pump, an intracorporeal axial flow catheter, and an extracorporeal membrane oxygenation (ECMO) pump. In the case of the TV pump, such a device , mechanically pumps blood from the left ventricle of the heart, thereby reducing left ventricular (LV) wall stress Rapidly reduces stroke volume and myocardial oxygen demand while simultaneously increasing overall body oxygen without the need for surgery. This increases the mean arterial pressure in the heart, helping to unload the heart. Pump use alone did not significantly reduce 30-day mortality in patients with cardiogenic shock. 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. 1287-1 296 (Non-Patent Document 1).

[0005] It has been proposed that the combination of mechanical support and primary reperfusion may limit myocardial injury in patients with AMI. Initial unloading of the LV with a TV pump while delaying coronary reperfusion is recommended. This (Primary Unloading) reduces the size of myocardial infarction by 40-50%. It has also been reported that myocardial levels of the cardioprotective chemokine stromal cell-derived factor 1α (SDF-1α) are increased. (N. Kapur, “Mechanical Pre-Conditioning with Acute Circulatory Support” rt 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 AMI model demonstrated primary reperfusion therapy with a percutaneously delivered extracorporeal To compare reperfusion therapy with a centrifugal pump to deferred reperfusion therapy until the left atrium was unloaded, It has been studied to prevent myocardial injury by delaying coronary reperfusion (P-unloading). Another study investigated the efficacy of transdermally delivered steroids. The valve pump was applied directly to the left ventricle of the animal, and coronary reperfusion was delayed for 60 minutes. The impact of downloading is being observed. Its impact on the treatment of MI in humans is not well understood. . [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] 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 2] 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 Summary of the Invention

[0008] overview The present disclosure relates to improved methods of cardiac assistance for human patients with persistent myocardial infarction. The order and timing of applying cardiac support before reperfusion may improve cardiac function and reduce infarction. This technology has the surprising result of reducing the effects of heart failure in human patients. This may further be applied to prevent or limit adverse reactions in patients, for example. This method (and its application) The system (configured for this purpose) stabilizes or reduces the size of the infarct; Beneficial to the heart. Specific applications include mechanical circulatory support to reduce infarct size. Some applications include applying reperfusion therapy after a delay period. wherein the heart is assisted by a mechanical circulatory device. The opposite approach to conventional methods and theories in the field - re-injecting patients who have had a heart attack Perfusion therapy is not applied immediately - it is applied by taking this method (and stem) first reduces myocardial oxygen demand for a period of time (e.g., unloading the heart) The heart is then assisted by the oxygen supply to the affected area of ​​the heart after the support period. Therefore, this method is useful for treating AMI and mechanical circulatory dysfunction. The aim is to shorten the time between the start of the treatment and the start of the treatment. This approach is called "door to unload." can increase myocardial salvage and reduce infarct size in the human heart Furthermore, such an approach could reduce maladaptive cardiac remodeling in patients, for example. The surprising efficacy of reducing blood pressure in preventing or limiting the effects of heart failure in human patients It has fruit.

[0009] According to one aspect of the present disclosure, there is provided a method of assisting the heart of a human patient, the method comprising: (i) inserting a mechanical circulatory assist device into a human patient after myocardial infarction; (ii) reperfusing the heart. before the operation, the mechanical circulatory assist device is operated for a certain assist time (assist period). and (iii) applying reperfusion therapy to the heart after the assistance period (e.g., by inserting a stent). (insertion of a catheter or application of medication to relieve narrowing or blockages in the coronary vasculature) The auxiliary period is preferably greater than 15 minutes. For example, the auxiliary period is at least 30 minutes. minutes and less than 60 minutes. Mechanical circulatory assist devices require at least 2.5 L / min It is a cardiac assist device that operates by pumping blood at a rate of 100 rpm.

[0010] According to another aspect of the present disclosure, there is provided a method of providing cardiac assistance to a patient having a sustained myocardial infarction. The method comprises percutaneously inserting a transvalve blood pump into a patient and connecting the left ventricle of the patient's heart. Positioning the pump across the aortic valve of the heart with the distal end of the pump in the ventricle. Then, before reperfusing the heart, the method includes operating the deployed pump. and for a pumping period of more than 15 minutes at a pumping rate of at least 2.5 L / min of blood flow. The process of unloading the left ventricle continues. After the pumping period, the method then proceeds to reperfusion. The method includes treating the heart with a therapy.

[0011] According to a further aspect of the present disclosure, there is provided a method for reducing the size of myocardial infarction scar in a patient's heart. The method comprises the steps of: A fluid pump is percutaneously inserted into the patient so that the distal end of the pump is positioned in the left ventricle of the patient's heart. The method then includes the step of: positioning the pump across the aortic valve of the heart in a circumferential position; Before reperfusing the heart, the deployed pump was turned on to provide a blood flow of at least 2.5 L / min. Unloading the left ventricle at the pump flow rate for a pumping period of greater than 15 minutes. After the pumping period, the method includes applying a reperfusion therapy to the heart.

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

[0013] According to another aspect of the present disclosure, there is provided a method of providing cardiac assistance to a patient having a myocardial infarction. This method involves (i) detecting BAX protein in patient cardiac tissue in the area of ​​myocardial infarction (area at risk). and (ii) reducing the level of activated caspase 3 antibody; and (ii) the myocardial infarction area. and increasing the levels of BCL-2 and BCL-XL proteins in cardiac tissue of the patient. .

[0014] According to another aspect of the present disclosure, there is provided a method of assisting the heart of a patient having a myocardial infarction, comprising: This method detects (i) BAX protein and activated cascades in patient cardiac tissue near myocardial infarction; (ii) reducing the level of BCL1 in the patient's cardiac tissue in the area of ​​myocardial infarction. (iii) increasing the levels of Bcl-2 and Bcl-XL proteins in the patient's heart in the area of ​​myocardial infarction; Increasing stromal cell-derived factor 1α (SDF-1α) protein levels in tissues; ) A method for maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients in the area of ​​myocardial infarction (v) Increased expression and activity of DPP-4 protein in cardiac tissues of patients with myocardial infarction (vi) limiting preregulation of brain natriuretic peptide in the patient's blood. (vii) reducing circulating levels of BNP in cardiac tissue of a patient near a myocardial infarction; (viii) increasing the mRNA level of RCA expression in the non-infarcted region of the patient's heart; The level of calcineurin activity in the myocardial infarction area was increased while maintaining the level of b-MHC in the affected area. The method includes at least one of the steps of reducing the levels of type I collagen and type II collagen.

[0015] According to another aspect of the present disclosure, stromal cell-derived factor 1 (SCF-1) is administered to a patient in the vicinity of a myocardial infarction. 1. A method for treating a patient with myocardial infarction, comprising increasing SDF-1α protein levels. The method further comprises: (a) determining whether MMP-2 is present in the cardiac tissue of a patient in the region of myocardial infarction; and maintaining the activity level of the MMP-9 enzyme. Upregulation of DPP-4 protein expression and activity in cardiac tissue of patients with rheumatoid arthritis Such methods may include restricting the flow of blood through a valve pump or an extracorporeal pump. , can be performed using mechanical circulatory assist devices.

[0016] According to a further aspect of the present disclosure, a method for detecting brain natriuretic peptide (BNP) in the blood of a patient is provided. A method of cardiac assistance for a patient having a myocardial infarction is provided, comprising the step of reducing the circulating level of This method also allows for the determination of the mRNA level of SERCA expression in cardiac tissues of patients with myocardial infarction. The method further comprises increasing b-MHC in the non-infarcted region of the patient's heart. Calcineurin activity in cardiac tissue from patients near myocardial infarction while maintaining the level of The method includes reducing the levels of type I collagen and type I stimulating hormone.

[0017] According to another aspect of the present disclosure, there is provided a method of assisting the heart of a patient having a myocardial infarction, comprising: This method detects (i) BAX protein and activated cascades in patient cardiac tissue in the area of ​​myocardial infarction. (ii) reducing the level of BCL1 in the patient's cardiac tissue in the area of ​​myocardial infarction. (iii) increasing the levels of Bcl-2 and Bcl-XL proteins in the patient's heart in the area of ​​myocardial infarction; Increasing stromal cell-derived factor 1α (SDF-1α) protein levels in tissues; ) A method for maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients in the area of ​​myocardial infarction (v) Increased DPP-4 protein expression and activity in cardiac tissues from patients with myocardial infarction (vi) limiting the regulation of brain natriuretic peptide (BNP) in the patient's blood; (vii) reducing circulating levels of SERC in cardiac cells of patients in the area of ​​myocardial infarction; (viii) increasing the mRNA level of A in the non-infarcted region of the patient's heart; The level of b-MHC in the patient's cardiac tissue in the area of ​​myocardial infarction was maintained while calcineurin was increased. The method includes reducing the level of collagen activity and the level of type I collagen.

[0018] According to one aspect of the present disclosure, there is provided a cardiac assist device for a patient with a persistent myocardial infarction. A protection system is provided, the system comprising a mechanical device configured to be inserted into a patient. The device includes a circulatory assist device and a reperfusion therapy device. The device operates for a duration of assistance greater than 15 minutes with a blood flow rate of at least 2.5 L / min. This system is configured.

[0019] According to another aspect of the present disclosure, there is provided a cardiac assist device for a patient with a persistent myocardial infarction. A cardiac protection system is provided that is percutaneously inserted into a patient after a myocardial infarction. a blood pump configured to be positioned across the aortic valve of the patient's heart. The pump is sized and shaped to fit within the left ventricle of the heart, with the distal end of the pump positioned within the left ventricle of the heart. The system also includes a reperfusion therapy device. The pump must be operated at a blood flow rate of at least 2.5 L / min for 15 minutes before and after activation of the reperfusion therapy device. The pump is configured to be programmed to pump blood for a pumping period of more than 10 minutes. It is done.

[0020] According to a further aspect of the present disclosure, a method of treating a human heart having a sustained myocardial infarction includes: The myocardial infarction has an infarct size and is located within a portion of the heart, The method includes reducing the infarct size.

[0021] According to another aspect of the present disclosure, a method for the treatment of maladaptive cardiac remodeling in a human patient with sustained myocardial infarction is provided. The present invention provides a method for preventing or limiting the effects of heart failure in patients by reducing the An adaptation of this method is to use a transvalve blood pump that includes a rotor and a cannula. The cannula is percutaneously inserted into the patient's vascular system, and the distal end of the cannula is positioned in the left ventricle of the patient's heart. With the proximal end of the pump positioned within the aorta, the cannula is inserted through the aortic valve of the heart. Prior to reperfusion of the heart, the method then includes placing the positioned port. Turn on the pump and perform a blood flow of at least 2.5 L / min for at least 30 to 60 minutes. After the assist period, the method includes unloading the left ventricle for an assist period of less than 10 minutes. The method includes administering coronary reperfusion therapy to the heart. , including, but not limited to, changes in cardiac size, shape, structure, and function. Or includes multiple.

[0022] According to a further aspect of the present disclosure, a method for treating maladaptive cardiac remote control in a human patient with persistent myocardial infarction is provided. To prevent or limit the effects of heart failure in patients by reducing deringing A system is provided, the system comprising a blood pump having a rotor and a cannula. The distal end of the cannula is located in the left ventricle of the patient's heart and the proximal end of the pump is located in the aorta. The blood port is positioned so that the cannula is positioned across the aortic valve of the heart. The system is configured to have a pump inserted percutaneously into the vascular system of a patient. The system may further include a controller coupled to the pump to control operation of the pump. The system also includes a coronary reperfusion therapy device. In this aspect, the controller Before activation of the blood therapy device, the patient should be monitored for at least 30 minutes at a pump flow rate of at least 2.5 L / min of blood flow. Program the blood pump to unload the left ventricle over the assist period until less than 0 min. Ram.

[0023] In certain embodiments, the support period is about 30 minutes, or may be between 15 and 30 minutes. In some embodiments, the support period is greater than 30 minutes or greater than 45 minutes. The mechanical circulatory assist device pumps at a blood flow rate of at least 3.5 L / min. In one embodiment, the device provides a cannula for placement within the patient's heart, the cannula In one embodiment, the device pumps blood through the heart. A microcomputer with a motor and mounted rotor-stator that is mechanically actuated to drive the a cross-axial blood pump; in one embodiment, the device is actuated by an external motor; The pump motor can be deployed outside the patient and can be routed through the patient's vascular system to the heart. An example of a suitable mechanical circulatory assist device is a transvalvular myocardial infarction (TMI). A axial pump (e.g., an Impella® blood pump, such as an Impella CP, or similar) The pump is inserted percutaneously or surgically into the aorta and across the aortic valve. The pump then pumps blood out of the left ventricle, thereby "unloading" the left ventricle. In some applications, the method includes a rotor and a cannula. A transvalve microaxial blood pump (TV pump) is inserted percutaneously into the patient's vascular system to The distal end of the cannula is located in the left ventricle of the heart and the proximal end of the pump is located in the aorta. and positioning the cannula across the aortic valve of the heart while the cannula is in the closed position. To unload a heart chamber (e.g., atrium or ventricle) according to the methods disclosed herein. An extracorporeal pump can also be used (e.g., Tandem Heart). The right ventricle can be unloaded as well.

[0024] In certain embodiments, the heart is reperfused simultaneously (e.g., after unloading the heart). Unloading by mechanical circulatory support. The duration of this unloading is at least 30 minutes. The method of the present disclosure can be carried out for a period of time ranging from 1 minute to at least 3 hours, or even longer. Mechanical circulatory assist devices such as intra-aortic valves, thrombus pumps, and thrombus pumps may be used alone or in combination. A cardiac pump can be used to provide cardiac assistance after a delay period. In some cases, a combination of devices is used, for example, a TV port to unload the left ventricle. pumps, and at the same time, extracorporeal membrane oxygenation (ECMO) pumps, intra-aortic balloon pumps, and In some embodiments, the present invention may be used in combination with other mechanical circulatory support systems. The reperfusion therapy in the presented method is similar to direct percutaneous coronary intervention (PCI) and The present invention includes at least one of the following:

[0025] In some embodiments, these methods include (i) detecting a myocardial infarction in a patient's cardiac tissue near the myocardial infarction. (ii) reducing the levels of BAX protein and activated caspase 3 antibody in myocardial infarction; Increasing the levels of BCL-2 and BCL-XL proteins in the patient's cardiac tissue near the occlusion (iii) stromal cell-derived factor 1α (SDF-1α) protein in cardiac tissue of patients near myocardial infarction (iv) increasing MMP-2 and MMP-3 levels in cardiac tissue of patients near the myocardial infarction; (v) maintaining the activity level of the MP-9 enzyme; and (v) detecting DPP-4 in the patient's cardiac tissue near the myocardial infarction. (vi) limiting the upregulation of protein expression and activity; and (vi) the patient's blood. (vii) reducing circulating levels of brain natriuretic peptide (BNP) in myocardial infarction; increasing the mRNA level of SERCA expression in the patient's cardiac cells near the thrombus; and i) Patients with near myocardial infarction while maintaining levels of b-MHC in non-infarcted areas of the patient's heart Reduces the level of calcineurin activity and type I collagen in cardiac tissue These methods may include any combination of the steps described above. The method of any of the above embodiments may be adapted to implement any (or all) of the above embodiments. performing one or more of steps (i) to (viii) of the method for determining the effects of heart failure in a human patient; This has the surprising result of preventing or limiting the incidence of, for example, This can be done by reducing adaptive cardiac remodeling.

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

[0027] In some embodiments, the myocardial oxygen demand of the heart is reduced in a portion of the heart that includes an infarct. and subsequently, by restoring oxygen supply to the portion of the heart containing the infarction, In certain embodiments, the method comprises: A method for reducing the levels of at least one of BAX protein and activated caspase 3. In another embodiment, the method comprises the step of: In a further embodiment, the method comprises increasing the level of The method includes increasing the myocardial salvage index (MSI).

[0028] In certain embodiments, the method also includes (i) inserting a blood pump into the patient's vascular system. (ii) a support period to regulate blood flow within the vasculature before applying reperfusion therapy to the heart; and (iii) applying reperfusion therapy to the heart after the assist period. In one embodiment, the support period is at least 15 minutes. In some cases, the supplementation period is at least 30 minutes, about 20 to about 40 minutes, or at least 45 minutes. be.

[0029] In a further embodiment, the method also includes pumping at least 2.5 L / min throughout the support period. In one embodiment, the blood pump comprises unloading the left ventricle of the heart with a pump flow. a microaxial blood pump, and the step of unloading the left ventricle comprises connecting the distal end of the pump to the left ventricle. and inserting the proximal end of the pump into the aorta, and driving the pump to In certain embodiments, the method includes: pumping blood from the ventricle to the aorta. (i) inserting a balloon pump into the aorta of the heart; and (ii) controlling the blood flow in the aorta. In another embodiment, the balloon is expanded and deflated to adjust the volume. The pump is a catheter-based intravascular blood pump.

[0030] In some embodiments, the method includes (i) increasing the left ventricular ejection fraction of the heart; (ii) reducing cardiac microvascular obstruction; and (iii) reducing cardiac left ventricular end-systolic volume. and (iv) reducing the left ventricular end-diastolic volume of the heart. In another embodiment, the method includes increasing myocardial oxygen levels in a portion of the heart that includes an infarct. Demand is reduced for at least 15 minutes, after which oxygen is released to the portion of the heart containing the infarct. In certain embodiments, the heart is subjected to reperfusion therapy. At the same time, the heart is unloaded by a mechanical circulatory assist device. Reperfusion therapy is a direct percutaneous coronary intervention (PCI) and fibrinolytic cyst. It includes at least one of these.

[0031] In a further embodiment, the method also includes (i) measuring cerebral natriuretic peptide levels in the patient's blood. (ii) reducing circulating levels of BNP in cardiac tissue of a patient near the myocardial infarction; (iii) increasing the mRNA level of SERCA expression in a non-infarcted region of the patient's heart; and carcinoma in cardiac tissue from patients near myocardial infarction while maintaining b-MHC levels in the In one embodiment, the method further comprises reducing the level of thyroid function and the level of type I collagen. In some embodiments, the method also includes removing the blood pump from the patient's heart after applying reperfusion therapy. In another embodiment, the method also includes delivering a steroid hormone to the patient's cardiac tissue near the myocardial infarction. The method includes increasing blood flow to the

[0032] In some embodiments, these methods according to any of the foregoing aspects further comprise the step of: In certain embodiments, the step of applying the solution may include continuing to operate the pump in parallel with the application of the solution. The pump was operated in parallel with the application of coronary reperfusion for a total support period of 3 hours. In other embodiments, these methods involve altering gene expression in cells within the myocardial infarct zone. The step of operating the pump to sufficiently unload the heart to allow the heart to Heart unloading has the benefit of preventing or limiting the effects of heart failure in human patients. This is a method that has advantages, for example, in reducing maladaptive cardiac remodeling in patients. In further embodiments, these methods can be performed by reducing the In certain embodiments, the method may include providing a drug therapy to the patient in combination with the activation of the pump. Pharmacological treatments include beta-blockers, afterload reducing agents, neurohormonal agents, and ACE inhibitors. The method may include providing the patient with a medication that includes at least one of the harmful substances.

[0033] Further advantageous embodiments of the present disclosure are described in the examples and claims below. It is provided as follows.

[0034] Numerous variations and modifications will occur to those skilled in the art after reviewing this disclosure. The disclosed features may be used in any combination with one or more of the other features described herein. and subcombinations (including multiple dependent combinations and subcombinations) Various features described or illustrated, including any components thereof, may be used in other systems. Furthermore, certain features may be omitted or implemented. This may not be possible. [Brief explanation of the drawings]

[0035] The above and other objects and advantages are realized in accordance with the appended claims wherein like reference characters refer to like parts throughout. This will become apparent from the following detailed description taken in conjunction with the drawings. [Figure 1] 1 illustrates an exemplary cardiac protection system according to an embodiment of the present disclosure. [Figure 2] 1 illustrates an exemplary method for cardiac assistance in a patient with persistent myocardial infarction. [Figure 3] 3 shows a flow chart outlining the methodology of the study of Example 1 using the method of FIG. 2. [Figure 4] 3 shows a scatter plot of unload to balloon times for the tests of Example 1 using the method of FIG. 2. [Figure 5] 5A-5C show CMR box plots stratified by ST elevation sum for the results of the study of Example 1 using the method of FIG. [Figure 6]Figure 6A shows a flow chart illustrating the effects of reperfusion alone (Group 1), left ventricular unloading for 15 minutes (Group 2) or 30 minutes (Group 3) before reperfusion, or left ventricular unloading after reperfusion (Group 4) in the study of Example 2 using the method of Figure 2. Figure 6B shows the infarct area as a percentage of the area at risk for each group from the study of Example 2 (one-way ANOVA = 0.017 for all 4 groups). [Figure 7] Figure 7A shows a genomic heatmap illustrating changes in gene expression between sham-operated controls treated with reperfusion alone (Group 1) and with left ventricular (LV) unloading for 30 minutes before reperfusion (Group 3) (n = 3 / group). Figure 7B shows a graph illustrating further results of the study mentioned in Figure 3, showing relative messenger ribonucleic acid levels of representative genes from key components of the electron transport chain from within the infarct zone of Group 1 (blue) or Group 3 (orange) in Figure 7A; * p < 0.05 vs. sham control; # p < 0.05 vs. primary reperfusion. Figure 7C shows representative transmission electron micrographs of cardiomyocyte mitochondria from the sham control in Figure 7A and from within the infarct zone of Groups 1 and 3. [Figure 8]Figures 8A and 8B show the results of a second study performed according to the method in Figure 2. They show Western blots and quantification graphs of left ventricular (LV) protein levels of stromal cell-derived factor-1α (SDF1α) and CXCR4 normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for sham controls and each group with quantified acute myocardial infarction (Group 1: reperfusion only; Group 2: LV unloading for 15 min before reperfusion; Group 3: LV unloading for 30 min before reperfusion; and Group 4: LV unloading 30 min after reperfusion; n = 4 / group). Figures 8C and 8D show quantification of SDF1 and CXCR4 mRNA levels harvested from the sham controls in Figure 8A and from tissue within the infarct zone for Groups 1 and 3 (n = 4 / group). Figures 8E and 8F show quantification of SDF1 and CXCR4 mRNA levels from samples taken from the sham controls in Figure 8A and from tissue within the infarct zone in Groups 1 and 3 (n = 4 / group). Figures 8G and 8H show quantification of dipeptidyl peptidase-4 (DPP4) protein levels and activity from samples taken from the sham controls in Figure 8A and from the infarct zone in Groups 1 and 3 (n = 4 / group); *p < 0.05 vs. sham controls; #p < 0.05 vs. Group 1. Figure 8I shows quantification of infarct size as a percentage of the area at risk between groups (n = 4 / group) that underwent 30 minutes of LV unloading followed by reperfusion with intracoronary delivery of either vehicle or the CXCR4 inhibitor AMD3100, using the method in Figure 2. Figure 8J shows quantification of phosphorylated and total Akt, phosphorylated and total extracellular signal-regulated kinase (ERK), and phosphorylated and total glycogen synthase kinase 3β (GSK3b) in the infarct zone after using the method in Figure 2 (n = 4 / group); *p < 0.05 vs. LV unload + vehicle. [Figure 9]Figures 9A-9C show Western blots and corresponding quantification of pro-apoptotic (Bax, caspase-3) and anti-apoptotic (B-cell lymphoma-2 [BCL-2] and large B-cell lymphoma [BCL-XL]) left ventricular (LV) protein levels normalized to β-actin levels from sham controls and the infarct zone of groups 1 and 3 (n = 3 / group) defined in Figure 8A; *p < 0.05 vs. sham controls; #p < 0.05 vs. group 1. Figures 9D and 9E show TUNEL-positive staining for deoxyribonucleic acid fragmentation from LV tissue from the sham controls in Figure 9A and from within the infarct zone of groups 1 and 3 (n = 3 / group). [Figure 10] Figure 10A shows quantification of LV scar size 28 days after primary reperfusion or primary unloading using late gadolinium enhancement (LGE) by cardiac magnetic resonance imaging (CMR) or by anatomic pathology (n = 6 / group) in the infarct zone after using the method in Figure 2. Figure 10B shows a regression plot demonstrating the correlation between LGE-CMR quantification of LV scar size and anatomic pathology quantification. Figures 10C and 10D show representative CMR images showing the LV scar within the blue or red circle. Figure 10E shows circulating levels of SDF-1α over 28 days after P-reperfusion (PR) or P-unloading (PU) (n = 4 / group). Figure 10F shows protein levels of SDF-1a within the infarct zone 28 days after sham surgery, P-reperfusion, or P-unloading (n = 6 / group). Figure 10G shows a regression plot showing the correlation between plasma SDF-1a levels and LV scar size as a percentage of the total left ventricle 28 days after myocardial infarction. *p<0.05 vs. sham control; †p<0.05 vs. P-reperfusion. [Figure 11]Figures 11A-11C show circulating levels, mRNA levels, and protein levels of B-type natriuretic peptide (BNP) from LV tissue (non-infarcted zone) 28 days after primary reperfusion or primary unloading using the method in Figure 2. Figures 11D-11G show messenger ribonucleic acid (mRNA) levels of sarcoplasmic / endoplasmic reticulum calcium ATPase (SERCA), calcineurin, type I collagen (COL1), and β-myosin heavy chain (b-MHC) from LV tissue (non-infarcted zone) 28 days after primary reperfusion or primary unloading using the method in Figure 2. [Figure 12] Schematic showing the effect of mechanically unloading the left ventricle for at least 30 minutes before reperfusion, which limits the expression of proteolytic enzymes that degrade stromal cell-derived factor-1α (SDF1a), thereby increasing cardioprotective signaling, improving cell survival, and reducing both acute infarct size and subsequent myocardial scar size 28 days after acute myocardial infarction. DPP-4 = dipeptidyl peptidase-4; LV = left ventricle; MMP = matrix metalloproteinase. DETAILED DESCRIPTION OF THE INVENTION

[0036] Detailed Description To provide a general understanding of the systems and methods, some exemplary implementations are provided. The embodiments and features described herein are directed to the use of circulation and reperfusion therapy. The components outlined below are specifically described for use in connection with the legal system. and other features may be combined with one another in any suitable manner, and other types of circulation may also be used. It will be appreciated that the present invention can be adapted for application in various reperfusion therapy and reperfusion therapy devices. Additionally, certain embodiments are described herein with respect to specific devices for circulation and reperfusion therapy. However, these various embodiments enhance the therapeutic effect and preserve the life of patients after AMI. It should be noted that various combinations may be used to

[0037] FIG. 1 illustrates a system for providing combined mechanical assistance and primary reperfusion according to an embodiment of the present disclosure. The system 100 is shown in a human patient 110 who has experienced an AMI in the heart 120. The system 100 is designed to limit myocardial damage. and a device 140 (or other source) for providing reperfusion therapy. The control unit 150 communicates with the circulation unit 130. and, in response, the device comprising the circulation unit 130 (or other source) These signals may indicate 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 cardiac status of the patient. Samples from AMI patients, such as blood or cardiac tissue, may be used to For evaluation and further testing, a circulation unit 130 or a device for reperfusion therapy 1 40 or from biopsy or other sources. To extract various symptoms from samples and enable clinicians to monitor them, This can be done through a test kit or laboratory. Such indications include, for example, cardiac Myocardial infarction scar size and related parameters detailed in the following sections are included.

[0038] The circulation unit 130 is a mechanical circulation unit that can be inserted, for example, into the left ventricle of the patient's heart. Such mechanical circulatory assist devices can significantly increase the heart's actual cardiac output. For example, mechanical circulatory assist devices can alter blood flow beyond the normal range of the heart in patients with AMI. for unloading the heart by pumping blood out of the left ventricle. This can assist the heart in several possible ways. The muscle wall stress is reduced, which means that the unloading mechanism helps salvage and repair myocardium. According to one embodiment of the present disclosure, the mechanical circulatory assist device is a transvalve Examples of such blood pumps include micro-axial blood pumps, such as those manufactured by Abiomed, Inc., Dan Impella 2.5™ and Impella CP® by Vers, MA, which Other types of mechanical circulatory support devices, such as extracorporeal pumps, may be used to Cardiac support can also be provided, for example, by an extracorporeal membrane oxygenation (ECMO) pump or intra-aortic pump. A balloon pump can be used. In some applications, a transvalve pump is another such pump. It is used in combination with the device.

[0039] In addition to mechanical circulatory assist devices, the circulation unit 130 also assists in unloading the heart. Additional pumping devices may be provided. Examples of such pumping support devices include an intra-aortic balloon. This includes, but is not limited to, one of the following: a pulmonary pump and an extracorporeal membrane oxygenation (ECMO) pump. For example, but not limited to, the patient may be further moved while the transvalve pump unloads the heart. A balloon pump or ECMO device is used to support the circulation. The cannula may have a cannula portion in fluid communication with the patient's The pump may be located within the heart, and the pump may be located within the heart (a) together with the cannula; The patient may be located either outside the patient but inside the patient, or (c) outside the patient.

[0040] In one embodiment of the present disclosure, the device 140 is configured to provide reperfusion therapy to a patient experiencing an AMI. Such reperfusion therapy includes, for example, direct percutaneous coronary intervention. These procedures include PCI (Percutaneous Coronary Intervention) to the distal left anterior descending artery. Such coronary interventions may include the use of coronary stents delivered to the left inferior artery (LAD). Examples of vascular stents include, but are not limited to, Promus PREMIER™ and REBEL™. ™ bare metal platinum-chromium coronary stent, and SYNERGY™ bioabsorbable and polymer stents, all of which are manufactured by Boston Scientific (Marlborough, MA). In certain embodiments, reperfusion therapy 140 can support fibrinolysis. The stent may also contain a drug or medication that may be effective in combination with other devices. and providing reperfusion therapy in addition to or as an alternative thereto.

[0041] The kit or laboratory can provide the following clinical signs associated with myocardial infarction: BAX, BCL-2, BCL-XL, and DPP-4 in patient cardiac tissue near or in the region of myocardial infarction and stromal cell-derived factor 1α (SDF-1α) protein levels, activated caspase-3 antibody levels. level, MMP-2 and MMP-9 enzyme levels in patient cardiac cells near or in the area of ​​myocardial infarction mRNA levels of SERCA expression in the myocardial infarction area; levels of phospholipid activity and type I collagen; brain saturates in blood collected from the left ventricle of patients; Brain natriuretic peptide (BNP) levels; myocardial salvage index; and electrocardiogram maps The sum of the ST elevations.

[0042] FIG. 2 is a flow chart of an exemplary method 200 for unloading the left ventricle of the heart of an AMI patient. The method begins in step S210, where a circulation device, such as the circulation unit of FIG. The mechanical circulatory device of the present invention is inserted into a patient after a myocardial infarction. Deployed into the right internal jugular vein, the left carotid artery, and one or more femoral arteries and veins This can be achieved by using a vascular access sheath. Further details and representative supporting data relating to method 200 are provided in Example 1 and in the following sections. and 2 for details.

[0043] Next, the method 200 continues to step S220, where the circulator is activated in step S230, e.g., It assists the heart by unloading it after a myocardial infarction. The device is configured to achieve a pumping rate of at least 2.5 L / min of blood flow from the left ventricle of the heart. In certain embodiments, the circulatory device provides a cardiac output of at least 3.5 L / min. The left ventricle is unloaded to achieve a blood flow rate of 100 bp. In one embodiment, the period is long enough to facilitate the The operation of the circulation device is terminated after the auxiliary period t_sp has elapsed. In another embodiment, the auxiliary period is , is simply used as a marker to indicate that time t_sp has elapsed since the circulator started operation. There is no need to shut down the circulation system after t_sp has elapsed. Example 1 illustrates the use of the method 200 of the present disclosure to unload a patient's heart after a myocardial infarction. According to one embodiment, the auxiliary period t_sp is 15 minutes. According to another embodiment, the supplemental period t_sp is greater than 30 minutes.

[0044] After the heart is unloaded for the assist period in step S230, the method proceeds to step S240. Here, reperfusion therapy is applied to the patient's heart. Reperfusion therapy can involve reperfusion devices, drugs, or or other techniques, and in FIG. 1, a reperfusion device 140 is applied. Clinical details of the method treatment and relevant representative supporting data for method 200 are provided in Example 1 and Example 2 below. According to certain embodiments of the present disclosure, reperfusion therapy involves a reperfusion of the left ventricle of the heart. After downloading, it can be applied to the patient's heart. Reperfusion therapy may be applied to the patient's heart while it is still unloaded by the pump. In this embodiment, after the heart is unloaded with the circulatory system for the length of the assist period t_sp, Only in this case is the concurrent use of a reperfusion device and a circulation device performed.

[0045] Currently, supporting the heart after MI with mechanical circulatory support before applying reperfusion therapy is It is believed to have a beneficial effect on the patient's heart. One or more benefits may be obtained from the patient. These benefits include the following: and one or more of: BAX protein in the patient's cardiac tissue near the myocardial infarction; Decreased levels of activated caspase-3 antibodies; BCL-2 and BCL-3 in cardiac tissue from patients with near myocardial infarction Increased levels of BCL-XL and BCL-XL proteins; derived from interstitial cells in cardiac tissue of patients near myocardial infarction Increased growth factor 1α (SDF-1α) protein levels in cardiac tissue from patients with myocardial infarction and MM Maintenance of activity levels of P-2 and MMP-9 enzymes; DPP-4 transcription factor in cardiac tissue of patients near myocardial infarction limited upregulation of protein expression and activity; collected from the left ventricle of patients Decreased circulating levels of brain natriuretic peptide (BNP) in blood; patients with near myocardial infarction Increased mRNA levels of SERCA expression in cardiac cells; b-MHC in the non-infarcted area of ​​the patient's heart Calcineurin activity in cardiac tissue from patients near myocardial infarction while maintaining the level of Decreased levels of erythropoietin and type I collagen; reduced infarct size; and cardiac myocardial salvage and cardiac ST elevation sum score greater than 6. These results are the subject of this disclosure. This can be achieved using the systems and methods defined.

[0046] Examples 1 and 2, detailed below, demonstrate the application of the method of the present invention to patients who have suffered a heart attack. These studies show the results of studies conducted by patients after they had an AMI. However, before applying reperfusion therapy to the heart, a blood pump is inserted into the patient's vascular system and the pump is It is driven throughout the support period to regulate blood flow within the vascular system, and then performs reperfusion therapy after the support period. The results were obtained immediately after the infarction (or as soon as possible after the infarction). Compared to conventional methods of applying reperfusion therapy (promptly), the infarct size was reduced and myocardial Further results show that this method reduces the salvage index of the left heart. Increases ventricular ejection fraction, reduces cardiac microvascular obstruction, and reduces the left ventricular end-systolic volume of the heart. and reduced left ventricular end-diastolic volume of the heart. [Example]

[0047] Example 1: DTU-STEMI Pilot Study Delaying reperfusion under unloading conditions improves myocardial salvage in human patients. To begin to explore whether delayed or delayed coronary reperfusion is beneficial, We tested the safety and feasibility of activating a door-to-door device in STEMI. The Door-To-Unload in STEMI pilot study demonstrated that patients without cardiogenic shock To test the feasibility and safety of left ventricular (LV) unloading before reperfusion in patients with STEMI This is the first exploratory study.

[0048] A. Method The DTU-STEMI trial aims to evaluate the efficacy of mechanical angioplasty before coronary reperfusion in patients presenting with anterior STEMI. A study of 14 U.S. centers was conducted to examine the feasibility, safety, and potential benefits of the modality. This was a prospective, multicenter, randomized pilot study. All patients received the Impella CP system. Two arms were administered acute mechanical unloading with a LV pump (Abiomed Inc., Danvers, MA). Unloading followed by immediate reperfusion (U-IR) or LV unloading followed by 30 min delayed reperfusion (U- The process flow of the U-IR and U-DR methodologies is shown in Figure 1. This comparison is shown in Figure 3. The myocardium was preconditioned for 30 minutes before reperfusion. It was specifically designed and performed by comparing the infarct size between the U-DR and U-IR arms. Patients who presented between 1 and 6 hours after the onset of chest pain and had ST-segment echocardiograms in two or more consecutive anterior leads ment elevation of 2 mm or more, or total ST segment deviation of all anterior leads of 4 mm or more, 21 to 80 Patients aged 18+ years were eligible for enrollment.

[0049] Patients were assigned to either the U-IR or U-DR arm immediately after femoral vascular access was obtained. Before diagnostic coronary angiography, Impella CP was placed to administer a second-generation drug-eluting Percutaneous coronary intervention (PCI) is performed using a protruding stent, and In the U-DR group, the attending physician was instructed to follow clinical guidelines for post-AMI care. The attending physician is authorized to shorten the time between unloading and reperfusion if deemed necessary. After PCI, the Impella CP was removed after a minimum of 3 hours of LV support.

[0050] The primary safety outcome was 30-day cardiovascular mortality, reinfarction, Major adverse cardiovascular or cerebrovascular events, including stroke or major vascular events The results were a composite of multiple myeloma, multiple myeloma cardiovascular, and multiple myeloma cerebrovascular events (MACCE). Table 1 shows the MACC Includes the definitions used to determine each element of E. Additional safety parameters include overall mortality and mortality, hemolysis, acute renal dysfunction, hospitalization for heart failure, ventricular arrhythmias, LV thrombus, bleeding, and The primary efficacy outcome was 30-day time to CMR. Secondary efficacy measures were assessment of infarct size as a percentage of total LV mass at each time point. Valuable outcomes included infarct size by CMR at 3-5 days and 30 days. Endpoints included group-specific infarct size normalized to the area at risk at 3-5 days. The CMR protocol used in this study has been previously described. Eligible 12-lead ECGs should be evaluated to identify well-established clinical markers of risk areas for STEMI. The sum of ST-segment elevations (ΣSTE), which is the measure of ST-segment elevation, was quantified. Specifically, ΣSTE was Compared with isoelectric segments in an independent core laboratory blinded to group assignment. By measuring the magnitude of ST segment elevation 0.08 seconds after the J point in the precordial leads This was quantified.

[0051] Table 1. Baseline characteristics TIFF2025131612000002.tif190128

[0052] Baseline demographic and clinical variables were summarized for the two treatment groups. This study estimated infarct size assuming the large standard deviations that can be expected in small STEMI studies. Specifically, assuming a standard deviation of 10%, the To detect an absolute difference in infarct size, a power of 0.88 and an alpha of 0.05 were used. All continuous variables were summarized as means with standard deviations as well as medians and interquartile ranges. First, compare the treatment groups using appropriate parametric or nonparametric tests. Categorical variables were summarized as frequencies and percentages and presented in contingency tables (co Using Pearson's chi-square test or Fisher's exact test on the Comparisons were made between treatment groups. All statistical tests and / or confidence intervals were performed as appropriate. , α = 0.05 (two-sided). All p-values ​​reported as greater than 0.01 are rounded to two decimal places. p values ​​between 0.01 and 0.001 were rounded to three decimal places. Comparability between treatment groups was , assessed for all clinically relevant demographic and baseline characteristics. Ta.

[0053] B. Results Between April 2017 and May 2018, a total of 50 patients with anterior STEMI and UI were enrolled. Patients were randomly assigned to either the R arm or the U-DR arm (n = 25 / group). Table 1 Baseline characteristics were not statistically different between groups, as shown in Figure 1. The median age was 59.7 years, and 38 patients (76%) were men. There were no statistically significant differences in the time from onset of chest pain to LV unloading between groups. (176.2 ± 73.4 min vs. 200.2 ± 151.8 min, U-DR vs. U-IR, p = 0.48). ΣSTE was observed in 90% of patients. (n=45 / 50) were >4. Before Impella CP placement, LV end-diastolic pressure was (25.0±9.6 and 24.0±8.1 mmHg, U-DR vs. U-IR, p=0.73). F indicates the required PCI arterial vascular access (femoral or radial access at the discretion of the attending physician). Left ventriculography was performed before randomization in 90% (n=45 / 50) of patients using either IV access The baseline LVEF was 37.4% (13.2) in the total population and 10.2% (10.2) in the U-DR group. The incidence of U-IR was lower than that of U-DR (41.9% (12.3%) vs. 32.7% (12.7%), U-IR vs. U-DR, p=0.02). Impella C The P was successfully implanted in all 50 patients, achieving the 3-hour follow-up required by the study protocol. During the support period, the mean power (P level) 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 to implantation and activation was 15.4 (8.4) minutes for the entire population. The parameters are shown in Table 2. Radial artery access was used for PCI in 60% of patients (n=30 / 50). The use of vascular occlusion devices was left to the discretion of the treating physician. Twenty-nine of the 50 patients had femoral artery Occlusion devices were used (14 / 25, 56% vs. 15 / 25, 60%, U-DR vs. U-IR, p=0.99). As shown, the left anterior descending coronary artery was identified as the culprit, and 98% (n=49 / 50) of patients had stage II coronary artery disease. One patient randomized to the U-DR arm underwent PCI. All patients undergoing PCI were required to receive a P2Y12 inhibitor before PCI. 8% of patients received bivalirudin and 94% received unfractionated heparin. Of these patients, one received both bivalirudin and unfractionated heparin. Eight percent of patients received dual antiplatelet therapy before PCI. After LV unloading was initiated, the patient received a glycoprotein 2b / 3a receptor inhibitor. Arteriography was performed.

[0054] (Table 2) Timing elements TIFF2025131612000003.tif110161 T Based on source documentation. Y One patient in the U-DR arm did not undergo PCI.

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

[0056] All patients assigned to the U-DR arm received emergency support, as shown in Figure 4. Thirty minutes of LV unloading was completed before reperfusion without the need for CI. Timing factors, including time to reperfusion, are shown in Table 2. Prolongation in the U-DR group The unloading-to-balloon time was prolonged by the U-DR arm (34.1 ± 3 min). The mean DTB time was longer (96.7±26 min) in U-DR vs. U-IR, p<0.001). minutes vs. 72.6 ± 24 minutes, U-DR vs. U-IR, p = 0.002).

[0057] The composite 30-day MACCE event rates for the combined cohort of 50 patients are shown in Table 3. As shown in Fig. 1, the prolongation of DTB time in the U-DR group was 10% (n=5 / 50). did not increase the risk of developing BRCA1-associated ... Overall cardiovascular mortality was 4% (n=2 / 50), with one death per group. No vascular mortality was observed. One patient suffered a stroke one day after enrollment (2%; n=1 / 50). ), and two patients had major vascular events involving flow-limiting dissection of the femoral artery upon device removal. showed this (4%; n = 2 / 50).

[0058] (Table 3) MACCE rate at 30 days TIFF2025131612000004.tif45149

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

[0060] Table 4. Cardiac magnetic resonance examination, all patients TIFF2025131612000005.tif186170 Δ One patient in the U-DR arm underwent a non-contrast scan and the core lab read only the LVEF. I was able to do this. T MVO: Microvascular occlusion. Y Myocardial salvage index (MSI) = 1 - infarct size / area at risk (AAR).

[0061] CMR was achieved in 82% of patients (n=41 / 50) on days 3-5 and in 80% of patients at 30-day follow-up. % (n=40 / 50). Major infarct size normalized to total LV mass at 30 days. The efficacy outcome was 14.1% (n=40 / 50) across the entire group. No significant differences were observed between the groups. No significant difference was observed (13.1±11.3% vs. 15.3±11.5%, U-DR vs. U-IR, p=0.53) at 3-5 days. Among secondary and exploratory endpoints, mean infarct size normalized to total LV mass was 17.9%. ±13.5% and area-at-risk normalized infarct size 47.9 ±21.4% in the entire group. Infarct size normalized to the area at risk was statistically significant between groups (n = 40; Table 4). There was no difference in mean microvascular obstruction (44.2 ± 18.9 vs. 51.6 ± 23.6, U-DR vs. U-IR, p = 0.28). was 1.3% vs. 2.7% in the U-DR and U-IR groups, respectively (p=0.22). and LV volumes were not statistically different between groups at 3-5 days and 30 days. Flow did not correlate with infarct size in the U-IR and U-DR groups.

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

[0063] C. Analysis of Results A DTU-STEMI safety and feasibility pilot study was conducted using the method 200 of the present disclosure. Mechanical unloading of the LV and intentional coronary reperfusion (primary unloading) in patients with wall STEMI These findings represent the first human experience of delaying myocardial oxygen consumption. STEMI by focusing on reducing (unloading) coronary artery pressure and then restoring coronary reperfusion This is the first indication that modifying therapy is feasible.

[0064] Although multiple attempts to limit infarct size have been tested, previous clinical trials have demonstrated cardioprotective There was no intentionally extended delay to reperfusion after initiating a treatment strategy. Based on the destructive concept of unloading the LV and delaying reperfusion, the DTU-STEMI strategy Key safety assessments were conducted to provide a rigorous and sensitive analysis of any potential risks associated with The 30-day MACCE was selected as the endpoint. Both the U-IR and U-DR arms showed a significant improvement in overall MACCE. The incidence of CE was relatively low, there was no incidence of reinfarction, and there were no safety signals sufficient to warrant prohibition. Among the individual MACCE components, CV mortality was observed in one patient per arm of the study, with a 30-day mortality rate of 1. This is comparable to the national benchmark for STEMI mortality. One patient developed acute pulmonary fibrosis on the third postoperative day. The second death was diagnosed as a stroke and died 10 days later from respiratory failure. The patient presented with cardiogenic shock. Survival rates after intra-aortic balloon counter in patients with non-shock acute anterior myocardial infarction Intra-aortic Balloon Counterpulsation and Infarct Size t Size in Patients with Acute Anterior Myocardial Infarction Without Shock:CRIS The overall BARC bleeding rate in DTU-STEMI was ≥2. This was lower than that reported in a recent analysis of bleeding events requiring a cardiac assist device. As expected, the use of medications or devices with lower French sizes This was higher than that reported in other STEMI trials. Important aspects are the time required to establish LV unloading before PCI and the door-to-door The objective of this study was to better understand the balloon and its impact on overall ischemic time. Table 2 As shown in Figure 1, a total of 50 patient trials were performed from the start of the procedure to the insertion and activation of the Impella CP. The average time required for the procedure was 15.4 minutes, including preparation, draping, vascular access, and left ventricular This observation was made in this pilot study. The findings highlight key insights, including: 1) the effectiveness of this unloading device during anterior STEMI; 2) It is feasible to implant and activate the device in a timely manner despite this inherent delay. Regardless, the attending physicians reported a mean door-to-balloon time of 84.4 (27.6) minutes across all 50 patients. and 3) despite this inherent delay, the overall size of the infarct was The mean age was lower than in recent reports including CRISP-AMI and was not correlated with DTB time. These findings support the safe testing of the DTU-STEMI strategy in a larger pivotal trial. We support the idea that it can be implemented.

[0065] By providing 30 min of LV unloading before reperfusion, we observed that myocardial signals We hypothesized that a cardioprotective shift in conduction and coronary perfusion would limit myocardial injury. Patients with a larger area of ​​myocardium at risk may benefit from mechanical preconditioning before reperfusion. This may result in more benefit than unloading and immediate reperfusion alone. In conclusion, 30 minutes of unloading before reperfusion was associated with adequate reperfusion of the myocardial area at risk in STEMI. Patients with a higher ΣSTE, a marker established in This is consistent with the observation that the index of the image increases with increasing brightness. Infarct size and cardiac function quantified by electron emission computed tomography (SPECT) or CMR Muscle salvage directly correlates with clinical outcomes, including MACE, 6 months after STEMI Infarct size normalized to the area at risk in both arms of the DTU-STEMI trial was This is lower than the values ​​reported in recent STEMI trials that included P or β-blocker therapy. Patients in the group showed lower EF and a higher incidence of ST elevation ≥6, which is Despite randomization, a small number of patients experienced larger infarcts at 30 days. These findings suggest that the DTU-STEMI strategy may be beneficial for infarction reduction. Furthermore, in patients with high ST elevation, the time to reperfusion was This suggests that prolonging the delay may improve myocardial salvage.

[0066] This DTU-STEMI pilot study demonstrated that delayed coronary reperfusion is possible and Therefore, LV unloading may precondition the myocardium and reduce ischemia-reperfusion injury in AMI. By suggesting for the first time that cardiac arrest can be prevented by allowing sufficient time for cardiac arrest to occur, Overcoming significant barriers to progress in the field of endocrine protection and myocardial recovery.

[0067] Example 2 In the setting of myocardial ischemia-reperfusion injury, matrix metalloproteinase (MMP)-2 and MMP Increased expression of proteases such as dipeptidyl peptidase-4 (DPP-4) and stromal cell proliferation It cleaves the N-terminus of cell-derived factor (SDF)-1α, thereby rendering the cytokine inactive. SDF-1α can bind to CXCR4, which in turn binds to extracellular signal-regulated kinase (Erk), protein RISK pathway linkers such as acetylcholine kinase b (Akt) and glycogen synthase kinase 3b (GSK3b). Activation of RISK promotes cellular proliferation by limiting apoptosis in cardiomyocytes. promotes cell survival and prevents the opening of the mitochondrial permeability transition pore, thereby The mechanisms underlying the cardioprotective effects of P-unloading and The rapid reduction in infarct size and left ventricular scarring resulted in a permanent reduction in left ventricular (LV) scar and improved cardiac function. This study will explore the importance of delayed myocardial reperfusion. We tested the efficacy of ATP and investigated the cardioprotective mechanisms, and investigated the effects of ATP on myocardial function associated with P-unloading. Late effects were investigated.

[0068] A. Method The study was conducted on adult Yorkshire boars. Tufts Medical Center The Institutional Animal Care and Use Committee of the Center The study protocol was approved, and all experiments were performed in accordance with the committee guidelines. and Telazol (0.8 ml / kg, intramuscularly; Zoetis Services LLC, Parsippany, New Jersey). General anesthesia was induced and maintained with isoflurane (1%-2%). Animals were intubated and mechanically ventilated with room air (Harvard Apparatus, Holliston, Massachusetts). Supplemental oxygen was administered to maintain physiological pH and oxygen saturation. An orogastric tube, a peripheral 18G intravenous catheter, and a rectal thermistor were placed in all animals. A heating pad was used to maintain a core body temperature >99°F. The vascular access sheath was then placed in the right Internal jugular vein (10-F), left carotid artery (7-F), and both femoral artery (7-F) and femoral vein (10-F) The target activated clotting time was 300-400 seconds. A continuous lidocaine infusion (1 mg / kg) and noradrenaline (0.16 mg / min) were administered to all animals. It began.

[0069] A 6-F Judkins right coronary artery catheter (Boston Scientific, Marlborough, Massachusetts) was used. A catheter (Figure 1) was inserted from the right femoral artery to the left coronary artery, and a baseline angiogram was recorded. A 0.14-inch guidewire was delivered to the distal left anterior descending artery (LAD) and a 3.0 × 8 mm guidewire was inserted for acute testing. Ametal stents (Boston Scientific) or 3.0 × 8 mm angioplasty ballasts for chronic studies A thrombus (Boston Scientific) was placed in the middle of the LAD after the first diagonal branch where LAD occlusion was confirmed by angiography. A coronary angiogram was performed immediately after reperfusion to confirm the patency of the LAD. The study was repeated after the completion of the study protocol. The exact location of the repeated balloon occlusion was marked during Evans blue counterstaining. After reperfusion, animals were euthanized with pentobarbital and phenytoin.

[0070] As shown in Figure 6A, the pigs were divided into four groups (n=4 / group). All groups Group 1 underwent LAD occlusion for 90 minutes. Group 2 underwent LAD occlusion followed by 120 minutes of reperfusion. In groups 2 and 3, LAD occlusion was followed by a TV pump (I A 14-F sheath was inserted into the left femoral artery (Pella CP, Abiomed, Danvers, MA). The patient was then inserted and activated, and maintained at maximum assistance (achieving 44,000 revs / min and 3.5 l / min). This was followed by an additional 15 minutes (group 2) or 30 minutes (group 3) of occlusion, respectively. This was followed by 120 minutes of reperfusion with LV unloading. In group 4, LAD occlusion was followed by reperfusion. After 30 minutes of reperfusion, a TV pump was inserted and operated for the remaining 90 minutes of reperfusion. .

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

[0072] To evaluate the functional role of SDF-1α / CXCR4 signaling or the cardioprotective effect of LV unloading To achieve this, an over-the-wire type coronary angioplasty balloon is used. In a closed-chest animal model of AMI, drugs targeting the SDF-1α receptor, CXCR4, were administered while maintaining LAD occlusion. A pharmacokinetic inhibitor (also known as AMD3100) was delivered to the risk area. Intracoronary infusion of either MD3100 (3 mg / kg / min, intracoronary over 10 min; n = 4 / group) Adult male pigs were treated with AMD3, starting at the beginning of LV unloading for 30 min before reperfusion. The dose of 100 was selected based on a previous report (Hu X, Dai S, Wu WJ, et al. Stromal cell derived factor-1 alpha confers protection against myocardial ischemia / reper fusion injury: role of the cardiac stromal cell derived factor-1 alpha CXCR4 axi s. Circ 2007;116:654-63).

[0073] To study the long-term effects of LV unloading on infarct size, 19 Yorkshire terriers were Adult male pigs underwent 90-minute mid-LAD ​​occlusion followed by immediate reperfusion (P-reperfusion) or Five animals underwent either 30 min of unloading (P-unloading) before reperfusion. Death occurred due to ventricular arrhythmia during LAD occlusion before randomization or pump implantation. Of the remaining 14 animals that successfully completed the course, 2 animals in the P-reperfusion group were refractory. Animals died within 6 hours of reperfusion due to persistent ventricular fibrillation. In total, 7 of 19 animals (37%) died during the study protocol. The 12 surviving animals were divided into the P-reperfusion group (n = 6) or the P- The unloaded group (n = 6) was used for analysis in the chronic study. , 76.7±6.9 kg in the P-unloading group and 76.2±2.4 kg in the P-reperfusion group (p=0 After reperfusion, all animals were allowed to recover and monitored for 28 days. The patient is anesthetized again and infarct size is assessed according to cardiac magnetic resonance imaging (MRI) and LV hemodynamics. Therefore, repeated catheterization was performed.

[0074] Changes in LV pressure and volume were measured using a 5-F conductance catheter deployed from the left carotid artery to the left ventricle. The cardiac output was evaluated using a cardiograph system (Sigma M, CD Leycom, Hengelo, The Netherlands). Pressure and volume were measured using solid-state pressure transducers, respectively, as previously described. By using a laser and dual-field excitation mode, the first post-infarction period was observed in chronic studies. Time-varying electrical conductance was measured at 28 days. Measurements were taken over 5 to 7 ventricular blood segments delineated by the catheter electrodes. Correct positioning of the conductance catheter along the axis was confirmed by fluoroscopy. Column conductance was measured by injecting 20 ml of hypertonic (6%) saline into the right internal jugular vein. The absolute LV volume was calculated by subtracting the parallel conductance from the total conductance. Stroke volume was calculated as the difference between the conductance at +dP / dtmax and -P / dtmin. LV stroke work is calculated as the product of peak LV peak systolic pressure and stroke volume. I calculated it.

[0075] A-1. Measurement of myocardial infarction size At the completion of the acute study protocol, balloon occlusion was performed within the mid-LAD ​​stent, and both Evans blue was injected into the coronary vessels to delineate the area at risk, followed by resection of the left ventricle. The stent was then deployed from the anterior apical left ventricle (infarct area) distal to the stent deployment site. Biopsy specimens were taken from the postero-basal wall (non-infarcted area) for pulmonary artery and molecular analysis. LV slices were then soaked in 1% triphenyltetrazolium chloride as previously described. To quantify LV scar size 28 days after MI, left ventricles were incubated in sodium. Divide into five 1 cm slices and in Evans blue-free triphenyltetrazolium chloride LV slices were then photographed and digitally analyzed by three blinded reviewers. Total myocardial area, area at risk, and infarct were determined using standardized planimetry. The area was quantified.

[0076] Animals in the chronic phase study were scanned in a Philips Achieva 1.5-T scanner (Philips Healthcare, Bes Late gadolinium imaging was performed 28 days after the initial infarction using a CT scan of the MRI machine. Patients underwent cardiac MRI with large vein enhancement (LGE). Breathhold cine images with precession were taken in three longitudinal and Consecutive short-axis slices were acquired from the atrioventricular ring to the apex. LV and right ventricular volumes were measured. , weight, and ejection fraction were measured using standard volumetric methods and cardiac magnetic resonance (CMR) ) were analyzed by an experienced blinded observer using commercially available software (QMASS version 7.4, Me The LGE images were analyzed at a 0.2 mm x 10 mm x 10 mm (Dermatological Imaging Systems, Leiden, The Netherlands). Cineradiography was performed 10-15 minutes after intravenous administration of 1 / kg gadolinium-diethylenetriaminepentaacetic acid. Co-located breath-hold 2D phase-sensitive inversion recovery The LGE region was measured at half maximum with manual adjustments as needed. The area with LGE was defined as the total volume of LGE. are summed to obtain and expressed as a percentage of total LV myocardium (LGE%).

[0077] Whole transcriptome expression analysis was performed using Porcine 1.0 ST microarrays in acute phase The study was performed on ribonucleic acid (RNA) isolated from the infarct zone after the protocol. The Online Appendix provides details.) All data from this microarray analysis were collected. Data and processing data are accessed in the Gene Expression Omnibus under accession number GSE108644. Quantitative polymerase chain reaction (PCR) and Western blot analysis were used to identify Significantly regulated gene expression and their activation in altered pathways were identified.

[0078] LV tissue samples were obtained from the center of the infarct zone and soaked in 3% glutaraldehyde in phosphate buffer. The cells were washed, fixed, and embedded in epoxy resin. Electron micrographs were taken to identify the mitochondria. Cardiomyocyte damage, including doria swelling and integrity, was analyzed.

[0079] A-2. Quantification of SDF-1α and CXCR4 levels Total protein was extracted from tissue homogenates as previously described ( 22 – 24 ). SDF-1α protein levels were measured by Western blot analysis and enzyme-linked immunosorbent assay. SDF-1α was quantified in LV tissue isolated from sham-operated animals and the infarct zone using a pulmonary artery occlusion assay. Circulating serum levels of α-glucan were measured by enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN). CXCR in LV tissue isolated from sham-operated animals and the infarcted area was quantified using a CXCR assay. The four levels were quantified by Western blot analysis (Abcam, Cambridge, UK). Immunoblot analysis was then performed as previously described.

[0080] A-3. Quantification of MMP-2, MMP-9, and DPP-4 levels and activity MMP-2 and MMP-9 activities in cardiac tissue homogenates were determined as previously described. The results were quantified by zymography. Briefly, the samples were prepared in a solution of 1 mg / ml porcine gelatin containing dodecyl sulfate. Gelatin zymography using sodium polyacrylamide gel electrophoresis gels Samples were prepared under non-reducing conditions. Gel electrophoresis was performed at 150 V for 1 hour. After electrophoresis, the gel was washed with 2.5% Triton X-100 solution at room temperature for 6 hours with gentle agitation. The mixture was then placed in a medium containing 50 mM Tris-HCl (pH 7.5), 0.2 M NaCl, 5 mM CaCl2, and 0.2% Brij-35. The gel was stirred at room temperature for 30 minutes and then placed in fresh developing buffer. The gel was then incubated overnight at 37°C. The next morning, the gel was resuspended in 0.5% ethanol and 10% acetic acid. Stain with Coomassie Brilliant Blue R-250 for 2-4 hours, then The gelatin digestion bands were visualized using ImageJ software. Scanning was performed using software (National Institutes of Health, Bethesda, MD). DPP-4 protein levels were quantified by immunoassay. and a commercially available activity assay kit (MilliporeSigma, Burlington, MA). The activity level was measured using

[0081] A-4. Quantification of apoptotic signaling pathways Immunoblot analysis was performed using porcine B-cell lymphoma (BCL)-2 (Cell Signaling Technology Cell Signaling Technology, Inc., Danvers, MA), BAX (Cell Signaling Technology), giant B cells B-cell lymphoma-extra-large: BCL-XL (Cell Signaling Technology) , caspase-3 (Cell Signaling Technology), and glyceraldehyde-3-phosphate The level of apoptosis-regulating proteins was measured using antibodies against dehydrogenases. Expression was measured both at the total protein level and for glyceraldehyde-3-phosphate dehydrogenase. TUNEL staining was performed in 4% paraformaldehyde / phosphate-buffered saline for 20 min. The study was performed using 10 mm thick sections obtained from the fixed periphery of the infarct zone. The sections were permeabilized with 0.1% Triton X-100 in sodium phosphate on ice, and then incubated at 37°C for 60 min in the dark. The slides were then rinsed in phosphate-buffered saline and stained with ProLong Gold antifade solution containing DAPI. The cells were labeled with an inhibitor (Life Technologies, Grand Island, NY). An ipse E800 fluorescence microscope (Nikon Corporation, Tokyo, Japan) and Openlab version 5 software were used. TUNEL positive. Cells were counted at 10x magnification by an expert blinded to the experimental groups. It is expressed as a percentage of the nucleus.

[0082] A-5. Other For all cell-based real-time PCR experiments, total RNA was purified using Trizol (Thermo Fisher Scientific). Direct extraction and high-capacity cDNA reverse transcription kit (Chemical Sciences, Waltham, MA) were used. (High Capacity cDNA Reverse Transcription Kit) (Thermo Fisher Scientific) In all real-time PCR experiments, samples were run in triplicate. and an ABI Prism 7900 sequence detection system (Thermo Fisher Scientific) using appropriate primers. ific) using 40 cycles of 94°C for 30 seconds, 60°C for 45 seconds, and 72°C for 45 seconds. and quantified.

[0083] Results are presented as mean ± SD. Unpaired Student's t-test or one-way correlation Analysis of variance was used to compare continuous variables between groups. All data within groups over time were analyzed. Data were analyzed using non-parametric two-way repeated measures analysis of variance. Regression analysis was used to assess the correlation between the two parameters. All statistical analyses were performed using GraphPad. Analysis was performed using Prism (GraphPad Software, La Jolla, CA). P<0.0 An alpha level of 5 was considered to indicate a significant effect or difference between groups.

[0084] B. Results B-1. LV unloading for 30 min before reperfusion reduced acute infarct size compared with reperfusion alone. Let LV unloading for 30 min before reperfusion reduced myocardial infarct size compared with reperfusion alone. (33.3±5% vs. 62.2±1.7% infarct / area at risk, Group 3 vs. Group 1, respectively; p<0.0) 1) (see Figure 6B). LV unloading followed by rapid reperfusion within 15 minutes (Group 2) or LV unloading after reperfusion (group 4) reduced myocardial infarct size compared with P-reperfusion alone. I didn't let him pee.

[0085] B-2. LV unloading induces global changes in gene expression associated with reduced damage within the infarct zone after AMI induces To begin to explore the cardioprotective mechanisms associated with LV unloading before reperfusion, we The authors compared total transcriptomes from within the infarct zone between sham control group 1 and group 3. The genome was analyzed to identify genes that were differentially expressed between treatment groups. Heatmap of regulated genes in LV unloaded for 30 min before reperfusion compared to sham controls We demonstrated that administration of acetaminophen attenuated the gene expression changes associated with reperfusion alone (see Figure 7A).

[0086] Compared with reperfusion alone, LV unloading for 30 min before reperfusion improved mitochondrial function and and limited downregulation of genes related to cellular respiration (see Table 5 below). Consistent with these observations, real-time PCR of LV tissue samples from the infarct zone showed Compared with group 1, group 3 had a higher number of major genes related to cellular respiration, as shown in Figure 7B. It was confirmed that the level of messenger ribonucleic acid (mRNA) was increased. From the examination, as shown in Figure 7C, mitochondria in the infarct zone from group 1 (but not group 3) were significantly increased. These findings further demonstrated a loss of chondrial integrity compared with reperfusion alone. LV unloading for 30 min before reperfusion significantly protects genes related to mitochondrial function It is clear that this induces widespread changes in gene expression within the infarct zone.

[0087] B-3. ​​LV unloading limits SDF-1α degradation in AMI Considering the importance of SDF-1α / CXCR4 signaling in cardioprotection during ischemia-reperfusion injury , SDF-1α and CXCR4 protein levels were quantified within the infarct zone. Compared with reperfusion alone (group 1), 15 min of LV unloading (group 2), or reperfusion Post-perfusion LV unloading (group 4) was associated with a decrease in SDF-1α protein levels within the infarct zone. We observed that the relapse rate was significantly higher in the sham control group compared to the control group (see Figures 8A and 8B). Only 30 min of LV unloading before perfusion (group 3) significantly increased SDF-1α protein levels in the infarct zone. CXCR4 levels remained unchanged in all four test groups compared to sham controls. It remains the same.

[0088] To determine whether the increase in SDF-1α levels was transcriptionally regulated, we performed a Real-time PCR was used to quantify mRNA expression, and no significant differences were observed in SDF-1α or CXCR4 gene expression. No differences were observed (see Figures 8C and 8D). SDF-1α is highly degraded by proteolysis. The major proteases known to degrade SDF-1α are then regulated by Compared with sham controls, reperfusion alone increased the activity levels of MMP-2 and MMP-9. The increase in LV activity was not due to 30 min of LV unloading before reperfusion (see Figures 8E and 8F). Reperfusion alone increased DPP-4 expression and activity levels within the infarct zone compared with sham controls. LV unloading for 30 min before reperfusion significantly increased DPP-4 expression and activity (see Figures 8G and 8H). These data were consistent with the 30 min of LV unloading prior to reperfusion. The effect of this method is to limit the activity of proteases known to degrade SDF-1α. This suggests that SDF-1α protein levels can be maintained.

[0089] B-4. Loss of SDF-1α / CXCR4 activity attenuates the cardioprotective effects of LV unloading We investigated whether SDF-1α / CXCR4 signaling is required for the cardioprotective effect of LV unloading in different animals. To investigate this, the group used intracoronary delivery of AMD3100 to block CXCR4 activity. Loss of CXCR4 activity compared with vehicle-treated controls subjected to 30 min of LV unloading before perfusion increases infarct size and inhibits Akt, extracellular signal-regulated kinase, and glycogen reduced cardioprotective signaling through the RISK pathway, including ribosomal synthase kinase 3b ( (See Figures 8I and 8J.) These findings suggest that SDF-1α / CXCR4 signaling contributes to LV angiogenesis prior to reperfusion. This suggests that it is necessary for the cardioprotective effects of load.

[0090] B-5. LV unloading limits proapoptotic signaling 30 min of LV unloading reduces the levels of apoptosis-related proteins in the infarct zone To further investigate whether this is the case, we performed a randomized controlled trial in which reperfusion alone (group A) was performed in comparison with a sham control. 1) increases the levels of pro-apoptotic proteins such as BAX and activated caspase-3. Adding α-amyloid to α-amyloid-β-lactamase (α-amyloid-β-lactam) further reduced levels of anti-apoptotic proteins such as BCL-2 and BCLXL. Compared with Group 1, Group 3 showed significantly higher levels of BAX and activity (see Figures 9A-9C). Decreased levels of the active form of caspase-3 and anti-apoptotic BCL-2 and BCL-XL proteins Compared with P-reperfusion, P unloading showed an increase in TUNEL-positive cells in the infarct zone. The number of leukocytes decreased (see Figures 9D and 9E).

[0091] B-6. Compared with primary reperfusion, primary unloading reduced myocardial infarct size 28 days after AMI. and maintain cardiac function To confer clinically meaningful cardioprotection, the observed reduction in infarct size must be met. The effects of P-unloading should be maintained beyond the acute treatment phase. To investigate the effect of P-reperfusion or P-unloading on LV scar size in adult male pigs, LV function, and molecular changes associated with heart failure were quantified 28 days after MI. Fourteen animals were included in this study. Two animals in the P-reperfusion group completed the ischemia-reperfusion phase of the protocol. All animals died within 2 days, and 12 animals survived to 28 days (6 per group).

[0092] Compared with P-reperfusion, P-unloading reduced LV scar size quantified using LGE (3.9±3.2% vs. 9±3.7%; p=0.03) and reduced anatomical pathology (7.2±4.9% vs. 14.9 ± 4.1%; p = 0.02) (Figure 5A). Histological planimetry of infarct size was compared with L from CMR. The CMR-derived volume directly correlated with the percentage of GE (R = 0.85) (see Figures 10B-10D). End-diastolic and end-systolic volumes 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 mass did not differ between groups (90.4 ±10.6g vs. 84.4±8.6g; P-reperfusion vs. P-unload [p=NS]). Hemodynamic analysis using an inductance catheter revealed that P-unloading resulted in a higher stroke volume (54±7ml vs. 40±6ml; 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). (See Table 5 below.)

[0093] Table 5. Hemodynamic variables 28 days after acute myocardial infarction TIFF2025131612000006.tif68128Values ​​are means ± SD. 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 during the acute phase and 28 days after AMI. Increase for days Compared with P-reperfusion, P-unloading increased circulating SDF-1α levels for 28 days after AMI, and AM In contrast, P-reperfusion showed peak SDF-1α levels 1 week after AMI (see Figure 10E). failed to increase circulating SDF-1α levels at any time point after treatment. In comparison, P-reperfusion reduced SDF-1α protein levels within the infarct zone of the left ventricle, whereas P- Circulating SDF-1α levels at 28 days after AMI correlated inversely with LV scar size. (See Figures 10F and 10G).

[0095] B-8. Primary unloading limits maladaptive cardiac remodeling Compared with P-reperfusion, P-unloading significantly increased circulating levels of B-type natriuretic peptide (BNP). Compared with sham controls, P-reperfusion reduced the infarct activity in the non-infarcted area 28 days after AMI (see Figure 11A). In contrast, P increased the mRNA and protein levels of BNP (see Figures 11B and 11C). Unloading attenuated the increase in tissue levels of BNP in the non-infarcted zone of the left ventricle compared with reperfusion. P-unloading increases the mRNA levels of sarcoplasmic / endoplasmic reticulum calcium ATPase, and reduced the levels of calcineurin and type I collagen, but not from the non-infarcted region of the left ventricle. These levels were not affected (see Figures 11D to 11F).

[0096] C. Discussion The central finding of this example is that P-unloading for 30 min before reperfusion significantly improved the P-dependent vasoconstriction in the vasoconstricted ... , several important biological pathways, including cellular respiration and post-translational regulation of SDF-1α levels. This alters the P- Unloading reduced LV scar size and improved cardiac function 28 days after AMI. We report the following: 1) P-unloading for 30 minutes limits infarct size. 2) P-unloading is necessary and sufficient to induce mitochondrial dysfunction within the infarcted area. 3) P-reperfusion induces comprehensive changes in gene expression related to the protection of endocrine integrity. In comparison, P-unloading for 30 min increased SDF-1 without changing SDF-1α mRNA levels in the infarct zone. maintains α protein levels and shifts anti-apoptotic signaling within the infarct zone 4) P-unloading promotes the degradation of SDF-1α by proteases known to degrade SDF-1α. 5) P-unloading reduces LV scar size 28 days after AMI. It reduces the infarct size, maintains cardiac output, reduces BNP expression, and prevents maladaptive remodeling within the non-infarcted zone. These data suggest that P-unloading limits the expression of related genes and proteins. This study aims to propose a novel approach to enhance cardioprotective mechanisms that can preserve cardiac function after AMI. and confirmed.

[0097] Thirty minutes of mechanical LV unloading with a TV pump before, but not after, reperfusion reduces acute infarction This observation suggests that the size of the left ventricle may be limited by the mere complementation of the dysfunctional left ventricle. This is the first time that LV unloading itself can be a therapeutic approach, as opposed to a supportive approach. The beneficial effect of 30 minutes of mechanical LV unloading before reperfusion was suggested by the One potential explanation is that the vasodilator biologically primes the myocardium for reperfusion. The effect of unloading the LV was to reduce infarct size and reduce the intra-infarct volume. A potential explanation is that SDF-1α protein levels can be increased.

[0098] Using a genomics approach, we demonstrated that 30 min of P-unloading significantly reduced ischemic heart failure compared with P-reperfusion. Pathway analysis identified differentially altered expression of over 600 genes within the occlusion zone. , P-unloading maintains the expression of genes related to cellular respiration and mitochondrial integrity These observations suggest that selective residues from each component of the electron transport chain involved in cellular respiration are involved. The findings of this study were confirmed by direct quantification of the gene. limits the effects of ischemia-reperfusion injury on mitochondrial integrity, thereby protecting cardiomyocytes These findings suggest that the serotonin-dependent pathway may promote survival.

[0099] In this study, P-unloading significantly increased SDF-1α mRNA levels in the infarct zone compared with P-reperfusion. However, P-reperfusion did not increase the infarct area compared with sham controls. In contrast, 30 min before reperfusion was observed to decrease SDF-1α protein levels. LV unloading during stenosis maintained SDF-1α protein levels.

[0100] SDF-1α levels are highly regulated by inflammation-related proteases, The inventors then identified the proteins and enzymes of key regulatory proteases such as MMP-2, MMP-9, and DPP-4. We investigated whether the activity levels of sham-treated rats were altered by P-reperfusion and P-unloading. Compared with controls, P-reperfusion increases the activity of these proteases, whereas P-unloading To further establish the downstream effects of P-unloading, we also observed a decrease in the expression of apoptosis-related proteins within the infarct zone. P unloading during infarction limits protease activity within the infarct zone, thereby preventing SDF-1 uptake in the setting of AMI. This is the first indication that α-decomposition is limited.

[0101] A preclinical study was designed in which animals were assigned to P-reperfusion or P-unloading. LV scar was quantified using cardiac MRI after 28 days. P-unloading was measured by LGE-CMR. Reduced infarct scar size, which was blindly quantified, an anatomical measure of myocardial scar size It was first observed that maladaptive remodeling in the non-infarcted area was highly correlated with Well-established molecular markers of vasoconstriction were quantified in the non-infarcted zone in response to extensive anterior MI. Compared with P-reperfusion, P-unloading , 28 days after AMI, while maintaining sarcoplasmic / endoplasmic reticulum calcium ATPase levels, It was observed that thrombin reduced thrombin levels, β-myosin heavy chain, and BNP levels. Circulating and LV tissue levels of BNP, a clinically relevant biomarker of heart failure, were significantly higher in P- These findings were consistent with those of the 2016 AMI model, which showed a significant decrease after unloading but not after P-reperfusion. Transvalve pump use significantly improved LV scar size and markers of maladaptive remodeling after 28 days. It is the first to demonstrate the lasting impact on both During this time, immediate reperfusion has been the primary focus in AMI; however, these data suggest that "reperfusion" The pre-reperfusion time period has a lasting effect on late cardiac remodeling. At critical moments, interventions such as LV unloading and delayed reperfusion may be possible to exert a positive effect. This is the first indication that there is.

[0102] Finally, we quantified SDF-1α levels after AMI and found that P-unloading, but not P-reperfusion, was the most common cause of SDF-1α levels. Increased circulating and LV tissue levels of SDF-1α were observed 28 days after injection. These findings suggest that LV scar size is inversely correlated with a rapid reduction in infarct size after MI. In addition, P-unloading promoted a more permanent reduction in LV scar size and improved cardiac function. CMR and circulating BNP levels have been shown to limit maladaptive remodeling after AMI. By using clinically relevant biomarkers of myocardial injury, such as The results demonstrate the potency of P-unloading as an approach to limit ischemic heart failure after AMI. This suggests potential translational potential.

[0103] D. Knowledge The findings of this study are consistent with the results of transvalvular thrombus treatment for 30 minutes before reperfusion, as in method 200 of FIG. 2 described above. The operation of the microaxial pump significantly reduced acute infarct size and subsequent scarring compared with P-reperfusion alone. The results of this study demonstrate that myocardial unloading is beneficial for both the function and size of the scar. These findings provide new mechanistic insights into the biological effects and activation of cardioprotective pathways within the infarct zone.

[0104] The foregoing is merely illustrative of the principles of the present disclosure, and it is to be understood that the present invention may be practiced in other ways than as described. These embodiments are presented for purposes of illustration and not limitation.

[0105] Numerous variations and modifications will occur to those skilled in the art after reviewing this disclosure. The disclosed features may be used in any combination with one or more of the other features described herein. and subcombinations (including multiple dependent combinations and subcombinations) The various features described above or exemplified above, including any of their components, may be It can be incorporated or integrated into other systems. Furthermore, certain features may be omitted. and may or may not be implemented.

[0106] Examples of changes, substitutions, and alterations are ascertainable by one skilled in the art and are disclosed herein. All references cited herein are hereby incorporated by reference in their entirety without departing from the scope of the information contained therein. The documents are incorporated herein by reference in their entirety and form part of this application.

Claims

1. 1. A method of providing cardiac assistance to a human patient having a sustained myocardial infarction, comprising: inserting a mechanical circulatory assist device into said patient after myocardial infarction; Before reperfusion, the heart was assisted for a period of more than 15 minutes with a blood flow rate of at least 2.5 L / min. operating the mechanical circulatory assist device; and applying reperfusion therapy to the heart after the assistance period. The method comprises:

2. The subsidy 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 approximately 30 minutes; about 20 minutes to about 45 minutes; and about 30 minutes to about 40 minutes The method of claim 1, wherein the

3. The mechanical circulatory assist device is operated at a rate that provides a cardiac output of at least 3.5 L / min of blood flow. The method of claim 1 or 2, wherein the

4. The method of claim 3 , wherein the inserted assist device comprises a blood pump.

5. the heart is unloaded by the mechanical circulatory assist device simultaneously with reperfusion; 10. The method of any one of claims 1 to 9.

6. 10. The method of claim 9, wherein the mechanical circulatory assist device comprises a cannula inserted into the heart.

10. The method according to any one of claims 1 to 9.

7. The blood pump comprises a microaxial transvalvular pump. The method according to claim 6.

8. The heart is supported by an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump. Assisting process 10. The method of any one of the preceding claims, comprising:

9. Reperfusion therapy is a treatment option for patients with coronary artery disease, such as direct percutaneous coronary intervention (PCI) and fibrinolytic cysts.

10. The method of claim 9, further comprising:

10. BAX protein and activated caspase-3 antibody in cardiac tissue from patients near myocardial infarction reducing the level; and Increased levels of BCL-2 and BCL-XL proteins in cardiac tissue from patients near myocardial infarction The process of 10. The method of any one of the preceding claims, comprising:

11. Stromal cell-derived factor 1α (SDF-1α) protein levels in cardiac tissue from patients near myocardial infarction increasing the amount of A method for maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients near myocardial infarction and Upregulation of DPP-4 protein expression and activity in cardiac tissue from patients with myocardial infarction Process for limiting modulation 10. The method of any one of the preceding claims, comprising:

12. reducing circulating levels of brain natriuretic peptide (BNP) in the patient's blood. Course; Increasing the mRNA level of SERCA expression in cardiac cells of a patient near a myocardial infarction; and The present invention provides a method for treating a patient suffering from a myocardial infarction, comprising administering a steroid hormone to a patient suffering from a myocardial infarction, while maintaining the level of b-MHC in the non-infarcted region of the patient's heart. Decreased levels of calcineurin activity and type I collagen in human cardiac cells The process of 10. The method of any one of the preceding claims, comprising:

13. the heart has a sum of ST-segment elevations (ΣSTE) of greater than 4, or greater than 5, or greater than 6, 10. The method according to any one of the preceding claims.

14. 14. The method of claim 13, wherein the heart has a ΣSTE of greater than 6.

15. 1. A method of providing cardiac assistance to a patient having a sustained myocardial infarction, comprising: A transvalvular blood pump is percutaneously inserted into the patient to pump blood into the patient's heart. With the distal end of the pump located in the left ventricle, the pump is guided across the aortic valve of the heart. placing; Before reperfusing the heart, the deployed pump was turned on to deliver at least 2.5 L / min of blood. unloading the left ventricle for a pumping period of greater than 15 minutes at a pump flow rate of 100 Hz; and treating said heart with reperfusion therapy after said pumping period. The method comprises:

16. The subsidy 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 to about 45 minutes more than 15 minutes and up to about 30 minutes; and about 30 minutes to about 40 minutes 16. The method of claim 15, comprising any one of:

17. 15 or 16, wherein the pump is operated at a pumping rate of at least 3.5 L / min of blood flow.

6. The method according to claim 6.

18. 15. The method of claim 14, wherein the heart is unloaded by a mechanical circulatory assist device simultaneously with reperfusion.

18. The method according to any one of claims 1 to 17.

19. removing the blood pump from the patient's heart after administering the reperfusion therapy. The method according to any one of claims 15 to 18, comprising:

20. Reperfusion therapy is a treatment option for patients with coronary artery disease, such as direct percutaneous coronary intervention (PCI) and fibrinolytic cysts. The method according to any one of claims 15 to 19, comprising at least one of the following:

21. BAX protein and activated caspase-3 antibody in cardiac tissue from patients near myocardial infarction reducing the level; and Increased levels of BCL-2 and BCL-XL proteins in cardiac tissue from patients near myocardial infarction The process of The method according to any one of claims 15 to 20, comprising:

22. Stromal cell-derived factor 1α (SDF-1α) protein levels in cardiac tissue from patients near myocardial infarction increasing the amount of A method for maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients near myocardial infarction and Upregulation of DPP-4 protein expression and activity in cardiac tissue from patients with myocardial infarction Process for limiting modulation The method according to any one of claims 15 to 21, comprising:

23. reducing circulating levels of brain natriuretic peptide (BNP) in the patient's blood. Course; Increasing the mRNA level of SERCA expression in cardiac cells of a patient near a myocardial infarction; and The present invention provides a method for treating a patient suffering from a myocardial infarction, comprising administering a steroid hormone to a patient suffering from a myocardial infarction, while maintaining the level of b-MHC in the non-infarcted region of the patient's heart. Decreased levels of calcineurin activity and type I collagen in human cardiac cells The process of The method according to any one of claims 15 to 22, comprising:

24. 1. A method of reducing myocardial infarction scar size in a patient's heart, comprising: A transvalve microaxial blood pump is percutaneously inserted into the patient and pumped into the left ventricle of the patient's heart. With the distal end of the pump positioned, the pump is positioned across the aortic valve of the heart. Process; Before reperfusing the heart, the deployed pump was turned on to deliver at least 2.5 L / min of blood. unloading the left ventricle for a pumping period of greater than 15 minutes at a pump flow rate of 100 Hz; and applying reperfusion therapy to the heart after the pumping period. The method comprises:

25. 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 to about 45 minutes more than 15 minutes and up to about 30 minutes; and about 30 minutes to about 40 minutes 25. The method of claim 24, wherein the

26. 24 or 2, wherein the pump is operated at a pumping rate of at least 3.5 L / min of blood flow.

5. The method described in 5.

27. Claims 24-26, wherein the heart is unloaded by the blood pump simultaneously with reperfusion 10. The method according to any one of the preceding claims.

28. removing the blood pump from the patient's heart after administering the reperfusion therapy.

28. The method according to any one of claims 24 to 27, comprising:

29. Reperfusion therapy is a treatment option for patients with coronary artery disease, such as direct percutaneous coronary intervention (PCI) and fibrinolytic cysts. The method according to any one of claims 24 to 28, comprising at least one of the following:

30. BAX protein and activated caspase-3 antibody in cardiac tissue from patients near myocardial infarction reducing the level; and Increased levels of BCL-2 and BCL-XL proteins in cardiac tissue from patients near myocardial infarction The process of 30. The method of any one of claims 24 to 29, comprising:

31. Stromal cell-derived factor 1α (SDF-1α) protein levels in cardiac tissue from patients near myocardial infarction increasing the amount of A method for maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients near myocardial infarction and Upregulation of DPP-4 protein expression and activity in cardiac tissue from patients with myocardial infarction Process for limiting modulation The method of any one of claims 24 to 30, comprising:

32. reducing circulating levels of brain natriuretic peptide (BNP) in the patient's blood. Course; Increasing the mRNA level of SERCA expression in cardiac cells of a patient near a myocardial infarction; and The present invention provides a method for treating a patient suffering from a myocardial infarction, comprising administering a steroid hormone to a patient suffering from a myocardial infarction, while maintaining the level of b-MHC in the non-infarcted region of the patient's heart. Decreased levels of calcineurin activity and type I collagen in human cardiac cells The process of 32. The method of any one of claims 24 to 31, comprising:

33. 1. A method of assisting a heart that has suffered a myocardial infarction, comprising: percutaneously inserting a mechanical circulatory assist device into a patient following a myocardial infarction of the patient's heart; The device was operated at a blood flow rate of at least 2.5 L / min for 15 minutes before the heart was reperfused. unloading the left ventricle for an unloading period of greater than 100 msec; and applying reperfusion therapy to the heart after the unloading period. The method comprises:

34. 34. The method of claim 33, wherein the unloading period is at least 30 minutes.

35. 33 or 34, wherein the mechanical circulatory assist device is operated at a blood flow rate of at least 3.5 L / min.

4. The method described in 4.

36. Unloading of the heart by the mechanical circulatory assist device is applied simultaneously with reperfusion therapy.

36. The method according to any one of claims 33 to 35.

37. 37. Any of claims 33 to 36, wherein the mechanical circulatory assist device comprises a blood pump, such as a TV pump. The method according to any one of claims 1 to 4.

38. The heart is supported by an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump. Assisting process 38. The method of any one of claims 33 to 37, comprising:

39. The reperfusion therapy may be direct percutaneous coronary intervention (PCI) or fibrinolytic 39. The method of any one of claims 33 to 38, comprising:

40. BAX protein and activated caspase-3 antibody in cardiac tissue from patients near myocardial infarction reducing the level; and Increased levels of BCL-2 and BCL-XL proteins in cardiac tissue from patients near myocardial infarction The process of 40. The method of any one of claims 33 to 39, comprising:

41. Stromal cell-derived factor 1α (SDF-1α) protein levels in cardiac tissue from patients near myocardial infarction increasing the amount of A method for maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients near myocardial infarction and Upregulation of DPP-4 protein expression and activity in cardiac tissue from patients with myocardial infarction Process for limiting modulation The method of any one of claims 33 to 40, comprising:

42. reducing circulating levels of brain natriuretic peptide (BNP) in the patient's blood. Course; Increasing the mRNA level of SERCA expression in cardiac cells of a patient near a myocardial infarction; and The present invention provides a method for treating a patient suffering from a myocardial infarction, comprising administering a steroid hormone to a patient suffering from a myocardial infarction, while maintaining the level of b-MHC in the non-infarcted region of the patient's heart. Decreased levels of calcineurin activity and type I collagen in human cardiac cells The process of 42. The method of any one of claims 33 to 41, comprising:

43. 1. A method of providing cardiac assistance to a patient having a myocardial infarction, comprising: The levels of BAX protein and activated caspase 3 antibody in cardiac tissue from patients with myocardial infarction lowering the bell; and Increased levels of BCL-2 and BCL-XL proteins in cardiac tissue from patients near myocardial infarction The process of The method comprises:

44. applying mechanical circulatory support to the patient to reduce blood flow from the left ventricle of the patient's heart; A process of increasing 44. The method of claim 43, comprising:

45. The increased blood flow continues for an unloading period of more than 15 minutes at a blood flow rate of at least 2.5 L / min.

45. The method of claim 44, wherein the method is provided by

46. 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 to about 45 minutes about 15 minutes to about 30 minutes; and about 30 minutes to about 40 minutes 46. ​​The method of claim 45, wherein the

47. Any of claims 43 to 46, wherein the increased blood flow is provided at a blood flow rate of at least 3.5 L / min.

1. The method according to claim 1.

48. applying reperfusion therapy to the patient's cardiac tissue near the myocardial infarction after applying mechanical circulatory support; The process 48. The method of any one of claims 43 to 47, comprising:

49. administering mechanical circulatory support to said patient simultaneously with reperfusion.

49. The method of any one of claims 43 to 48, comprising:

50. 50. The method of claim 49, wherein the mechanical circulatory assist device comprises a blood pump, such as a TV pump. method.

51. After or during operation of the transvalve microaxial pump, the intra-aortic balloon pump and the assisting the heart with one or more extracorporeal membrane oxygenation (ECMO) pumps.

51. The method of claim 50, comprising:

52. Reperfusion is the most common treatment for coronary artery disease after direct percutaneous coronary intervention (PCI) and fibrinolysis.

52. The method of any one of claims 48 to 51, comprising at least one of:

53. 1. A method of providing cardiac assistance to a patient having a myocardial infarction, comprising: The levels of BAX protein and activated caspase 3 antibody in cardiac tissue from patients with myocardial infarction lowering the bell; Increased levels of BCL-2 and BCL-XL proteins in cardiac tissue from patients near myocardial infarction a step of: Stromal cell-derived factor 1α (SDF-1α) protein levels in cardiac tissue from patients near myocardial infarction increasing the amount of A method for maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients near myocardial infarction Course; Upregulation of DPP-4 protein expression and activity in cardiac tissue from patients with myocardial infarction limiting the modulation; 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 a myocardial infarction; and The present invention provides a method for treating a patient suffering from a myocardial infarction, comprising administering a steroid hormone to a patient suffering from a myocardial infarction, while maintaining the level of b-MHC in the non-infarcted region of the patient's heart. Decreased levels of calcineurin activity and type I collagen in human cardiac tissue The process of The method includes at least one of the following:

54. 1. A method of providing cardiac assistance to a patient having a myocardial infarction, comprising: Stromal cell-derived factor 1α (SDF-1α) protein levels in cardiac tissue from patients near myocardial infarction increasing the amount of A method for maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients near myocardial infarction and Upregulation of DPP-4 protein expression and activity in cardiac tissue from patients with myocardial infarction Process for limiting modulation The method comprises:

55. Increasing blood flow to cardiac tissue of a patient near the myocardial infarction 55. The method of claim 53 or 54, comprising:

56. applying mechanical circulatory support to the patient's heart.

56. The method of claim 55, comprising:

57. The mechanical circulatory support may include applying a device including a blood pump, such as a TV pump. The method of claim 56.

58. One of the TV pumps, intra-aortic balloon pumps, and extracorporeal membrane oxygenation (ECMO) pumps assisting the heart by one or more of 58. The method of claim 57, comprising:

59. unloading the left ventricle of the patient's heart using a transvascular pump.

59. The method of any one of claims 54 to 58, comprising:

60. The left ventricle is activated for an unloading period of more than 15 minutes with a blood flow rate of at least 2.5 L / min.

60. The method of claim 59, wherein the

61. 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 to about 45 minutes about 15 minutes to about 30 minutes; and about 30 minutes to about 40 minutes 61. The method of claim 60, wherein the

62. Any of claims 59 to 61, wherein the left ventricle is unloaded at a blood flow rate of at least 3.5 L / min.

1. The method according to claim 1.

63. applying mechanical circulatory support to the patient's heart followed by reperfusion therapy.

63. The method of any one of claims 59 to 62, comprising:

64. administering mechanical circulatory support to said patient simultaneously with reperfusion.

64. The method of claim 63, comprising:

65. Claims 56-64, wherein the mechanical circulatory support is provided by a TV pump or other blood pump.

10. The method according to any one of the preceding claims.

66. Reperfusion is the most common treatment for coronary artery disease after direct percutaneous coronary intervention (PCI) and fibrinolysis.

66. The method of any one of claims 63 to 65, comprising at least one of:

67. 1. A method of providing cardiac assistance to a patient having a myocardial infarction, comprising: reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood. ； Increasing the mRNA level of SERCA expression in cardiac tissue of a patient near myocardial infarction; and The present invention provides a method for treating a patient suffering from a myocardial infarction, comprising administering a steroid hormone to a patient suffering from a myocardial infarction, while maintaining the level of b-MHC in the non-infarcted region of the patient's heart. Decreased levels of calcineurin activity and type I collagen in human cardiac tissue The process of The method includes at least one of the following:

68. increasing blood flow to said patient's cardiac tissue near the myocardial infarction.

68. The method of claim 67, comprising:

69. applying mechanical circulatory support to said patient's heart for a period of unloading or other assistance; Process used 69. The method of claim 68, comprising:

70. The increased blood flow is maintained for an unloading period of more than 15 minutes at a flow rate of at least 2.5 L / min.

70. The method of claim 69, wherein the method is provided by

71. 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 15 minutes to about 30 minutes up to about 20 minutes to about 45 minutes; and about 30 minutes to about 40 minutes 71. The method of claim 70, wherein the

72. Any of claims 68 to 71, wherein the increased blood flow is provided at a rate of at least 3.5 L / min 10. The method according to claim 1.

73. applying mechanical circulatory support to the patient's heart for the support period followed by reperfusion therapy applying the 73. The method of any one of claims 69 to 72, comprising:

74. applying mechanical circulatory support to said patient's heart simultaneously with reperfusion therapy.

74. The method of any one of claims 69 to 73, comprising:

75. The mechanical circulatory support is performed by applying a device including a TV pump or other blood pump.

75. The method of any one of claims 69 to 74, comprising:

76. The heart is supported by an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump. Assisting process 76. The method of any one of claims 67 to 75, comprising:

77. Reperfusion is the most common treatment for coronary artery disease after direct percutaneous coronary intervention (PCI) and fibrinolysis.

77. The method of any one of claims 73 to 76, comprising at least one of:

78. 1. A method of providing cardiac assistance to a patient having a myocardial infarction, comprising: The levels of BAX protein and activated caspase 3 antibody in cardiac tissue from patients with myocardial infarction lowering the bell; Increased levels of BCL-2 and BCL-XL proteins in cardiac tissue from patients near myocardial infarction a step of: Stromal cell-derived factor 1α (SDF-1α) protein levels in cardiac tissue from patients near myocardial infarction increasing the amount of A method for maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients near myocardial infarction Course; Upregulation of DPP-4 protein expression and activity in cardiac tissue from patients with myocardial infarction limiting the modulation; 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 a myocardial infarction; and The present invention provides a method for treating a patient suffering from a myocardial infarction, comprising administering a steroid hormone to a patient suffering from a myocardial infarction, while maintaining the level of b-MHC in the non-infarcted region of the patient's heart. Decreased levels of calcineurin activity and type I collagen in human cardiac tissue The process of The method comprises:

79. 1. A cardioprotective system for assisting the heart of a patient having a sustained myocardial infarction, comprising: The system comprises: a mechanical circulatory assist device configured to be inserted into the patient; and Reperfusion therapy device Equipped with Before activation of the reperfusion therapy device, the mechanical circulatory assist device is operated at a blood flow rate of at least 2.5 L / min. configured to operate for an assistance period of greater than five minutes; The system.

80. The subsidy 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 to about 45 minutes more than 15 minutes and up to about 30 minutes; and about 30 minutes to about 40 minutes 80. The system of claim 79, wherein:

81. the mechanical circulatory assist device is configured to operate at a blood flow rate of at least 3.5 L / min; 81. The system of claim 79 or 80,

82. The mechanical circulatory assist device is configured to operate simultaneously with the reperfusion therapy device. The system of any one of claims 79 to 81.

83. Any of claims 79 to 82, wherein the mechanical circulatory assist device comprises a TV pump or other blood pump.

2. The system according to claim 1 .

84. The following device is activated after or during the operation of the mechanical circulatory assist device: an intra-aortic balloon; and an extracorporeal membrane oxygenation (ECMO) pump. Item 84. The system of item 83.

85. 1. A cardioprotective system for assisting the heart of a patient having a sustained myocardial infarction, comprising: The system comprises: The device is configured to be percutaneously inserted into the patient after a myocardial infarction, and to control the aorta of the patient's heart. The blood pump is sized and shaped to be positioned across the cardiac valve, and the distal end of the blood pump is the blood pump configured to be positioned in the left ventricle of the heart; and Reperfusion therapy device Equipped with The blood pump is activated before activation of the reperfusion therapy device and thereafter delivers at least 2.5 L / min of blood. The pump is programmed to pump blood at a flow rate for a period of more than 15 minutes. are The system.

86. 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 to about 45 minutes more than 15 minutes and up to about 30 minutes; and about 30 minutes to about 40 minutes 86. The system of claim 85, wherein:

87. 85 or 8, wherein the mechanical circulatory assist device is operated at a blood flow rate of at least 3.5 L / min.

6. The system according to claim 6.

88. 88. Any one of claims 85 to 87, wherein the blood pump is operated simultaneously with the reperfusion therapy device. Item 10. The system according to item 10.

89. 1. A method of treating a human heart having a persistent myocardial infarction, comprising: the myocardial infarction has an infarct size and is located within a portion of the heart, and the method , reducing the infarct size.

90. reducing the myocardial oxygen demand of the heart in a portion of the heart that includes an infarct, and subsequently and reducing the infarct size by restoring oxygen supply to the portion of the heart comprising 90. The method of claim 89, further comprising the step of:

91. BAX protein and / or activated caspase-3 in cardiac tissue Step of reducing the level 91. The method of claim 89 or 90, comprising:

92. increasing the level of at least one of BCL-2 and BCL-XL 92. The method of any one of claims 89 to 91, comprising:

93. increasing the myocardial salvage index (MSI) of said heart 93. The method of any one of claims 89 to 92, comprising:

94. 94. The method of claim 93, wherein the heart has a sum of ST elevations (ΣSTE) greater than 6.

95. inserting the blood pump into the patient's vascular system; and administering a period of assistance to regulate blood flow within the vascular system prior to administering reperfusion therapy to the heart. driving the pump throughout the applying reperfusion therapy to the heart after the assistance period.

95. The method of any one of claims 89 to 94, comprising:

96. 96. The method of claim 95, wherein the support period is at least 15 minutes.

97. 97. The method of claim 96, wherein the support period is at least 20 minutes.

98. 97. The method of claim 96, wherein the support period is at least 30 minutes.

99. The assistance period is at least 30 minutes, about 20 minutes to about 40 minutes, or at least 45 minutes. The method of claim 96.

100. During the assist period, the left ventricle of the heart is unloaded with a pump flow rate of at least 2.5 L / min. The process of 100. The method of any one of claims 95 to 99, comprising:

101. The blood pump is a microaxial blood pump and unloads the left ventricle of the heart. The step of 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.

101. The method of claim 100, comprising:

102. inserting a balloon pump into the aorta of the heart; and Inflating and deflating the balloon to regulate blood flow within the aorta.

100. The method of any one of claims 95 to 99, comprising:

103. applying an extracorporeal membrane oxygenation system to the patient.

103. The method of any one of claims 95 to 102, comprising:

104. Any one of claims 95 to 103, wherein the pump is a catheter-based intravascular blood pump. The method described in paragraph .

105. increasing the left ventricular ejection fraction of said heart; reducing microvascular obstruction in said heart; reducing the left ventricular end-systolic volume of said heart; and reducing the left ventricular end-diastolic volume of said heart. The method of any one of claims 89 to 104, comprising at least one of:

106. The myocardial oxygen demand of the heart in the portion of the heart containing the infarct was measured over a period of at least 15 minutes. and then restoring oxygen supply to the portion of the heart containing the infarct.

106. The method of any one of claims 89 to 105, comprising:

107. The heart is subjected to reperfusion therapy while the heart is supported by a mechanical circulatory assist device.

107. The method of any one of claims 89 to 106, wherein unloading.

108. Reperfusion therapy is a treatment option for patients with coronary artery disease, such as direct percutaneous coronary intervention (PCI) and fibrinolytic cysts. The method according to any one of claims 89 to 107, comprising at least one of:

109. reducing circulating levels of brain natriuretic peptide (BNP) in the patient's blood. Course; Increasing the mRNA level of SERCA expression in cardiac cells of a patient near a myocardial infarction; and The present invention provides a method for treating a patient suffering from a myocardial infarction, comprising administering a steroid hormone to a patient suffering from a myocardial infarction, while maintaining the level of b-MHC in the non-infarcted region of the patient's heart. Decreased levels of calcineurin activity and type I collagen in human cardiac tissue The process of 109. The method of any one of claims 89 to 108, comprising:

110. removing the blood pump from the patient's heart after administering the reperfusion therapy.

110. The method of any one of claims 89 to 109, comprising:

111. Increasing blood flow to cardiac tissue of a patient near the myocardial infarction 111. The method of any one of claims 89 to 110, comprising:

112. By reducing maladaptive cardiac remodeling in human patients with persistent myocardial infarction 1. A method for preventing or limiting the effects of heart failure in a patient, comprising: A transvalve blood pump comprising a rotor and a cannula is percutaneously inserted into the patient's vascular system. The distal end of the cannula is located in the left ventricle of the patient's heart and the pump is inserted into the aorta. positioning the cannula with the proximal end positioned across the aortic valve of the heart; Before reperfusing the heart, the deployed pump was turned on to deliver at least 2.5 L / min of blood. and pumping the left ventricle at a pump flow rate of 100 rpm for a period of at least 30 minutes but not more than 60 minutes. unloading; and applying coronary reperfusion therapy to said heart after said assist period. The method comprises:

113. 113. The method of claim 112, wherein the pump is operated for a 30 minute assist period.

114. 113. The method of claim 112, wherein the pump is operated at a pumping rate of at least 3.5 L / min of blood flow. method.

115. Continuing operation of the pump in parallel with application of coronary reperfusion.

113. The method of claim 112, comprising:

116. The pump was operated in parallel with the application of coronary reperfusion for a total assist period of at least 3 hours. Continued operation of 113. The method of claim 112, comprising:

117. Reducing at least one of infarct size and left ventricular scar size.

113. The method of claim 112, comprising:

118. The heart is then fully unroofed to alter gene expression in cells within the myocardial infarction area. operating the pump to 113. The method of claim 112, comprising:

119. The levels of BAX protein and activated caspase 3 antibody in cardiac tissue from patients with myocardial infarction lowering the bell; Increased levels of BCL-2 and BCL-XL proteins in cardiac tissue from patients near myocardial infarction a step of: Stromal cell-derived factor 1α (SDF-1α) protein levels in cardiac tissue from patients near myocardial infarction increasing the amount of A method for maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients near myocardial infarction Course; Upregulation of DPP-4 protein expression and activity in cardiac tissue from patients with myocardial infarction limiting the modulation; reducing circulating levels of brain natriuretic peptide (BNP) in the patient's blood; Increasing the mRNA level of SERCA expression in cardiac cells of a patient near a myocardial infarction; and The present invention provides a method for treating a patient suffering from a myocardial infarction, comprising administering a steroid hormone to a patient suffering from a myocardial infarction, while maintaining the level of b-MHC in the non-infarcted region of the patient's heart. Decreased levels of calcineurin activity and type I collagen in human cardiac tissue The process of 119. The method of claim 118, comprising at least one of:

120. 113. The method of claim 112, wherein the heart has a sum of ST segment elevation (ΣSTE) greater than 4. 。

121. 121. The method of claim 120, wherein the heart has a ΣSTE of greater than 6.

122. 113. The method of claim 112, wherein the patient is not in cardiogenic shock.

123. The heart is supported by an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump. Assisting process 113. The method of claim 112, comprising:

124. providing a drug therapy to the patient in combination with actuation of the pump.

113. The method of claim 112, comprising:

125. Pharmacological treatments include beta-blockers, afterload reducing agents, neurohormonal agents, and ACE inhibitors.

125. The method of claim 124, further comprising providing the patient with a medication comprising at least one of the following substances: How to post.

126. Reperfusion therapy is a treatment option for patients with coronary artery disease, such as direct percutaneous coronary intervention (PCI) and fibrinolytic cysts.

113. The method of claim 112, comprising at least one of:

127. 127. The method of claim 126, wherein PCI comprises implanting a stent in the patient.

128. By reducing maladaptive cardiac remodeling in human patients with persistent myocardial infarction 1. A cardioprotective system for preventing or limiting the effects of heart failure in a patient, comprising: A blood pump comprising a rotor and a cannula, the rotor being inserted into the left ventricle of the patient's heart. The cannula is inserted into the aorta with the distal end of the cannula positioned within the aorta and the proximal end of the pump positioned within the aorta. the blood pump is percutaneously inserted into the patient's vascular system so as to be positioned across the aortic valve of the heart. the blood pump configured to be manually inserted; Coronary reperfusion therapy devices; and Before activation of the coronary reperfusion therapy device, a pump flow rate of at least 2.5 L / min of blood flow is used. and (c) providing a second ventricular flow to the left ventricle to unload the left ventricle for an assist period of from 30 minutes to less than 60 minutes. a controller coupled to the pump for programming the pump; The system comprises:

129. 129. The system of claim 128, wherein the pump is operated for a 30 minute assist period.

130. The pump is configured to operate in parallel with the application of a coronary reperfusion device. The system of claim 128.

131. 12. The method of claim 1, wherein the pump is configured to operate for a total assistance period of 3 hours.

30. The system according to claim 30.

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