System and method for left ventricular unloading for treating myocardial infarction

Abstract

We provide herein a method of preventing or limiting the effects of heart failure in a human patient with persistent myocardial infarction by reducing poorly adapted cardiac remodeling in the patient. The method includes percutaneously inserting a transcatheter blood pump comprising a trochanter and a cannula into the vasculature of the patient and positioning the cannula across the aortic valve of the heart of the patient with the distal end of the cannula located in the left ventricle of the heart and the proximal end of the pump located in the aorta. The method then includes operating the positioned pump to unload the left ventricle at a blood flow pumping rate of at least 2.5 L / min for a support period of between at least 30 minutes and less than 60 minutes prior to reperfusion of the heart. Then, after the support period, the method includes applying coronary reperfusion therapy to the heart.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority under 35 U.S.C. §119(e) from U.S. Provisional Application Serial No. 62 / 615,462 filed on January 10, 2018, U.S. Provisional Application Serial No. 62 / 732,936 filed on September 18, 2018, and U.S. Provisional Application Serial No. 62 / 758,164 filed on November 9, 2018, the contents of which are hereby incorporated by reference in their entirety. Background Art

[0002] Acute myocardial infarction (AMI) due to coronary artery occlusion is the leading cause of morbidity and mortality in humans worldwide. The current paradigm for the treatment of AMI focuses on primary reperfusion, that is, rapid restoration of coronary blood flow as soon as possible after AMI to reestablish myocardial oxygen supply. However, despite timely reperfusion, up to 25% of patients experiencing their first AMI will develop heart failure (HF) within one year. Contemporary ST-segment elevation AMI (STEMI) hospitalization management focuses on reducing the door-to-balloon (DTB) time to reduce infarct size. However, despite intensive resource allocation within 90 minutes to achieve DTB time, the incidence of heart failure after AMI remains high. For every 5% increase in myocardial infarction size, 1-year all-cause mortality and HF hospitalization rates increase by 20%, which imposes a significant burden on medical resources. For these reasons, new methods to limit myocardial damage and subsequent ischemic HF remain a major unmet need for AMI patients.

[0003] One explanation for these adverse outcomes is that primary reperfusion paradoxically may aggravate myocardial damage, which is called ischemia-reperfusion injury (IRI). Previous attempts to limit IRI include vascular regulation methods and pharmacological methods for activating the activity of the reperfusion injury rescue kinase (RISK) pathway, but the clinical benefits of those methods are not necessarily optimal. The key obstacle to these cardioprotective strategies is the requirement for rapid coronary reperfusion, which potentially leaves enough time for any therapeutic effect on myocardial damage. Therefore, there is a need for an improved strategy for limiting myocardial damage by promoting a cardioprotective mechanism that reduces or eliminates IRI.

[0004] Over the past decade, there has been an increasing reliance on mechanical support devices in routine clinical practice. Support devices include percutaneously delivered transvalvular axial flow pumps (TV-pumps), intra-aortic balloon pumps, intracorporeal axial flow catheters, and extracorporeal membrane oxygenation (ECMO) pumps, and have become popular in the treatment of myocardial injury. In the case of TV-pumps, such devices help mechanically pump blood out of the left ventricle of the heart and thereby unload the heart, rapidly reducing left ventricular (LV) wall pressure, stroke work, and myocardial oxygen demand, while amplifying systemic mean arterial pressure without the need for surgery. However, it has been reported that the use of TV-pumps alone did not significantly reduce the 30-day mortality of patients with cardiogenic shock, and on the contrary, in some patients, TV-pumps complicated acute myocardial infarction (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).

[0005] It has been proposed that a combination of mechanical support and primary reperfusion can limit myocardial damage in patients with AMI. It has been reported that by first unloading the LV with a TV-pump while delaying coronary reperfusion (primary unloading), myocardial infarct size was reduced by 40-50%, and myocardial levels of the cardioprotective chemokine stromal-derived factor 1 alpha (SDF-1 alpha) were increased (N. Kapur, "Mechanical Pre-Conditioning with Acute Circulatory Support Before Reperfusion Limits Infarct Size in Acute Myocardial Infarction", JACC: Heart Failure, Vol. 3, No. 11, November 2015).

[0006] A preliminary porcine model of AMI has been studied to compare primary reperfusion therapy with delayed reperfusion therapy until after unloading of the left atrium using a percutaneously delivered extracorporeal centrifugal pump, with preliminary indications that delayed coronary reperfusion (P-unloading) may reduce myocardial injury. Another study has applied a percutaneously delivered transvalvular pump directly into the left ventricle of animals and observed the consequences of unloading when coronary reperfusion was delayed for 60 minutes. The consequences for treating MI in humans are not well understood. Summary of the invention

[0007] The present disclosure relates to an improved method of supporting the heart of a human patient with a persistent myocardial infarction, with the following surprising results: the order and timing of applying support to the heart before reperfusion can improve the heart and reduce the effects of the infarction. The technology can be further applied to prevent or limit the effects of heart failure in human patients. This can be accomplished, for example, by reducing maladaptive cardiac remodeling in the patient. The method (and system configured for application) stabilizes or reduces the size of the infarction, which is beneficial to the patient's heart. Certain applications include applying a mechanical circulatory support device to reduce the size of the infarction; some applications include applying reperfusion therapy after a period of delay, wherein the heart is supported by the mechanical circulatory device. In general, the method is applied by taking an approach contrary to the conventional patterns and theories in the art, rather than immediately applying reperfusion therapy to a patient who has suffered a heart attack, the method (and system) first supports the heart by reducing myocardial oxygen demand (e.g., by unloading the heart) for a period of time, and then, after the support period, restores oxygen supply to the affected area of ​​the heart (e.g., by reperfusion). Thus, the method seeks to reduce the time between AMI and initiation of mechanical circulatory support, such a period conveniently referred to as "gate-to-unload". It has been found that taking such an approach can increase myocardial salvage in human hearts and reduce the size of infarcts in human hearts. Additionally, such an approach has the surprising effect of preventing or limiting the effects of heart failure in human patients, for example by reducing maladaptive cardiac remodeling in the patient.

[0008] According to an embodiment of the present disclosure, a method for supporting the heart of a human patient is provided. The method comprises the following steps: (i) inserting a mechanical circulatory support device into a human patient after a myocardial infarction, (ii) operating the mechanical circulatory support device for a predefined support time (support period) before reperfusing the heart, and (iii) applying reperfusion therapy to the heart after the support period (e.g., inserting a stent, or applying drug therapy to release a narrowed or occluded area in the coronary vasculature). The support period is preferably longer than 15 minutes. For example, the support period can be at least 30 minutes and less than 60 minutes. A mechanical circulatory support device is a heart assist device that operates to pump at a blood flow rate of at least 2.5 L / min.

[0009] According to another embodiment of the present disclosure, a method of supporting the heart of a patient with a persistent myocardial infarction is provided. The method includes the steps of percutaneously inserting a transvalvular blood pump into the patient and positioning the pump across the aortic valve of the patient's heart, wherein the distal end of the pump is located in the left ventricle of the heart. Then, before reperfusing the heart, the method continues with the steps of operating the positioned pump to unload the left ventricle at a blood flow pumping rate of at least 2.5 L / min for a pumping period of greater than 15 minutes. After the pumping period, the method then includes the step of treating the heart with reperfusion therapy.

[0010] According to another embodiment of the present disclosure, a method of reducing the size of a myocardial infarction scar in a patient's heart is provided. The method includes the steps of percutaneously inserting a transvalvular micro-axis blood pump into the patient and positioning the pump across the aortic valve of the patient's heart, wherein the distal end of the pump is located in the left ventricle of the heart. The method then includes, prior to reperfusing the heart, operating the positioned pump to unload the left ventricle at a blood flow pumping rate of at least 2.5 L / min for a pumping period longer than 15 minutes. After the pumping period, the method includes applying reperfusion therapy to the heart.

[0011] According to another embodiment of the present disclosure, a method of supporting a heart with myocardial infarction is provided. The method includes percutaneously inserting a mechanical circulatory support device into a patient after myocardial infarction of the patient's heart, operating the device to unload the left ventricle at a blood flow rate of at least 2.5 L / min (e.g., 3.5 L / min) during an unloading period of longer than 15 minutes before reperfusing the heart, and applying reperfusion therapy to the heart after the unloading period.

[0012] According to another embodiment of the present disclosure, a method of supporting the heart of a patient with myocardial infarction is provided. The method comprises the following steps: (i) reducing the levels of BAX protein and active caspase-3 antibody in the patient's heart tissue in the myocardial infarction area (at-risk area), and (ii) increasing the levels of BCL-2 and BCL-XL proteins in the patient's heart tissue in the myocardial infarction area.

[0013] According to another embodiment of the present disclosure, a method for supporting the heart of a patient with myocardial infarction is provided, the method comprising at least one of the following: (i) reducing the levels of BAX protein and active caspase-3 antibody in the patient's heart tissue near the myocardial infarction, (ii) increasing the levels of BCL-2 and BCL-XL proteins in the patient's heart tissue in the myocardial infarction area, (iii) increasing the protein level of matrix-derived factor 1α (SDF-1α) in the patient's heart tissue in the myocardial infarction area, (iv) maintaining the activity levels of MMP-2 and MMP-9 enzymes in the patient's heart tissue in the myocardial infarction area, (v) limiting the upregulation of DPP-4 protein expression and activity in the patient's heart tissue near the myocardial infarction, (vi) reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood, (vii) increasing the mRNA level of SERCA expression in the patient's heart cells near the myocardial infarction, and (viii) reducing calcineurin activity and type I collagen levels in the myocardial infarction area, while maintaining the b-MHC level in the non-infarct area of ​​the patient's heart.

[0014] According to another embodiment of the present invention, a method of supporting the heart of a patient with myocardial infarction is provided, the method comprising increasing the protein level of stromal derived factor 1 alpha (SDF-1 alpha) in the patient's heart tissue near the myocardial infarction. The method may include maintaining the activity levels of MMP-2 and MMP-9 enzymes in the patient's heart tissue in the area of ​​myocardial infarction. The method may also include limiting the upregulation of DPP-4 protein expression and activity in the patient's heart tissue in the area of ​​myocardial infarction. Such a method may be performed using a mechanical circulatory support device such as a transvalvular or extracorporeal pump.

[0015] According to another embodiment of the present disclosure, a method for supporting the heart of a patient with myocardial infarction is provided, the method comprising reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood. The method also comprises increasing the mRNA level of SERCA expression in the patient's heart tissue in the myocardial infarction area. The method further comprises reducing the level of calcineurin activity and type I collagen in the patient's heart tissue near the myocardial infarction, while maintaining the b-MHC level in the non-infarcted area of ​​the patient's heart.

[0016] According to another embodiment of the present disclosure, a method for supporting the heart of a patient with myocardial infarction is provided, the method comprising (i) reducing the levels of BAX protein and active caspase-3 antibody in the patient's heart tissue in the myocardial infarction area, (ii) increasing the levels of BCL-2 and BCL-XL proteins in the patient's heart tissue in the myocardial infarction area, (iii) increasing the protein level of stromal derived factor 1α (SDF-1α) in the patient's heart tissue in the myocardial infarction area, (iv) maintaining the activity levels of MMP-2 and MMP-9 enzymes in the patient's heart tissue in the myocardial infarction area, (v) limiting the upregulation of DPP-4 protein expression and activity in the patient's heart tissue in the myocardial infarction area, (vi) reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood, (vii) increasing the mRNA level of SERCA expression in the patient's heart cells in the myocardial infarction area, and (viii) reducing calcineurin activity and type I collagen levels in the patient's heart tissue in the myocardial infarction area, while maintaining the b-MHC level in the non-infarct area of ​​the patient's heart.

[0017] According to an embodiment of the present disclosure, a cardiac protection system for supporting the heart of a patient with a persistent myocardial infarction is provided. The system includes a mechanical circulatory support device and a reperfusion therapy device configured to be inserted into the patient. The system is configured so that before operating the reperfusion therapy device, the mechanical circulatory support device is configured to operate at a blood flow rate of at least 2.5 L / min for a support period of greater than 15 minutes.

[0018] According to another embodiment of the present disclosure, a cardiac protection system for supporting the heart of a patient with a persistent myocardial infarction is provided. The system includes a blood pump configured to be percutaneously inserted into a patient after a myocardial infarction, the pump being sized and shaped to be positioned across the aortic valve of the patient's heart, wherein the distal end of the pump is configured to be located in the left ventricle of the heart. The system also includes a reperfusion therapy device. The system is configured so that the blood pump is programmed to operate before operating the reperfusion therapy device, and thereafter pumps blood at a blood flow rate of at least 2.5 L / min within a pumping period longer than 15 minutes.

[0019] According to further embodiments of the present disclosure, there is provided a method of treating a human heart having a persistent myocardial infarction having an infarct size and located within a portion of the heart, the method comprising reducing the infarct size.

[0020] According to another embodiment of the present disclosure, a method is provided for preventing or limiting the effects of heart failure in a human patient with a persistent myocardial infarction by reducing maladaptive cardiac remodeling within the patient. An adaptation of the method includes 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, wherein 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. Prior to reperfusing the heart, the method then includes the steps of operating the positioned pump to unload the left ventricle at a blood flow pumping rate of at least 2.5 L / min for a support period of between at least 30 minutes and less than 60 minutes. After the support period, the method then includes the step of applying coronary reperfusion therapy to the heart. Maladaptive cardiac remodeling includes, but is not limited to, one or more of the following: changes in the size, shape, structure, and function of the heart.

[0021] According to another embodiment of the present disclosure, a system is provided for preventing or limiting the effects of heart failure in a human patient with a persistent myocardial infarction by reducing maladaptive cardiac remodeling in the patient. The system includes a blood pump comprising a rotor and a cannula, the blood pump being configured to be percutaneously inserted into the patient's vascular system so that the cannula is positioned across the aortic valve of the patient's heart, wherein 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. The system may additionally include a controller coupled to the pump to control the operation of the pump. The system also includes a coronary reperfusion therapy device. In this embodiment, the controller programs the blood pump to unload the left ventricle at a blood flow pumping rate of at least 2.5 L / min during a support period of between at least 30 minutes and less than 60 minutes before operating the coronary reperfusion therapy device.

[0022] In some embodiments, the support period is approximately 30 minutes, or can be between 15 and 30 minutes. In some embodiments, the support period is longer than 30 minutes or longer than 45 minutes. In some embodiments, the mechanical circulatory support device pumps at a blood flow rate of at least 3.5L / min. In some embodiments, the device provides a cannula that is placed in the patient's heart and pumps blood through the cannula. In some embodiments, the device is a microaxial blood pump having a motor and an onboard rotor and stator, which microaxial blood pump is mechanically operated to pump blood from the heart; in some embodiments, the device is operated by an external motor, and the pump motor can be deployed outside the patient and rely on a long cannula extending through the patient's vasculature to the heart. An example of a suitable mechanical circulatory support device is a transvalvular microaxial pump (e.g., such as the Impella CP In some embodiments, the method comprises inserting a transvalvular microaxial blood pump (TV pump) comprising a rotor and a cannula percutaneously into the patient's vasculature and positioning the cannula across the aortic valve of the patient's heart, wherein 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. An extracorporeal pump (e.g., a Tandem heart) may also be used to unload a heart chamber (such as the atrium or ventricle) according to the methods disclosed herein. The left or right atrium may be unloaded, and the right ventricle may also be unloaded.

[0023] In some embodiments, the mechanical circulatory support device unloads the heart simultaneously with reperfusion (e.g., after unloading the heart). The unloading period can be at least 30 minutes, 3 hours, or longer. Various mechanical circulatory support devices can be used alone or in combination in the methods of the present disclosure. For example, an intra-aortic balloon pump can be used to provide support to the heart after a period of delay. In some embodiments, a combination of devices is used. For example, a TV-pump can be used to unload the left ventricle while also using an extracorporeal membrane oxygenation (ECMO) pump, or an intra-aortic balloon pump or other mechanical circulatory support system in combination. In some embodiments, the reperfusion therapy in the methods of the present disclosure includes at least one of primary percutaneous coronary intervention (PCI) and fibrinolysis.

[0024] In some implementations, the method includes one or more of the following steps: (i) reducing the level of BAX protein and active caspase-3 antibody in cardiac tissue of patients near myocardial infarction; (ii) increasing the level of BCL-2 and BCL-XL proteins in cardiac tissue of patients near myocardial infarction; (iii) increasing the protein level of matrix-derived factor 1α (SDF-1α) in cardiac tissue of patients near myocardial infarction; (iv) maintaining the activity level of MMP-2 and MMP-9 enzymes in cardiac tissue of patients near myocardial infarction; (v) limiting the upregulation of DPP-4 protein expression and activity in cardiac tissue of patients near myocardial infarction; (vi) reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood; (vii) increasing the mRNA level of SERCA expression in cardiac cells of patients near myocardial infarction; and (viii) reducing the level of calcineurin activity and type I collagen in cardiac tissue of patients near myocardial infarction, while maintaining the level of b-MHC in non-infarcted areas of the patient's heart. The method can be applied so that any combination (or all) of the aforementioned steps are performed. Implementing one or more of steps (i)-(viii) in any of the methods of the foregoing embodiments has the surprising result of preventing or limiting the effects of heart failure in a human patient. This can be accomplished, for example, by reducing maladaptive cardiac remodeling in the patient.

[0025] In some implementations, the method can be used to reduce infarct size in patients with elevated ∑STE levels. For example, the method can be applied by unloading the left ventricle of a patient with an MI and ∑STE level of at least 4 (e.g., 5 or 6 or greater than 6), and reducing the infarct size in the patient. In certain implementations, the method can be used to reduce infarct size and left ventricular scar size. In some implementations, the method also includes increasing blood flow from the left ventricle of the patient's heart by applying mechanical circulatory support to the patient. In certain implementations, increased blood flow is provided at a blood flow rate of at least 2.5 L / min during an unloading period of longer than 15 minutes. In certain implementations, the method also includes a step of applying reperfusion therapy to the patient's heart tissue near the myocardial infarction after applying mechanical circulatory support. In other implementations, the system includes one or more of the following devices that operate after or during the operation of the mechanical circulatory support device: an intra-aortic balloon pump and an extracorporeal membrane oxygenation (ECMO) pump.

[0026] In some implementations, reducing infarct size is accomplished by reducing myocardial oxygen demand of the heart in the portion of the heart containing the infarct, followed by restoring oxygen supply to the portion of the heart containing the infarct. In certain implementations, the method includes reducing the level of at least one of BAX protein and active caspase-3 in cardiac tissue. In other implementations, the method includes increasing the level of at least one of BCL-2 and BCL-XL. In additional implementations, the method includes increasing the myocardial salvage index (MSI) of the heart.

[0027] In some implementations, the method further comprises the steps of: (i) inserting a blood pump into the patient's vasculature, (ii) actuating the pump to adjust blood flow within the vasculature during a support period before applying reperfusion therapy to the heart, and (iii) applying reperfusion therapy to the heart after the support period. In some implementations, the support period is at least 15 minutes. In other implementations, the support period is at least 30 minutes, between about 20 minutes and about 40 minutes, or at least 45 minutes.

[0028] In other implementations, the method further comprises the step of unloading the left ventricle of the heart at a pumping rate of at least 2.5 L / min during the support period. In some implementations, the blood pump is a micro-axis blood pump, and unloading the left ventricle of the heart comprises inserting the distal end of the pump into the left ventricle and inserting the proximal end of the pump into the aorta, and actuating the pump to pump blood from the left ventricle into the aorta. In certain implementations, the method comprises the steps of: (i) inserting a balloon pump into the aorta of the heart, and (ii) inflating and defl ucing the balloon to adjust blood flow in the aorta. In other implementations, the pump is a catheter-based intravascular blood pump.

[0029] In some implementations, the method includes at least one of: (i) increasing the left ventricular ejection fraction of the heart, (ii) reducing microvascular obstruction in the heart, (iii) reducing the left ventricular end-systolic volume of the heart, and (iv) reducing the left ventricular end-diastolic volume of the heart. In other implementations, the method includes reducing the myocardial oxygen demand of the heart in the portion of the heart containing the infarction over a period of at least 15 minutes, followed by restoring oxygen supply to the portion of the heart containing the infarction. In certain implementations, simultaneously with performing reperfusion therapy on the heart, the heart is unloaded by a mechanical circulatory support device. In some implementations, the reperfusion therapy includes at least one of primary percutaneous coronary intervention (PCI) and fibrinolysis.

[0030] In other implementations, the method further comprises the following steps: (i) reducing the circulating level of brain natriuretic peptide (BNP) in the patient's blood, (ii) increasing the mRNA level of SERCA expression in the patient's heart cells near the myocardial infarction, and (iii) reducing the level of calcineurin activity and type I collagen in the patient's heart tissue near the myocardial infarction, while maintaining the b-MHC level in the non-infarcted area of ​​the patient's heart. In some implementations, the method further comprises removing the blood pump from the patient's heart after applying reperfusion therapy. In other implementations, the method further comprises increasing blood flow to the patient's heart tissue near the myocardial infarction.

[0031] In some implementations, the method according to any of the foregoing embodiments may include continuing the operation of the pump in parallel with the application of coronary reperfusion. In certain implementations, the pump operates in parallel with the application of coronary reperfusion for a total support period of at least 3 hours. In other implementations, the method may include operating the pump so as to fully unload the heart, thereby changing gene expression in cells within the myocardial infarction area. Unloading the heart in this manner has the advantage of preventing or limiting the effects of heart failure in human patients. This can be accomplished, for example, by reducing maladaptive cardiac remodeling in the patient. In other implementations, the method may include providing drug therapy to the patient in combination with operating the pump. In certain implementations, drug therapy may include providing the patient with an agent comprising at least one of the following: a beta blocker, an afterload reducer, a neurohormonal agent, and an ACE inhibitor.

[0032] Further advantageous implementations of the present disclosure are provided in the examples and embodiments listed below.

[0033] After reviewing this disclosure, variations and modifications will occur to those skilled in the art. The disclosed features may be implemented with any combination and sub-combination (including multiple dependent combinations and sub-combinations) of one or more other features described herein. The various features described or illustrated, including any components thereof, may be combined or integrated in other systems. In addition, certain features may be omitted or not implemented. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] The foregoing and other objects and advantages will become apparent upon consideration of the following detailed description considered in conjunction with the accompanying drawings, in which like reference characters refer to like parts throughout, and in which: Figure 1 An illustrative cardiac protection system according to an implementation of the present disclosure is shown; Figure 2 An illustrative method of supporting the heart of a patient having an ongoing myocardial infarction is shown; Figure 3 Shows the use of Figure 2 A flowchart of the research method in Example 1 is provided for the method overview; Figure 4 Shows the use of Figure 2 Scatter plot of the time of unloading to the balloon studied in Example 1 of the method; Figures 5A-5C Shows the use of Figure 2 CMR box-and-whisker plot of study results stratified by ST-elevation sum in Example 1 of the method; Fig. 6A A flow chart is shown which illustrates the Figure 2 In the study of Example 2 of the method, the effect 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); Figure 6B The percentage of infarcted area to area at risk for each group according to the study of Example 2 is shown (1-way analysis with variance = 0.017 across all 4 groups); Fig. 7A Shown are genomic heatmaps illustrating shifts in gene expression between reperfusion alone (Group 1) and sham controls with left ventricular (LV) unloading for 30 min prior to reperfusion (Group 3) (n=3 per group); Figure 7B Shown in figure Figure 3 A graph of additional results from the study cited in Fig. 7ARelative messenger RNA levels of representative genes of key components of the electron transport chain within the infarct zone of Group 1 (blue) or Group 3 (orange), *p < 0.05 vs. sham control group; #p < 0.05 vs. primary reperfusion; Figure 7C The sham control group and the Fig. 7A Representative transmission electron micrographs of cardiomyocyte mitochondria in the infarcted area of ​​Groups 1 and 3; Fig. 8A and Figure 8B Shown according to Figure 2 Results of a second study performed using the method of , which shows Western blots and quantification of left ventricular (LV) protein levels of stromal derived factor-1α (SDF1α) and CXCR4 normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for a sham control group and each group had acute myocardial infarction with quantification (Group 1: reperfusion alone; Group 2: LV unloading within 15 min before reperfusion; Group 3: LV unloading 30 min before reperfusion; and Group 4: LV unloading 30 min after reperfusion; n=4 for each group); Figure 8C and Fig.8D The results from the sham control group and Fig. 8A Quantification of SDF1 and CXCR4 mRNA levels obtained in tissues within the infarct area of ​​Groups 1 and 3 (n=4 per group); Fig. 8E and Fig.8F The results from the sham control group and Fig. 8A Quantification of SDF1 and CXCR4 mRNA levels obtained in tissues within the infarct area of ​​Groups 1 and 3 (n=4 per group); Figure 8G and Figure 8H The results show that the Fig. 8A Quantification of dipeptidyl peptidase-4 (DPP4) protein levels and activity in samples obtained from the infarct area of ​​groups 1 and 3 (n=4 per group), *p<0.05 versus sham control group, #p<0.05 versus group 1; Figure 8I Shown in use Figure 2 Quantification of infarct size as a percentage of the area at risk in groups subjected to LV unloading for 30 min (with intracoronary delivery of vector or CXCR4 inhibitor AMD3100) followed by reperfusion (n=4 per group); Figure 8J Shows the use of Figure 2Quantification of phosphorylated and total Akt, phosphorylated and total extracellular-regulated kinase (ERK), and phosphorylated and total glycogen synthase kinase 3β (GSK3b) in the infarct area (n=4 per group) after the method of , *p<0.05 vs. LV unloading+vehicle; Figures 9A-9C The sham control group and Fig. 8A Western blots of pro-apoptotic (Bax, caspase-3) and anti-apoptotic (B-cell lymphoma-2 [BCL-2] and B-cell lymphoma-extra large [BCL-XL]) proteins normalized to beta-actin levels in the infarcted areas of groups 1 and 3 (n=3 per group) as defined in Figure 2 and corresponding quantification of left ventricular (LV) protein levels, *p<0.05 versus sham control group; #p<0.05 versus group 1; Fig.9D and Fig.9E Shown is TUNEL-positive staining of DNA fragments from LV tissue from sham control group and from Fig. 9A within the infarct area in Groups 1 and 3 (n = 3 in each group); Fig. 10A Shown in use Figure 2 Quantification of LV scar size 28 days after primary reperfusion or primary unloading using late gadolinium enhancement (LGE) following the methods of cardiac magnetic resonance imaging (CMR) or according to anatomical pathology in the infarct zone (n=6 per group); Fig. 10B Regression plots showing the correlation between LGE-CMR and anatomic pathological quantification of LV scar size are shown; Fig. 10C and Fig. 10D Representative CMR images showing LV scar within blue or red circles are shown; Fig.10E Circulating SDF-1α levels within 28 days after P-reperfusion (PR) or P-unloading (PU) are shown (n=4 per group); Fig.10F Shown are the protein levels of SDF-1a in the infarct area 28 days after sham operation, P-reperfusion, or P-unloading (n=6 per group); Figure 10G Regression plots are shown showing the correlation between LV scar size as a percentage of total left ventricle versus plasma SDF-1a levels 28 days after myocardial infarction. *p<0.05 vs. sham control group; Relative to P-reperfusion; Figures 11A-11C Shown in use Figure 2Methods Circulating, mRNA, and protein levels of B-type natriuretic peptide (BNP) from LV tissue (non-infarcted area) 28 days after primary reperfusion or primary unloading; Figures 11D-11G Shown in use Figure 2 Messenger RNA (mRNA) levels of sarcoplasmic / endoplasmic reticulum calcium ATPase (SERCA), calcineurin, type I collagen (COL1), and beta-myosin heavy chain (b-MHC) from LV tissue (non-infarcted area) 28 days after primary reperfusion or primary unloading; and Fig.12 Schematic illustration of the effect of mechanically unloading the left ventricle for a minimum of 30 min prior to reperfusion, which limits the expression of proteolytic enzymes that degrade stromal-derived factor-1α (SDF1a), thereby increasing cardioprotective signaling that improves cell survival, and reduces 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

[0035] In order to provide an overall understanding of the systems and methods, certain illustrative implementations will be described. Although the implementations and features described herein are specifically described as being used in combination with a circulatory and reperfusion therapy system, it will be understood that the components and other features outlined below may be combined with one another in any suitable manner and may be applicable and applied to other types of circulatory therapy and reperfusion therapy devices. In addition, it should be noted that while certain implementations are discussed herein with respect to specific devices for circulatory and reperfusion therapy, these various implementations may be used in various combinations to both increase the efficacy of the treatment and maintain the life of a patient following an AMI.

[0036] Figure 1A system 100 for providing a combination of mechanical support and primary reperfusion according to an implementation of the present disclosure is illustrated. The system 100 is intended to limit myocardial damage in a human patient 110 who has experienced an AMI in a heart 120. The system 100 includes a circulation unit 130 and a device (or other source) 140 for providing reperfusion therapy. The circulation unit 130 communicates with a control unit 150. The control unit 150 can monitor signals emitted by the circulation unit 130 and thus control the operation of the device (or other source) including the circulation unit 130. These signals can indicate any of the following: the operating state of the circulation unit 130, the position and state of the device 140 for reperfusion therapy, and the state of the patient's heart. Samples from AMI patients such as blood or heart tissue can be obtained from the circulation unit 130 or the device 140 for reperfusion therapy, or from a biopsy or other source for characterization and further testing. This can be done by extracting various indicators from these samples via a test kit or laboratory so that clinicians can monitor them. Such indicators may include, for example, myocardial infarction scar size, and associated parameters as will be described in detail in the following sections.

[0037] The circulatory unit 130 includes a mechanical circulatory support device that can be inserted, for example, into the left ventricle of a patient's heart. Such a mechanical circulatory support device is capable of altering blood flow above and beyond the actual cardiac output of the heart. For example, a mechanical circulatory support device can be inserted into the left ventricle of a patient's heart having an AMI and actuated to unload the heart by pumping blood out of the ventricle. This can assist the heart in several possible ways. For example, myocardial wall stress is reduced. This is beneficial because the unloading mechanism may aid in myocardial salvage and repair. According to an implementation of the present disclosure, the mechanical circulatory support device may include a transvalvular microaxial blood pump. Examples of such blood pumps include, but are not limited to, the Impella 2.5 TM and Impella Other types of mechanical circulatory support devices may be used to assist the heart, such as an extracorporeal pump. For example, extracorporeal membrane oxygenation (ECMO) or an intra-aortic balloon pump may be used. In some adaptations, a transvalvular pump is used in combination with another such device.

[0038] In addition to the mechanical circulatory support device, the circulation unit 130 may also include an additional pump device to assist in unloading the heart. Examples of such pump-assisted devices include, but are not limited to, any of the following: an intra-aortic balloon pump and an extracorporeal membrane oxygenation (ECMO) pump. For example, a transvalvular pump can unload the heart, while the balloon pump or ECMO device is used to further assist the patient. Additionally, the circulation device may include a cannula portion that is fluidically connected to the pump, wherein the distal end of the cannula can be positioned within the patient's heart, and the pump can be positioned in any of the following: (a) within the heart with the cannula, (b) outside the heart but within the patient, and (c) outside the patient.

[0039] In an implementation of the present disclosure, device 140 is used to administer reperfusion therapy to a patient experiencing an AMI. Such reperfusion therapy includes, for example, primary percutaneous coronary intervention (PCI). These procedures may involve the use of a coronary stent delivered into the distal left anterior descending artery (LAD). Examples of such coronary stents include, but are not limited to, the Promus PREMIER TM and REBEL TM Bare metal platinum-chromium coronary stents, and SYNERGY TM Bioresorbable polymer stents, all manufactured by Boston Scientific Corporation of Marlborough, Mass. In certain embodiments, reperfusion therapy 140 may include a drug or agent capable of assisting fibrinolysis, thereby providing reperfusion therapy in combination with, or as an alternative to, a stent or other device.

[0040] The kit or laboratory is capable of generating the following clinical indicators associated with myocardial infarction: protein levels of BAX, BCL-2, BCL-XL, DPP-4 and matrix-derived factor 1α (SDF-1α), active caspase-3 antibody levels, MMP-2 and MMP-9 enzyme levels in patient myocardial tissue near the site of myocardial infarction or in the area of ​​myocardial infarction; mRNA levels of SERCA expression in patient cardiac cells near the site of myocardial infarction or in the area of ​​myocardial infarction; calcineurin activity levels and type I collagen levels near the site of myocardial infarction or in the area of ​​myocardial infarction; brain natriuretic peptide (BNP) levels in blood taken from the left ventricle of the patient's heart; myocardial salvage index; and the sum of (one or more) ST elevations from the electrocardiogram.

[0041] Figure 2 A flow chart of an illustrative method 200 for unloading the left ventricle of a heart in a patient with AMI is shown. The method begins at step S210, where a circulatory device (such as a Figure 1The mechanical circulation device of the central circulation unit 130 is inserted into the patient. Such insertion can be achieved by using a vascular access sheath deployed into the right internal jugular vein, the left carotid artery, and one or more lateral arteries and veins of the patient. Additional clinical details of such an insertion process and associated exemplary supporting data of the method 200 are detailed in Examples 1 and 2 in the following sections.

[0042] The method 200 then continues to step S220, wherein in step S230 the circulation device is operated to support the heart, for example by unloading the patient's heart after a myocardial infarction. Here the circulation device is operated to achieve a pumping rate of at least 2.5 L / min of blood flow from the left ventricle of the heart. In certain implementations, the circulation device is operated to achieve a blood flow rate from the left ventricle of the heart of at least 3.5 L / min of blood flow per cardiac output. Unloading is performed for a period of time (support period t_sp) that is long enough to promote a reduction in infarct size. In some implementations, the operation of the circulation device is terminated after the support period t_sp has passed. In other implementations, the support period is used only as a marker indicating that time t_sp has passed since the circulation device began operating, and the operation of the circulation device does not need to be stopped after t_sp has passed. As described in detail in the following section, Example 1 provides supportive data for the step of unloading the patient's heart after a myocardial infarction using the method 200 of the present disclosure. According to some implementations, the support period t_sp is longer than 15min. In other implementations, the support time t_sp is longer than 30 minutes.

[0043] After the heart has been unloaded for the support period in step S230, the method proceeds to step S240 in which reperfusion therapy is applied to the patient's heart. Reperfusion therapy is administered using a reperfusion device, drug, or other technique. Figure 1 A reperfusion device 140 is applied. Clinical details of such a reperfusion therapy procedure and associated exemplary supporting data for method 200 are provided in Examples 1 and 2 below. According to an implementation of the present disclosure, reperfusion therapy may be applied to the patient's heart after the left ventricle of the heart is unloaded. In other implementations, reperfusion therapy may be applied to the patient's heart while the left ventricle is still unloaded by the circulator unit. In this implementation, the concurrent use of the reperfusion device and the circulation device is only performed after the heart has been unloaded by the circulation device for the length of the support period t_sp.

[0044] It is currently believed that supporting the heart after MI using mechanical circulatory support prior to the application of reperfusion therapy will have a beneficial effect on the patient's heart. One or more benefits may be detected in a tissue or blood sample taken from the patient. Such benefits may include one or more of the following results: reducing the levels of BAX protein and active caspase-3 antibody in cardiac tissue of patients near myocardial infarction; increasing the levels of BCL-2 and BCL-XL proteins in cardiac tissue of patients near myocardial infarction; increasing the protein levels of stromal derived factor 1 alpha (SDF-1 alpha) in cardiac tissue of patients near myocardial infarction; maintaining the activity levels of MMP-2 and MMP-9 enzymes in cardiac tissue of patients near myocardial infarction; limiting the upregulation of DPP-4 protein expression and activity in cardiac tissue of patients near myocardial infarction; reducing the circulating levels of brain natriuretic peptide (BNP) in blood taken from the left ventricle of the patient's heart; increasing the mRNA level of SERCA expression in cardiac cells of patients near myocardial infarction; reducing the levels of calcineurin activity and type I collagen in cardiac tissue of patients near myocardial infarction, while maintaining the levels of b-MHC in non-infarcted areas of the patient's heart; reducing infarct size; increasing the myocardial salvage index of the heart; and exhibiting a sum of cardiac ST elevations greater than six. These results can be achieved using the systems and methods identified in the present disclosure.

[0045] Examples 1 and 2, detailed below, illustrate the results of studies performed by applying the methods of the present invention to patients who have suffered a heart attack. These studies were conducted by inserting a blood pump into the vasculature of a patient after the patient has suffered an AMI, but before reperfusion therapy is applied to the heart, actuating the pump to adjust blood flow within the vasculature during a support period; and then applying reperfusion therapy to the heart after the support period. The results indicate that infarct size is reduced and the myocardial salvage index is increased compared to conventional methods of applying reperfusion therapy immediately (or as quickly as possible) after the infarction. Additional results indicate that the method increases the left ventricular ejection fraction of the heart, reduces microvascular obstruction in the heart, reduces the left ventricular end-systolic volume of the heart, and reduces the left ventricular end-diastolic volume of the heart.

[0046] Example 1: DTU-STEMI pilot study The safety and feasibility of activating an unloading device with or without delayed coronary reperfusion was investigated to begin exploring whether delayed reperfusion improves myocardial salvage in human patients in the setting of unloading. The Gate-to-Unloading in STEMI Pilot trial is the first exploratory study to test the feasibility and safety of left ventricular (LV) unloading prior to reperfusion in STEMI in the absence of cardiogenic shock.

[0047] A. Methods The DTU-STEMI study is a prospective, multicenter, randomized pilot trial involving 14 centers in the United States to explore the feasibility, safety, and potential benefits of mechanical unloading prior to coronary reperfusion in patients presenting with anterior STEMI. All patients underwent acute mechanical unloading using the Impella CP system (Abiomed, Danvers, Mass.), and were then randomized to one of two arms: LV unloading, followed by immediate reperfusion (U-IR), or LV unloading with a 30-minute delay to reperfusion (U-DR). The process flow of the U-IR and U-DR methods is described in Figure 3 The comparison was specifically designed to precondition the myocardium for 30 minutes prior to reperfusion by comparing infarct size in the U-IR versus U-DR branches. Patients aged 21-80 years, with symptoms between 1 and 6 hours from the onset of chest pain, and with ST-segment elevation of ≥2 mm in two or more adjacent anterior leads or a total ST-segment deviation sum of ≥4 mm in the anterior leads were eligible for enrollment.

[0048] Patients were randomized to either the U-IR or U-DR branch immediately after femoral vascular access was obtained. The Impella CP was placed before diagnostic coronary angiography, and operators were instructed to perform percutaneous coronary intervention (PCI) using second-generation drug-eluting stents and follow guideline-directed post-AMI care. In the U-DR group, operators were allowed to shorten the time between unloading and reperfusion if clinically deemed necessary. After PCI, the Impella CP was implanted after a minimum of 3 hours of LV support.

[0049] The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events (MACCE), which included cardiovascular mortality, reinfarction, stroke, or major vascular events at 30 days. Table 1 contains the definitions of each component used to adjudicate MACCE. Additional safety parameters included all-cause mortality, hemolysis, acute renal insufficiency, hospitalization for heart failure, ventricular arrhythmias, LV thrombus, bleeding, and small vessel events. The primary efficacy endpoint was the percentage of infarct size to total LV mass assessed using CMR at 30 days. Secondary efficacy endpoints included infarct size at 3-5 days and 30 days using CMR. Exploratory endpoints included comparisons of infarct size standardized to the area at risk at 3-5 days between groups. The CMR protocol used in this study has been described previously. Eligible 12-lead electrocardiograms were evaluated to quantify the sum of ST segment elevations (∑STE), a confirmed clinical marker for the area at risk in STEMI. Specifically, ∑STE was quantified by measuring the amplitude of ST-segment elevation 0.08 seconds after the J-point across precordial leads in comparison with isoelectric segmentation in an independent core laboratory, regardless of study-group assignment. Table 1 Baseline characteristics.

[0050] Baseline demographic and clinical variables of the two treatment groups were summarized. It was assumed that the large standard deviation expected in a small STEMI study would allow the study to have the power to detect large differences in infarct size. Specifically, a power of 0.88 and an alpha of 0.05 were used to detect an absolute difference of 10% in infarct size, assuming a standard deviation of 10%. All continuous variables were summarized as means with standard deviations, as well as medians and interquartile ranges, and compared between treatment groups using appropriate parametric or nonparametric tests. Categorical variables were summarized as frequencies and percentages, and compared between treatment groups using Pearson χ2 tests or Fisher's exact tests for contingency tables, as appropriate. All statistical tests and / or confidence intervals were performed at α=0.05 (2-side), as appropriate. All p values ​​reported to be greater than 0.01 were rounded to two decimal places, and those p values ​​between 0.01 and 0.001 were rounded to three decimal places. Comparability between treatment groups was assessed with respect to all clinically relevant demographic and baseline characteristic variables.

[0051] B. Results Between April 2017 and May 2018, a total of 50 patients with anterior STEMI were enrolled and randomized to the U-IR or U-DR branch (n=25 / group). As shown in Table 1, there were no statistical differences in baseline characteristics between the groups. The mean age of the trial participants was 59.7 years, and 38 patients (76%) were male. The patients presented with hypertension, with no statistical differences in the time from the onset of chest pain to LV unloading between the groups (176.2±73.4 minutes vs. 200.2±151.8 minutes, U-DR vs. U-IR, p=0.48). ∑STE>4 in 90% (n=45 / 50) of the patients. Before placement of the Impella CP, LV end-diastolic pressure was elevated in both groups (25.0±9.6 and 24.0±8.1 mmHg, U-DR vs. U-IR, p=0.73). Prior to randomization, a baseline LVEF was obtained using left ventriculography in 90% (n=45 / 50) of patients with arterial vascular access for the required PCI (either femoral or radial artery at the discretion of the operator). Baseline LVEF was 37.4% (13.2) in the total population and was lower in the U-DR group (41.9% (12.3) vs. 32.7% (12.7), U-IR vs. U-DR, p=0.02). The Impella CP was successfully implanted in all 50 patients with a mean power (P-level) of 7.6±1.0 and a mean device flow of 2.8±0.4 L / min during the 3-hour support period required by the study protocol, indicating successful LV unloading. The mean time from the start of the procedure to Impella CP implantation and activation was 15.4 (8.4) minutes for the total population. All timing elements are shown in Table 2. PCI was performed using radial artery access in 60% (n=30 / 50) of patients. The use of vascular closure devices was at the discretion of the operator. Femoral artery closure devices were used in 29 / 50 patients (14 / 25, 56% vs. 15 / 25, 60% U-DR vs. U-IR, p=0.99). As shown in Table 2, in 98% (n=49 / 50) of patients, the left anterior descending artery was identified as the culprit coronary artery and treated with a stent. One patient randomized to the U-DR branch did not have any coronary lesions requiring PCI. All patients who underwent PCI received a P2Y12 inhibitor prior to PCI. 8% of patients received bivalirudin, and 94% of patients received unfractionated heparin. Among these patients, one patient received both bivalirudin and unfractionated heparin. 8% of patients received a glycoprotein 2b / 3a receptor inhibitor in addition to dual antiplatelet therapy prior to PCI. After initiation of LV unloading, coronary angiography was performed. Table 2 Timing elements.

[0052] Prior to PCI, Thrombolysis in Myocardial Infarction (TIMI) 0 to 1 flow was observed in 52% (n=26 / 50) of patients. Post-PCI TIMI 3 flow was observed in 100% (n=49 / 49) of patients undergoing PCI.

[0053] like Figure 4 As shown in , all patients assigned to the U-DR branch completed 30 minutes of LV unloading before reperfusion without the need for urgent PCI in any patient. The timing elements including device implantation to balloon reperfusion are shown in Table 2. The mean DTB time was longer in the U-DR branch (96.7±26 vs. 72.6±24 min, U-DR vs. U-IR, p=0.002), which was driven by the prolonged unloading to balloon time in the U-DR group (34.1±3 vs. 10.5±7 min, U-DR vs. U-IR, p<0.001).

[0054] The combined 30-day MACCE event rate for the combined 50-patient group is shown in Table 3 as 10% (n=5 / 50). The extension of DTB time in the U-DR group did not increase the 30-day MACCE (12% [3 events] vs. 8% [2 events], U-DR vs. U-IR, p=1.00). The overall cardiovascular mortality rate was 4% (n=2 / 50), with 1 death in each group. No non-cardiovascular mortality was observed. One patient had a stroke one day after registration (2%; n=1 / 50), and two patients had major vascular events related to flow-limiting dissection of the femoral artery when removing the device (4%; n=2 / 50). Table 3 MACCE rates at 30 days.

[0055] Bleeding in the Academic Research Consortium (BARC) epsilon 2 bleeding was observed in 14% (n=7 / 50) of patients. No BARC 3C (intracranial), 4 (CABG-related) or 5 (fatal) events were observed. Blood transfusions were given to 6% (n=3 / 50) of patients, with each patient requiring only a single unit of packed red blood cells. Tables 3 and 4 provide details of all additional clinical events. Table 4 Cardiac magnetic resonance studies, all patients.

[0056] Between days 3 and 5, CMR was performed in 82% (n=41 / 50) of patients, and at day 30 of follow-up, in 80% (n=40 / 50) of patients. The primary efficacy endpoint of infarct size normalized to total LV mass at 30 days was 14.1% (n=40 / 50) for the total group. No differences were observed between the groups (13.1±11.3% vs. 15.3±11.5%, U-DR vs. U-IR, p=0.53). Among the secondary and exploratory endpoints, a mean infarct size normalized to total LV mass of 17.9±13.5% and an infarct size normalized to the area at risk of 47.9±21.4% were observed for the total group (n=40; ​​Table 4) at days 3-5. There was no statistical difference in infarct size normalized to the area at risk between the groups (44.2±18.9 vs. 51.6±23.6, U-DR vs. U-IR, p=0.28). Mean microvascular occlusion was 1.3% vs. 2.7% for the U-DR and U-IR groups, respectively (p=0.22). There were no statistical differences in LV ejection fraction and LV volumes between the groups at 3-5 days and 30 days. TIMI flow did not correlate with infarct size in the U-IR and U-DR groups.

[0057] Among patients with CMR data available on days 3-5, ∑STE>4, ∑STE>5, and ∑STE>6 were observed in 88% (n=35 / 40), 83% (n=33 / 40), and 75% (n=30 / 40) of patients, respectively. Infarct size normalized to the area at risk was significantly reduced in the U-DR group with ∑STE>6 compared to the U-IR group (44.1% vs. 59.9%, U-DR vs. U-IR, p=0.04, as shown in FIG5 ).

[0058] C. Result Analysis The DTU-STEMI Safety and Feasibility Pilot Study represents the first human experience of mechanically unloading the LV and intentionally delaying coronary reperfusion (primary unloading) in anterior STEMI using the disclosed method 200. These findings demonstrate for the first time that it is feasible to modify STEMI treatment by first focusing on reducing myocardial oxygen consumption (unloading) and then restoring coronary reperfusion.

[0059] Multiple attempts to limit infarct size have been tested, but after initiating a cardioprotective treatment strategy, no previous clinical trial intentionally extended the delay to reperfusion. Considering the destructive concept of first unloading LV and delaying reperfusion, 30-day MACCE was selected as the primary safety endpoint to provide a strict and sensitive analysis of any potential risks associated with the DTU-STEMI strategy. In both U-IR and U-DR branches, the overall MACCE rate is relatively low, without the incidence of any reinfarction or any prohibitive safety signal. Among the separate MACCE elements, CV mortality was observed in a patient for each branch of the study, and was close to the national benchmark for 30-day STEMI mortality. A patient was diagnosed with acute exacerbation of pulmonary fibrosis on the 3rd day after surgery, and died of respiratory failure 10 days later, and the second mortality rate was a patient presenting cardiogenic shock, which was only detected after registration. The major vascular event rate in the DTU-STEMI study is comparable to the infarct size in the pump branch of intra-aortic balloon counterpulsation and the patient with acute anterior myocardial infarction without shock (CRISP-AMI) study. The overall BARC bleeding of >2 in DTU-STEMI was lower than reported in a recent analysis of bleeding events involving percutaneous ventricular assist devices, and as expected, was higher than those reported in other STEMI trials involving medical therapy or lower French-sized devices. A key aspect of testing the feasibility of the concept was to gain a better understanding of the time required to establish LV unloading prior to PCI and its impact on door-to-balloon and overall ischemic time. As shown in Table 2, an average of 15.4 minutes was required from the start of the procedure to insertion and activation of the Impella CP for a total of 50 patients studied. This time includes preparation, draping, vascular access, left ventricle angiography, and insertion of the Impella device. This observation highlights key insights gained from this pilot study, including: 1) it is feasible to implant and activate this offloading device in a timely manner during anterior STEMI, 2) despite this inherent delay, operators were able to achieve a mean door-to-balloon time of 84.4 (27.6) minutes across all 50 patients, and 3) despite this inherent delay, overall infarct size was low relative to recent reports including CRISP-AMI and was not associated with DTB time. These findings support that the DTU-STEMI strategy can be safely tested in a larger pivotal trial.

[0060] By providing 30 minutes of LV unloading before reperfusion, we assume that the cardioprotective conversion in myocardial signaling and coronary perfusion limits myocardial damage. For this reason, patients with larger myocardial areas at risk may achieve more benefits by mechanical pretreatment before reperfusion. This is consistent with the following observation, which is that the observation is compared with unloading and immediate reperfusion alone, and in the case of 30 minutes of unloading before reperfusion, the patient with higher ∑STE (confirmed marker of myocardial areas at risk in STEMI) shows lower infarct size and higher myocardial salvage index. Multiple studies have confirmed that the infarct size and myocardial salvage quantified by single photon emission computed tomography (SPECT) or CMR are directly related to the clinical results including MACE 6 months after STEMI. In the two branches of the DTU-STEMI study, the infarct size standardized to the area at risk is lower than the reported value in the recent STEMI study involving IABP or beta blocker treatment. Patients in the U-DR group presented with lower EF and high ST elevation rates ≥ 6 - although given the small number of patients seen at randomization - this did not translate into larger infarcts or lower EF at day 30. These findings suggest that the DTU-STEMI strategy does not increase infarct size and further suggest that among patients with high ST elevation, a prolonged delay to reperfusion may improve myocardial salvage.

[0061] The DTU-STEMI pilot study overcame a key barrier to progress in the field of cardioprotection and myocardial recovery by demonstrating for the first time that it is possible to delay coronary reperfusion, thereby allowing sufficient time for LV unloading to precondition the myocardium and reduce ischemia-reperfusion injury and overall myocardial damage in AMI.

[0062] Example 2 In the setting of myocardial ischemia-reperfusion injury, increased expression of proteases including matrix metalloproteinases (MMP)-2 and MMP-9 and dipeptidyl peptidase-4 (DPP-4) cleaves the N-terminus of stromal-derived factor (SDF)-1α, rendering the cytokine inactive. Any remaining SDF-1α can bind to CXCR4, which promotes phosphorylation of the RISK pathway, including extracellular-regulated kinase (Erk), protein kinase b (Akt), and glycogen synthase kinase 3b (GSK3b). RISK activation promotes cell survival by limiting cardiomyocyte apoptosis and maintains mitochondrial integrity by preventing the opening of mitochondrial permeability pores. Here we further explain the mechanisms underlying the cardioprotective benefits of P-unloading and whether the acute reduction in infarct size leads to a durable reduction in left ventricular (LV) scar and improvements in cardiac function. This study tested the importance of delayed myocardial reperfusion, explored the cardioprotective mechanisms, and determined the late effects on myocardial function associated with P-unloading.

[0063] A. Methods The study was conducted in adult male Yorkshire pigs. The Institutional Animal Care and Use Committee at Tufts Medical Center approved the study protocol. All experiments were performed according to the committee's guidelines. Animals were premedicated with telazol (0.8 ml / kg, intramuscularly; Zoetis Services LLC, Parsippany, New Jersey). General anesthesia was induced and maintained using isoflurane (1% to 2%). All animals were intubated and mechanically ventilated (Harvard Apparatus, Holliston, Massachusetts) with room air and supplemental oxygen to maintain physiological pH and oxygen saturation. Surface electrocardiogram leads, orogastric tubes, peripheral 18G intravenous catheters, and rectal thermistors were placed in all animals. A heating pad was used as needed to maintain core body temperature>99°F. Vascular access sheaths were then deployed in the right internal jugular vein (10-F), the left carotid artery (7-F), and both the femoral artery (7-F) and vein (10-F). An unfractionated heparin bolus with a target activated clotting time of 300 to 400 s, continuous lidocaine infusion (1 mg / kg), and norepinephrine (0.16 mg / min) was initiated in all animals.

[0064] 6-F Judkins right coronary catheter (Massachusetts Marlborough Boston Scientific) is engaged with the left coronary artery via the right femoral artery, and baseline angiograms are recorded. 0.014 inch guidewire is delivered into the distal left anterior descending branch (LAD), and after the angiographic confirmation of the first diagonal branch with LAD occlusion, the bare metal stent (Boston Scientific) of 3.0 × 8mm for acute research or the angioplasty balloon (Boston Scientific) of 3.0 × 8mm for chronic research is deployed in the middle LAD. Also perform immediately after reperfusion and perform coronary angiography again after the end of the research protocol, confirm the patency of LAD. Use LAD stent to mark the exact position of repeated balloon occlusion during Evans blue contrast dyeing in acute animal research. After reperfusion 120min, then utilize pentobarbital and phenytoin to euthanize the animal.

[0065] The pigs were divided into 4 groups (n=4 in each group), as Fig. 6A In shown.All groups have experienced 90min of LAD occlusion.In group 1, LAD occlusion is followed by 120min of reperfusion and serves as a control group.In group 2 and group 3, LAD occlusion is followed by insertion and activation of TV-pump (Impella CP of Abiomed, Danvers, Massachusetts) via 14-F sheath in left femoral artery, and is maintained at maximum support (44000 rev / min, realizes 3.5l / min).This action is followed by occlusion (group 3) of additional 15min (group 2) or 30min respectively, and then is the reperfusion of 120min with LV unloading.In group 4, LAD occlusion is followed by reperfusion, and after 30min of reperfusion, TV-pump is inserted and activated in the remaining 90min of reperfusion.

[0066] At the end of each study, animals were euthanized to determine myocardial infarction size. Three sham-operated animals were intubated, anesthetized, and mechanically ventilated without myocardial infarction or mechanical unloading. LV tissue samples obtained from the sham control group were used for tissue analysis.

[0067] To evaluate the functional role of SDF-1α / CXCR4 signaling or the cardioprotective effect of LV unloading, an over-the-wire coronary angioplasty balloon was used to deliver a pharmacological inhibitor of the SDF-1α receptor, CXCR4 (termed AMD3100), to the area at risk while maintaining occlusion of the LAD in a closed-chest animal model of AMI. Adult male pigs were treated with intracoronary injections of vehicle or AMD3100 (3 mg / kg / min, intracoronary injection within 10 min; n=4 per group) initiated at the beginning of LV unloading 30 min before reperfusion. The dose of AMD3100 was selected based on a previous report (Hu X, Dai S, Wu WJ et al. Stromal cell derived factor-1alpha confers protection against myocardial ischemia / reperfusion injury: role ofthe cardiacstromal cell derived factor-1alpha CXCR4 axis. Circ 2007;116:654–63).

[0068] To investigate the long-term effects of LV unloading on infarct size, 19 adult male Yorkshire pigs were subjected to 90 min of intermediate LAD occlusion, followed by immediate reperfusion (P-reperfusion), or 30 min of unloading prior to reperfusion (P-unloading). Five animals died from ventricular arrhythmias during LAD occlusion before randomization or pump implantation. Of the remaining 14 animals that successfully completed the protocol, 2 animals in the P-reperfusion group died within 6 h after reperfusion due to refractory ventricular fibrillation. No animals died in the P-unloading group. In total, 7 of the 19 animals (37%) died during the study protocol. In the chronic study, 12 animals surviving in the P-reperfusion group (n=6) or the P-unloading group (n=6) were used for analysis, as shown in Table 1. Fig. 6A The weight of animals in the P-unload group was 76.7 ± 6.9 kg, and that in the P-reperfusion group was 76.2 ± 2.4 kg (p = 0.84). After reperfusion, all animals were recovered and monitored for 28 days. After 28 days, animals were re-anesthetized and underwent repeat catheterization to assess infarct size based on cardiac magnetic resonance imaging (MRI) and LV hemodynamics.

[0069] By using the 5-F conductance catheter system (Sigma M, CDLeycom, Hengelo, Netherlands) deployed into the left ventricle via the left carotid artery to assess changes in LV pressure and volume. As previously described, in the study of the chronic phase, 28 days after the initial infarction, ventricular pressure and volume were measured by using a solid-state pressure sensor and a dual-field excitation mode, respectively. The time-varying conductance across 5 to 7 ventricular blood segments depicted by the selected catheter electrode has been measured. Fluoroscopic examination confirmed the correct positioning of the conductive catheter along the long axis of the left ventricle. Parallel conductance was assessed by injecting 20ml of hypertonic (6%) saline into the right internal jugular vein. Absolute LV volume was measured by subtracting parallel conductance from the total conductance volume. Stroke volume is calculated as the difference in the conductance volume at +dP / dtmax and –P / dtmin. LV stroke work is calculated as the product of peak LV peak systolic pressure and stroke volume.

[0070] A-1. Determination of myocardial infarction size After completion of the acute study protocol, balloon occlusion was performed within the mid-LAD ​​stent, and Evans blue was injected into both coronary vessels to delineate the area at risk, followed by removal and sectioning of the left ventricle. Biopsy specimens were obtained from the anterior apex of the left ventricle distal to the stent deployment site (infarct zone) and from the basal posterior wall (non-infarct zone) for molecular analysis; LV sections were then cultured in 1% triphenyltetrazolium chloride as previously described. To quantify LV scar size 28 days after MI, the left ventricle was sectioned into five 1-cm sections and then cultured in triphenyltetrazolium chloride without Evans blue. LV sections were then photographed, and 3 blinded reviewers used digital planimetry to quantify total myocardial area, area at risk, and infarct zone.

[0071] Animals in the chronic phase of the study underwent cardiac MRI with late gadolinium enhancement (LGE) 28 days after the initial infarction using a Philips Achieva 1.5-T scanner (Philips Healthcare, Best, The Netherlands). Steady-state free precession breath-hold cine images were obtained in 3 long-axis planes and consecutive short-axis slices from the atrioventricular annulus to the apex. LV and right ventricular volumes, mass, and ejection fraction were measured using standard volumetric techniques and analyzed by a blind observer experienced in cardiac magnetic resonance (CMR) analysis using commercially available software (QMASS version 7.4, Medis Medical Imaging Systems, Leiden, The Netherlands). LGE images were acquired 10 to 15 min after intravenous injection of 0.2 mmol / kg of gadolinium diethylenetriamine pentaacetic acid using a breath-hold 2-dimensional phase-sensitive inversion recovery sequence in the same position as the cine images. The LGE area was defined by using the full width at half maximum (>50% of the maximum myocardial signal intensity) adjusted manually when necessary. Areas with LGE were summed to generate the total LGE volume and expressed as a proportion of the total LV myocardium (% LGE).

[0072] Following the acute phase protocol, whole transcriptome expression analysis was performed on RNA isolated from the infarct area using a porcine 1.0ST microarray. (Details are presented in the online appendix). All raw and processed data from this microarray analysis can be accessed under the Gene Expression Omnibus accession number GSE108644. Quantitative polymerase chain reaction (PCR) and Western blot analysis confirmed the expression of significantly regulated genes and their activation in altered pathways.

[0073] LV tissue samples were obtained from the center of the infarct area, washed and fixed with 3% glutaraldehyde in phosphate buffer, and then embedded in epoxy resin. Electron micrographs were acquired and analyzed for cardiomyocyte damage, including mitochondrial swelling and integrity.

[0074] A-2. Quantification of SDF-1α and CXCR4 levels Total protein was extracted from tissue homogenates and isolated as previously described (22–24). SDF-1α protein levels in LV tissue isolated from sham-operated animals and infarcted areas were quantified using Western blot analysis and enzyme-linked immunosorbent assay. Circulating serum levels of SDF-1α were quantified by using an enzyme-linked immunosorbent assay (R&D Systems, Minneapolis, MN). CXCR4 levels in LV tissue isolated from sham-operated animals and infarcted areas were quantified by Western blot analysis (Abcam, Cambridge, UK). Immunoblotting analysis was then performed as previously described.

[0075] A-3. Quantification of MMP-2, MMP-9 and DPP-4 levels and activities MMP-2 and MMP-9 activities in cardiac tissue homogenates were determined by zymography as previously described. Briefly, gelatin zymography was performed using sodium dodecyl sulfate polyacrylamide gel electrophoresis gels containing 1 mg / ml porcine gelatin. Samples were prepared under non-reducing conditions. Gel electrophoresis was performed at 150 V for 1 h. After electrophoresis, the gel was washed in a 2.5% Triton X-100 solution with gentle agitation for 6 h at room temperature, followed by replacement with a developing buffer containing 50 mM Tris-HCl (pH 7.5), 0.2 M NaCl, 5 mM CaCl2, and 0.2% Brij-35. The gel was stirred at room temperature for 30 min, placed in fresh developing buffer, and incubated overnight at 37°C. On the next morning, the gel was stained with 0.5% Coomassie Brilliant Blue R-250 in 40% methanol and 10% acetic acid for 2 to 4 h and destained in 40% methanol and 10% acetic acid at room temperature. Gel dissolution bands were quantified by scanning densitometry using ImageJ software (National Institutes of Health, Bethesda, MD). DPP-4 protein levels were quantified by immunoassay, and activity levels were measured by using a commercially available activity assay kit (MilliporeSigma, Burlington, MA).

[0076] A-4. Quantification of apoptotic signaling pathways Immunoblot analysis was performed using antibodies against porcine B-cell lymphoma (BCL)-2 (Cell Signaling Technology, Danvers, MA), BAX (Cell Signaling Technology), B-cell lymphoma-extra large (BCL-XL) (Cell Signaling Technology), caspase-3 (Cell Signaling Technology), and glyceraldehyde-3-phosphate dehydrogenase. The expression of apoptosis-regulated protein levels was normalized to total protein levels and glyceraldehyde-3-phosphate dehydrogenase. TUNEL staining was performed using 10-mm thick sections obtained from the peri-infarct area, which were fixed in 4% paraformaldehyde / phosphate-buffered saline for 20 min. Slides were permeabilized with 0.1% Triton X-100 in 0.1% sodium citrate on ice, and the sections were labeled in the dark at 37°C for 60 min. Slides were rinsed with phosphate-buffered saline, and nuclei were labeled with ProLong Gold Antifade with DAPI (Life Technologies, Grand Island, NY). Images were acquired using an Eclipse E800 fluorescence microscope (Nikon Corporation, Tokyo, Japan) and Openlab version 5 software (Perkin Elmer, Waltham, Mass.) TUNEL-positive cells were counted at 10× magnification by an investigator blinded to the experimental groups and expressed as a percentage of all nuclei.

[0077] A-5. Others For all cell-based real-time PCR experiments, total RNA was directly extracted using Trizol (Thermo Fisher Scientific, Waltham, MA) and converted to complementary deoxyribonucleic acid using a high-capacity cDNA reverse transcription kit (ThermoFisher Scientific). For all real-time PCR experiments, samples were quantified in triplicate using 40 cycles of 94°C for 30 s, 60°C for 45 s, and 72°C for 45 s using an ABI Prism 7900 sequence detection system (Thermo Fisher Scientific) using appropriate primers.

[0078] Results are presented as mean ± SD. Unpaired student's t-test or one-way ANOVA were used to compare continuous variables between each group. By using nonparametric 2-way repeated measures ANOVA, all data in each group over time were analyzed. Simple linear regression analysis was used to assess the correlation between two parameters. GraphPad Prism (GraphPad Software, La Jolla, California) was utilized to perform all statistical analyses. The alpha level of p<0.05 was considered to indicate a significant effect or group difference.

[0079] B. Results B-1. LV unloading 30 min before reperfusion reduces acute infarct size compared with reperfusion alone LV unloading 30 min before reperfusion reduces acute infarct size compared with reperfusion alone (33.3 ± 5% vs. 62.2 ± 1.7% infarct / area at risk in group 3 vs. group 1, respectively; p < 0.01) (see Figure 6B LV unloading followed by rapid reperfusion within 15 min (Group 2) or after reperfusion (Group 4) failed to reduce myocardial infarct size compared with P-reperfusion alone.

[0080] B-2. LV unloading after AMI induces global shifts in gene expression associated with reduced damage within the infarct zone To begin exploring the cardioprotective mechanisms associated with LV unloading prior to reperfusion, we analyzed the complete transcriptome from within the infarct zone in the sham control group, Group 1, and Group 3 to identify genes differentially expressed between treatment groups. A heat map of all differentially regulated genes showed that LV unloading 30 min prior to reperfusion mitigated changes in gene expression associated with reperfusion alone compared to the sham control group (see Fig. 7A ).

[0081] Relative to reperfusion alone, LV unloading 30 min prior to reperfusion limited the downregulation of genes associated with mitochondrial function and cellular respiration (see Table 5 below). Consistent with these observations, real-time PCR of LV tissue samples from the infarct area demonstrated that Group 3 exhibited increased messenger RNA (mRNA) levels of key genes associated with cellular respiration compared to Group 1, such as Figure 7B As shown in Figure 7C As shown in , electron microscopy further showed loss of mitochondrial integrity within the infarct zone from Group 1, but not Group 3. These findings identify that LV unloading 30 min prior to reperfusion triggers a broad shift in gene expression within the infarct zone compared to reperfusion alone, with significant protection for genes associated with mitochondrial function.

[0082] B-3. ​​LV unloading limits SDF-1α degradation in AMI Given 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. We observed that reperfusion alone (Group 1), LV unloading for 15 min (Group 2), or LV unloading followed by reperfusion (Group 4) were associated with decreased protein levels of SDF-1α within the infarct zone compared with sham controls (see Fig. 8A and Figure 8B ). In contrast, only LV unloading for 30 min prior to reperfusion (Group 3) maintained SDF-1α protein levels within the infarct zone compared to the sham control group. CXCR4 levels remained unchanged across all 4 study groups compared to the sham control group.

[0083] To determine whether increased SDF-1α levels were transcriptionally regulated, we quantified mRNA expression by using real-time PCR between groups and observed no differences in SDF-1α or CXCR4 gene expression (see Figure 8C and Fig.8D ). Because SDF-1α is highly regulated by proteolytic degradation, we next explored the expression of key proteases known to degrade SDF-1α. Reperfusion alone increased MMP-2 and MMP-9 activity levels compared with sham controls, but LV unloading for 30 min before reperfusion did not (see Fig. 8E and Fig.8F Reperfusion alone increased the expression and activity of DPP-4 in the infarct area compared with the sham control group (see Figure 8G and Figure 8H LV unloading for 30 min before reperfusion limited the upregulation of DPP-4 expression and activity. These data suggest that LV unloading for 30 min before reperfusion can preserve SDF-1α protein levels by limiting the activity of proteases known to degrade SDF-1α.

[0084] B-4. Loss of SDF-1α / CXCR4 activity attenuates the cardioprotective effects of LV unloading To explore whether SDF-1α / CXCR4 signaling is necessary for the cardioprotective effects of LV unloading, in a separate group of animals, we blocked CXCR4 activity using intracoronary delivery of AMD3100. Loss of CXCR4 activity increased infarct size and reduced cardioprotective signaling via the RISK pathway, including Akt, extracellular regulated kinase, and glycogen synthase kinase 3b, compared with vehicle-treated controls subjected to LV unloading for 30 min prior to reperfusion (see Figure 8I and Figure 8J ). These findings suggest that the cardioprotective effect of LV unloading prior to reperfusion requires SDF-1α / CXCR4 signaling.

[0085] B-5. LV unloading limits pro-apoptotic signaling To further explore whether LV unloading for 30 min reduces the levels of proteins associated with apoptosis in the infarct zone, we observed that reperfusion alone (group 1) increased the levels of pro-apoptotic proteins including BAX and active caspase-3 and further decreased the levels of anti-apoptotic proteins including BCL-2 and BCLXL compared with the sham control group (see 9A to 9C ). Group 3 exhibited decreased BAX and active caspase-3 levels, and increased anti-apoptotic BCL-2 and BCL-XL protein levels compared to Group 1. P-unloading reduced the number of TUNEL-positive cells in the infarct zone compared to P-reperfusion (see Fig.9D and Fig.9E ).

[0086] B-6. Primary unloading reduces myocardial infarct size compared to primary reperfusion and preserves cardiac function 28 days after AMI In order to give clinically relevant cardioprotection, the observed effect of P-unloading on infarct size reduction must be maintained after the acute treatment phase. To test this theory, adult male pigs were treated with P-reperfusion or P-unloading, and LV scar size, LV function, and molecular changes associated with heart failure were quantified 28 days after MI. Fourteen animals completed the ischemia-reperfusion phase of the protocol. Two animals in the P-reperfusion group died within 6 h after reperfusion, and 12 animals survived to 28 days (6 in each group).

[0087] Compared with P-reperfusion, P-unloading reduced LV scar size as quantified using LGE (3.9±3.2% vs. 9±3.7%; p=0.03) and anatomic pathology (7.2±4.9% vs. 14.9±4.1%; p=0.02). Figure 5A Histological measurements of infarct size correlated directly with the percentage of LGE from CMR (R2 = 0.85) (see FIG. 10B to FIG. 10DUsing CMR-derived volumes, end-diastolic and end-systolic volumes were similar between groups (end-diastolic volume: 152±29 ml vs. 142±14 ml; P-reperfusion vs. P-unload [p=NS]; end-systolic volume: 86±26 ml vs. 74±6 ml; P-reperfusion vs. P-unload [p=NS]). CMR-derived LV mass did not differ between groups (90.4±10.6 g vs. 84.4±8.6 g; P-reperfusion vs. P-unload [p=NS]). Hemodynamic analysis using the LV conductance catheter showed that P-unloading was associated with higher stroke volume (54±7 ml vs. 40±6 ml; p=0.02), cardiac output (3.9±0.6 l / min vs. 2.5±0.2 l / min; p=0.006), and stroke work (3075±339 ml×mm Hg vs. 2195±307 ml×mm Hg; p=0.008) compared with P-reperfusion (see Table 5 below). Table 5 Hemodynamic variables 28 days after acute myocardial infarction.

[0088] B-7. Primary unloading increases circulating and tissue levels of SDF-1α levels acutely and 28 days after AMI Compared with P-reperfusion, P-unloading increases circulating SDF-1α levels during the 28 days after AMI, with peak SDF-1α levels 1 week after AMI (see Fig.10E ). In contrast, P-reperfusion failed to increase circulating SDF-1α levels at any time point after AMI. P-reperfusion, but P-unloading, reduced SDF-1α protein levels within the infarct zone of the left ventricle compared with sham controls. Circulating SDF-1α levels at day 28 after AMI were inversely correlated with LV scar size (see Fig.10F and Figure 10G ).

[0089] B-8. Primary unloading limits maladaptive cardiac remodeling Compared with P-reperfusion, P-unloading reduces circulating levels of B-type natriuretic peptide (BNP) 28 days after AMI (see Fig.11A Compared with sham controls, P-reperfusion increased BNP mRNA and protein levels in the non-infarcted area (see Fig. 11B and Fig. 11C ). In contrast, P-unloading attenuated any increase in BNP tissue levels in the non-infarcted regions of the left ventricle. Compared with P-reperfusion, P-unloading increased the mRNA levels of sarcoplasmic / endoplasmic reticulum calcium ATPase and decreased the levels of calcineurin and type I collagen, without affecting the levels from the non-infarcted regions of the left ventricle (see FIG. 11D to FIG. 11F ).

[0090] C. Discussion The central finding of this example is that P-unloading for 30 min prior to reperfusion alters several key biological pathways involved in cellular respiration and post-translational regulation of SDF-1α levels, thereby reducing acute infarct size, such as Fig.12 As shown in . In addition, P-unloading reduced LV scar size and improved cardiac function 28 days after AMI. Specifically, we report that: 1) P-unloading 30 min before reperfusion is necessary and sufficient to limit infarct size; 2) P-unloading triggers a global shift in gene expression associated with protecting mitochondrial integrity in the infarct zone; 3) P-unloading for 30 min maintained SDF-1α protein levels without changing SDF-1α mRNA levels in the infarct zone compared with P-reperfusion, and further promoted the shift towards anti-apoptotic signaling in the infarct zone; 4) P-unloading reduced the activity levels of proteases known to degrade SDF-1α; and 5) P-unloading reduced LV scar size, maintained cardiac output, reduced BNP expression, and limited the expression of genes and proteins associated with maladaptive remodeling in the non-infarct zone 28 days after AMI. This data identifies P-unloading as a novel approach to enhance cardioprotective mechanisms that can preserve cardiac function after AMI.

[0091] It has been identified that mechanical LV unloading using a TV-pump for 30 min before, but not after, reperfusion limits acute infarct size. This observation suggests for the first time that LV unloading itself may be a treatment rather than simply an adjunct supportive approach for left ventricular dysfunction. A potential explanation for the beneficial effect of mechanical LV unloading 30 min before reperfusion is that LV unloading biologically prepares the myocardium for reperfusion. A potential explanation for the effect of unloading the LV is that it may reduce infarct size and increase protein levels of SDF-1α within the infarct zone.

[0092] By using a genomic approach, it was identified that P-unloading 30min differentially altered the expression of >600 genes in the infarct zone compared to P-reperfusion. Pathway analysis identified that P-unloading maintained gene expression associated with cellular respiration and mitochondrial integrity. It has been demonstrated that these observations have direct quantification of selected genes from each component of the electron transport chain involved in cellular respiration. This finding indicates that the initiation of LV unloading before reperfusion can limit the effects of ischemia-reperfusion injury on mitochondrial integrity, thereby promoting myocardial cell survival.

[0093] In the present study, it was observed that P-unloading failed to increase SDF-1α mRNA levels within the infarct zone compared with P-reperfusion. However, it was observed that P-reperfusion decreased SDF-1α protein levels within the infarct zone compared with the sham control group. In contrast, LV unloading for 30 min before reperfusion maintained SDF-1α protein levels.

[0094] Because SDF-1α levels are highly regulated by proteases associated with inflammation, we next explored whether the protein and activity levels of key regulatory proteases such as MMP-2, MMP-9, or DPP-4 were altered by P-reperfusion and P-unloading. It was observed that P-reperfusion increased but P-unloading alleviated the activity of these proteases compared to the sham control group. To further establish the downstream effects of P-unloading, we also observed reduced protein expression associated with apoptosis within the infarct zone. These findings demonstrate for the first time that 30 minutes of P-unloading limits protease activity within the infarct zone, which limits SDF-1α degradation in the AMI setting.

[0095] A preclinical study was designed in which animals were assigned to P-reperfusion or P-unloading, and LV scar was then quantified after 28 days using cardiac MRI. It was observed for the first time that P-unloading reduced infarct scar size as blindly quantified by LGE-CMR, which correlated closely with anatomical measures of myocardial scar size. Confirmed molecular markers of maladaptive remodeling in non-infarcted areas were then quantified, with most compensatory remodeling occurring in response to a large anterior MI. It was observed that P-unloading reduced calcineurin, beta-myosin heavy chain, and BNP levels compared to P-reperfusion, while maintaining sarcoplasmic / endoplasmic reticulum calcium adenosine triphosphatase levels 28 days after AMI. In addition, circulating and LV tissue levels of BNP, a clinically relevant biomarker of heart failure, were reduced after P-unloading, but not after P-reperfusion. These findings identify for the first time that the use of a transvalvular pump at the time of AMI has a lasting effect on both LV scar size and markers of maladaptive remodeling after 28 days. For decades, immediate reperfusion in AMI has been the primary focus; however, these data demonstrate for the first time that the “pre-reperfusion period” is a critical moment that may allow interventions such as LV unloading and delayed reperfusion to have a lasting effect on late cardiac remodeling.

[0096] Finally, SDF-1α levels after AMI were quantified, and increases in circulating and LV tissue levels of SDF-1α levels were observed 28 days after P-unloading but not after P-reperfusion. Circulating SDF-1α levels were negatively correlated with LV scar size. These findings identify that, in addition to providing an acute reduction in infarct size after MI, P-unloading also promotes a more sustained reduction in LV scar size, improves cardiac function, and limits maladaptive remodeling after AMI. Using clinically relevant biomarkers of myocardial injury, including CMR and circulating BNP levels, the findings of this study suggest that P-unloading has strong translational potential as a method to limit ischemic heart failure after AMI.

[0097] D. Discovery The findings of this study show that, compared with P-reperfusion alone, as described previously Figure 2 In method 200 of , activation of a transvalvular microaxial flow pump 30 min prior to reperfusion limited both acute infarct size and subsequent scar size. The results of this study provide new mechanistic insights into the biological impact of myocardial unloading and activation of cardioprotective pathways within the infarct zone.

[0098] The foregoing is merely illustrative of the principles of the present disclosure and the device may be practiced in other than the described implementations, which are presented for purposes of illustration and not limitation.

[0099] After reviewing this disclosure, variations and modifications will occur to those skilled in the art. The disclosed features may be implemented with any combination and sub-combination (including multiple dependent combinations and sub-combinations) of one or more other features described herein. The various features described or illustrated above, including any components thereof, may be combined or integrated in other systems. In addition, certain features may be omitted or not implemented.

[0100] Examples of changes, substitutions, and alterations are ascertainable by those skilled in the art and may be made without departing from the scope of the information disclosed herein.All references cited herein are incorporated by reference in their entirety and become part of this application.

Claims

1. A method of supporting the heart of a human patient with ongoing myocardial infarction, comprising the steps of: Insertion of mechanical circulatory support devices into patients following myocardial infarction; Prior to reperfusing the heart, operating a mechanical circulatory support device at a blood flow rate of at least 2.5 L / min for a support period greater than 15 minutes; and After the support period, reperfusion therapy is applied to the heart.

2. The method of claim 1, wherein the support period is any one of the following: Longer than 20 minutes; longer than 25 minutes; longer than 30 minutes; longer than 35 minutes; longer than 40 minutes; longer than 45 minutes; longer than 15 minutes and up to about 30 minutes; between about 20 minutes and about 45 minutes; and between about 30 minutes and about 40 minutes.

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

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

5. A method according to any one of the preceding claims, wherein the heart is unloaded by a mechanical circulatory support device simultaneously with reperfusion.

6. A method according to any one of the preceding claims, wherein the mechanical circulatory support device comprises a cannula inserted into the heart.

7. The method of claim 6, wherein the blood pump comprises a microaxial transvalvular pump.

8. A method according to any one of the preceding claims, comprising the step of supporting the heart by an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump.

9. The method of any of the preceding claims, wherein reperfusion therapy comprises at least one of primary percutaneous coronary intervention (PCI) and fibrinolysis.

10. The method according to any one of the preceding claims, comprising the steps of: Reduced levels of BAX protein and active caspase-3 antibodies in cardiac tissue of patients near myocardial infarction; and Increased levels of BCL-2 and BCL-XL proteins in heart tissue of patients near myocardial infarction.

11. The method according to any one of the preceding claims, comprising the steps of: Increased protein levels of stromal-derived factor 1α (SDF-1α) in cardiac tissue of patients near myocardial infarction; Maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of patients near myocardial infarction; and Limiting upregulation of DPP-4 protein expression and activity in cardiac tissue of patients near myocardial infarction.

12. The method according to any one of the preceding claims, comprising the steps of: Reduce the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; Increased mRNA levels of SERCA expression in cardiac cells of patients near myocardial infarction; and Reduces calcineurin activity and type I collagen levels in cardiac tissue of patients near myocardial infarction, while maintaining b-MHC levels in non-infarcted areas of the patient's heart.

13. The method of any of the preceding claims, wherein the heart has a sum of ST segment elevations (ΣSTE) greater than 4, or greater than 5, or greater than 6. The method of claim 13 , wherein the heart has a ΣSTE greater than 6.

15. A method of supporting the heart of a patient with ongoing myocardial infarction, comprising the steps of: percutaneously inserting a transvalvular blood pump into a patient and positioning the pump across the aortic valve of the patient's heart with a distal end of the pump located in the left ventricle of the heart, Prior to reperfusing the heart, operating the pump positioned to unload the left ventricle at a blood flow pumping rate of at least 2.5 L / min for a pumping period of greater than 15 minutes, and After the pumping period, the heart is treated with reperfusion therapy.

16. The method of claim 15, wherein the support period includes any one of the following: Longer than 20 minutes; Longer than 25 minutes; Longer than 30 minutes; Longer than 35 minutes; Longer than 40 minutes; Longer than 45 minutes; Between about 20 minutes and about 45 minutes; greater than 15 minutes and up to about 30 minutes; and Between about 30 minutes to about 40 minutes.

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

18. The method of any one of claims 15-17, wherein the heart is unloaded by a mechanical circulatory support device simultaneously with reperfusion.

19. The method according to any one of claims 15 to 18, comprising the steps of: After reperfusion therapy is applied, the blood pump is removed from the patient's heart.

20. The method of any one of claims 15-19, wherein reperfusion therapy comprises at least one of primary percutaneous coronary intervention (PCI) and fibrinolysis.

21. The method according to any one of claims 15 to 20, comprising the steps of: Reduced levels of BAX protein and active caspase-3 antibodies in cardiac tissue of patients near myocardial infarction; and Increased levels of BCL-2 and BCL-XL proteins in heart tissue of patients near myocardial infarction.

22. The method according to any one of claims 15 to 21, comprising the steps of: Increased protein levels of stromal-derived factor 1α (SDF-1α) in cardiac tissue of patients near myocardial infarction; Maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of patients near myocardial infarction; and Limiting upregulation of DPP-4 protein expression and activity in cardiac tissue of patients near myocardial infarction.

23. The method according to any one of claims 15 to 22, comprising the steps of: Reduce the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; Increased mRNA levels of SERCA expression in cardiac cells of patients near myocardial infarction; and Reduces calcineurin activity and type I collagen levels in cardiac tissue of patients near myocardial infarction, while maintaining b-MHC levels in non-infarcted areas of the patient's heart.

24. A method of reducing the size of a myocardial infarction scar in the heart of a patient, comprising the steps of: percutaneously inserting a transvalvular microaxial blood pump into a patient and positioning the pump across an aortic valve of the patient's heart with a distal end of the pump located in the left ventricle of the heart; Prior to reperfusing the heart, operating a pump positioned to unload the left ventricle at a blood flow pumping rate of at least 2.5 L / min for a pumping period greater than 15 minutes; and Reperfusion therapy is applied to the heart after the pumping period.

25. The method of claim 24, wherein the pumping period is any one of: Longer than 20 minutes; Longer than 25 minutes; Longer than 30 minutes; Longer than 35 minutes; Longer than 40 minutes; Longer than 45 minutes; Between about 20 minutes and about 45 minutes; longer than 15 minutes and up to about 30 minutes; and between about 30 minutes and about 40 minutes.

26. The method of claim 24 or 25, wherein the pump is operated at a pumping rate of at least 3.5 L / min of blood flow.

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

28. The method according to any one of claims 24 to 27, comprising the steps of: After reperfusion therapy is applied, the blood pump is removed from the patient's heart.

29. The method of any one of claims 24-28, wherein reperfusion therapy comprises at least one of primary percutaneous coronary intervention (PCI) and fibrinolysis.

30. The method according to any one of claims 24 to 29, comprising the steps of: Reduced levels of BAX protein and active caspase-3 antibodies in cardiac tissue of patients near myocardial infarction; and Increased levels of BCL-2 and BCL-XL proteins in heart tissue of patients near myocardial infarction.

31. The method according to any one of claims 24 to 30, comprising the steps of: Increased protein levels of stromal-derived factor 1α (SDF-1α) in cardiac tissue of patients near myocardial infarction; Maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of patients near myocardial infarction; and Limiting upregulation of DPP-4 protein expression and activity in cardiac tissue of patients near myocardial infarction.

32. The method according to any one of claims 24 to 31, comprising the steps of: Reduce the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; Increased mRNA levels of SERCA expression in cardiac cells of patients near myocardial infarction; and Reduces calcineurin activity and type I collagen levels in cardiac tissue of patients near myocardial infarction, while maintaining b-MHC levels in non-infarcted areas of the patient's heart.

33. A method of supporting a heart suffering from myocardial infarction, comprising the steps of: percutaneously inserting a mechanical circulatory support device into a patient following a myocardial infarction of the patient's heart; Prior to reperfusing the heart, operating the device to unload the left ventricle at a blood flow rate of at least 2.5 L / min for an unloading period greater than 15 minutes; and After the unloading period, reperfusion therapy is applied to the heart.

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

35. The method of claim 33 or 34, wherein the mechanical circulatory support device operates at a blood flow rate of at least 3.5 L / min.

36. The method of any one of claims 33-35, wherein unloading is applied to the heart by a mechanical circulatory support device simultaneously with reperfusion therapy.

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

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

39. The method of any one of claims 33-38, wherein reperfusion therapy comprises primary percutaneous coronary intervention (PCI) or fibrinolysis.

40. The method according to any one of claims 33 to 39, comprising the steps of: Reduced levels of BAX protein and active caspase-3 antibodies in cardiac tissue of patients near myocardial infarction; and Increased levels of BCL-2 and BCL-XL proteins in heart tissue of patients near myocardial infarction.

41. The method according to any one of claims 33 to 40, comprising the steps of: Increased protein levels of stromal-derived factor 1α (SDF-1α) in cardiac tissue of patients near myocardial infarction; Maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of patients near myocardial infarction; and Limiting upregulation of DPP-4 protein expression and activity in cardiac tissue of patients near myocardial infarction.

42. The method according to any one of claims 33 to 41, comprising the steps of: Reduce the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; Increased mRNA levels of SERCA expression in cardiac cells of patients near myocardial infarction; and Reduces calcineurin activity and type I collagen levels in cardiac tissue of patients near myocardial infarction, while maintaining b-MHC levels in non-infarcted areas of the patient's heart.

43. A method of supporting the heart of a patient having a myocardial infarction, comprising the steps of: Reduced levels of BAX protein and active caspase-3 antibodies in cardiac tissue of patients near myocardial infarction; and Increased levels of BCL-2 and BCL-XL proteins in heart tissue of patients near myocardial infarction.

44. The method according to claim 43, comprising the steps of: Mechanical circulatory support is applied to the patient to increase blood flow from the left ventricle of the patient's heart.

45. The method of claim 44, wherein the increased blood flow is provided at a blood flow rate of at least 2.5 L / min over an unloading period of greater than 15 minutes.

46. ​​The method of claim 45, wherein the unloading period is any one of: Longer than 20 minutes; Longer than 25 minutes; Longer than 30 minutes; Longer than 35 minutes; Longer than 40 minutes; Longer than 45 minutes; Between about 20 minutes and about 45 minutes; from about 15 to about 30 minutes; and Between about 30 minutes to about 40 minutes.

47. The method of any one of claims 43-46, wherein the increased blood flow is provided at a blood flow rate of at least 3.5 L / min.

48. The method according to any one of claims 43 to 47, comprising the steps of: Reperfusion therapy is applied to the patient's heart tissue near myocardial infarction after the application of mechanical circulatory support.

49. The method according to any one of claims 43 to 48, comprising the steps of: Mechanical circulatory support is applied to the patient concurrently with reperfusion.

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

51. The method according to claim 50, comprising the steps of: After or during operation of the transvalvular miniaxial pump, the heart is supported by one or more of: an intra-aortic balloon pump and an extracorporeal membrane oxygenation (ECMO) pump.

52. The method of any one of claims 48-51, wherein reperfusion comprises at least one of primary percutaneous coronary intervention (PCI) and fibrinolysis.

53. A method of supporting the heart of a patient having a myocardial infarction, comprising at least one of the following steps: Reduced levels of BAX protein and active caspase-3 antibodies in cardiac tissue of patients near myocardial infarction; Increased levels of BCL-2 and BCL-XL proteins in heart tissue of patients near myocardial infarction; Increased protein levels of stromal-derived factor 1α (SDF-1α) in cardiac tissue of patients near myocardial infarction; Maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of patients near myocardial infarction; Limiting the upregulation of DPP-4 protein expression and activity in cardiac tissue of patients near myocardial infarction; Reduce the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; Increased mRNA levels of SERCA expression in cardiac cells of patients near myocardial infarction; and Reduces calcineurin activity and type I collagen levels in cardiac tissue of patients near myocardial infarction, while maintaining b-MHC levels in non-infarcted areas of the patient's heart.

54. A method of supporting the heart of a patient having a myocardial infarction, comprising the steps of: Increased protein levels of stromal-derived factor 1α (SDF-1α) in cardiac tissue of patients near myocardial infarction; Maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of patients near myocardial infarction; and Limiting upregulation of DPP-4 protein expression and activity in cardiac tissue of patients near myocardial infarction.

55. The method according to claim 53 or 54, comprising the steps of: Increase blood flow to the patient's heart tissue near the myocardial infarction.

56. The method according to claim 55, comprising the steps of: Apply mechanical circulatory support to the patient's heart.

57. The method of claim 56, wherein mechanical circulatory support comprises applying a device comprising a blood pump, such as a TV-pump.

58. The method according to claim 57, comprising the steps of: The heart is supported by a TV-pump and one or more of the following: an intra-aortic balloon pump and an extracorporeal membrane oxygenation (ECMO) pump.

59. The method according to any one of claims 54 to 58, comprising the steps of: The left ventricle of the patient's heart is unloaded using a transvascular pump.

60. The method of claim 59, wherein: The left ventricle was unloaded at a blood flow rate of at least 2.5 L / min during an unloading period greater than 15 minutes.

61. The method of claim 60, wherein the unloading period is any one of: Longer than 20 minutes; Longer than 25 minutes; Longer than 30 minutes; Longer than 35 minutes; Longer than 40 minutes; Longer than 45 minutes; Between about 20 minutes to about 45 minutes; from about 15 minutes to about 30 minutes; and between about 30 minutes to about 40 minutes.

62. The method of any one of claims 59-61, wherein the left ventricle is unloaded at a blood flow rate of at least 3.5 L / min.

63. The method according to any one of claims 59 to 62, comprising the steps of: Reperfusion therapy is applied after mechanical circulatory support is applied to the patient's heart.

64. The method according to claim 63, comprising the steps of: Mechanical circulatory support is applied to the patient concurrently with reperfusion.

65. The method according to any one of claims 56-64, wherein mechanical circulatory support is provided by a TV-pump or other blood pump.

66. The method of any one of claims 63-65, wherein reperfusion comprises at least one of primary percutaneous coronary intervention (PCI) and fibrinolysis.

67. A method of supporting the heart of a patient having a myocardial infarction, comprising at least one of the following steps: Reduce the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; Increased mRNA levels of SERCA expression in cardiac tissue of patients near myocardial infarction; and Reduces calcineurin activity and type I collagen levels in cardiac tissue of patients near myocardial infarction, while maintaining b-MHC levels in non-infarcted areas of the patient's heart.

68. The method according to claim 67, comprising the steps of: Increase blood flow to the patient's heart tissue near the myocardial infarction.

69. The method according to claim 68, comprising the steps of: Apply mechanical circulatory support to the patient's heart during periods of unloading or other support.

70. The method of claim 69, wherein the increased blood flow is provided at a rate of at least 2.5 L / min over an unloading period of greater than 15 minutes.

71. The method of claim 70, wherein the unloading period is any one of: Longer than 20 minutes; Longer than 25 minutes; Longer than 30 minutes; Longer than 35 minutes; longer than 40 minutes; longer than 45 minutes; from about 15 minutes to about 30 minutes; between about 20 minutes to about 45 minutes; and between about 30 minutes to about 40 minutes.

72. The method of any one of claims 68-71, wherein increased blood flow is provided at a rate of at least 3.5 L / min.

73. The method according to any one of claims 69 to 72, comprising the steps of: Reperfusion therapy is applied after mechanical circulatory support is applied to the patient's heart during the support period.

74. The method according to any one of claims 69 to 73, comprising the steps of: Mechanical circulatory support is applied to the patient's heart concurrently with reperfusion therapy.

75. The method of any one of claims 69-74, wherein mechanical circulatory support comprises applying a device comprising a TV-pump or other blood pump.

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

77. The method of any one of claims 73-76, wherein reperfusion comprises at least one of primary percutaneous coronary intervention (PCI) and fibrinolysis.

78. A method of supporting the heart of a patient having a myocardial infarction, comprising the steps of: Reduced levels of BAX protein and active caspase-3 antibodies in cardiac tissue of patients near myocardial infarction; Increased levels of BCL-2 and BCL-XL proteins in heart tissue of patients near myocardial infarction; Increased protein levels of stromal-derived factor 1α (SDF-1α) in cardiac tissue of patients near myocardial infarction; Maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of patients near myocardial infarction; Limiting the upregulation of DPP-4 protein expression and activity in cardiac tissue of patients near myocardial infarction; Reduce the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; Increased mRNA levels of SERCA expression in cardiac cells of patients near myocardial infarction; and Reduces calcineurin activity and type I collagen levels in cardiac tissue of patients near myocardial infarction, while maintaining b-MHC levels in non-infarcted areas of the patient's heart.

79. A cardioprotective system for supporting the heart of a patient having a sustained myocardial infarction, the system comprising: a mechanical circulatory support device configured to be inserted into a patient; and Reperfusion therapy equipment, Wherein prior to operating the reperfusion therapy device, the mechanical circulatory support device is configured to operate at a blood flow rate of at least 2.5 L / min for a support period of greater than 15 minutes.

80. The system of claim 79, wherein the support period is any one of: Longer than 20 minutes; Longer than 25 minutes; Longer than 30 minutes; Longer than 35 minutes; Longer than 40 minutes; Longer than 45 minutes; Between about 20 minutes and about 45 minutes; longer than 15 minutes but up to about 30 minutes; and between about 30 minutes and about 40 minutes.

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

82. The system of any one of claims 79-81, wherein the mechanical circulatory support device is configured to operate simultaneously with a reperfusion therapy device.

83. The system of any one of claims 79-82, wherein the mechanical circulatory support device comprises a TV-pump or other blood pump.

84. The system of claim 83, comprising one or more of the following devices operated after or during operation of a mechanical circulatory support device: an intra-aortic balloon pump and an extracorporeal membrane oxygenation (ECMO) pump.

85. A cardioprotective system for supporting the heart of a patient having a sustained myocardial infarction, the system comprising: a blood pump configured to be percutaneously inserted into a patient following a myocardial infarction, the pump being sized and shaped to be positioned across an aortic valve of a heart of the patient, wherein a distal end of the pump is configured to be located in a left ventricle of the heart; and Reperfusion therapy equipment, Wherein the blood pump is programmed to operate prior to operating the reperfusion therapy device and thereafter to pump blood at a blood flow rate of at least 2.5 L / min for a pumping period longer than 15 minutes.

86. The system of claim 85, wherein the pumping period is any of: Longer than 20 minutes; Longer than 25 minutes; Longer than 30 minutes; Longer than 35 minutes; Longer than 40 minutes; Longer than 45 minutes; Between about 20 minutes and about 45 minutes; longer than 15 minutes but up to about 30 minutes; and between about 30 minutes and about 40 minutes.

87. The system of claim 85 or 86, wherein the mechanical circulatory support device operates at a blood flow rate of at least 3.5 L / min.

88. The system of any one of claims 85-87, wherein the blood pump operates simultaneously with a reperfusion therapy device.

89. A method of treating a human heart having a persistent myocardial infarction having an infarct size and localized within a portion of the heart, the method comprising reducing the infarct size.

90. The method of claim 89, wherein: Infarct size is reduced by decreasing the myocardial oxygen demand of the heart in the portion of the heart containing the infarct, followed by restoring oxygen supply to the portion of the heart containing the infarct.

91. The method of any one of claims 89-90, comprising reducing the level of at least one of BAX protein and active caspase-3 in cardiac tissue.

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

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

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

95. The method according to any one of claims 89 to 94, comprising the steps of: inserting a blood pump into the patient's vasculature; actuating the pump to regulate blood flow within the vasculature during a support period prior to applying reperfusion therapy to the heart; and After the support period, reperfusion therapy is applied to the heart.

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

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

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

99. The method of claim 96, wherein the support period is at least 30 minutes, between about 20 minutes and about 40 minutes, or at least 45 minutes.

100. The method according to any one of claims 95-99, comprising the steps of: The left ventricle of the heart is unloaded during the support period at a pumping rate of at least 2.5 L / min.

101. A method according to claim 100, wherein the blood pump is a miniature axis blood pump, and unloading the left ventricle of the heart includes inserting the distal end of the pump into the left ventricle and inserting the proximal end of the pump into the aorta, and actuating the pump to pump blood from the left ventricle to the aorta.

102. The method according to any one of claims 95-99, comprising the steps of: Inserting a balloon pump into the heart's aorta; and The balloon is inflated and deflated to adjust blood flow within the aorta.

103. The method according to any one of claims 95-102, comprising the steps of: The patient was given an extracorporeal membrane oxygenation system.

104. The method of any one of claims 95-103, wherein the pump is a catheter-based intravascular blood pump.

105. The method according to any one of claims 89-104, comprising at least one of the following steps: Increase the heart's left ventricular ejection fraction, Reduces blockage of microvessels in the heart, Decreases the heart's left ventricular end-systolic volume, and Reduces the left ventricular end-diastolic volume of the heart.

106. The method according to any one of claims 89 to 105, comprising the steps of: The myocardial oxygen demand of the heart in the portion of the heart containing the infarct is reduced for a period of at least 15 minutes, followed by restoration of oxygen supply to the portion of the heart containing the infarct.

107. The method of any one of claims 89-106, wherein: The heart is unloaded by a mechanical circulatory support device while reperfusion therapy is performed on the heart.

108. The method according to any one of claims 89 to 107, wherein: Reperfusion therapy includes at least one of primary percutaneous coronary intervention (PCI) and fibrinolysis.

109. The method according to any one of claims 89-108, comprising the steps of: Reduce the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; Increased mRNA levels of SERCA expression in cardiac cells of patients near myocardial infarction; and Reduces calcineurin activity and type I collagen levels in cardiac tissue of patients near myocardial infarction, while maintaining b-MHC levels in non-infarcted areas of the patient's heart.

110. The method according to any one of claims 89 to 109, comprising the steps of: After reperfusion therapy is applied, the blood pump is removed from the patient's heart.

111. The method according to any one of claims 89-110, comprising the steps of: Increase blood flow to the patient's heart tissue near the myocardial infarction.

112. A method of preventing or limiting the effects of heart failure in a human patient with a sustained myocardial infarction by reducing maladaptive cardiac remodeling in the patient, the method comprising the steps of: percutaneously inserting a transvalvular blood pump comprising a rotor and a cannula into the vasculature of the patient and positioning the cannula across an 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; Prior to reperfusing the heart, operating the pump positioned to unload the left ventricle at a blood flow pumping rate of at least 2.5 L / min for a support period of between at least 30 minutes and less than 60 minutes; and After the support period, coronary reperfusion therapy is applied to the heart.

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

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

115. The method according to claim 112, comprising the steps of: Pump operation was continued in parallel with application of coronary reperfusion.

116. The method according to claim 112, comprising the steps of: Pump operation was continued concurrently with application of coronary reperfusion for a total support period of at least 3 hours.

117. The method according to claim 112, comprising the steps of: At least one of infarct size and left ventricular scar size is reduced.

118. The method according to claim 112, comprising the steps of: The pump was operated to sufficiently unload the heart to alter gene expression in cells within the infarcted area of ​​the myocardium.

119. The method according to claim 118, comprising at least one of the following steps: Reduced levels of BAX protein and active caspase-3 antibodies in cardiac tissue of patients near myocardial infarction; Increased levels of BCL-2 and BCL-XL proteins in heart tissue of patients near myocardial infarction; Increased protein levels of stromal-derived factor 1α (SDF-1α) in cardiac tissue of patients near myocardial infarction; Maintaining the activity levels of MMP-2 and MMP-9 enzymes in the heart tissue of patients near myocardial infarction; Limiting the upregulation of DPP-4 protein expression and activity in cardiac tissue of patients near myocardial infarction; Reduce the circulating levels of brain natriuretic peptide (BNP) in the patient's blood; Increased mRNA levels of SERCA expression in cardiac cells of patients near myocardial infarction; and Reduces calcineurin activity and type I collagen levels in cardiac tissue of patients near myocardial infarction, while maintaining b-MHC levels in non-infarcted areas of the patient's heart.

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

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

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

123. The method according to claim 112, comprising the steps of: The heart is supported by an intra-aortic balloon pump or an extracorporeal membrane oxygenation (ECMO) pump.

124. The method according to claim 112, comprising the steps of: Medication therapy is provided to the patient in conjunction with operating the pump.

125. The method of claim 124, wherein the drug therapy comprises providing the patient with an agent comprising at least one of: a beta blocker, an afterload reducing agent, a neurohormonal agent, and an ACE inhibitor.

126. The method of claim 112, wherein reperfusion therapy comprises at least one of primary percutaneous coronary intervention (PCI) and fibrinolysis.

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

128. A cardioprotective system for preventing or limiting the effects of heart failure in a human patient with a sustained myocardial infarction by reducing maladaptive cardiac remodeling in the patient, the system comprising: a blood pump comprising a rotor and a cannula, the blood pump being configured to be percutaneously inserted into the vasculature of a patient such that the cannula is positioned across an aortic valve of a heart of the patient, wherein a distal end of the cannula is located in a left ventricle of the heart and a proximal end of the pump is located in the aorta; Coronary reperfusion therapy devices; and A controller coupled to the pump, The controller programs the blood pump to unload the left ventricle at a blood flow pumping rate of at least 2.5 L / min during a support period of between at least 30 minutes and less than 60 minutes prior to operating the coronary reperfusion therapy device.

129. The system of claim 128, wherein the pump operates for a support period of 30 minutes.

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

131. The system of claim 130, wherein the pump is configured to operate for a total support period of 3 hours.

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