Device for assessing microvascular dysfunction

Abstract

Methods and devices for assessment of microvascular dysfunction, such as microvascular occlusion (MVO), and other dysfunctional diseases of the microvasculature of many organs, including the heart. The present subject matter provides novel devices and methods for successfully diagnosing, restoring patency, opening and maintaining flow, and limiting reperfusion injury in organs and cases affected by microvascular dysfunction. The present subject matter provides apparatus and methods for detecting, measuring, and treating microvascular dysfunction in real time during scenarios such as invasive angiography / therapy procedures. Such procedures include therapies for organ systems, including the heart (acute myocardial infarction - primary percutaneous coronary intervention (PPCI)), stroke (CVA), bowel ischemia / infarction, pulmonary embolism / infarction, critical limb ischemia / infarction, renal ischemia / infarction, and others. The present subject matter provides various systems, including infusion and sensing catheters, diagnostic agents, therapeutic agents, and control consoles.

Description

Technical Field

[0001] (Technical Field) Assessment of microvascular dysfunction (MVD) and other diseases of the microvasculature of many organs, including the heart.

[0002] (Priority Claims and Related Applications) This application claims the benefit under 35 U.S.C. Section 119(e) (Title 119, United States Patent Law) of U.S. Provisional Application No. 62 / 734,364, filed on September 21, 2018, which is incorporated herein by reference in its entirety.

[0003] This application relates to U.S. Patent Application No. 15 / 398,470, filed on January 4, 2017, published as US2017 / 0189654 A1 on July 6, 2017, which claims the benefit of U.S. Provisional Application No. 62 / 274,744, filed on January 4, 2016, U.S. Provisional Application No. 62 / 320,230, filed on April 8, 2016, U.S. Provisional Application No. 62 / 358,433, filed on July 5, 2016, and U.S. Provisional Application No. 62 / 379,074, filed on August 24, 2016, all of which are collectively referred to as the "incorporated applications" and are incorporated herein by reference in their entirety. This application also claims the priority of all of the foregoing patent applications, and relates to PCT Patent Application No. PCT / US17 / 12181, published as WO2017120229A1 on July 13, 2017, U.S. Provisional Patent Application No. 62 / 560,545, filed on September 19, 2017, and U.S. Provisional Patent Application No. 62 / 640,932, filed on March 9, 2018. All of the incorporated applications are incorporated herein by reference in their entirety.

Background Art

[0004] (Background) A heart attack or STEMI ("STEMI" is defined as acute ECG ST-segment myocardial infarction) typically results from a sudden thromboembolism of the extrapericardial coronary artery with a fibrin and platelet-rich clot, accompanied by associated embolic plaque and debris. The electrocardiographic sign of acute transmural myocardial infarction (heart attack) is elevation of the ST segment (STEMI) in multiple anatomical leads. ST segment elevation is a characteristic of severe coronary thromboembolism or stenosis, leading to ischemic myocardial injury and cell death. Larger vascular thromboembolisms are often associated with smaller vascular stenosis thromboembolisms (microvascular thromboembolism, i.e., referred to as MVO), due to circulatory collapse, clots with embolic debris, and other effects that lead to reduced blood supply. To date, MVO is an independent predictor of late-stage adverse events, including death and heart failure, without successful therapy.

[0005] Interventional cardiology is adept at opening severely narrowed or embolusted extrapericardial coronary arteries in the cardiac catheterization laboratory using catheters, guidewires, balloons, and stents. However, microvascular occlusions cannot be diagnosed or treated in the catheterization laboratory. Importantly, MVOs cannot be treated, even when they can be accurately diagnosed.

[0006] Myocardial rescue (saving muscle from death due to ischemia / lack of blood and oxygen) is a critical concern for ensuring good long-term outcomes in patients with STEMI. A key component of a good long-term outcome involves minimizing the time between coronary thromboembolism (at home or outside the hospital) and deposition of the embolusciatory artery in the catheterization laboratory. Interventional cardiologists can shorten the time of arterial thromboembolism by implementing a streamlined and efficient emergency medical system, with the aim of transporting STEMI patients to the catheterization laboratory as quickly as possible and avoiding long-term STEMI complications. Complications resulting from STEMI and MVO include systolic and diastolic heart failure, arrhythmias, aneurysms, ventricular rupture, and several other serious complications. These complications can significantly shorten lifespan and impose serious limitations on quality of life.

[0007] Modern interventional therapies for acute myocardial infarction are developing over time with remarkable clinical outcomes. The 30-day cardiac attack / STEMI mortality rate has decreased from over 30% to less than 5% by reperfusing the heart with blood as quickly as possible after coronary thromboembolism. This goal is achieved by streamlining the clinical procedure system to open the coronary arteries in the catheterization laboratory as rapidly as possible after the onset of a cardiac attack. Emergency procedures, including stent placement and balloon angioplasty, are undeniably necessary to improve the early and late clinical outcomes of acute cardiac attack therapy.

[0008] However, substantial challenges remain in treating STEMI patients and reducing long-term complications. These problems include heart failure (insufficient cardiac function and cardiac hypertrophy), cardiac / ventricular rupture, persistent ischemic chest pain / angina, left ventricular artery aneurysms and blood clots, and malignant arrhythmias.

[0009] Late-stage heart failure (STEMI) exacerbates 25–50% of STEMI cases and consists of inadequate left ventricular function and damaged myocardium. Heart failure worsens as the heart reshapes and resizes in response to associated functional loss. Nearly half of all new-onset heart failure cases in patients under 75 years of age are linked to STEMI.

[0010] Long-term studies of STEMI therapy have shown that opening the epicardial / greater coronary arteries is insufficient to save the myocardium and optimize long-term patient outcomes. A very common reason for unfavorable late outcomes after a heart attack is microvascular occlusion (MVO). MVO is an embolus or severe restriction of flow within the internal cardiac microvessels. Due to their size and number, these microvessels are unaffected by stent placement and conventional thrombolytic therapy. Therefore, despite the extracardiac coronary arteries being widely patent, residual MVO obstructs blood flow into the heart, causing cellular ischemia and death, resulting in severe long-term myocardial damage.

[0011] MVOs, therefore, remain a significant unexplored area in cardiology. Cardiac microvessels consist of arterioles, arterioles, capillaries, and venules, which are frequently collapsed during STEMI and filled with cells, blood clots, and debris (platelets, fibrin, and embolic plaque material). Often, occluded microvessels (MVOs) do not decompose even after stent placement, leading to serious and long-term negative prognostic consequences.

[0012] MVO is very common in STEMI patients despite successful stent placement and balloon angioplasty in opening the extrapericardial coronary artery. MVO occurs in more than half of all STEMI patients, even when there is good blood flow through the open epicardial artery and newly placed stent.

[0013] The extent of the muscle void (MVO) is important for the severity of myocardial injury and patient outcomes. MVO is best imaged via cardiac MRI, which measures the location, extent, and severity of the MVO. However, because MRI requires the patient to be in a separate imaging area and a separate, large MRI scanner, it cannot be performed in emergencies or during cardiac catheterization procedures.

[0014] The key characteristics of MVO can be summarized as follows:

[0015] 1. MVO and microvascular dysfunction in STEMI are major causes of significant complications in both the early and late stages following a heart attack.

[0016] 2. "No reflow" or "low reflow" on angiography is caused by microvascular voids (MVOs), resulting from occluded microvessels within the heart. In severe cases, MVOs are characterized fluoroscopy by filling the extrapericardial coronary arteries with radiographic contrast at a very slow rate, so that they can be visualized during coronary artery treatment in the catheterization laboratory. However, radiographic contrast filling is only capable of diagnosing severe no-reflow cases and is therefore incapable of detecting the majority of patients with MVOs.

[0017] 3. MVO causes cardiomyocyte damage and death due to prolonged ischemia / lack of essential metabolic nutrients such as oxygen, blood, and glucose. Microscopic analysis of MVO reveals collapsed microvessels along occluded intramyocardial capillaries, accompanied by red blood cells, platelets and fibrin clots, dead cardiomyocytes, inflammatory cells, myocyte death, and endothelial cell death.

[0018] 4. The examined MVO strongly indicates cardiac arterioles and capillaries completely embolusted by platelet and fibrin-rich thrombi, platelet and neutrophil aggregates, dying blood cells, and embolic debris.

[0019] 5. When MVO worsens acute STEMI / myocardial infarction, much greater cardiac / myocardial damage occurs, and insufficient ventricular function occurs early.

[0020] 6. MVO is very common. It occurs in the following.

[0021] a. Irrespective of epicardial flow, in 53% of all STEMI and NSTEMI,

[0022] b. In 90% of large transmural STEMI,

[0023] c. In 40% of MIs with TIMI classification grade III (normal) angiographically visible flow, and

[0024] d. MVO is the single most powerful prognostic marker of events after controlling for infarct size.

[0025] 7. Patients with microvascular obstruction have more late major cardiovascular adverse events (MACE) than those without MVO (45% vs 9%).

[0026] 8. MVO is the best predictor of acute and chronic cardiovascular adverse outcomes.

[0027] 9. MVO acutely progresses to a late fibrotic scar state, causing insufficient cardiac function.

[0028] MVO cannot be diagnosed in a conventional catheter treatment room. Also, effective conventional therapies were not available. All previously considered possible therapies were essentially ineffective and, in some cases, proven dangerous.

[0029] The major complications from myocardial infarction are cell death or ischemia. Myocardial infarction can occur as a short-lived but severe ischemia ("stunned state") that is reversible, chronic ischemia ("hibernating state") where the myocardial cells are alive but lack sufficient oxygen or nutrients to contract normally, or necrosis and infarction via prolonged ischemia. This typically starts from the endocardium and spreads like a wave, traversing the myocardial wall. These events can each be characterized by non-invasive imaging and tests such as nuclear, echo, and PET methods. However, significantly superior tests are provided by cardiac MRI. The use of gadolinium contrast agents can visualize microvascular obstruction.

[0030] Myocardial infarction (MI) resulting in microvascular obstruction (MVO) has a significant clinical impact. Epicardial coronary artery embolism is well-known, but it is also hypothesized that thrombi, i.e., microscopic / microvascular embolization by platelets and fibrin in the microvascular system, also occur. Histopathological examinations have firmly shown limited fibrin and platelet aggregation in both human cases and animal models. Microvascular embolization can also occur due to erythrocytes, leukocytes, and fibrin-platelet aggregates that are invisible to the light microscope and can only be recognized via immunostaining and EM / SEM / TEM. So far, ectopic platelet aggregation has been considered a possibility but has not been proven.

[0031] However, MVO is just one of several disorders under the broader classification of microvascular dysfunction. Microvascular dysfunction also occurs in patients without epicardial artery embolism and thus affects a much larger patient population than the group of patients with ST-segment elevation myocardial infarction (STEMI). The impact of embolism of vessels less than 200 microns in diameter in patients without epicardial artery (vessels larger than 2 mm) embolism is poorly understood despite years of investigation and the failure of many treatment strategies.

[0032] Therefore, there is a need in the art for devices and methods that can assess microvascular function and dysfunction in a larger patient population. Such devices and methods can benefit patients by providing real-time or near-real-time assessment. There is also a need in the art for devices and methods that can diagnose and treat microvascular dysfunction, including microvascular occlusion (MVO) and tissue necrosis / infarction. Furthermore, there is a need for devices and methods that enhance the assessment of the problem in real-time or near-real-time, enable treatment decisions, and / or enable real-time estimation of microvascular dysfunction and the effectiveness of treatment. [Overview of the project] [Means for solving the problem]

[0033] (summary) Methods and apparatus for real-time or near-real-time assessment of microvascular dysfunction. In various embodiments, microvascular dysfunction includes clinical syndromes such as STEMI / NSTEMI, microvascular occlusion (MVO), no-reflow, cardiogenic shock, and other dysfunctional diseases of the microvascular system. The subject matter is applicable to many organs, including the heart. More specifically, non-limiting embodiments include novel devices and methods for normal diagnosis, restoration of patency, opening and maintaining flow, and limiting reperfusion injury in organs and cases suffering from microvascular dysfunction. The application includes, but is not limited to, therapies for organ systems including the heart (acute myocardial infarction - primary percutaneous coronary intervention (PPCI)), stroke (CVA), intestinal ischemia / infarction, pulmonary embolism / infarction, severe limb ischemia / infarction, renal ischemia / infarction, liver, peripheral vascular, neurovascular, and others.

[0034] Using various embodiments of this subject, a system comprising a special infusion and sensing catheter, a diagnostic agent, a therapeutic agent, and a control console with a special algorithm can be used to both diagnose and treat microvascular dysfunction in general and diseases belonging to its classification, such as MVO, by eliminating microvascular clots and debris that cause narrowing and / or occlusion. This technique includes various embodiments of novel device, method, and software combinations for the simultaneous diagnosis and treatment of microvascular dysfunction such as MVO. This subject enables real-time operation with real-time operator feedback for diagnostic and therapeutic decision-making, thereby creating a system capable of performing interventional procedures.

[0035] The subject includes systems and apparatus configured to perform microvascular function assessments. In various embodiments, such assessments are performed in real time. Systems and apparatus for diagnosing and treating microvascular dysfunctions such as microvascular occlusion (MVO) are also included in various embodiments. In various embodiments, the systems and apparatus enable real-time use using invasive catheter placement methods. In various embodiments, the subject provides controlled coronary fluid infusion (CoFI) because catheter-based techniques enable accurate, continuous, real-time microvascular function assessments. CoFI was used to investigate the effects of STEMI on microvascular function.

[0036] Methods are provided for assessing microvascular occlusion within an organ using defined fluid infusion into a site and superimposed pressure measurements resulting from the infusion and the innate fluid. These methods include applying a first fluid pulse at a defined high pressure and / or flow rate to open the microvessels, and then applying a defined flow rate of the infusion at a defined pressure / flow rate, typically (but not necessarily) lower than the high pressure, to treat the microvascular occlusion and reduce, avoid, or eliminate ischemia and necrosis of organ tissue. The disclosure also provides controllable fluid / pressure to a vessel or organ while simultaneously providing various catheter designs for the delivery of infusions, drugs, and / or other fluids and pharmaceuticals. In particular, open and closed-loop delivery devices and methods are provided that can provide customized assessment of tissue by adjusting variables such as infusion pressure, flow rate, concentration, oxygenation, and mixing of innate blood flow into the infusion. The system is also programmable to provide feedback for controlling flow rate, pressure, intra-coronary ECG, and / or other variables. This system can also be programmed to synchronize with the patient's cardiac rhythm for several different assessment options.

[0037] This summary is an overview of some of the teachings of this application and is not intended to be an exclusive or exhaustive representation of the subject matter. Further details relating to the subject matter are found in the modes for carrying out the invention and the appended claims. The scope of the invention is defined by the appended claims and their legal equivalents. The present invention provides, for example, the following: (Item 1) A device for measuring microvascular dysfunction within an organ or limb, comprising blood vessels and a microvascular system connected to the blood vessels, wherein the device is An infusion catheter comprising a plurality of inflatable structures connected to one or more lumens of the catheter, and remotely controlling the expansion and contraction of the inflatable structures and at least one infusion lumen for the delivery of an infusion fluid to the catheter proximal to the inflatable structures, An injection pump communicating with the injection lumen of the injection catheter, Multiple separate solutions in a separate reservoir communicating with the injection pump, A computerized controller, which communicates with the injection pump and is configured to control the operation of the injection pump, to perform controlled fluid infusion of at least a first solution from the plurality of solutions into the injection lumen of the catheter and a second solution from the plurality of solutions into the injection lumen of the catheter, Equipped with, An apparatus in which the first solution is associated with the assessment of microvascular function, and the second solution is associated with changes in microvascular function. (Item 2) The apparatus described in item 1, wherein the first solution is a solution associated with the dilation of the microvascular system. (Item 3) The apparatus according to any of the above items, wherein the first solution is a Newtonian fluid selected to improve the linearity of the flow and to better assess microvascular parameters. (Item 4) The apparatus according to any of the above items, wherein the first solution lacks oxygenation to control hypoxia. (Item 5) The apparatus according to any of the above items, wherein the first solution lacks oxygenation to dilate the microvascular system. (Item 6) The apparatus described in any of the above items, wherein the first solution is crystalline. (Item 7) The apparatus according to any of the above items, wherein the second solution is a solution for reducing, avoiding, or eliminating ischemia and necrosis of the tissue of the organ or limb. (Item 8) The apparatus according to any of the above items, wherein the second solution is a solution for dissolving microvascular blood clots or debris in the heart. (Item 9) The controller controls the pump, Applying pulses to the first solution at a defined and high pressure or flow rate, Applying a defined flow to the second solution at a defined and high pressure or flow rate, and A device according to any of the above items, which is programmed to perform the following action. (Item 10) The device according to any of the above items, wherein the controller is configured to automatically perform a real-time assessment of microvascular function. (Item 11) The apparatus according to item 10, further comprising a pressure sensor configured to sense the pressure within the blood vessel, wherein the controller is configured to use the sensed pressure to perform an assessment of the microvascular function. (Item 12) The pressure sensor is attached to the injection catheter, as described in item 11. (Item 13) The apparatus according to any of the items, wherein the controller is configured to perform an assessment of microvascular function using the sensed pressure resulting from the superposition of injection and innate fluids. (Item 14) The device according to any of the above items, wherein the controller is configured to determine microvascular resistance and assess microvascular function using the determined microvascular resistance. (Item 15) The apparatus according to any of the above items, wherein the controller is configured to control the pump and perform controlled coronary artery fluid infusion (CoFI).

[0038] This disclosure includes, but is not limited to, examples of the same reference material shown in the accompanying drawings illustrating similar elements. [Brief explanation of the drawing]

[0039] [Figure 1]Figure 1 illustrates an example of a modular, computerized diagnostic and infusion system for coronary arteries and other human / animal vascular systems, according to several embodiments of this subject.

[0040] [Figure 2A] Figures 2A-2B illustrate examples of an infusion catheter having an embolization balloon according to several embodiments of this subject. [Figure 2B] Figures 2A-2B illustrate examples of an infusion catheter having an embolization balloon according to several embodiments of this subject.

[0041] [Figure 3A] Figure 3A illustrates an example of the central portion of an injection catheter according to several embodiments of this subject.

[0042] [Figure 3B] Figure 3B illustrates an example of the distal portion of an injection catheter according to several embodiments of this subject.

[0043] [Figure 3C] Figure 3C illustrates an embodiment of the distal portion of an infusion catheter having a pressure chamber, according to several embodiments of this subject.

[0044] [Figure 3D] Figure 3D illustrates an exemplary cross-section of the distal portion of an injection catheter having a pressure chamber, according to several embodiments of this subject.

[0045] [Figure 4] Figures 4A-4B illustrate graphs of injection sequences according to several embodiments of this subject.

[0046] [Figure 5A]Figure 5A illustrates the distal portion of an infusion catheter, according to several embodiments of this subject, which includes a hemodynamic vane or fin for compressing the distal portion of the catheter within a blood vessel or organ where flow is measured.

[0047] [Figure 5B] Figure 5B illustrates the distal portion of an infusion catheter, according to several embodiments of this subject, including a hole for an infusion fluid to be delivered into a blood vessel or organ, where the flow is measured.

[0048] [Figure 5C] Figure 5C illustrates the distal portion of an infusion catheter, including a jet for an infusion fluid to be delivered into a blood vessel or organ, according to some embodiments of the subject, where the flow is measured.

[0049] [Figure 6A] Figures 6A–6D illustrate infusion catheters according to several embodiments of this subject, featuring coaxial injection and guidewire lumen, guidewire, injection port, and the ability to direct forward and reverse injection fluid. [Figure 6B] Figures 6A–6D illustrate infusion catheters according to several embodiments of this subject, featuring coaxial injection and guidewire lumen, guidewire, injection port, and the ability to direct forward and reverse injection fluid. [Figure 6C] Figures 6A–6D illustrate infusion catheters according to several embodiments of this subject, featuring coaxial injection and guidewire lumen, guidewire, injection port, and the ability to direct forward and reverse injection fluid. [Figure 6D] Figures 6A–6D illustrate infusion catheters according to several embodiments of this subject, featuring coaxial injection and guidewire lumen, guidewire, injection port, and the ability to direct forward and reverse injection fluid.

[0050] [Figure 7A]Figures 7A–7E illustrate infusion catheters with coaxial injection and guidewire lumen, pressure sensor, integrated intra-coronary ECG electrode, and injection port according to several embodiments of this subject. [Figure 7B] Figures 7A–7E illustrate infusion catheters with coaxial injection and guidewire lumen, pressure sensor, integrated intra-coronary ECG electrode, and injection port according to several embodiments of this subject. [Figure 7C] Figures 7A–7E illustrate infusion catheters with coaxial injection and guidewire lumen, pressure sensor, integrated intra-coronary ECG electrode, and injection port according to several embodiments of this subject. [Figure 7D] Figures 7A–7E illustrate infusion catheters with coaxial injection and guidewire lumen, pressure sensor, integrated intra-coronary ECG electrode, and injection port according to several embodiments of this subject. [Figure 7E] Figures 7A–7E illustrate infusion catheters with coaxial injection and guidewire lumen, pressure sensor, integrated intra-coronary ECG electrode, and injection port according to several embodiments of this subject.

[0051] [Figure 8] Figure 8 shows an open-loop block diagram of a system for delivering pre-pulses and subsequent pulses / injections according to one embodiment of this subject.

[0052] [Figure 9] Figure 9 shows a closed-loop block diagram of a system for delivering pre-pulses and subsequent pulses / injections according to one embodiment of this subject.

[0053] [Figure 10] Figure 10 shows plots of microvascular resistance, distal pressure, and pump flow rate for controlled fluid injection, as performed according to one embodiment of this subject.

[0054] [Figure 11]Figure 11 shows a plot of coronary artery pressure versus pump flow rate for controlled fluid infusion, as performed according to one embodiment of this subject.

[0055] [Figure 12] Figure 12 shows a chart of microvascular resistance before and after STEMI from a certain test.

[0056] [Figure 13] Figure 13 shows a plot of dynamic myocardial vascular resistance (dMVR) convection rate from a certain test, demonstrating that microcirculation decreases exponentially as the flow rate approaches zero. [Modes for carrying out the invention]

[0057] (Detailed explanation) The following detailed description of the subject matter refers to the subject matter in the accompanying drawings, which illustrate specific aspects and embodiments in which the subject matter may be practiced. These embodiments are described in sufficient detail to enable those skilled in the art to practice the subject matter. References to “an,” “one,” or “various” embodiments in this disclosure do not necessarily mean identical embodiments, and such references assume more than one embodiment. The following detailed description is empirical and should not be taken as restrictive. The scope of the subject matter is defined by the accompanying claims, in addition to the entire scope of legal equivalents to which such claims are granted.

[0058] This subject includes devices, systems, and methods for a unique technique for measuring dynamic microvascular resistance (dMVR) to assess, diagnose, and treat microvascular dysfunctions such as STEMI / NSTEMI, microvascular occlusion (MVO), no-reflow, cardiogenic shock, and other dysfunctional diseases of the microvascular system. This subject is applicable to the assessment of many organs, including the heart. More specifically, non-limiting embodiments include novel devices and methods for successfully diagnosing, restoring patency, opening and maintaining flow, and limiting reperfusion injury in organs and cases suffering from microvascular dysfunction. This application includes, but is not limited to, procedures for organ systems including the heart (acute myocardial infarction - primary percutaneous coronary intervention (PPCI)), stroke (CVA), intestinal ischemia / infarction, pulmonary embolism / infarction, severe limb ischemia / infarction, renal ischemia / infarction, liver, peripheral vascular, neurovascular, and other microvascular occlusions (MVO) and tissue necrosis / infarction.

[0059] Figure 1 illustrates embodiments of a modular, computerized diagnostic and infusion system 100 (hereinafter, the "infusion system") for coronary arteries and other human / animal vascular systems and organs, according to several embodiments of the subject. The infusion system 100 may be a clinically ready modular system and may be configured in the form of a mobile console. The infusion system 100 can enable the direct measurement and diagnosis of microvascular dysfunction, including MVO and other microvascular abnormalities, by:

[0060] Real-time coronary artery pressure and flow rate,

[0061] Pressure / resistance time parameter,

[0062] Water pressure or coronary artery wedge pressure or coronary artery residual pressure,

[0063] Coronary electrocardiogram (ECG), and / or

[0064] The fractional flow reserve (FFR) measurement value in the epicardial artery.

[0065] The infusion system 100 can enable the following therapies:

[0066] Injection of approved drugs,

[0067] Targeted and controlled low-flow injection, and / or

[0068] Continuous monitoring of diagnostic parameters.

[0069] Figure 2A illustrates an embodiment 200 of an infusion catheter according to several embodiments of the subject, having an embolus balloon 206, balloon markers 208 and 210, and an infusion port 202, all of which are in fluid communication with an infusion lumen 212. A guidewire lumen 204 is provided so that the infusion catheter can slide along the guidewire to a desired position.

[0070] Figure 2B illustrates an embodiment 300 of an infusion catheter 250 having an embolus balloon 206 positioned across a 0.014-inch pressure-measuring guidewire 201 in a rapid-replace (RX) configuration, according to several embodiments of the subject. In the shown embodiment, the catheter 250 can slide across the guidewire 201 via the guidewire lumen 204. The infusion port 202 can deliver fluid through the infusion lumen 212 while the guidewire 201 is positioned within the lumen 204.

[0071] Figure 3A illustrates an embodiment of the central portion of the injection catheter 310 according to several embodiments of this subject. The central portion shows a cross-section with an injection lumen 312 surrounding a guidewire lumen 311. It should be understood that in various embodiments, the injection lumen may be lateral or in a non-linear path centered on the guidewire lumen. Other configurations are also possible. One aspect is to provide a small cross-sectional area to allow the catheter to be introduced into smaller blood vessels for therapy.

[0072] Figure 3B illustrates an embodiment of the distal portion of an infusion catheter according to several embodiments of this subject. In this embodiment, the guidewire 301 can exit from the distal portion of the catheter and be used for catheter placement at an appropriate anatomical site. In embodiments in which the guidewire also provides pressure sensing, the guidewire can be positioned outside or inside the catheter lumen and can provide various pressure sensing at the distal end of the catheter at that location.

[0073] Figure 3C illustrates an embodiment of the distal portion of an infusion catheter having a pressure chamber 306, according to several embodiments of the subject. The pressure chamber is designed to provide a stable pressure measurement area within the distal arterial segment. It is an integrated component of the device that holds the guidewire 301 and allows for pressure measurement at a location different from that close to or distal to the catheter tip.

[0074] Figure 3D illustrates exemplary cross-sections of the distal portion of an infusion catheter having a pressure chamber, according to several embodiments of this subject. In various embodiments, the pores, slits, or slots 323 provided by this design provide both better dispersion of the infusion fluid and more precise pressure measurement at the distal end of the catheter. Such pores, slits, or slots 323 can also be patterned to provide an infusion fluid flow pattern desired for a particular therapy. In various embodiments, different lumen configurations such as lumens 321 and 322 may be used, which can be used for guidewire lumen, infusion lumen, or other lumen and port applications.

[0075] Figure 5A illustrates the distal portion of an infusion catheter, including a hemodynamic vane or fin 509, to facilitate the articulation of the distal portion of the catheter within a blood vessel or organ where fluid flow is measured, according to several embodiments of this subject. The fluid force is symmetrical and facilitates the articulation of the distal end of the catheter within the fluid field.

[0076] Figure 5B illustrates the distal portion of an infusion catheter 520, including a hole for an infusion fluid 523 to be delivered into a blood vessel or organ, in some embodiments of the subject. In various embodiments, the front end of the catheter has a tapered section 505 so that the transition from the guidewire 501 to the catheter diameter is more gradual.

[0077] Figure 5C illustrates the distal portion of an infusion catheter, including a jet for an infusion fluid to be safely delivered into a blood vessel or organ, where the flow is measured, according to several embodiments of the subject. The figure demonstrates that the jets may be intended to provide a jet of the infusion fluid flow 536 when desired in relation to a particular therapeutic benefit, and that their variability will produce slower flow, and therefore lower jet velocities, resulting in a lower likelihood of vasotomy due to injury. The jets can be reverse 533 or forward 534 jets in various combinations. In various embodiments, the front end of the catheter has a tapered section 535 so that the transition from the guidewire 501 to the catheter diameter is more gradual.

[0078] Figures 6A-6D illustrate an injection catheter 610 comprising a coaxial injection lumen 612 and guidewire lumen 611, a guidewire, an injection port 623, and a cap 613. This design allows for directing the injection fluid in both forward 634 and reverse 633 directions, according to several embodiments of the subject. The resulting flow can be combined to provide a high-flow region 636.

[0079] Figures 7A–7E illustrate an infusion catheter with a coaxial injection and guidewire lumen, a pressure sensor, an integrated intra-coronary ECG electrode, and an injection port, according to several embodiments of this subject. Figure 7A shows a design 710 having a central lumen 711 surrounded by an injection lumen 712 in a coaxial configuration. In various embodiments, the central lumen may be used to receive a guidewire 701. In various embodiments, the guidewire may be pressure-sensing with a sensor 719. While the embodiment in Figure 7A is coaxial, it should be understood that the lumens may be configured differently, such as side-by-side. Therefore, variations in cross-section and dimensions are possible without departing from the scope of this subject. Figure 7C shows the guidewire lumen portion of the catheter, in which a pressure-sensing guidewire 701 can be used to deploy the catheter. The guidewire may be retracted to perform pressure sensing. In various embodiments, the guidewire lumen may include a pressure port to facilitate the sensing of injection pressure. Infusion pressure sensing can be performed using different sensing configurations, such as a pressure transducer 719, at or near the distal end of the catheter 720, near the proximal end of the catheter, and / or other locations along the catheter. In various embodiments, a guidewire lumen or guidewire may be used for sensing or measuring intra-coronary ECG. Figure 7D shows a portion of the infusion catheter, including the infusion lumen and a guidewire lumen with a guidewire extending from the guidewire lumen. Figure 7E shows a portion of the infusion catheter 740 with an ECG electrode 741 for sensing the ECG signal. In various embodiments, the ECG electrode is integrated into the catheter to acquire the intra-coronary ECG signal. In various embodiments, various sensing aspects of the infusion catheter can be combined to provide various sensing functions by the same infusion catheter. For example, the catheter may include, among other things, both pressure sensing and ECG sensing. Thus, the subject matter is demonstrated by these embodiments, but is not limited to the specific combinations shown.

[0080] Infusion catheters, such as those shown in Figures 2-3 and 5-7, are used within the systems / devices / methods described herein to controllably embolus a desired blood vessel, inject a desired fluid, and measure the pressure inside the blood vessel and distal to the embolus balloon in real time. Infusion catheters, such as those shown in Figures 2-3 and 5-7, may include a catheter compatible with a 6F guide sheath and a flexible 5 × 10 mm embolus balloon, which can be received across a 0.014 inch pressure guidewire. Infusion catheters, such as those shown in Figure 2-3, may include a wide fluid infusion range, e.g., 5–50 ml / min, and may include axial fluid infusion.

[0081] In some embodiments, the catheter can be inserted into a myocardial vascular system that supplies blood to the patient's myocardium. In some embodiments, the myocardial vascular system or nearby vascular systems may or may not contain microvascular dysfunction such as MVO, and may or may not contain myocardial infarction. The catheter can controllly block forward blood flow in the myocardial vascular system surrounding the catheter by inflating a balloon. In some embodiments, the myocardial vascular system may contain a stent, and the catheter can block forward blood flow from within the stent by inflating a balloon.

[0082] Figures 4A–4B illustrate graphs 400 of embolization and infusion algorithms according to several embodiments of this subject. In various embodiments, the infusion algorithm is generated by a modular computerized infusion system 100, such as the one shown in Figure 1. The infusion system 100 can perform vascular diagnostics as described in incorporated applications, including, but not limited to, the one described in U.S. Provisional Patent Application No. 62 / 560,545, filed September 19, 2017 (which is incorporated as a whole by reference).

[0083] The system may contain an injectable fluid at a higher flow rate or pressure and provides an initial flow or pressure pulse of variable duration, i.e., a “preliminary pulse” 402, for expanding, opening, or otherwise clearing channels of the microvascular system that are collapsed and have occluded debris. The system then provides pulses of similar, or possibly smaller, pulse amplitude (404, 406, 410, etc.) for providing therapeutic infusion into blood vessels or organs, as described herein.

[0084] The injection pressure, step count, pulse, and time may vary within the scope of this disclosure. An example of the pressure response is shown in Figure 4B, where line 420 is the water pressure (WP), which is the baseline pressure of the tissue under analysis. Curves 422 and 424 show the variation in applied pressure and applied pressure associated with blood flow resulting from the application of pulses in Figure 4A. Flow improves over the course of the applied therapeutic pulse.

[0085] Figure 8 shows an open-loop block diagram 800 relating to the delivery of a pre-pulse and subsequent pulse / injection according to one embodiment of the subject. In the open-loop configuration, a fluid or pressure pulse is injected at a fixed or predetermined parameter. In various embodiments, a pump controller 810 receives inputs (e.g., 801, 803) and performs algorithmic control of the pump and the injected fluid or multiple injected fluids to be delivered (e.g., 811, 812, and / or 813 in Figure 8). The injected fluid is delivered to the injection lumen of the injection catheter 830. In various embodiments, the system can control the delivery of the injected fluid, including the type, pressure, flow rate, dose, temperature, and other parameters of the injected fluid. In various embodiments, the system can control the pressure and inflation of one or more embolic balloons. In various embodiments, the system can control multiple aspects of the system, such as injected fluid and balloon parameters, among others.

[0086] Figure 9 shows a closed-loop block diagram 900 relating to the delivery of a pre-pulse and subsequent pulse / infusion according to one embodiment of the subject. In this configuration, the infusion pressure, flow rate, volume, or rate can be controlled in real time or according to measured / sensed vascular parameters, including flow rate, anatomical structure, pressure, resistance, intracoronary ECG, or similar physiological measurements. In various embodiments, the pump controller 910 receives input from the operator (e.g., 901, 903, etc.) and input from one or more feedback signals (950, 925, 915) sensed by one or more sensors (e.g., 930, 941, etc.) to perform closed-loop algorithmic control of the pump and the delivered infusion fluid or multiple infusion fluids (e.g., 909, 912, and / or 913 in Figure 9). The infusion fluid is delivered into the infusion lumen of the infusion catheter 930. Such a design allows feedback from sensed signals to help the controller provide algorithmically controlled infusion fluid. Such sensors can modify the infusion based on physiological conditions and / or measured parameters. Some of the sensed parameters include, but are not limited to, pressure, flow rate, impedance, and cardiac cycle. In various embodiments, the system can use the measured parameters to control the delivery of the infusion, including the type, pressure, flow rate, dose, temperature, and other parameters of the infusion. In various embodiments, the system can use the measured parameters to control the pressure and inflation of one or more embolic balloons. In various embodiments, the system can use the measured parameters to control multiple aspects of the system, such as, among other things, infusion and balloon parameters.

[0087] Therapy based on the restoration of microvascular flow

[0088] In the process of examining microvascular dysfunction, i.e., MI and MVO, it has been observed that extrapericardial coronary artery occlusion causes acute and severe loss of distal pressure, particularly in the intramyocardial capillaries. The intrawall pressure of a contracting ventricle is periodic with a systolic-diastolic cycle. Capillaries are therefore more likely to occlude, either completely or partially, and to open more widely than would occur in the case of normal blood flow and normal blood pressure in the extrapericardial coronary arteries supplying the microvascular system. This is shown by epicardial flow velocity measurements and in histological evaluation of acute myocardial infarction, which shows capillaries too small to accommodate red or white blood cells (e.g., microvascular diameter less than 10 μm) and is accompanied by scattered thrombotic elements such as platelets or fibrin. These observations strongly suggest that extrapericardial coronary artery thromboembolism causes microvascular hypotension and generates conditions for catastrophic dynamic collapse and partial or complete microvascular occlusion.

[0089] One way to model microvascular collapse is to perform a hydrodynamic analysis of the microvascular system within the myocardial contractile tissue. Laplace's law governs the pressure required to sustain open capillaries, as follows:

[0090] T = P × R

[0091] In the equation, T is the tension within the blood vessel wall (e.g., in units of kg / (s²)), P is the pressure across the blood vessel wall (e.g., kPa), and R is the radius of the blood vessel (e.g., mm). From Laplace's equation, it can be observed that as the radius becomes very small, the pressure required to open a closed capillary becomes very large. Furthermore, Poiseuille's equation provides a method for modeling resistance to flow, as follows: Vascular resistance (VR) is proportional to (blood viscosity × vascular length) / R4.

[0092] Therefore, assuming that blood viscosity is relatively constant, vascular resistance is inversely proportional to the fourth power of the vascular radius. As the vascular radius contracts by half, the original vascular resistance VRO increases 16-fold, as follows: VR=VRO / (0.54)=VRO / (0.0625)=16VRO

[0093] Therefore, the restoration of blood pressure and blood flow through interventions such as coronary artery stenting does not supply sufficient pressure to open the closed capillary bed, leaving the capillaries partially or completely closed due to the continuous periodic compression / relaxation between cardiac cycles. These physiological disturbances of normal capillary function are a significant component of microvascular occlusion, chronic capillary thromboembolism (with slow flow as evidenced by MRI imaging, showing very late gadolinium enhancement at the site of infarction).

[0094] This topic provides a mechanism not only for opening the extrapericardial coronary arteries but also for reversing capillary thrombosis caused by low pressure and for mitigating other causes of low or no fluidity in capillaries that lead to thrombosis, microvascular spasm, and cardiomyocyte death. Therefore, this topic addresses the chronic complications of MI and the resulting ischemia, congestive heart failure, arrhythmias, ventricular aneurysms, myocardial rupture, unfavorable prognosis, recurrent clinical events, and various severe negative cardiac complications. It should be further understood that this topic may also be applicable to other diseases such as peripheral vascular disease (limbs), stroke (cerebral), renal failure (kidneys), and diseases affecting blood flow to other parts of the body.

[0095] therapy Some therapeutic components of this application include the physiological and biophysical mitigation of microvascular dysfunction, including stenosis, occlusion, inflammation, reperfusion injury, and chronic dysfunction. In various embodiments, the addition of chemotherapeutic agents, which is locally injected systemically through a coronary catheter, may be followed over longer time periods via intravenous or other routes. In various embodiments, direct coronary drug infusion becomes systemic infusion. Several classes of drugs are described, but are not limited to, antiplatelet agents, acute and chronic thrombin inhibitors (both direct and indirect), and vasodilators, including nitric oxide donors and nitric oxide synthase stimulants.

[0096] For example, in various embodiments, antiplatelet agents in the form of antiaggregants such as direct thrombin inhibitors (hirudin and its molecular analogues, platelet receptor inhibitors, i.e., GP IIb / IIIa inhibitors, factor X inhibitors, low molecular weight heparin, and fibrin inhibitors and fibrin fibrinolytic agents) are available for use.

[0097] Vasodilators with therapeutic and diagnostic properties may be used to dilate the microvascular system in real time as the dissolving therapeutic agent is injected. Some examples include nitroglycerin (TNG), low-dose dopamine, adenosine, acetylcholine, papaverine, hydralazine, channel blockers, and others.

[0098] Devices for therapeutic infusion This subject provides various infusion catheters for assessing microvascular dysfunction. In various embodiments, the catheter is adapted to receive a guidewire, which may have pressure-sensitive capabilities, for delivering the distal end of the catheter to a site and for delivering an infusion fluid from the proximal end of the catheter through the lumen to the distal end of the catheter. In various embodiments, the infusion fluid is delivered by an infusion lumen. In various embodiments, the catheter includes a guidewire lumen for receiving a pressure-sensitive or standard guidewire.

[0099] In some embodiments, the catheter includes various lumens. In embodiments including an injection lumen and a guidewire lumen, the injection lumen and the guidewire lumen are separate and may be oriented adjacent to each other or coaxial to each other. The injection lumen may be used for the delivery of an infusion fluid for drug delivery, or for diagnostic or therapeutic infusion, or a combination thereof. In various embodiments, the catheter includes a lumen for pressure monitoring, either directly or via a pressure-sensing wire. In various embodiments, the lumen for pressure monitoring may accommodate a pressure-sensing guidewire. In various embodiments, the catheter includes a dedicated lumen for the delivery of an infusion fluid and pressure sensing. In various embodiments, the catheter includes a dedicated lumen for the delivery of an infusion fluid, pressure sensing, and for housing a guidewire. In various embodiments, the catheter includes a dedicated lumen for the delivery of an infusion fluid, drug delivery, and pressure sensing. In various embodiments, the catheter includes a dedicated lumen for the delivery of an infusion fluid, drug delivery, pressure sensing, and for housing a guidewire. The injection fluid lumen may have holes, slots, or otherwise allow for diffusion of the fluid (diagnostic or therapeutic) for safer injection into the blood vessel.

[0100] In various embodiments, the catheter includes a vane or fin, which is adapted to push the catheter away from the wall of the blood vessel in which it resides, thereby providing safer and more consistent pressure measurement. In various embodiments, the vane or fin is adapted to center the catheter within the blood vessel in which it resides. In various embodiments, the vane or fin includes a hydrodynamic quality adapted to push the catheter away from the wall of the blood vessel and / or to center the catheter within the blood vessel.

[0101] In various embodiments, a shaft design, vane, or fin with hydrodynamic impact is positioned distally on the surface of the catheter to equalize the hydrodynamic flow around the catheter and push the catheter into the central flow of blood flow via the Bernoulli principle.

[0102] These fins can also direct blood into the open chamber at the distal end of the catheter to facilitate accurate pressure measurement within the surrounding arteries or vascular structures.

[0103] In various embodiments of the catheter, at least a portion of the distal end of the catheter is fabricated to be more flexible. In various embodiments, flexibility is improved by variations in the durometer of the catheter material, the pattern of notches, or both. In various embodiments, notches are implemented to create swirling or other patterns for fluid diffusion (to avoid spraying for safer injection). In various embodiments, the patterns are all circular, irregular patterns, typically created by laser or other micromachining methods. Differential stiffness can be generated by these patterns, or by other methods such as varying the size and density of holes in various patterns, allowing the tip compartment to have differential flexibility in the pattern, which is beneficial not only for tracking but also for containing blood in the distal pressure chamber.

[0104] In various embodiments, multiple micropores with varying sizes, shapes, and densities allow for variations in the flexibility of the catheter tip or proximal component.

[0105] In various embodiments, a distal opening or lumen for inserting and withdrawing a guidewire through the distal tip of the catheter allows the pressure guidewire to be utilized to position the catheter using a standard intervention method, including a “rapid replacement” configuration. Once proper positioning is achieved, the pressure guidewire may be retracted in the reverse direction to facilitate pressure sensing mode. The wire is retracted into a chamber within the catheter body, ensuring full exposure to blood pressure through a notch, opening, or slot so that blood or other combined fluids (such as diagnostic agents and / or infusion fluids) can provide accurate pressure measurements.

[0106] In various embodiments, the system enables measurement of intra-coronary ECG across an electrode located on the distal end of a guidewire, pressure guidewire, or catheter.

[0107] In various embodiments, differential pore patterns can vary longitudinally to modify not only flexibility but also resistance to the flow of the injectable fluid. In this configuration, differential venting of the flow along the longitudinal direction of the catheter can be achieved. In various embodiments, equal venting of the flow can be achieved using pores, vortices, and their patterns, which are varied systemically to decrease or increase resistance as a function of the longitudinal direction along the axis of the catheter. In various embodiments, the pore, notch, and vortex patterns are multifunctional for controlling relative fluid venting at various pressures and for facilitating catheter maneuvering and tracking across a guidewire, which may be a pressure wire to modify the flexibility of the distal tip and enable distal pressure sensing.

[0108] In wire-based embodiments that allow for guidewire insertion, the distal tip of the catheter may also include various holes, notches, wedges, spirals, or other openings. In various embodiments, the opening pattern is chamfered or beveled to push or inject blood into the resulting containment chamber.

[0109] The incorporated application, namely, U.S. Patent Application No. 15 / 398,470, which claims the interests of U.S. Provisional Application No. 62 / 274,744, filed on January 4, 2016, U.S. Provisional Application No. 62 / 320,230, filed on April 8, 2016, U.S. Provisional Application No. 62 / 358,433, filed on July 5, 2016, and U.S. Provisional Application No. 62 / 379,074, filed on August 24, 2016, and the preceding Additional catheter designs are provided, such as those described in PCT Patent Application No. PCT / US17 / 12181, published on 13 July 2017 as WO2017120229A1, claiming priority to all of the aforementioned patent applications, and in U.S. Provisional Patent Application No. 62 / 560,545, filed on 19 September 2017 (all of which are incorporated herein by reference as a whole).

[0110] Local drug and infusion fluid infusion profiles Acute, subacute, and chronic myocardial infarction all result from microvascular thrombosis, microvascular occlusion, and catastrophic microvascular collapse, which can lead to both intraluminal embolization by thrombi, cells, and proteinaceous materials, as well as relative local myocardial hypotension, which reduces capillary size, impedes normal blood flow, and generates severe ischemia and necrosis. In various embodiments of this subject, therapy involves infusion protocols and local medications to be infused.

[0111] Various embodiments of this subject provide controlled infusion profiles for treating microvascular collapse resulting from hypertension. It has been found that microvascular vessels can be opened much better by utilizing sustained flow, such as from an external pump, than by utilizing periodic blood pressure supplied to the arteries via the heart.

[0112] For example, an external pump typically allows for a sustained application of pressure, rather than the periodically fluctuating systolic-diastolic pressure supplied through innate cardiac contraction. This can be demonstrated by calculating the pressure / time integral (and using RMS equivalent pressure), which shows that sustained pressure over the microvascular system, both for initial release and maintaining that release, is far better at maintaining flow to the tissue of interest. In some calculations, the improvement in flow is as large as 10 times or more with respect to the equivalent pressure provided by the pump.

[0113] Another therapeutic benefit of an external pump is that the pressure from the pump can be injected at hyperphysiological values. For example, in some embodiments of this subject, high pump pressure is generated by continuous or periodic fluid infusion. Infusion into the distal microvascular system generates back pressure via Ohm's law P=Q×VR (i.e., pressure is equal to flow rate × microvascular resistance VR) as applied to fluid dynamics.

[0114] In various applications of this subject, fluid injection can be placed within a closed-loop system to achieve "real-time," regular, continuous, and precise pressure control. Significantly high intravascular pressure does not necessarily adversely affect the cardiac pressure generated through the supply from the left or right ventricle. For example, the high pressure values ​​(200 mmHg or higher, etc.) generated by the left ventricle in hypertension place excessive stress and strain on the myocardial wall, and therefore exert strong occlusal pressure on the microvascular system during systole. Furthermore, these extremely high pressures expose the entire body to hypertension, which can lead to even more rapid and severe negative clinical consequences. Therefore, it is very difficult to consider increasing local myocardial intravascular pressure and hemodynamically opening capillaries that have been occluded by the induction of hypertension.

[0115] Conversely, it can be achieved to supply substantially high local pressure by a catheter. In various embodiments of this subject, the proximal blood vessels are blocked by a balloon, thus protecting the body from local hypertension.

[0116] In various additional embodiments, balloon embolization is not essential. A controlled flow rate can be adjusted to vary the pressure microvascular resistance and establish flow into the microvascular system to a level considered therapeutic, regardless of whether the drug is present in the infusion fluid.

[0117] Injection pressure at a variable injection rate is a direct measure of microvascular resistance and, as discussed in the incorporated application, is a diagnosis of function or dysfunction of local microvascular structures.

[0118] Specifically, the high pressure supplied by the pump, which should be used for the initial opening of hydrostatically closed capillaries, is a “preparatory pulse” used to prepare the microvessels and better receive the therapeutic solution. As these capillaries open, a measurable drop in distal infusion pressure, reflecting the decrease in hydrodynamic resistance, will be visualized. This pressure change or drop can be measured in real time and used as feedback to the operator for when hydrostatic opening occurs. The pressure drop can also be measured and applied to a closed-loop control program that adjusts the infusion pressure for the desired result. For example, the controller can be adjusted to maintain a constant infusion fluid flow. The controller can be adjusted to maximize the rate of drug delivery to the microvascular system. The controller can also generate pulsed pressure waveforms and be used to obtain dynamic measurements of microvascular dysfunction, such as MVO.

[0119] The infusion of drugs containing the infusion solution can clear aggregated and stagnant cells. Such procedures can affect platelets, leukocytes, erythrocytes, and proteinaceous substances found within the occluded microvascular system during ischemic events.

[0120] Injection pulse sequence

[0121] In various embodiments of this subject, employing an injection fluid pump, the delivered controlled injection can be applied in a variety of distinctly different, coupled, and temporally related flow rate / pressure and / or pulse sequences. The pulse sequence can be controlled manually or by an automatic control system which may include a feedback mechanism for stabilizing and generating a precise flow pattern by the pump. The safety of the injection is enhanced through feedback and closed-loop control. For example, if the flow generates excessively high pressure, the pump flow can be stopped, reduced, or otherwise limited according to system principles and control theory. In various embodiments, in addition to real-time visualization of pressure, resistance, and flow rate, visual or audible alarms may be triggered to warn the operator of overpressure or underpressure conditions.

[0122] In various embodiments of this subject, the injection profile may be separated within its components. For example, in various approaches, the pulse sequence may include "pre-pulses" and "successor pulses" or fluid injection.

[0123] "Reserve pulse"

[0124] A “preparatory pulse” is a preparation step for drug delivery, while simultaneously preparing the microvessels to receive, open, or extend fluid flow. A preparatory pulse is a preparation step for opening a narrowed or embolusted microvascular system and, in some cases, initiating drug delivery. A preparatory pulse can be, for example, a high flow rate or high pressure designed to open a hydrostatically embolusted microvessel. The injectable fluid for this may be a simple liquid such as Ringer's lactate solution, sodium, chlorine, potassium, glucose, lactate, and other crystalloid solutions containing beneficial concentrates of these, or it may also be a drug-containing solution.

[0125] In various embodiments, the duration of the pre-pulse may be induced by local distal pressure measurements and feedback from real-time observations of myocardial resistance, flow, or cardiac function (pressure and ventricular function measurements or intracoronary ECG). In various embodiments, the duration of the pre-pulse may be limited or stopped when the calculated pressure or resistance drops to a predetermined value or a relative percentage of the initial pressure or resistance.

[0126] The pre-pulse can be high pressure, but it is not generated by the ventricle itself and does not produce high intramyocardial pressure that would cause microvessels to close in clinical syndromes of high pressure, making it safer than "hypertension."

[0127] In various embodiments, the preliminary pulse may be timed over diastole using a QRS complex with electrocardiogram, or via periodic distal pressure measurement, or via any other means for determining lower pressures within the intramural components of the ventricular wall. Furthermore, periodic innate myocardial contractions and microvascular pulsations themselves provide potentially useful agitation of the diagnostic / therapeutic solution.

[0128] In various embodiments, the preliminary pulse is induced through feedback, tracking an increase in distal pressure that saturates at a given value, indicating that the capillaries in the microvascular system are completely filled and cannot accept further flow without an increase in pressure in a fixed pattern.

[0129] Subsequent pulse or fluid injection

[0130] Following a preliminary pulse, a subsequent fluid infusion is performed to maximize drug delivery to embolused vessels of the microvascular system compared to patent or partially patent microvessels. In various embodiments, the subsequent pulse or fluid infusion is a controlled fluid infusion with monitoring of distal pressure for safety and efficacy purposes. If the measured distal pressure rises to a dangerous level, the fluid can be automatically and controllably reduced or stopped using a computer-controlled algorithm. In various embodiments, the fluid can be controllably reduced or stopped by a manually controlled operator-based system that provides a signal to the operator.

[0131] In various embodiments, low pressure may be employed during the infusion phase, advantageously, to generate a rapid increase in microvascular resistance at low pressure. The test shows a natural logarithmic relationship between myocardial flow rate (Q) and resistance (R), with a rapid increase in resistance as the flow rate decreases. In various embodiments, this low-flow-low-pressure infusion strategy can more equalize the resistance of the occluded and patent microvascular systems (resulting from low-pressure-low-flow infusion). This, in turn, equalizes these two parallel resistances (occluded / unoccluded microvascular systems), which therefore delivers proportionally and absolutely greater flow to the occluded or partially occluded microvessels. The preparatory and impulse sequences may be chained and repeated over time.

[0132] In various embodiments of this subject, proximal balloon embolization is part of these preliminary and therapeutic infusion sequences. As the proximal vessel is embolized, substantially all of the pump flow is directed into the distal vessel.

[0133] In various embodiments of this subject, partial balloon embolus is achieved by monitoring distal pressure. The pressure value existing between residual coronary pressure (CRP) and systolic pressure indicates partial balloon embolus and can be used in a feedback loop to maintain the vessel in a partially embolusced state. Experimental and theoretical modeling studies demonstrate that the infusion-flow relationship forms a linear system. Because this system is linear, the superposition of flow (pump flow and innate coronary flow) is a viable modality. One advantage of this approach is that the vessel is perfused by a mixture of infusion fluid and forward innate (oxygenated) blood, and therefore such pulse sequences can be performed over very long periods of time without the risk of distal myocardial ischemia. The linear superposition of flow in a linear system allows for accurate measurement of distal microvascular resistance via the required infusion pressure via the pump, which is parallel to the innate forward blood flow.

[0134] In various embodiments, the superposition of double or greater (e.g., triple, quadruple, or greater) flow, as described, also enables the measurement of the innate flow. In this approach, an incremental flow supplied by a pump is added to the innate flow, providing an incremental pressure increase. Linearity allows for distal resistance measurement, which is equal to the incremental pressure, divided by the known controlled flow (from the pump). This known resistance can then be used to calculate the innate flow.

[0135] For example, while the pump flow is still operating, the total flow is the sum of the intrinsic and pump flow. If the resistance is known, the flow can be calculated individually. When the pump flow is stopped and the resistance and residual pressure are known, the intrinsic flow can similarly be calculated.

[0136] Flow superposition provides additional measurement options. For example, coronary artery flow can be measured using methods such as the following: In various embodiments, a catheter is placed in position, a pressure wire is installed, and flow injection is initiated. The incremental pressure divided by the known inserted flow is equal to the resistance. As a result, the total flow is calculated, and the innate flow is the total flow minus the innate flow.

[0137] Blood flow reserve ratio

[0138] Another measurement that can be performed using the fluid superposition described herein includes the measurement of the fractional flow reserve (FFR), i.e., a parameter for determining the severity of stenosis in the extrapericardial coronary artery. In one embodiment of this subject, a method for measuring FFR is obtained by a combination of the following steps: A fluid infusion catheter is delivered proximal to the stenosis. Aortic pressure is measured by a guide catheter or by a separate pressure guidewire that measures the pressure proximal to the stenosis. A pressure-sensing guidewire is used to cross the stenosis. Incremental fluid is initiated by a pump through the infusion catheter. Incremental pressure measurements are obtained with the known fluid from the pump. Stenosis resistance is calculated as the pressure drop across the stenosis divided by the known coronary flow, which can be calculated as total fluid - injected fluid.

[0139] Absolute myocardial resistance

[0140] In various embodiments, the methods described herein provide an approach for measuring absolute dynamic myocardial vascular resistance (dMVR). MVR is called “dynamic” because the resistance fluctuates at different flow infusion rates and increases exponentially at low flow values. Figure 13 shows a plot of dynamic myocardial vascular resistance (dMVR) convection rates from a certain examination, demonstrating that microcirculation decreases exponentially as flow approaches zero. Calculations utilizing known flow rates and distal pressures can provide the absolute myocardial resistance (resistance = pressure / flow rate) at each flow rate. The approaches provided herein enable simultaneous measurement of distal microvascular resistance and stenosis FFR.

[0141] In various embodiments, a constant pressure method will also provide a determination of microvascular resistance within an organ. In one embodiment of this method, a pump is used with or without input arterial embolus (by a balloon or other occlusion device, etc.). Pressure is monitored as infusion begins. In various embodiments, an infusion sequence that increases or decreases the pressure level is established by adjusting the pump rate, monitoring back pressure, and recording the pump flow rate at each pressure level. The result is within a pressure-flow composite set or within any desired range. Flow rates are measured in each range and generate pressure-flow relationships that can be analyzed as described below.

[0142] Assessment of microvascular resistance: The importance of the injectable fluid.

[0143] A diagnostic method for controlled fluid infusion and controlled pressure to determine the microvascular resistance of any organ can be modified depending on the infusion fluid used as the infusion or diagnostic fluid.

[0144] Specifically, the importance of whether the fluid is a Newtonian or non-Newtonian fluid significantly impacts the resistance outcome. The use of Newtonian fluids, such as any electrolyte-based medical fluid, is far superior to blood or other non-Newtonian fluids. The use of Newtonian fluids allows for a much more accurate demonstration of microvascular resistance, which, as experimentally demonstrated, is highly linear, particularly in the heart. The use of non-Newtonian fluids can cause the microvascular resistance of such organs to appear non-linear. Newtonian fluids also serve as excellent diagnostic solutions and can be used to better control ischemia, typically due to their oxygen deficiency. Newtonian fluids also act as potent vasodilators, thus preventing clogging in cardiac tissue and further linearizing flow, which improves diagnostic testing and therapeutic perfusion. The use of Newtonian fluids can therefore provide improved pressure response at relatively low flow rates. In various applications, flow rates as low as 5 mL / min can yield excellent pressure response, enabling diagnostic and therapeutic applications at pressure levels that are safe for tissues.

[0145] Physiological saline, Ringer's lactate solution, or other water-based electrolyte fluids are useful for several reasons. They offer the following diagnostic effects and benefits: (1) Linearity can be demonstrated within the microvascular system. (2) Low-viscosity fluids provide easier access to distal microvessels within the pericardium, for example, representing terminal capillaries that are very small and subject to resistance that varies depending on their microscopic size and distal location. The distal location of these vessels generates secondary challenges that occur at the distal end of the blood pressure cascade, significantly exacerbating uninterrupted flow problems during the diagnostic sequence. (3) Induced controlled hypoxia: (a.) Electrolyte solutions as described are also highly recommended as they induce ischemia in the myocardium. The use of blood or other oxygen-containing fluids modifies the diagnostic effect as oxygen maximizes vasodilation. The crystalline fluids mentioned above contain little to no oxygen and therefore fulfill a separate role not only as hydrodynamic chemicals but also as optimal fluids for inducing hypoxic vasodilation due to their lack of oxygen. (b) While manufactured crystalloid solutions such as Ringer's lactate solution also provide highly consistent product comparisons within patients or across patient populations, the use of drugs or blood as infusion fluids negatively impacts the quality of diagnosis as the diagnostic fluid generates undesirable changes within the diagnostic system due to its effect on the microvascular system, thus inducing substantial errors in determining population values ​​or even in the diagnostic process within the same patient, consistent across processes and patients. The use of blood, blood products, or other biofluids may have benefits for other diagnoses, but altering the properties of blood such as hemoglobin, proteins, and microthrombi, and other biological modifications, will induce inaccuracies in determining microvascular resistance.

[0146] Fluids with high protein content can similarly induce nonlinearity.

[0147] In summary, the nonlinearity of the coronary microvascular system is comparable to the non-Newtonian hydrodynamic properties of blood. Experiments have demonstrated that microvascular resistance is linear when using Newtonian fluids such as crystalloid injectors.

[0148] Molar osmotic pressure

[0149] The injectable fluid can be selected based on several parameters, including molar osmotic pressure concentration. For example, a hyperosmolar injectable fluid can be used to draw fluid out of the tissue. For example, an osmotic gradient can be used to reduce or prevent edema in the tissue being treated.

[0150] Therefore, the injectable solution can be selected, though not limited to, based on several properties including the degree to which the solution is Newtonian, the rate of oxygenation of the solution, and the molar osmotic pressure concentration of the solution.

[0151] Method for determining microvascular resistance

[0152] Determining microvascular resistance within an organ by simply dividing the injection pressure by the injection flow rate is inaccurate. This is especially true when there is an offset pressure (either constant or variable) that complicates the resistance calculation.

[0153] Utilizing a differential approach across a series of stepwise increases or decreases in flow or pressure eliminates this offset and yields highly accurate microvascular resistance measurements. Experiments show that, in the case of biological organs, resistance is highly linear, resulting from a plot of pressure / flow derivatives. The curve that fits the main line generates an accurate record of vascular resistance as its slope, while its intercept is "zero flow pressure," which reflects the DC offset and is therefore equally useful for diagnosis.

[0154] In a typical heart, the pressure DC offset arises as a result of collateral capillary flow into the distal myocardial bed and is often referred to as "coronary wedge pressure." This pressure is the most obvious source of substantial error when measuring microvascular resistance. While this can be eliminated by subtraction, a drawback of this method is that they require wedge pressure measurement and can vary throughout the process.

[0155] This differential section diagnostic method can be used with or without the presence of embolic devices such as balloons. However, due to the nonlinearity induced by non-Newtonian fluids, it is likely to be less accurate when using flowing blood for the reasons mentioned above. Conventional methods for measuring microvascular resistance suffer from this problem with respect to IMR, FFR, CFR, and similar indices.

[0156] Therapeutic effects of fluid replacement

[0157] The therapeutic effects from the injected fluid also benefit from Newtonian fluids. These fluids not only convert nonlinear systems into linear systems, but their lower crystalline viscosity also allows therapeutic fluids containing drugs or other therapeutic agents to access the smallest microvessels of the biological system. Other therapeutic agents may include those containing oxygen (e.g., after the diagnostic process is performed without oxygen), and all therapeutic agents are combinations of drugs described above, such as glucose-insulin-potassium (GIK), which provide a hyperosmotic solution for removing fluid from edematous biological organs where edema is causing interference with normal organ function.

[0158] Catheters for use with diagnostic and therapeutic fluid infusion using a constant flow rate or defined pressure method.

[0159] Infusion catheters are a crucial element for accurately assessing microvascular function, including microvascular resistance. Key features include: (i) Proximal pressure measuring sensor (ii) Ability to place a pressure measuring guidewire or other sensor distal to the catheter tip (iii) The PQ differential intercept method is applicable when the injection is generated by appropriate parameters. Vascular occlusion by balloon or other means is not required for this method to function.

[0160] The pressure measurement capability does not require vascular thrombosis because this method is not affected by a continuous, constant blood flow. The defined fluid injection generates a perturbation to the baseline flow, which is used in the differential calculation.

[0161] New diagnostic considerations

[0162] The vulnerability of the cardiac endocardium to ischemia and infarction is well known. Models for assessing myocardial infarction size can be derived from myocardial microvascular resistance. Anatomical considerations of the distal myocardial microvascular system result in clearly defined shapes for ischemic and infarcted myocardial tissue, which typically appear as linear intrapericardial segments, which can be present in various states of health, defined by the level and duration of ischemia. Myocardial infarction size is related to the thickness of the myocardial necrotic wave, which progresses from the endocardium to the epicardium over time.

[0163] Diagnostic methods for measuring infarct size using catheterization may eliminate the need for external imaging techniques such as magnetic resonance imaging.

[0164] Microvascular resistance is therefore measured from the epicardium (where the larger epicardial coronary arteries are the blood source) along the capillary network, which represents the terminal region of capillary blood supply, to the distal endocardium of Terry.

[0165] Parallel systems analysis methods model microvascular resistance as a parallel resistance from the epicardium to the endocardium. Typical analytical approaches may include the following: (i) A three-compartment model consisting of 1) healthy, 2) edematous but viable, 3) viable but non-functional, or 4) dead tissue visualized by rendering enhancement, which has been adopted in recent years using CMR techniques. (ii) This cascade of healthy, dying, or dead cells is characterized by three or more compartment models that utilize tissue conduction, resulting from capillary patency or progressive occlusion, the area of ​​muscle to be examined, and, in the case of cardiac wall thickness, muscle thickness. (iii) A system of simultaneous equations relating microvascular resistance, measured from the extrapericardial coronary artery to myocardial infarction size, can be described using the equation R = ρL / A.

[0166] absolute coronary collateral circulation

[0167] In various embodiments, the methods described herein enable an approach for measuring absolute coronary collateral circulation. In various embodiments of this subject, coronary collateral circulation is measured by: 1. As described above, the proximal balloon embolus is placed in the coronary artery using distal controlled fluid infusion via an infusion catheter and pressure sensing. 2. Providing incremental fluid infusion with incremental pressure changes results in distal myocardial resistance. 3. The balloon remains inflated, and the pump flow remains stopped. 4. Residual pressure with balloon embolus is measured. The known coronary residual pressure divided by distal resistance is equal to the collateral circulation in absolute terms (mmHg / flow rate (ml)).

[0168] These techniques may, but are not limited to, be used for the flow of other organs such as the brain, lungs, kidneys, internal organs, and distal limbs.

[0169] Distal pressure control feedback loop for pump flow

[0170] In various embodiments, the controlled fluid injection system may operate in either an open-loop or closed-loop function. In the open-loop function, the injected fluid is set to a predetermined given value or a set of values, and the distal pressure is measured in the open-loop configuration.

[0171] In a feedback configuration, an input signal is used to control the pump and regulate the flow. One useful output signal for feedback is peripheral resistance, measured by the pressure distal to the balloon. Multiple applications exist for feedback signals. For example, a servo loop can be generated so that precise pressure control, and therefore resistance, is possible by maintaining a constant distal pressure through flow changes.

[0172] In various embodiments, the feedback system provides an important safety mechanism. For example, preventing overpressurization due to increased resistance or high pump-base flow rate can be achieved by limiting the maximum obtainable pressure. This pressure would typically be a physical and physiological pressure, such as 90 mmHg or any other value, applied by the user. The pressure limit measured can be preset and / or dynamically changed during the procedure.

[0173] In various embodiments, feedback systems are used to test the integrity of the endothelial smooth muscle-vascular tone mechanism. Autoregulation is a natural physiological mechanism that maintains cardiac flow at a desired value, such as that obtained by multiple physiological input signals. The integrity of the autoregulatory system can be tested with clinical laboratory use by the methods described herein and implemented by setting a fixed high level of flow value and observing the vascular response to this high level of flow. Specifically, the microvascular system gradually constricts as an attempt is made to limit the flow. In doing so, the body increases resistance, which manifests as a pressure line that increases over time. This experiment has been performed, validated, and documented in animal models. Several methods for complex physiological measurements (currently not available) are enabled by this feedback control loop, including, but not limited to, the following:

[0174] self-regulation

[0175] In embodiments where the pressure output is controlled to be relatively constant, the input signal for maintaining constant flow, i.e., the feedback in the control loop, can be used as an accurate representation of resistance and a measure of dynamic self-regulation. In various embodiments, such measurements can be performed in real time. The components of self-regulation include flow sensing by endothelial shear, feedback to the smooth muscle within the arterial wall, and blood supply to the included coronary arteries.

[0176] Viability

[0177] In various embodiments, myocardial viability is measured because it relates to the magnitude of the phase pressure resulting from myocardial contraction of the intramyocardial coronary artery capillaries. In various embodiments, the determination of phase pressure may be used to determine myocardial viability by either injecting drugs such as dopamine, dobutamine, epinephrine, or other inotropic agents that will stimulate new or increased myocardial contractility. This is reflected by an increase in the phase resistance signal and an increase in phase resistance. The stress test for viability is interpreted by the failure or graded level of the response to myocardial capillary contraction based on the mechanism. Larger or increased pressure pulsations indicate stronger contraction in a fixed, measurable manner.

[0178] Discrimination from myocardial insomnia or hibernation and permanent cell death

[0179] Transient ischemia physiologically "shocks" the myocardium, causing it to fail to contract and thus resulting in reduced or absent phase myocardial microvascular resistance. A drug response suggests viability as phase resistance increases with drug infusion. Conversely, a lack of response to drug infusion suggests little to no viability. Similarly, dormant myocardium can be detected as contractility-enhancing drugs either enhance or fail to enhance microvascular resistance.

[0180] Bubble filter

[0181] In various embodiments of this controlled feedback system, a bubble filter is incorporated into the proximal portion of the injection system. This comprises a chamber including an inlet, followed by passage through a screen of highly hydrophobic material.

[0182] Servo Loop Control System

[0183] Various embodiments of the controlled feedback system include a closed-loop mode in which the pressure in the distal muscle after balloon embolization is fed back to the pump computer system for safety. For example, a predetermined flow safety threshold may be manually set, or it may be automatically set and determined by systemic blood pressure at the time of vascular embolization or prior to vascular embolization. In another embodiment, the method is adapted to ensure that the distal pressure generated by the flow is never excessive. Excessive pressure can be obviously harmful to the distal microvascular and epicardial vascular systems. In another embodiment, by using measured or set limits, the pump-directed flow can never reach a value that is potentially harmful or dangerous, such that the value never exceeds a physiological magnitude. Those skilled in the art will understand that other safety benefits are provided by the closed-loop system, and that what is described herein is not intended to be exclusive or inclusive.

[0184] Balloon inflation / deflation during injection

[0185] In various embodiments, the inflation and deflation of the coronary artery embolus balloon are automated and computer-controlled by an algorithm. This allows the system to control the inflation and deflation of the balloon as part of a therapeutic or diagnostic sequence, as well as associated parameters such as injection pressure and concentration, enabling reoxygenation and promoting prolonged perfusion. Resistance can be adjusted from low to high values ​​by adjusting balloon inflation. The system allows for intermittent calculation of pressure values ​​and relaxation times following balloon embolusation. This also allows for control of flow rate and oxygenation. The protocol of the system can be automated over relatively long time cycles. The system can maintain drug flow at lower concentrations, and mixing and ratios can be set and adjusted. It is conceivable that the system can adaptively change these settings as needed in relation to any given therapeutic requirements.

[0186] diagnosis This procedure can be performed with or without an embolization balloon, i.e., an embolization balloon with a variable inflation level to correct the degree of embolization. The resulting distal pressure, perceived as the superposition of the injected fluid and ambient pressure, is recorded and used as part of a control algorithm adapted to adjust one or more of the following variables: The injection rate and profile of the delivered (isotonic or otherwise) crystalline fluid, The transfusion rate of blood or blood products being delivered, The infusion rate and profile of the delivered drug, and / or The amount of embolization provided by the embolization device.

[0187] The amount of embolus can vary from complete embolus to partial embolus to virtually non-embolusent, depending on the device inserted into the blood vessel or organ. The timing of infusion can also be timed to the level of embolus and cardiac activity. Other variables may also be applied without deviating from the scope of this subject.

[0188] Waveform and flow

[0189] This subject includes a programmable system that can provide a constant fluid infusion, combined with embolic control between a complete embolic delivery state, a partial embolic delivery state, and a substantially non-embolic delivery state, in order to controllably adjust and control one or more of the following: the concentration of the delivered fluid, the local concentration of the delivered and innate fluid, the flow rate of blood beyond the embolic device (e.g., a balloon or other embolic device), the supply or resupply of blood to the vessel or organ under therapy, reperfusion therapy, microvascular resistance measurements (which may be obtained concurrently with other control aspects), bolus or infusion delivery, and ischemic therapy to provide prolonged local infusion to reduce or avoid ischemia. In various embodiments, these control aspects may be provided simultaneously or sequentially, as needed, in various combinations. Other controls, including modulation of the oxygenation level of the locally infused fluid or blood at the distal end of the catheter device site, cell therapy, and others, may also be performed alone, sequentially, or in parallel, in various combinations.

[0190] In various embodiments, the system may utilize known waveform insertions, including constant flow, as a method for discriminating inherent resistance changes from inserted flow determinations of resistance changes. For example, the flow into the microvascular system resulting from the collateral vascular system is inherently periodic. By inserting a constant flow waveform, the resulting changes in pressure / voltage are determined by the inserted flow compared to the "inherent flow" originating from the heart itself. This method may also utilize other potentially different waveforms besides constant flow to enable querying of distal resistance features.

[0191] The "coronary residual pressure waveform" arises from internal cardiac function and is related to microvascular flow. In the absence of direct forward coronary flow, this flow must originate from collateral vessels. Therefore, the perceived pressure drive for collateral circulation, which appears as "zero flow pressure" or "coronary residual pressure," is actually collateral circulation. This is, therefore, a direct way to assess the state of collateral circulation. Importantly, collateral circulation is dynamic, changes with cardiovascular conditions, and is not fixed in time. Knowledge of this flow will be extremely useful clinically for understanding microvascular occlusion and ischemia.

[0192] The use of parameters consisting of distal embolus / wedge pressure of the coronary arteries, related to systemic pressure or other pressures within the heart, may be useful in assessing major vessel occlusion. For example, the ratio of systemic non-occluded coronary artery pressure to occlusion / wedge pressure is a direct assessment of a combination of microvascular occlusion and collateral circulation.

[0193] To address microvascular occlusion, in various embodiments, the determination of therapeutic effectiveness is at least partially indicated by the time course of effectiveness via distal flow through the “corpus cavernosum and bulk mass” comprising the microvascular system. In various embodiments, the system determines the “wavefront of microvascular occlusion.”

[0194] In various embodiments, the system enhances microvascular clot dissolution by applying fluid and pressure agitation and by starting / stopping a pump in conjunction with balloon inflation / deflation. These physical phenomena will assist in creating drugs or accessible materials for dissolving microvascular thrombi.

[0195] In various embodiments, dIMR or the differential dP / dQ represents the instantaneous gradient or flow rate through the coronary arteries or microvascular system. This resistance is directly measured as back pressure in the extrapericardial coronary arteries under zero flow conditions. P / Q is valid and directly measures resistance when microvascular resistance is a linear function of pressure and flow rate. Conversely, the differential dP / dQ is more generalizable because it measures the differential change of resistance in real time.

[0196] The use of this subject is applicable to procedures involving the kidneys, brain (e.g., treatment or prevention of stroke), or other nervous tissue (peripheral nerves, spinal cord), peripheral vascular system, intestines (large or small intestine), pancreas, liver, spleen, and other abdominal organs.

[0197] This subject can also be used to determine the state of endothelial function in any artery or vein. In various applications, this subject can be used to diagnose and / or treat large or microvessel size changes and subsequent flow changes associated with stimuli such as hypoxia, electrolyte changes, and drug infusions such as acetylcholine or other endothelium-dependent vasodilators.

[0198] This subject is also useful for detecting and quantifying the autoregulation of specific biological tissues that control optimal flow within and outside their organs, such as in the heart, brain, kidneys, muscles, and others. Direct injection and quantitative methods of fluid into these organs allow for the quantification of the organ-vascular response to that fluid. This, therefore, is a direct quantification of the undamaged state and magnitude of autoregulation.

[0199] This subject can also be used for procedures that involve placing unipolar, bipolar, or multipolar lead wires within a guidewire and using intracardiac electrocardiography to measure myocardial injury status as a complement to determining the effectiveness of fluid infusion for dissolving microvascular clots.

[0200] This subject can also be used to mitigate reperfusion injury caused by chemical or physical properties (low temperature, heat, etc.). Furthermore, this subject can be used for the injection of solvents, typically administered directly into the coronary arteries or veins, allowing for precise concentration control and significantly improved concentration for better efficacy.

[0201] This subject can provide, for example, an "algorithmic" injection that involves changing the amplitude and timing in a state where resting periods are intermittent, thereby improving injection and dissolution capabilities.

[0202] This subject provides, in particular, the ability to "close the loop" according to system analysis and theory, to utilize real-time diagnosis in conjunction with therapy to understand the effectiveness of progress, and to determine the completion of the procedure.

[0203] Distal pressure control feedback loop for pump flow

[0204] In various embodiments, the controlled fluid injection system may operate in either an open-loop or closed-loop function. In the open-loop function, the injected fluid is set to a predetermined given value or a set of values, and the distal pressure is measured in the open-loop configuration.

[0205] In a feedback configuration, the input signal is used to control the pump and regulate the flow. One output signal is the peripheral resistance, measured by the pressure distal to the balloon. Multiple applications exist for the feedback signal. For example, a servo loop can be generated so that precise pressure control, and therefore resistance, is possible by maintaining a constant distal pressure through the flow change.

[0206] In various embodiments, the feedback system provides an important safety mechanism. For example, preventing overpressurization due to increased resistance or high pump-base flow rate can be achieved by imposing a system limit on the maximum obtainable pressure. This pressure would typically be a physical and physiological pressure, such as 90 mmHg or any other value, applied by the user. The measured pressure limit can then be used for further diagnosis and determination of therapeutic effectiveness.

[0207] In various embodiments, feedback systems are used to test the integrity of the endothelial smooth muscle vascular tone mechanism. Autoregulation is a mechanism that maintains cardiac flow at a desired value, such as that obtained by multiple physiological input signals. The integrity of the autoregulatory system can and is available to be tested in the clinical laboratory by placing it in a fixed high level of flow and observing the vascular response to this high level of flow. Specifically, the microvascular system gradually constricts as an attempt is made to limit the flow, thereby increasing resistance. This, in turn, manifests as a pressure that increases over time. This experiment has been performed and documented several times in animal models. Several methods for complex physiological measurements (currently unavailable) are made possible by this feedback control loop, including, but not limited to, the following:

[0208] self-regulation

[0209] In embodiments where the pressure output is controlled to be relatively constant, the input signal is used as an inverting input feedback operational amplifier to maintain constant flow, and the feedback in the control loop can be used as an accurate representation of resistance and as a measure of dynamic self-regulation. In various embodiments, such measurements can be performed in real time. The components of self-regulation include flow sensing by endothelial shear, feedback to smooth muscle within the arterial wall, and blood supply to the included coronary arteries.

[0210] Viability

[0211] In various embodiments, myocardial viability is measured because it relates to the magnitude of the phase pressure resulting from myocardial contraction of the coronary artery capillaries. In various embodiments for testing myocardial viability during infusion, test drugs such as dopamine, dobutamine, epinephrine, or other inotropic agents that will stimulate increased myocardial contractility may be added. This is reflected by increasing the phase resistance signal. The stress test for viability is interpreted by the failure or graded level of the response to myocardial capillary contraction based on the mechanism. Larger or increased pressure pulsations indicate stronger contraction in a fixed, measurable manner.

[0212] Discrimination from myocardial insomnia or hibernation and permanent cell death

[0213] Myocardium in a stunned or hibernating state survives with viable cardiomyocytes that are not contracting at all or are hypocontractile, resulting from transient myocardial ischemia or real-time ischemia or lack of myocardial energy to contract. As previously viability tests are performed using inotropic agents, the stunned or hibernating myocardium remains viable and can be restored, provided that adequate conditions for normalization of electrolytes and glucose for physiological energy are met. A viable response to the drug suggests viable and potentially functional cells as phase resistance increases with drug infusion. Conversely, a lack of response to drug infusion suggests little to no viability.

[0214] New air and gas bubble filters

[0215] In various embodiments of this controlled feedback system, a bubble filter is incorporated into the proximal portion of the injection system. This comprises a chamber including an inlet, followed by passage through a screen of a highly hydrophobic material. In various embodiments, special bubble filters are fabricated for the device. These bubble filters have a fine screen of a hydrophobic polymer and are installed in a capsule aligned with the pump flow. The hydrophobicity will prevent bubbles from passing through the screen. High flow rates can be achieved with this method, while safety from bubbles is maintained.

[0216] Valves and connectors

[0217] The valves and connectors are manufactured in a "block configuration" so that a single plug can connect all fluids to the appropriate forward source. The devices are indexed to ensure they mate in a certain direction and that a proper and secure connection is made.

[0218] Various embodiments of the controlled feedback system include a closed-loop mode, thereby feeding back distal intramuscular pressure after balloon embolization to a pump computer system for safety. For example, a predetermined flow safety threshold may be manually set, or it may be automatically set and determined by systemic blood pressure at the time of vascular embolization or prior to vascular embolization. In another embodiment, the method is adapted to ensure that distal pressure, such as that generated by the flow, will never be excessive. Excessive pressure can be obviously harmful to the distal microvascular and epicardial vascular systems. In another embodiment, by using measured or set limits, the pump-directed flow can never set values ​​that are potentially harmful or dangerous, such that the values ​​never exceed physiological magnitudes. Those skilled in the art will understand that other safety benefits are provided by the closed-loop system, and that what is described herein is not intended to be exclusive or inclusive.

[0219] Characterization of innate microvascular resistance: Mathematical representation of microvascular resistance

[0220] The study demonstrates the benefits of modeling microvascular resistance at the time of therapy, during therapy, and prior to therapy to establish baseline microvascular status. Microvascular resistance is not a single number, but is variable and depends on the flow rate, i.e., MVR(Q). The study shows that this feature is modeled very well in a closed-form approximation using an inverse natural logarithm function with two constants α and β.

[0221] MVR(Q) = -α × ln(Q) + β

[0222] Closed-form equations are useful for quantitatively measuring functions, are available in real time, and the constants provide a simple method for determining the state of myocardial resistance distal to the coronary balloon or infusion catheter at any given time. This is therefore a method for 1) determining the need for therapy, 2) observing the therapeutic effect in real time, and 3) determining when therapy can be discontinued.

[0223] The determination of the two constants is performed by step function injection at a rate varying from 0.1 ml / min to a maximum of 50 ml / min or more, and by performing a nonlinear curve fitting method on the resulting flow step function resistance response.

[0224] Balloon inflation / deflation during injection

[0225] In various embodiments, balloon inflation and deflation are automated and computer-controlled by an algorithm. This allows the system to control balloon inflation and deflation as other parameters such as injection pressure and concentration are changed, enabling reoxygenation and promoting prolonged perfusion. Resistance can be adjusted from low to high by adjusting balloon inflation. The system allows for intermittent calculation of Tau, i.e., pressure decay, following coronary balloon embolus. This also allows for control of flow rate and oxygenation. The system protocol can be automated over relatively long time cycles. The system can maintain drug flow at lower concentrations, and mixing and ratios can be set and adjusted. It is conceivable that the system can adaptively change these settings as needed in relation to any given therapeutic requirements.

[0226] In various embodiments, the control of the embolization balloon is automated using an algorithm for alternating inflation and deflation of the balloon in a strategic time. For example, during drug infusion, the algorithm would maintain drug infusion at a predetermined level, and the embolization balloon would alternately inflate and deflate rhythmically. The timing of this inflation / deflation would be such that, during deflation, sufficient proximal blood flows into the distal vessels, keeping the heart properly oxygenated and supplied with adequate electrolytes.

[0227] Expansion / contraction will also agitate the drug solution, allowing for improved entry into slow or occluded microchannels. Note that slow flow will increase microvascular resistance, resulting in a more complete match between flow between open and closed channels. By running a series of gradually increasing and decreasing stepwise flows, evidence of this match and improved drug delivery can be obtained, and the solution to this equilibrium point is a function of parallel resistance by algorithm. These infusion algorithms in a stepwise manner can be run continuously in real time and adjusted to optimize flow into these closed channels so that their resistance decreases and additional drug flow is possible.

[0228] The alternating inflation and deflation of the balloon causes changes in injection pressure.

[0229] In various embodiments, alternating balloon inflation and deflation can cause changes in injection pressure and alter drug concentration. In various embodiments, the system allows for simultaneous reoxygenation between embolic cycles. In various embodiments, the system allows for very long-term perfusion. The blood vessels remain perfused and simultaneously receive drugs for therapeutic relief of microvascular occlusion.

[0230] In various embodiments, each balloon inflation allows for repeatable, nearly constant Tau pressure decay calculations. In various embodiments and applications, this is a secondary means of confirming microvascular resistance, useful for determining the effectiveness of a drug in improving flow. In various embodiments and applications, this process also ensures that the drug flows at lower concentrations. It also allows for setting and instantaneously changing the mixing and ratios during injection.

[0231] Controlled fluid infusion and dynamic examination of coronary artery microvascular function

[0232] Dynamic coronary microvascular function can be characterized by controlled coronary fluid infusion (CoFI, Figure 1), a sustained outcome of real-time, catheter-based, precise yield. Controlled fluid infusion testing was performed to characterize microvascular function and dysfunction across various flow rates, including those occurring in clinical syndromes such as STEMI / NSTEMI, microvascular occlusion, no-reflow, and cardiogenic shock.

[0233] Dynamic microvascular resistance and function were assessed in animal studies using controlled flow infusion (CoFI). An intracoronary catheter with proximal balloon inflation completely occluded lateral coronary blood flow, and a distal infusion port was used for precise crystalloid delivery to the distal coronary microvascular system via an external pump. Distal intracoronary pressure was measured via a pressure wire, generating back pressure derived from the microvascular flow from the pump. Pump flow infusion was a step function with a range across a wide flow range. The time-dependent pump flow rate Q(t) and distal pressure P(t) were linearly related according to the equation P(t) = R(t) × Q(t) + P0, where R is resistance and P0 is a linear constant. The dynamic microvascular resistance was therefore as follows: R(t) = dP(t) / dQ(t) + R0 In the formula, R0 is zero flow resistance. dMVR was evaluated in steps of 5, 10, 20, 30, and 40 ml / min at 15-second intervals across a wide flow range of 0–40 ml / min. Coronary artery pressure waveforms at each flow step, derived from basal tension and periodic intramyocardial compression, showed both tonic and phase microvascular resistance (Figure 10). Figure 10 shows plots of microvascular resistance, distal pressure, and pump flow rate for controlled flow infusion performed according to one embodiment of this subject.

[0234] Figure 10 shows the resulting real-time dMVR (vascular resistance) and coronary artery pressure (distal pressure) for controlled fluid infusion performed according to one embodiment of this subject. The dMVR varied inversely and linearly with the infusion range, from 3.17 (5 ml / min) to 0.85 (40 ml / min). The dMVR was derived from controlled flow step functions (5, 10, 20, 30, and 40 ml / min).

[0235] Figure 11 shows a plot of coronary artery pressure versus pump flow rate for controlled fluid infusion performed according to one embodiment of this subject. The pressure / flow rate relationship is very linear across flow rates from 5 to 40 ml / min. dMVR varied uniformly inversely and linearly with respect to the infusion flow rate range across all subjects. The linearity of the relationship is R 2 This is reflected by =0.9925. The mean dMVR was 0.53 + 0.14 mWU with respect to the intermediate LAD location.

[0236] As the CoFI flow rate decreased to less than 10–15 ml / min, the mean microvascular resistance increased to a mean of 1.67 + 0.8 mWU, i.e., a threefold increase (3.06 + 0.89). The pressure corresponding to this flow threshold was approximately 25–30 mmHg on average, with a peak systolic pressure of approximately 55 mmHg.

[0237] The results of this test confirm that controlled fluid infusion is a novel catheter-based method for determining dynamic microvascular resistance. It is rapid, simple, accurate, and, if desired, provides real-time measurements. In this application, microvascular resistance is dynamic and fundamentally linear across physiological pressure and flow rate. This is in contrast to previous tests, which exhibit nonlinear PQ microvascular relationships, likely stemming from physiological mechanisms such as the non-Newtonian nature and autoregulation of blood.

[0238] This examination has an important impact on clinical practice. During acute coronary syndromes (STEMI / NSTEMI / shock), coronary embolism limits blood flow to the distal microvasculature and thus induces ischemia based on low flow. Low flow results from low intraluminal pressure and in turn causes microvascular instability and dysfunction with a rapid and significant increase in resistance. This data suggests that this phenomenon starts at 50 - 60 mmHg (systolic), which correlates well with clinical experience. Prevention and therapy of microvascular dysfunction can be alleviated by restoring normal pressure and flow, assisted by both hydrodynamic and pharmacological means.

[0239] Real-time absolute dynamic microvascular resistance using a controlled flow infusion test

[0240] Distal microvascular dysfunction from coronary embolism in STEMI is common. Its impact remains poorly understood despite years of investigation and the failure of many therapeutic strategies. Controlled coronary flow infusion (CoFI, Figure 1) is a novel catheter-based technique that is capable of performing accurate and continuous microvascular function assessment in real time. This preclinical examination used CoFI to investigate the impact of STEMI on the microvascular system function in a porcine model.

[0241] STEMI was induced in 12 target pigs by LAD balloon embolism over 90 minutes. CoFI used LAD coronary artery balloon embolism to assess the distal microvasculature in order to block forward flow, along with simultaneous crystalloid infusion into the distal coronary microvascular bed via a digitally controlled pump with a step function. Coronary backpressure from the controlled step infusion flow rate Q(t) was measured by a pressure wire. This examination characterized the LAD microvascular system at steps of 5, 10, 20, 30, and 40 ml / min every 15 seconds across a large dynamic flow range of 0 - 40 ml / min.

[0242] Absolute dynamic microvascular resistance (dMVR) was derived as the time-dependent slope of the function P(t) / Q(t). R(t)=dP(t) / dQ(t)+R0 Where R(t) is the time-dependent resistance, P(t) is the coronary artery pressure, Q(t) is the coronary artery flow, and R0 is a constant zero-flow resistance. The coronary artery pressure waveform at each flow step showed both the tonic and phasic microvascular resistances derived from basal tone and periodic myocardial compression (Figure 11). Figure 11 shows a plot of coronary artery pressure versus pump flow for controlled flow infusion, implemented according to one embodiment of the present subject matter.

[0243] Figure 12 shows a chart of microvascular resistance before and after STEMI from a certain examination. The microvascular resistance dMVR, derived from the pressure / flow relationship before and after STEMI, showed a significant increase in microvascular resistance (mWU) after STEMI, 0.49 + 0.07 vs. 0.71 + 0.1 mean values, a 44% increase.

[0244] Dynamic myocardial vascular resistance (dMVR) was also examined. Figure 13 shows a plot of dynamic myocardial vascular resistance (dMVR) versus flow rate from a certain examination demonstrating that the microcirculation decreases exponentially as flow approaches zero.

[0245] Microvascular resistance increased substantially in the anterior wall, and STEMI was measured efficiently and safely by controlled flow infusion. Severe microvascular dysfunction and collapse at low perfusion pressures can be substantial in both normal and infarcted myocardial regions. This dynamic resistance may explain the profound clinical instability in STEMI patients that predisposes them to cardiogenic shock and no-reflow syndrome. Therapeutic catheter-based strategies can be devised to limit microvascular dysfunction to prevent potentially severe early and late complications.

[0246] Dynamic microvascular resistance may explain the significant clinical instability in STEMI patients that makes them more susceptible to cardiogenic shock and no-liflow syndrome. Therapeutic catheter-based strategies may be devised to limit microvascular dysfunction in order to prevent potentially severe early and late complications.

[0247] (Examples) Several aspects of this subject include one or more of the following:

[0248] Example 1 of this subject includes a method for assessing microvascular dysfunction within an organ or limb, using an apparatus for providing controlled fluid infusion of at least a first solution into a vascular vessel for assessment and diagnosis of microvascular function, and for providing a second solution into a vascular vessel for the therapeutic benefit of microvascular function.

[0249] Example 2 includes the subject matter of Example 1, wherein the first solution is a Newtonian fluid selected to improve the linearity of the flow and to better assess the microvascular parameters.

[0250] Example 3 includes the subject matter of Example 1, wherein the first solution lacks oxygenation to control hypoxia.

[0251] Example 4 includes the subject matter of Example 1, wherein the first solution lacks oxygenation to vasodilate the microvascular system.

[0252] Example 5 includes the subject matter of Example 1, and the first solution is crystalline.

[0253] Example 6 includes the subject matter of any one of Examples 1-5 or any combination thereof, and further includes injecting the first and second solutions into the blood vessels using a computerized diagnostic and infusion system, and electronically performing a real-time, automated assessment of microvascular function using a computerized diagnostic and infusion system.

[0254] Example 7 includes the subject matter of any one of Examples 1-6 or any combination thereof, and further includes applying the method to treat acute myocardial infarction, wherein controlled fluid infusion includes controlled coronary artery fluid infusion (CoFI).

[0255] Example 8 includes the subject matter of Example 7 and further includes applying the method to treat microvascular occlusion (MVO).

[0256] Example 9 includes the subject matter of Example 8, and the therapeutic benefits include the elimination of microvascular clots and debris.

[0257] Example 10 includes the subject matter of any one of Examples 1-9 or any combination thereof, and the assessment and diagnosis of microvascular function includes measuring intravascular pressure.

[0258] Example 11 includes the subject matter of Example 10, and the measurement of intravascular pressure includes measuring the pressure resulting from the superposition of injected and innate fluids.

[0259] Example 12 includes the subject matter of Example 10, and the assessment and diagnosis of microvascular function includes determining microvascular resistance.

[0260] Example 13 includes the subject matter of any one of Examples 1-12 or any combination thereof, wherein the assessment of microvascular dysfunction includes applying pulses of a first solution at a defined and high pressure or flow rate to open the microvessels, and applying a defined flow of a second solution at a defined and high pressure or flow rate to reduce, avoid, or eliminate ischemia and necrosis of organ tissue.

[0261] Example 14 of the present subject matter includes an apparatus for measuring microvascular dysfunction within an organ or limb having a vasculature and a microvasculature connected to the vasculature. The apparatus includes an infusion catheter connected to one or more lumens of a catheter and having a plurality of inflatable structures for remotely controlling inflation and deflation of at least one infusion lumen for delivery of an infusion fluid to the catheter proximal to the inflatable structure, an infusion pump in communication with the infusion lumen of the infusion catheter, a plurality of distinct solutions within a separate reservoir in communication with the infusion pump, and a computerized controller in communication with the infusion pump for controlling the operation of the infusion pump and effecting a controlled flow infusion of at least a first solution of the plurality of solutions into the infusion lumen of the catheter and a second solution of the plurality of solutions into the infusion lumen of the catheter, wherein the first solution is associated with the assessment of microvascular function and the second solution is associated with a change to microvascular function.

[0262] Example 15 includes the subject matter of Example 14 and the first solution is a solution associated with dilation of the microvasculature.

[0263] Example 16 includes the subject matter of Example 15 and the first solution is a Newtonian fluid selected to improve the linearity of flow and better assess microvascular parameters.

[0264] Example 17 includes the subject matter of Example 15 and the first solution is oxygenation free to control hypoxia.

[0265] Example 18 includes the subject matter of Example 15 and the first solution is oxygenation free to vasodilate the microvasculature.

[0266] Example 19 includes the subject matter of Example 15 and the first solution is crystalline.

[0267] Example 20 includes the subject matter of Example 15 and the second solution is a solution for reducing, avoiding, or eliminating ischemia and necrosis of the tissue of the organ or limb.

[0268] Example 21 includes the subject matter of Example 20, wherein the second solution is a solution for dissolving microvascular blood clots or debris in the heart.

[0269] Example 22 includes the subject matter of any one of Examples 15-21 or any combination thereof, wherein the controller is programmed to cause the pump to apply pulses of a first solution at a defined and high pressure or flow rate, and to apply a defined flow of a second solution at a defined and high pressure or flow rate, at least one of the defined and high pressure or flow rate.

[0270] Example 23 includes the subject matter of any one of Examples 14-22 or any combination thereof, and the controller is configured to perform a real-time, automatic assessment of microvascular function.

[0271] Example 24 includes the subject matter of Example 23 and further includes a pressure sensor configured to sense intravascular pressure, and a controller configured to use the sensed pressure to perform an assessment of microvascular function.

[0272] Example 25 includes the subject matter of Example 24, wherein the pressure sensor is attached to the infusion catheter.

[0273] Example 26 includes the subject matter of any one of Examples 14 and 25 or any combination thereof, wherein the controller is configured to perform an assessment of microvascular function using the sensed pressure resulting from the superposition of injection and innate fluids.

[0274] Example 27 includes the subject matter of any one of Examples 14-26 or any combination thereof, wherein the controller is configured to determine microvascular resistance and use the determined microvascular resistance to assess microvascular function.

[0275] Example 28 includes the subject matter of any one of Examples 14-27 or any combination thereof, wherein the controller is configured to control the pump and perform controlled coronary artery fluid infusion (CoFI).

[0276] Example 29 includes a method for assessing microvascular occlusion within an organ or limb using controlled fluid injection into a site and the superimposed pressure measurement response resulting from the injection and the innate fluid.

[0277] Example 30 incorporates the themes of Example 29 and includes applying a first fluid pulse at a high pressure to open the microvessels and applying a constant flow of an injectable fluid at a second pressure lower than the high pressure to treat microvascular occlusion, reduce or avoid ischemia, and avoid organ tissue necrosis.

[0278] Example 31 includes the subject matter of Example 29 and, in combination, includes calculating microvascular resistance over a flow range, which constitutes dynamic microvascular resistance at different flow rates.

[0279] Example 32 includes the subject matter of Example 31 and includes applying a first fluid pulse at a high pressure to open the microvessels, applying a constant flow of injectable fluid at a second pressure lower than the high pressure to reduce or avoid ischemia, and using calculated microvascular resistance to define the status of the microvascular system.

[0280] Example 33 of this subject includes a method for infusing a therapeutic agent into the distal microcirculation during a congenital vascular thromboembolism at a physiologically adapted infusion rate, using values ​​already measured prior to vascular thromboembolism, dynamic microvascular resistance, or other physiological values ​​such as intracoronary ECG to induce infusion rate and infusion gradient.

[0281] Example 34 incorporates the subject matter of Example 33 in an automated feedback loop for controlling the timing of the embolization balloon and optimizing the therapeutic effect.

[0282] Example 35 incorporates the subject matter of Example 33 in a non-automatic feedback loop that allows the operator to manually control the timing of the embolization balloon and optimize the therapeutic effect.

[0283] Embodiment 36 of this subject includes a method for using the slope of dynamic microvascular resistance in an automated feedback loop to control the injection rate, drug selection, and / or balloon expansion / deflation timing.

[0284] Example 37 of this subject includes a method for controlling the injection rate, drug selection, and / or balloon expansion / deflation timing using the absolute value and relative change over time of dynamic microvascular resistance in an automated feedback loop.

[0285] Example 38 of this subject includes a method for controlling the injection rate, drug selection, and / or balloon expansion / deflation timing using absolute and relative changes in intracoronary ECG ST segment elevation in an automated feedback loop.

[0286] Example 39 includes the themes of Examples 36, 37, and 38, and includes enabling the user to manually control the injection rate, drug selection, and / or balloon expansion / deflation timing.

[0287] Example 40 includes an apparatus for carrying out any of the above-described methods, comprising an infusion pump, a controller, and a plurality of separate solutions, the system being programmable to provide one of the separate solutions to an infusion catheter for delivery of the infusion fluid to the catheter.

[0288] Example 41 is an apparatus for measuring microvascular dysfunction in an organ or limb having blood vessels and a microvascular system connected to the blood vessels, comprising: an infusion catheter having multiple inflatable structures connected to one or more lumens of the catheter and remotely controlling the inflation and deflation of at least one infusion lumen for delivery of an infusion fluid to the catheter proximal to the inflatable structures; an infusion pump communicating with the infusion lumen of the infusion catheter; a plurality of separate solutions in a separate reservoir communicating with the infusion pump; and a computerized controller communicating with the infusion pump and configured to control the operation of the infusion pump and to perform controlled fluid infusion of at least a first solution of the plurality of solutions into the infusion lumen of the catheter and a second solution of the plurality of solutions into the infusion lumen of the catheter, wherein the first solution is associated with an assessment of microvascular function and the second solution is associated with a change in microvascular function.

[0289] Example 42 includes the subject matter of Example 41, wherein the first solution is a solution associated with the dilation of the microvascular system.

[0290] Example 43 incorporates the subject matter of either Example 41 or 42, wherein the first solution is a Newtonian fluid selected to improve the linearity of the flow and to better assess the microvascular parameters.

[0291] Example 44 incorporates the subject matter of any of Examples 41-43, wherein the first solution lacks oxygenation to control hypoxia.

[0292] Example 45 incorporates the subject matter of any of Examples 41-44, wherein the first solution lacks oxygenation to vasodilate the microvascular system.

[0293] Example 46 includes the subject of any of Examples 41-45, and the first solution is crystalline.

[0294] Example 47 includes the subject matter of any of Examples 41-46, wherein the second solution is a solution for reducing, avoiding, or eliminating ischemia and necrosis of organ or limb tissue.

[0295] Example 48 comprises the subject of any of Examples 41-47, wherein the second solution is a solution for dissolving microvascular clots or debris in the heart.

[0296] Example 49 includes the subject matter of any of Examples 41-48, wherein the controller is programmed to cause the pump to apply pulses of a first solution at a defined and high pressure or flow rate, and to apply a defined flow of a second solution at a defined and high pressure or flow rate.

[0297] Example 50 incorporates the subject matter of any of Examples 41-49, and the controller is configured to perform a real-time, automatic assessment of microvascular function.

[0298] Example 51 includes the subject matter of Example 50 and further comprises a pressure sensor configured to sense intravascular pressure, and a controller configured to use the sensed pressure to perform an assessment of microvascular function.

[0299] Example 52 includes the subject matter of Example 51, wherein the pressure sensor is attached to the infusion catheter.

[0300] Example 53 incorporates the subject matter of any of Examples 41-52, and the controller is configured to perform an assessment of microvascular function using the sensed pressure resulting from the superposition of injected and innate fluids.

[0301] Example 54 incorporates the subject matter of any of Examples 41-53, and the controller is configured to determine microvascular resistance and use the determined microvascular resistance to assess microvascular function.

[0302] Example 55 incorporates the subject matter of any of Examples 41-54, wherein the controller is configured to control the pump and perform controlled coronary artery fluid infusion (CoFI).

[0303] The aspects and embodiments described herein are not limiting or exclusive, and the scope of this subject matter should be determined by this specification as a whole, including the claims and drawings.

[0304] The above description includes references to accompanying drawings that form part of the modes for carrying out the invention. The drawings illustrate various embodiments in which the invention may be put into practice. This application also refers to “Examples.” Such embodiments may include elements in addition to those shown or described. The aforementioned embodiments are not intended to be an exhaustive or exclusive enumeration of embodiments and modifications of the subject matter.

[0305] Aspects and embodiments of the methods described herein can be implemented, at least in part, mechanically or computer-readably. Some embodiments may include computer-readable or machine-readable media encoded with instructions that can be operated to constitute an electronic device for carrying out methods such as those described in the above embodiments. Such implementations of methods may include code such as microcode, assembly language code, higher-level language code, or equivalents. Such code may include computer-readable instructions for carrying out various methods. The code may form part of a computer program product. Furthermore, in some embodiments, the code may be tangibly stored on one or more volatile, non-transient, or non-volatile tangible computer-readable media during execution or at other times. Embodiments of these tangible computer-readable media may include, but are not limited to, hard disks, removable magnetic disks, removable optical disks (e.g., compact disks and digital video disks), magnetic cassettes, memory cards or sticks, random-access memory (RAM), read-only memory (ROM), and equivalents.

[0306] The above description is illustrative and not restrictive. For example, the embodiments (or one or more aspects thereof) described above may be used in combination with each other. Other embodiments may also be used by those skilled in the art as a result of a closer examination of the above description.

[0307] The scope of the present invention should be determined by referring to the appended claims, along with the entire range of equivalents enjoyed by such claims.

Claims

1. An apparatus for measuring microvascular dysfunction within an organ or limb, wherein the organ or limb has blood vessels and a microvascular system connected to the blood vessels, and the apparatus is An infusion catheter comprising an inflatable structure and at least one infusion lumen for delivery of an infusion fluid, A pressure sensor configured to sense the pressure inside the blood vessel, An injection pump communicating with the injection lumen of the injection catheter, Multiple separate solutions in multiple separate reservoirs, which are in communication with the injection pump, A computerized controller communicating with the injection pump, wherein the computerized controller is configured to control the operation of the injection pump to perform controlled fluid infusion of at least a first solution from the plurality of solutions into the injection lumen of the catheter, and subsequently a second solution from the plurality of solutions into the injection lumen of the catheter. Equipped with, The first solution is associated with the assessment of microvascular function, and the second solution is a solution for reducing, avoiding, or eliminating ischemia or necrosis of the tissues of the organ or limb. The controlled fluid injection of the first solution includes fluid injection at multiple flow rates, The pressure sensor is configured to sense a plurality of pressure measurements associated with the plurality of flow rates, The computerized controller is configured to determine a linear pressure-flow rate relationship between the plurality of pressure measurements and the plurality of flow rates delivered during the controlled flow injection of the first solution, and to measure the differential change of resistance from the linear pressure-flow rate relationship. The computerized controller is further configured to determine the dynamic microvascular resistance based on the sum of the differential change of the resistance and a constant resistance value, wherein the constant resistance value is independent of the controlled fluid infusion of the first solution in the apparatus.

2. The first solution is a solution associated with the dilation of the microvascular system, as described in claim 1. A mounted device.

3. The apparatus according to claim 1 or 2, wherein the first solution is a Newtonian fluid selected to better assess microvascular parameters by improving the linearity of the flow.

4. The apparatus according to any one of claims 1 to 3, wherein the first solution lacks oxygen.

5. The apparatus according to any one of claims 1 to 4, wherein the first solution is a crystalloid liquid.

6. The apparatus according to any one of claims 1 to 5, wherein the second solution is a solution for dissolving microvascular blood clots or debris in the heart.

7. The aforementioned controller, Applying pulses of the first solution at a first pressure and / or flow rate to open microvessels, Applying the flow of the second solution at a second pressure and / or flow rate to reduce, avoid, or eliminate ischemia and necrosis of the tissue of the organ or limb, The apparatus according to any one of claims 1 to 6, wherein the pump is programmed to perform the above.

8. The apparatus according to any one of claims 1 to 7, wherein the controller is configured to perform a real-time, automatic assessment of microvascular function.

9. The apparatus according to claim 1, wherein the pressure sensor is attached to the injection catheter.

10. The apparatus according to any one of claims 1 to 9, wherein the controller is configured to perform an assessment of microvascular function using the sensed pressure resulting from the superposition of injection and innate fluids.

11. The apparatus according to any one of claims 1 to 10, wherein the controller is configured to perform controlled coronary artery fluid infusion (CoFI) by controlling the pump.

12. The apparatus according to any one of claims 1 to 11, wherein the controlled fluid injection of the second solution includes fluid injection at a plurality of flow rates.

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