Apparatus and method for determining and / or treating microvascular obstruction - Patents.com

Abstract

Methods and systems are provided for the diagnosis and / or treatment of microvascular dysfunction, such as microvascular occlusion (MVO), by injecting volumetric flow into a blood vessel using an injection system to block or reverse intrinsic antegrade flow such that equilibrium values ​​of volumetric flow rate and corresponding pressure can be determined, which in turn allows for calculation of MVO, absolute hydrodynamic resistance, fractional flow reserve, fractional coronary flow reserve, and other physiological parameters in real time or near real time.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 136,174, filed January 11, 2021, the entire contents of which are incorporated herein by reference.

[0002] Methods and devices are provided for the diagnosis and / or treatment of microvascular function and dysfunction (MVD) and other diseases of the microvasculature of organs, including the heart. [Background technology]

[0003] Heart attacks or acute ECG ST-segment elevation myocardial infarction ("STEMI") are caused by sudden occlusion of an epicardial coronary artery, typically a fibrin- and platelet-rich thrombus with associated embolic plaque and debris. The electrocardiographic sign of acute transmural myocardial infarction (heart attack) is ST-segment elevation that appears across multiple anatomical ECG leads. ST-segment elevation is characteristic of severe coronary artery occlusion or narrowing, which causes ischemic myocardial injury and cell death. Occlusion of large vessels is often associated with severe narrowing or occlusion of smaller vessels (referred to as microvascular occlusion or MVO), hemodynamic collapse, thrombus with embolic debris, and other effects that reduce blood supply. MVO is an independent predictor of late adverse events, including death and heart failure, and no successful MVO therapy has been identified to date.

[0004] Interventional cardiology is adept at opening severely narrowed or blocked epicardial coronary arteries using catheters, guidewires, balloons, and stents in the cardiac catheterization laboratory. However, microvascular occlusion cannot be diagnosed or treated in the catheterization laboratory. Also, MVO typically cannot be effectively treated even when it is accurately diagnosed.

[0005] Myocardial salvage (i.e., preserving muscle from ischemia-induced necrosis) is a key concern to ensure good long-term outcomes in patients with STEMI. A key component of achieving a positive long-term outcome requires minimizing the interval between the onset of coronary artery occlusion (at home or outside the hospital) and the reopening of the occluded artery in the catheterization laboratory. Interventional cardiologists can reduce the duration of arterial occlusion time by implementing a streamlined and efficient emergency care system. The goal of such procedures is to transport STEMI patients to the catheterization laboratory as soon as possible, thereby avoiding long-term STEMI complications. Complications resulting from STEMI and MVO include systolic and diastolic heart failure, arrhythmias, aneurysms, ventricular rupture, and multiple other serious complications. These complications can significantly shorten life expectancy and / or impose severe limitations on quality of life.

[0006] Modern interventional therapy for acute myocardial infarction has matured over time with impressive clinical outcomes. In recent years, the 30-day post-event heart attack / STEMI mortality rate has dropped from over 30% to less than 5%. This improvement has been achieved by reperfusing the heart with blood as soon as possible after coronary artery occlusion, which in turn has been brought about by streamlining the clinical treatment system to open the coronary arteries in the catheterization laboratory as soon as possible after the onset of a heart attack. There is no doubt that emergency procedures, including stent placement and balloon angioplasty, have improved the early and late clinical outcomes of acute heart attack therapy.

[0007] However, substantial challenges remain for treating STEMI patients and reducing long-term complications, including heart failure (poor myocardial function and cardiac enlargement), cardiac / ventricular rupture, persistent ischemic chest pain / angina, left ventricular aneurysms and thrombi, and malignant arrhythmias.

[0008] Late-stage heart failure worsens 25-50% of STEMI cases and consists of poor left ventricular function and damaged myocardium. Heart failure typically worsens as the heart remodels in shape and size, with associated functional loss. Nearly half of all new heart failure cases in patients under 75 years of age are STEMI-related.

[0009] Years of STEMI therapy investigations have shown that patenting epicardial / major coronary arteries is insufficient to completely salvage the myocardium and improve long-term patient outcomes. A very common reason for poor late outcomes after a heart attack is microvascular occlusion (MVO). MVO is an obstruction or severe flow limitation in small internal cardiac microvessels. These microvessels are so small and inaccessible that they cannot be stented or treated with conventional drug / thrombolytic therapy due to the size and number of the microvessels. Thus, despite widely patent epicardial coronary arteries, residual MVO impedes blood flow to the myocardium, resulting in ischemia and tissue necrosis and severe long-term myocardial damage.

[0010] MVO therefore remains an important frontier in cardiology. Cardiac microvasculature comprises small arterioles, capillaries, and venules that frequently collapse and fill with cells, thrombus, and debris (platelets, fibrin, and embolic plaque material) during STEMI. Very often, obstructed microvasculature (MVO) does not resolve even after stent placement, presenting serious long-term negative prognostic implications.

[0011] MVO is very common in STEMI patients, even when stent placement and balloon angioplasty have been successful in patenting the great epicardial coronary arteries. MVO occurs in more than half of all STEMI patients, even with patent epicardial arteries and good blood flow through the newly placed stent.

[0012] MVO extent is important to the severity of myocardial injury and patient outcome. MVO can only be accurately detected and measured via cardiac MRI imaging, which identifies MVO location, extent, and severity. However, MRI cannot be performed in an emergency or during a cardiac catheterization procedure, as it requires the patient to be located within a separate imaging area, can require up to an hour to complete, and is a separate, expensive procedure.

[0013] The key features of MVO can be summarized as follows:

[0014] 1.MVO and microvascular dysfunction in STEMI are the leading causes of serious early and late complications after a heart attack.

[0015] 2. Angiographic "no reflow" or "low reflow" is caused by MVO, i.e., obstructed microvessels in the myocardium. MVO in severe cases is angiographically characterized by very slow radiographic contrast filling and flow in the epicardial coronary arteries, as 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 not capable of detecting MVO in the majority of patients.

[0016] 3.MVO causes myocardial cell injury and death due to prolonged ischemia, poor blood flow, and failure to replenish vital metabolic nutrients such as glucose.MVO microscopic analysis shows collapsed microvessels with red blood cells, platelets causing fibrin clots, dead cardiomyocytes, inflammatory cells, myocyte death, and endothelial cell swelling with death along the obstructed intramyocardial capillaries.

[0017] 4. Acute MVO manifests as small vessel collapse due to very low intraluminal pressure caused by cardiac arterioles and capillaries and proximal vascular occlusion that are completely occluded by platelet- and fibrin-rich emboli, platelet-neutrophil aggregates, dying blood cells, and embolic debris.

[0018] 5. When MVO complicates acute STEMI / MI, much greater cardiac / myocardial damage occurs and poorer ventricular function occurs earlier.

[0019] 6. MVO is very common. It occurs in a. approximately 53% of all STEMI and non-ST-segment elevation myocardial infarctions (NSTEMI) regardless of epicardial flow, b. 90% of large transmural STEMIs, c. 40% of MIs with TIMI III (normal) radiographically visible flow, and d. MVO is the single most effective prognostic marker of the event after controlling for myocardial infarction size.

[0020] 7. Patients with microvascular occlusion have more late major adverse cardiovascular events (MACE) than patients without MVO (45% vs. 9%).

[0021] 8. MVO is the best predictor of acute and chronic adverse cardiovascular outcomes.

[0022] 9. MVO rapidly leads to late fibrotic scarring and poor cardiac function.

[0023] MVO cannot be effectively diagnosed and measured in a conventional catheterization laboratory, and no effective conventional therapy is currently commercially available. All previously proposed therapies have proven essentially ineffective and, in some cases, dangerous.

[0024] Myocardial infarction, by definition, is cell death and is frequently accompanied by myocardial ischemia. Myocardial infarction can result in brief but significant ischemia that is reversible ("stunned myocardium"), chronic ischemia that occurs when myocardial cells are alive but without sufficient oxygen or nutrients to contract normally ("hibernating myocardium"), or necrosis and infarction via prolonged ischemia. Infarction typically spreads as a wave that begins in the endocardium and spreads across the myocardial wall to the epicardium. Each of these events can be characterized by non-invasive imaging and tests such as nuclear, echo, and PET methods. A very good test is provided by cardiac MRI, where gadolinium contrast can be used to visualize microvascular occlusions.

[0025] Myocardial infarction (MI) resulting in microvascular occlusion (MVO) has significant clinical impact. Although epicardial coronary artery occlusion is well known, it has been hypothesized that microscopic / microvascular embolization by embolic platelets and fibrin in the microvasculature also occurs. To date, ectopic platelet aggregates have also occurred.

[0026] Histopathological studies have shown endothelial cell edema with fibrin and platelet clumps in both human cases and animal models. Microvascular plugging also occurs due to red blood cells, white blood cells, and fibrin-platelet clumps, often not visible to light microscopy but can be seen via immunostaining and EM / SEM / TEM.

[0027] MVO is only one of several disorders under the larger classification of microvascular dysfunction. Microvascular dysfunction also occurs in patients without epicardial artery occlusion, and encompasses a much larger patient population than the acute coronary artery occlusion (STEMI) patient group. The effect of occlusion of blood vessels less than 200 microns in diameter in patients without epicardial artery (blood vessels larger than 2 mm) occlusion is not fully understood, despite many years of research and many failed treatment strategies.

[0028] Thus, there is a need in the art for devices and methods that can assess microvascular function and dysfunction in a larger MVD 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, quantify, and treat microvascular dysfunction, including microvascular occlusion and tissue necrosis / infarction. Still further, there is a need for devices and methods that allow for real-time or near-real-time assessment, diagnosis, and / or treatment of problems, allow for treatment decisions, and / or allow for real-time estimation of microvascular injury and ongoing treatment efficacy. Summary of the Invention [Means for solving the problem]

[0029] Methods and apparatus are provided for the assessment, diagnosis, and / or treatment of microvascular dysfunction in real time or near real time. In various embodiments, microvascular dysfunction may include clinical syndromes such as STEMI / NSTEMI, microvascular occlusion, no reflow, microvascular spasm cardiogenic shock, and other dysfunctional diseases of the microvasculature. The principles of the present invention are applicable to the diagnosis and / or treatment of many organs, including the heart, brain, kidney, and several other organs. More specifically, non-limiting embodiments include devices and methods for successfully diagnosing, restoring patency, recanalizing and preserving flow, and / or limiting reperfusion injury in vessels and organs with microvascular dysfunction. Applications include therapy for organ systems including, but not limited to, cardiac (acute myocardial infarction - primary percutaneous coronary intervention (PPCI)), cerebral (cerebral stroke (CVA)), intestinal ischemia / infarction, pulmonary embolism / infarction, critical limb ischemia / infarction, renal / renal ischemia / infarction, liver, peripheral vascular, neurovascular, and others.

[0030] According to one aspect of the invention, a system is provided that includes specialized infusion and sensing catheters for delivering diagnostic and / or therapeutic agents and a control console. The control console is programmed with specialized algorithms that can be used to diagnose and / or treat microvascular dysfunction by determining physiological parameters that can be used to predict physiological events such as microvascular occlusion, myocardial infarction, and myocardial ischemia. Methods of operating the system of the invention for diagnosing and / or treating microvascular dysfunction such as MVO are also provided.

[0031] Systems and devices are included that are configured to perform real-time or near real-time microvascular function assessments. The systems and devices of the present invention may also be used to diagnose and treat microvascular dysfunction, such as microvascular occlusion (MVO). According to one aspect of the present invention, the systems and devices enable real-time diagnosis and treatment using invasive catheterization employing a controlled coronary flow injection (CoFI) technique that can provide accurate prediction of physiological events.

[0032] According to some aspects, a method for determining one or more vascular physiological parameters for a patient is provided. The method may include advancing a catheter having a lumen into an arterial blood vessel of the patient, the arterial blood vessel having antegrade blood flow and the lumen having a distal end, measuring a reference arterial pressure at a location proximal to the distal end of the lumen, delivering a fluid through the lumen into the arterial blood vessel at a first volumetric flow rate, measuring a first arterial pressure in the arterial blood vessel, the first arterial pressure corresponding to the first volumetric flow rate, delivering a fluid through the lumen into the arterial blood vessel at a second volumetric flow rate, measuring a second arterial pressure in the arterial blood vessel, the second arterial pressure corresponding to the second volumetric flow rate, and / or determining an equilibrium volumetric flow rate of the fluid based on the first volumetric flow rate, the first arterial pressure, the second volumetric flow rate, and the second arterial pressure, where the pressure proximate the distal end of the lumen corresponds to the reference arterial pressure.

[0033] Microvascular resistance may be determined based on a reference arterial pressure and an equilibrium volumetric flow rate. The first arterial pressure may correspond to one of a first peak systolic pressure, a first peak diastolic pressure, a first RMS pressure, or a first mean pressure. The second arterial pressure may correspond to one of a second peak systolic pressure, a second peak diastolic pressure, a second RMS pressure, or a second mean pressure. The fluid may contain little or no free oxygen. The volumetric flow rate may be determined using regression analysis.

[0034] According to some aspects, a stenosis may be located in an arterial blood vessel, and the method / system may be used to characterize the stenosis. For example, the system / method may include delivering a fluid at an equilibrium volume flow rate through a lumen into the arterial blood vessel, measuring a third arterial pressure proximal to the stenosis, and measuring a fourth arterial pressure distal to the stenosis. The stenosis may be characterized based on the third arterial pressure and the fourth arterial pressure. Stenosis resistance may be determined based on the third arterial pressure, the fourth arterial pressure, and the equilibrium volume flow rate. A flow reserve ratio may be determined based on a ratio of the fourth arterial pressure to the third arterial pressure.

[0035] In some embodiments, the fluid is delivered from the catheter into the arterial vessel through an exit port at the distal end of the catheter. The fluid may be delivered from the catheter into the arterial vessel through a number of holes disposed at the distal end of the catheter. The catheter may be balloon-less. For example, the catheter may not include a balloon or other expansion element.

[0036] The reference arterial pressure may be the pressure on the proximal section of the catheter. For example, the reference arterial pressure may be the aortic pressure.

[0037] According to some aspects, a device for assessing a patient suffering from vascular stenosis and / or dysfunction is provided. For example, the device may include a catheter, a pressure sensor, a reference pressure sensor, and / or a controller. The catheter may have a distal region that is sized and shaped to be advanced into the arterial blood vessel. The catheter may include a lumen for delivering fluid into the arterial blood vessel. The pressure sensor may be disposed at the distal region of the catheter to measure pressure. The reference pressure sensor may be configured to measure a reference pressure at a location proximal to the distal region. The controller may be operatively coupled to the reference pressure sensor and the pressure sensor. The controller may be configured to cause the fluid to be delivered into the arterial blood vessel through the lumen at a first volumetric flow rate, measure a first arterial pressure in the arterial blood vessel while the fluid is delivered at the first volumetric flow rate, cause the fluid to be delivered into the arterial blood vessel through the lumen at a second volumetric flow rate, measure a second arterial pressure in the arterial blood vessel while the fluid is delivered at the second volumetric flow rate, and / or determine an equilibrium volumetric flow rate at which the pressure corresponds to the reference pressure.

[0038] The controller may be further configured to calculate microvasculature resistance by dividing the baseline pressure by the equilibrium volumetric flow rate. The fluid may contain little or no available oxygen. The pressure sensor may be located on the catheter. The pressure sensor may be located on a guidewire coupled to the catheter. The catheter may be balloon-less. For example, the catheter may not include a balloon or other expansion element.

[0039] The controller may be further configured to determine an equilibrium volumetric flow rate using the regression analysis. The controller may be further configured to deliver the fluid at an equilibrium volumetric flow rate. The pressure sensor may be configured to be advanced from a proximal side of the stenosis to a distal side of the stenosis. The device may include an additional pressure sensor, such as a second pressure sensor. The pressure sensor and the second pressure sensor may be configured to be positioned on opposite sides of the stenosis. The catheter may deliver the fluid through an outlet port positioned at the distal region. The catheter may deliver the fluid through a plurality of holes positioned at the distal region. A reference pressure sensor may be positioned on the catheter at a location proximal to the distal region. The reference pressure sensor may be positioned within the aorta of the patient. The controller may measure a third arterial pressure and a fourth arterial pressure (e.g., in response to a signal from the pressure sensor). The third arterial pressure may be measured at a point proximal to the stenosis in the arterial vessel, and the fourth arterial pressure may be measured at a point distal to the stenosis. The controller may characterize the stenosis based on the third arterial pressure and the fourth arterial pressure. The controller may determine a stenosis resistance based on the third arterial pressure, the fourth arterial pressure, and an equilibrium volume flow rate. The controller may determine a fractional flow reserve based on a ratio of the fourth arterial pressure to the third arterial pressure.

[0040] Methods are provided for determining a patient's microvascular arterial physiological parameters. These methods may include delivering fluid into a patient's blood vessel at a known flow delivery rate, determining a resultant arterial pressure associated with the known delivery rate, determining an equilibrium condition, and determining microvasculature resistance. In some embodiments, these methods include advancing a catheter into the patient's arterial vessel, delivering fluid into the arterial vessel at a first volumetric flow rate, and measuring a first arterial pressure in the arterial vessel. Fluid may subsequently be delivered into the arterial vessel at a second volumetric flow rate, and the second arterial pressure is measured. The equilibrium arterial pressure and volumetric flow rate corresponding to the interruption of antegrade blood flow through the vessel are then calculated. At this calculated equilibrium point, the intrinsic driving pressure is equal to the distal vascular pressure induced by the administered flow, resulting in zero pressure gradient in the proximal vascular compartment, and therefore zero flow. The microvasculature resistance is then calculated by dividing the equilibrium arterial pressure by the corresponding injected volumetric flow rate. In some embodiments, the balanced arterial pressure and the corresponding arterial volumetric flow rate and resulting pressure exhibit an approximately linear relationship. The resistance may therefore be calculated using a linear regression analysis of the flow-pressure parameters. It should be understood that the linear regression analysis may include interpolation and extrapolation.

[0041] A method for determining arterial physiological parameters of a patient's larger vessels (such as epicardial coronary arteries) is also provided.

[0042] The system of the present invention may include an apparatus for assessing microvascular dysfunction in a patient, the apparatus including a catheter having a pressure sensor and a controller configured to deliver fluid through the catheter, the controller configured to calculate an equilibrium pressure value based on at least two fluid flow rates and pressures. In some embodiments, the apparatus may include a catheter having a distal end, a lumen for delivering fluid into a blood vessel having a blood flow, a pressure sensor disposed near the distal end of the catheter, and a controller programmed to deliver fluid to the catheter at a plurality of flow rates. The controller is programmed to calculate an equilibrium volumetric fluid flow rate and pressure based on the injected fluid flow rate and the resulting pressure, and calculate a value that matches a cardiac MRI MVO measurement. The catheter may, but need not, include an occlusion balloon. According to one aspect of the present invention, the calculated MVO is useful because it provides an MVO value that is comparable to that determined by MRI. [Brief description of the drawings]

[0043] The foregoing and other objects, features, and advantages of the present disclosure described herein will become apparent from the following description of specific embodiments of those inventive concepts, as illustrated in the accompanying drawings. It should be noted that the drawings are not necessarily to scale, with emphasis instead being placed on illustrating the principles of the inventive concepts. Also, in the drawings, like reference characters may refer to the same or similar parts throughout the different views. It is intended that the embodiments and figures disclosed herein be considered illustrative, and not limiting.

[0044] [Figure 1] FIG. 1 is a perspective view of an exemplary modular system for assessment of MVD in accordance with the principles of the present invention.

[0045] [Figure 2A] 2A-2C are perspective views of the distal end of an alternative embodiment of an infusion catheter constructed in accordance with the present invention. [Figure 2B] 2A-2C are perspective views of the distal end of an alternative embodiment of an infusion catheter constructed in accordance with the present invention. [Figure 2C] 2A-2C are perspective views of the distal end of an alternative embodiment of an infusion catheter constructed in accordance with the present invention.

[0046] [Figure 3A] FIG. 3A is a perspective view of a central portion of an infusion catheter suitable for use with the distal ends depicted in FIGS. 2A-2D.

[0047] [Figure 3B] 3B and 3C are side cross-sectional and perspective views, respectively, of an alternative embodiment of a distal portion of an infusion catheter having a pressure chamber. [Figure 3C] 3B and 3C are side cross-sectional and perspective views, respectively, of an alternative embodiment of a distal portion of an infusion catheter having a pressure chamber.

[0048] [Figure 4] FIG. 4 is a side view of the distal end of a preferred embodiment of a catheter having one or more pressure sensors / transducers.

[0049] [Diagram 5] FIG. 5 is a schematic diagram of a system constructed in accordance with the principles of the present invention.

[0050] [Figure 6A] FIG. 6A is a graph depicting an example relationship between infusate pump flow and the resulting pressure at the infusate delivery site.

[0051] [Figure 6B] FIG. 6B is a graph depicting an example relationship between intrinsic flow rate and infusate flow rate that may be used to demonstrate balanced flow rate and pressure in accordance with the present invention.

[0052] [Figure 7] FIG. 7 is an exemplary electrical circuit model depicting the resistance of physiological components embodied in the methodology algorithm for calculating MVD in accordance with the principles of the present invention.

[0053] [Figure 8] FIG. 8 is a flow chart for generating estimates of physiological parameters employed in calculating MVO.

[0054] [Figure 9] FIG. 9 is a flow chart for determining coronary flow reserve (CFR) in accordance with the principles of the present invention.

[0055] [Figure 10] FIG. 10 is a side view of a distal end of an infusion catheter positioned in a blood vessel with a stenosis, in accordance with an embodiment of the present invention.

[0056] [Figure 11] FIG. 11 is a flow chart for calculating stenosis resistance, fractional flow reserve (FFR), and other physiological hydraulic vascular parameters and function in the large epicardial arteries in accordance with the principles of the present invention.

[0057] [Figure 12] FIG. 12 is a schematic diagram of components that may be utilized in the system of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0058] Detailed Description The present invention is directed to devices, systems, and methods for implementing techniques for determining parameters for predicting physiological events, and is applicable to the diagnosis and / or treatment of many organs, including the heart. More specifically, the systems and methods of the present invention allow for successful prediction of physiological events such as microvascular occlusion, myocardial infarction, and myocardial ischemia. Applications of the systems and methods of the present invention include the diagnosis and treatment of heart (acute myocardial infarction-primary percutaneous coronary intervention (PPCI)), brain (cerebral stroke (CVA)), intestinal ischemia / infarction, pulmonary embolism / infarction, critical limb ischemia / infarction, renal ischemia / infarction, liver, peripheral vascular, neurovascular, and other occlusions (MVO) and tissue necrosis / infarction.

[0059] 1, an exemplary modular computerized diagnostic and infusion system 100 for coronary arteries and other human / animal vascular systems and organs is described. Infusion system 100 is illustratively packaged as a mobile console and programmed to enable characterization of physiological systems and events, including real-time or near real-time measurements of coronary pressure and flow, pressure / flow time parameters, coronary physiology measures such as CFR measurements, FFR measurements, autoregulation, hemodynamic resistance determination, balanced flow determination, and / or balanced pressure determination. Infusion system 100 includes controller 101, display 102, infusion pump 103, and pressure measurement system 104, all mounted on mobile platform 105.

[0060] 2A, the distal end of an exemplary infusion catheter 200 is illustrated. The infusion catheter 200 includes an infusion port 202 in fluid communication with an infusion lumen 212 extending from the proximal end of the catheter and coupled to an infusion pump 103. A guidewire lumen 204 extends through the catheter 200, allowing the infusion catheter to be advanced along a guidewire to a desired location within the patient's vasculature. The catheter 200 may have an enlarged diameter section 206 that serves to increase hydrodynamic resistance for diagnostic purposes. When exposed to fluid flow, section 206 generates a hydrostatic pressure gradient within the body lumen, as described in U.S. Patent Application Publication No. 17 / 327,433, published as U.S. Patent Application Publication No. 2021 / 0361170 and assigned to CorFlow Therapeutics AG, the entire contents of which are incorporated by reference. A pressure sensor 208 may be located within the body of the catheter 200 and coupled to the pressure measurement system 204 to determine the pressure of the fluid flow within the patient's vasculature.

[0061] 2B, an alternative embodiment of an infusion catheter is described, namely, the distal end of catheter 210. Guidewire 201, which may be a 0.014 inch pressure measuring guidewire, may be inserted through catheter 210 in a rapid exchange (RX) fashion, such that the distal end of guidewire 201 extends from the exit of guidewire lumen 204. Infusion port 202 is located on the distal end of catheter 201 adjacent the exit of guidewire lumen 204 and delivers fluid via infusion lumen 212, shown in dotted line.

[0062] In FIG. 2C, the distal end of another alternative embodiment is illustrated, in which an infusion catheter 230 has an occlusion balloon 236 and radiopaque markers 238 and 240. An infusion exit port 232 is disposed in fluid communication with an infusion lumen 242, shown in dotted lines. A guidewire lumen 234 is also provided and may be arranged for either over-the-wire or rapid exchange use. Additional embodiments of infusion catheters, such as those described in U.S. Pat. No. 10,315,016 to Schwartz or U.S. Patent Application Publication No. 2018 / 0280172 to Hoem, the entire contents of each of which are incorporated herein by reference, may be used herein.

[0063] 3A, a central portion of an infusion catheter constructed in accordance with the principles of the present invention is described. The central portion of catheter 310 includes an infusion lumen 312 that illustratively coaxially surrounds a guidewire lumen 311. In alternative embodiments, infusion lumen 312 may be arranged side-by-side or otherwise relative to guidewire lumen 311. In a preferred embodiment, the diameter of catheter 310 is small, thereby allowing the catheter to be introduced into smaller blood vessels for diagnosis and therapy. Guidewire lumen 311 preferably has a diameter sufficient to receive a guidewire that provides pressure sensing.

[0064] In Figures 3B and 3C, a distal portion of an exemplary infusion catheter is illustrated having a pressure chamber 306 disposed on a guidewire 301. The pressure chamber 306 is designed to provide an area of ​​stable pressure measurement in the distal arterial compartment, allowing pressure measurements at locations other than near or distal to the catheter tip. As shown in Figure 3C, the exterior surface of the catheter may include pores, slits, or slots 323 to provide better distribution of infusate at the distal end of the catheter, and also more precise pressure measurements. The pores, slits, or slots 323 may also be arranged to direct the infusate flow pattern as may be desired for a particular type of diagnosis or therapy. Additional catheter configurations for injecting fluids into blood vessels, including mechanisms for centering the distal end of the catheter within the vessel to evenly distribute flow and direct injected flow preferentially in an antegrade and / or retrograde direction within the vessel, are described with respect to Figures 5A-7E of co-pending, commonly assigned U.S. Patent Application No. 16 / 577,962, filed September 20, 2019, and published as U.S. Patent Application Publication No. US2020 / 0093991 A1, which is incorporated herein by reference.

[0065] Referring now to Figures 4 and 5, an exemplary embodiment of an infusion system constructed in accordance with the present invention is described, which includes one or more pressure sensors. Figure 4 depicts the distal end 400 of a preferred embodiment of a catheter, including distal pressure sensors / transducers 402 and 404. The pressure sensors / transducers 402 and 404 are preferably mounted longitudinally at a distance greater than 1 cm apart, and more preferably spaced at a distance to allow the sensors to be located on either side of a typical stenosis. A guidewire 406 is disposed within the guidewire lumen 408. The distal end 410 of the catheter body 412 includes a cap 414, which contains a plurality of holes 416 in communication with the infusion lumen, through which infusate may be controllably released. The pressure sensor configuration shown in Figure 4 allows for the measurement of axial intravascular (longitudinal) pressure gradients. The longitudinally measured pressure gradients may be used to understand the relationship between vessel / arterial inlet size and flow, thus allowing for an assessment of the resistance of the large vessel in which the catheter is located.

[0066] For example, fractional flow reserve (FFR) is a parameter that allows assessment of the hemodynamic significance of coronary stenosis and is typically determined at maximal vasodilation. The two pressure sensor / transducer configuration of FIG. 4 facilitates this measurement without the need for maximal vasodilation. Coronary flow infusion using an infusion pump and pressure measurements also allows for simple and direct absolute stenosis and hemodynamic / hydraulic quantification. Other important physiological parameters may be measured as well, including coronary flow reserve (CFR) and microvascular resistance as described below. Fluid infusion without oxygen content, such as electrolyte solutions, avoids the need to pharmacologically induce maximal vasodilation using intravenous or arterial vasodilators such as adenosine. This is due to an induced oxygen-deficient state with subsequent physiological vasodilation. In addition, the present sensor configuration shown in FIG. 4 allows absolute hydrodynamic resistance to be quantified, which in turn allows for flow reserve calculation using mathematical conversion methods.

[0067] With reference to FIG. 5, a system 500 constructed in accordance with the principles of the present invention as may be embodied in the modular mobile system depicted in FIG. 1 is described. The system 500 includes a catheter 502 having a localized or generalized diameter increase forming a ridge 504 and a distal end 506. The catheter 502 may be advanced to a desired location within a patient's vasculature over a pressure-sensing guidewire 508. The catheter 502 may be constructed with an internal lumen for receiving the guidewire 508 in an over-the-wire or rapid exchange modality. A pressure sensor 510 and an infusion hole 512 are disposed near the distal end 506. Infusate located in a reservoir 514 is selectively pumped through the catheter 502 via the infusate lumen and exits through the infusion hole 512 by a pump 516. A controller 518, which may include a processor and programmed algorithms, is configured to communicate with the pressure sensor 510 and the pressure guidewire 508 and receive pressure readings from those devices.

[0068] The controller 518 is also configured to communicate with the pump 516 and control the flow rate of the infusate infused through the pump 516. Feedback from the calculation of the equilibrium flow rate as described below may be used to adjust the operation of the pump, balloon pressure (in embodiments, with a balloon present), or other system components to make desired changes in system function and improve diagnostic or therapeutic system function. The controller further includes a storage medium 520, which may include RAM, ROM, disk drive, or other known storage media. In some embodiments, the storage medium 520 may store the algorithms and mathematical calculations disclosed herein. In some embodiments, the storage medium 520 is used to store data received from the pressure sensor 510 and the pressure guidewire 508, and to store the equilibrium pressure and volumetric flow values, FFR, and other calculated values. In some embodiments, the storage medium 520 may include machine learning algorithms that control the flow rate, perform measurements, and calculate results. In some embodiments, controller 518 may communicate with an external wide area network, such as the Internet 522, and / or a computing device 524 to communicate data that may be used to refine the algorithms in storage medium 520. Controller 518 may also be programmed to access a database of MRI images and parameters derived from those images used to assess microvascular occlusive dysfunction that may be correlated to MVO values ​​calculated using the flow analysis methods of the present invention.

[0069] It is desirable to have a reference pressure in the patient's vasculature, which in preferred embodiments is a proximal arterial reference pressure, and in some embodiments may be an aortic pressure. The reference pressure (and other pressures referenced herein and in the figures) may correspond to peak systolic pressure, peak diastolic pressure, average pressure, pressure determined using a root mean square (RMS) method, other types of known pressure measurements, or any combination of these types of pressure measurements. The system 500 may optionally further include a pressure sensor 526 located a proximal distance from the distal end 506. In some preferred embodiments, the pressure sensor 526 is located sufficiently proximal to the distal end 506 such that readings taken with the pressure sensor 526 may represent the proximal arterial reference pressure. In such embodiments, infusate flow from the distal end 506 has negligible effect, if any, on pressure measurements taken by the pressure sensor 526. Alternatively, or in addition to pressure sensor 526, system 500 may include pressure sensor 528 or pressure sensor 530 attached to a second catheter, guidewire, or other delivery device. In some embodiments, pressure sensor 528 is configured to be placed at a location different from catheter 502 and used to determine the baseline pressure. In yet other embodiments, system 500 may be in communication with one or more remote pressure sensors used to determine the baseline pressure. The proximal arterial baseline pressure may also be obtained using other methods, such as those described in U.S. Patent Application Serial No. 17 / 327,433, published as U.S. Patent Application Publication No. 2021 / 0361170 and assigned to CorFlow Therapeutics AG, the entire contents of which are incorporated by reference.

[0070] In a preferred embodiment, an infusion catheter such as that shown in Figures 2-5 may be in communication with a controller configured to control the pump such that the pump provides infusate through the infusate lumen at a known flow rate or flow rates. The controller also communicates with one or more pressure sensors, which may be located on the guidewire or elsewhere on the catheter. As discussed in more detail below, the controller is configured to determine a balanced arterial pressure and a balanced volumetric flow rate at which antegrade blood flow ceases. Those skilled in the art will appreciate that the disclosed invention will provide an apparatus and method for reducing or stopping antegrade blood flow through the controlled release of infusate.

[0071] In one preferred embodiment, system 500 employs an infusion catheter as described with respect to FIG. 4, while in other embodiments, an infusion catheter as depicted in FIG. 2 or 3 or as described in U.S. Patent Application Publication No. US2020 / 0093991 A1, incorporated above, may be employed. System 500 may also employ an infusion catheter as described in U.S. Patent Application No. 17 / 327,433, incorporated by reference. Preferably, an infusion catheter suitable for use with system 500 is compatible with a 6F guide sheath, includes a guidewire that receives a 0.014 inch pressure guidewire, and is capable of infusing a volumetric flow rate in the range of 5-50 ml / min. Optionally, the infusion catheter may include a compliant or semi-compliant occlusion balloon.

[0072] In accordance with the principles of the present invention, an infusion catheter is inserted into an epicardial vessel supplying blood to a patient's myocardium to assess whether myocardial vessels distal to or proximal to the vessel may contain dysfunctional vessels that may manifest as microvascular dysfunction such as MVO and / or be involved in myocardial infarction or ischemia. Volumetric flow is introduced through the infusion lumen of the catheter at sequentially increasing flow rates to totally or partially block antegrade blood flow within the epicardial or intramyocardial vessel.

[0073] The proximal arterial reference pressure will now be discussed with reference to FIG. 6A, and is defined as the aortic pressure P AO The proximal arterial reference pressure is expressed as: The proximal arterial reference pressure may be determined in a variety of ways known by those skilled in the art, such as by obtaining the aortic pressure using a sensor placed in communication with the patient's aorta. In addition, the proximal arterial reference pressure may be determined using pressure sensor 526. The proximal arterial reference pressure may also be determined by taking a reading with a distal pressure sensor, such as pressure sensor 510, prior to advancing the sensor distally, such as may occur as catheter 502 is advanced to the treatment site. It should be understood that these two methods may not yield the same determination of the proximal arterial reference pressure, as the latter method may not take into account increased resistance from the catheter once it is advanced to the treatment site.

[0074] Once a catheter according to the present invention is placed at or near a treatment site, distal pressure measurements may be taken as infusate is provided at one or more flow rates. For example, with reference to system 500, catheter 502 may be advanced to a treatment site. A clinician may cause system 500 to deliver infusate at a first flow rate. As infusate is being delivered to the patient, one or more pressure measurements may be taken using pressure sensor 510 and compared to one or more pressure measurements taken using sensor 526 representing a proximal arterial reference pressure. Continuing with the example, at the first flow rate, the pressure determined using pressure sensor 510 may be determined to be pressure P1, and the proximal arterial reference pressure determined using pressure sensor 526 may be determined to be pressure P2. AO , each of which is depicted on the chart of FIG. 6A, where P AO6A. The operator or automated control system may then increase the infusate flow rate to a second flow rate and make a determination of the pressure at pressure sensor 510, illustrated in FIG. 6A as pressure P2. It should be understood that the infused flow rate may continue to increase and the operator or automated control system may determine the associated pressure using pressure sensor 510, such pressure determinations may be illustrated in FIG. 6A as pressures P3, P4, P5, and P6. It should be understood that although preferred embodiments of the present invention involve an increase in flow rate (which may be stepped in a fixed amount, although not required) from one pressure determination to the next, embodiments may determine a prior pressure at a higher flow rate and then decrease the flow rate to determine a subsequent pressure.

[0075] It is desired to determine the infusate flow rate that results in a pressure at the infusate delivery site that is the same as, or sufficiently close to, the proximal arterial reference pressure (which may be the aortic pressure). In the example shown in FIG. 6A, the flow rate Q MVR , the corresponding pressure P5 is the proximal arterial reference pressure P AO is the same as the flow rate Q MVR It can be hypothesized that represents flow through the microvasculature or flow through a stenosis.

[0076] In some embodiments, the operator or the system may adjust the infusate flow rate higher or lower until the pressure measurements taken with pressure sensor 510 are sufficiently close to the proximal arterial reference pressure P AO Multiple measurements may be taken at different flow rates that result in pressures between pressures P1 and P6 before identifying a flow rate that results in a pressure P5 that is the same as pressure P1. Such a determination may be made simply as a function of a comparison between the pressure determined at the treatment site and a proximal arterial reference pressure.

[0077] In some embodiments, the proximal arterial reference pressure P may be calculated without having to resort to determining pressures corresponding to different flow rates in a trial and error process.AO In this regard, it is desirable to determine a pressure P5 corresponding to the proximal arterial reference pressure P. In this regard, the inventors have found that a linear relationship exists between the infusate flow rate and the pressure determined at the site to which the infusate is being delivered. In light of this linear relationship, a clinician may determine the pressure at a first flow rate, then determine the pressure at a second flow rate, and then use these pressures to determine, using linear regression, a flow rate that mathematically corresponds to the proximal arterial reference pressure. For example, with reference to FIG. 6A, a clinician may determine that a pressure P4 occurs at one flow rate and a pressure P6 occurs at another flow rate. Using linear regression, the clinician may determine that pressure P5 (proximal arterial reference pressure P AO ) corresponds to the flow rate Q MVR Thus, the desired flow rate can be found after making pressure determinations at only two different flow rates.

[0078] The clinician may wish to avoid delivering infusate at or above a rate that results in a pressure at the delivery site that exceeds the proximal arterial reference pressure. Utilizing linear regression, the clinician in a preferred embodiment may determine the resulting pressure at the infusate delivery site for two different infusate flow rates, each of which results in a pressure lower than the proximal arterial reference pressure. For example, referring again to FIG. 6A, infusate is delivered at two relatively low infusate flow rates, resulting in pressures P1 and P2 at the infusate delivery site. The linear regression determines the resulting pressure at the infusate delivery site for the infusate flow rate Q MVR6A to arrive at point P5, which corresponds to . Referring now to FIG. 6B, a method for determining an equilibrium volumetric flow rate and corresponding arterial pressure, which may be used to calculate microvascular resistance, large vessel vascular or stenotic resistance, FFR, and CFR, is described. In particular, FIG. 6B illustrates the relationship between controlled flow infusion ("CoFI") flow and the resulting intrinsic vascular flow. Infusate flow is provided by the device and method of the present invention. In FIG. 6B, equilibrium flow is reached when infusate flow into the distal myocardium creates a pressure equal to the intrinsic driving pressure. At this point, the net driving pressure gradient is zero, and therefore the intrinsic proximal flow is zero. As the infusate volumetric flow rate provided by the system 500 is increased, which may be in a stepwise manner in some embodiments, the increased arterial pressure resulting from the infusate flow causes a corresponding decrease in the intrinsic antegrade blood flow rate. For example, at point C, when the infused fluid flow rate has a value of 4 ml / min, the intrinsic volumetric flow rate drops to a value of about 0.5 ml / min. As the infused volumetric flow rate increases further, the intrinsic antegrade blood flow stops and then becomes retrograde (reversed) in the direction when the distal pressure becomes large enough to reverse the gradient. Negative values ​​of intrinsic flow rate depicted in the chart of FIG. 6B are associated with retrograde flow. The infused fluid flow rate at which antegrade flow ceases is referred to herein as the "equilibrium" condition, and in FIG. 6B, this equilibrium condition occurs when the infused fluid flow rate is about 4.5 ml / min.

[0079] Applicants have discovered that the relationship between infusate volumetric flow rate and intrinsic volumetric flow rate has a roughly inverse linear relationship. In the example depicted in Figure 6B, for the specific arterial vasculature tested, the correlation between intrinsic volumetric flow rate and infusate flow rate was determined to be approximated by the equation y = (-0.88) x + 4, where y is the value of the intrinsic volumetric flow rate in milliliters per minute and x is the value of the infusate volumetric flow rate.

[0080] According to an aspect of the invention, the relationship between the volumetric infusate flow rate and the measured vascular pressure may be used to determine the equilibrium condition. Based on the measured approximately linear relationship between those volumetric flow rates and pressures in both animals and humans, the equilibrium condition may be determined using as few as two data points and linear regression analysis. For example, using the equation (y=mx+b) for any two of the points P1-P6 and the line in the chart of FIG. 6A, the equation may be solved to determine the infusate flow rate corresponding to the reference pressure that results in a zero driving pressure gradient and thus a zero intrinsic volumetric flow rate in the proximal vascular compartment. Methods for determining fractional flow reserve (FFR), absolute myocardial resistance, microvascular resistance, and other parameters are described in the above-incorporated U.S. patent application Ser. No. 16 / 577,962. For example, as described in that application, the distal microvascular resistance associated with MVO may be calculated by dividing the equilibrium pressure by the equilibrium volumetric flow rate, and the MVO may thus be estimated.

[0081] 7 is a schematic diagram illustrating a model, according to some embodiments of the present invention, that may be used to assess stenosis in large epicardial arteries. Specifically, FIG. 7 depicts a hemodynamic model that uses electrical analogs to which the phenomena described herein relate to assessing stenosis. The model is based on the idea that pressure P distal The model depicts the intrinsic fluid flow through the catheter and stenosis to a point distal to the stenosis, identified as R. The model also shows the intrinsic flow resistance due to the catheter (catheter-R), the intrinsic flow resistance due to the stenosis (stenosis-R), and the intrinsic flow resistance along the collateral channels (collateral-R).

[0082] The model is illustrated with reference to system 500 as a non-limiting example. In some embodiments, distal end 506 is positioned near the proximal end of the stenosis. Using the model described above, infusate is delivered at one or more fluid flow rates and the pressure measured by pressure guidewire 508 (shown as P in FIG. 7) is cofiThis allows for the determination of a flow rate at which it is determined that the pressure at the fluid delivery site is at or sufficiently close to the proximal arterial reference pressure (corresponding to an equilibrium flow rate), such as when the pressure at the proximal arterial reference pressure (expressed as Q ) is the same as the pressure measured by pressure sensor 526. The flow rate through the stenosis is expressed as the flow rate Q pump,e and may be maintained as the pressure guidewire 508 is advanced to the distal end of the stenosis. Once the pressure guidewire 508 is at the distal end of the stenosis, the pressure P distal However, the injection flow rate is Q pump,e The resistance of the stenosis can then be measured by the pressure guidewire 508 as the pressure continues to be delivered at (P cofi -P distal ) / Q pump,e It can be calculated using:

[0083] In other embodiments, such as the configuration depicted with reference to FIG. cofi and pressure P distal is the flow rate of the injected fluid, Q pump,e may be determined simultaneously by pressure sensor 802 and pressure sensor 804 when pressure is being delivered at

[0084] In FIG. 8, a flow chart illustrating the use of the system 500 according to the present invention is illustrated. The system 500 may be used to determine an infusate rate corresponding to a proximal arterial reference pressure, known or measured in a patient. The method 1100 begins at step 1102, where an infusion catheter of the system 500 is inserted into a blood vessel to deliver infusate to the patient. At step 1104, an initial infusate flow rate is selected, which may be accomplished using a controller 518 to set the volumetric flow rate at which the pump 516 delivers infusate through the infusion catheter 502. At step 1106, one or more readings are taken inside the patient's blood vessel, such as with a pressure sensor or transducer located on a catheter or guidewire, to determine the pressure of the flow at the treatment site. At step 1108, a determination is made whether additional data points are desired. For linear regression analysis, data for at least two infusate volumetric flow rates is required, but data for additional flow rates may be desired for redundancy or safety purposes, or if the data already collected are in close proximity to one another. If additional data is desired, the process proceeds along path 1110 to step 1112, where the infusate flow quality is modified, for example, by selecting a higher volumetric flow rate. The process proceeds to steps 1102-1106, where infusate is delivered to the patient at the additional flow rate and pressure values ​​are measured. The foregoing process continues until it is determined in step 1108 that sufficient data points exist, after which a flow-pressure relationship is determined to allow calculation of an equilibrium flow rate, such as by using linear regression analysis in steps 1116 and 1118, as discussed above. The infusate flow rate corresponding to the proximal arterial reference pressure may thus be determined.

[0085] It will be appreciated by those skilled in the art that the devices and methods described herein may be advantageously used to determine fractional flow reserve (FFR). FFR may be calculated as the instantaneous ratio of pressure in a blood vessel across a hemodynamic resistance, such as a stenosis, at a specific volumetric flow rate. Advantageously, this is an instantaneous and absolute value that depends on microvascular flow, unlike traditional FFR methods that obtain a single FFR value corresponding to "maximum hyperemia," a highly arbitrary value that may vary from patient to patient or may exhibit variability within the same patient over time when hyperemic flow changes occur.

[0086] Coronary flow reserve (CFR) is the ratio of resting coronary vascular flow at baseline conditions compared to coronary flow at full adenosine maximum microvasodilation. CFR can be obtained by capturing data at the time infusate flow is initiated. Progressive distal hypoxia occurs when the infusate fluid has little or no oxygen content, which in turn elicits a natural ischemic vasodilatory response in the patient. This response thus allows the process described in FIG. 8 to be performed repeatedly without the need for vasodilators such as adenosine or others, which are currently used and are essential to conventional techniques for determining CFR.

[0087] According to yet another aspect of the invention, the CFR may be determined as illustrated in FIG. 9. A method 1200 for determining the CFR involves, in step 1202, placing the infusion catheter of the system 500 at a desired location within a patient's blood vessel or organ, such as within an artery or other lumen. In step 1204, one or more initial conditions may be obtained, such as obtaining a pressure measurement within the patient's lumen prior to or at the beginning of treatment. Preferably, step 1204 occurs prior to or immediately after infusion fluid is delivered to the patient by pump 516. In step 1206, infusion fluid is delivered to the patient through the infusion catheter, the infusion fluid preferably having little or no oxygen content to induce ischemia. It is generally understood that when perfused with a fluid having little or no free oxygen, the resulting ischemia will cause the blood vessel to undergo vasodilation, typically within 3-7 seconds. In step 1208, the pressure within the blood vessel is monitored to determine when the pressure reaches an asymptotic low value. The flow rate may then be increased and the pressure measured, and these steps repeated as described with respect to FIG. 8 until no further change in pressure is detected and an equilibrium flow rate is established. This condition has been shown to occur in 7-10 seconds. Once the equilibrium flow rate has been determined, this will correspond to the flow rate at maximum hyperemia, in step 1210. In step 1212, the CFR may then be determined as the ratio of the initial pressure determined in step 1204 to the pressure measured at the equilibrium infusion flow rate at maximum hyperemia.

[0088] Those skilled in the art will recognize that method 1200 may be performed with or without an occlusion balloon. Advantageously, if a device without any occlusion balloon is utilized for method 1200, the practitioner may access body lumens having narrower diameters, thus enabling diagnosis in small spaces that were previously unavailable because they were too small for balloon utilization. Additionally, assessing parameters without an occlusion balloon is a safer procedure since there is no balloon-artery contact that may induce dissection, tearing, or vascular occlusion.

[0089] Determining stenosis resistance or FFR in a large epicardial artery in accordance with the principles of the present invention is described with reference to the flow charts of Figures 10 and 11. A method 1300 for determining stenosis resistance or FFR involves, at step 1302, placing an infusion catheter at a desired location within a patient, such as within an artery or other lumen. Preferably, the infusion catheter is placed such that one or more pressure sensors are located proximal and distal to a treatment site. As an example, Figure 10 shows the distal end 800 of the infusion catheter positioned across a stenosis such that distal pressure sensor 802 is positioned proximal to the stenosis and distal pressure sensor 804 is positioned distal to the stenosis. Referring again to Figure 11, at step 1304, one or more initial conditions may be obtained, such as pressures distal and proximal to the stenosis as obtained by sensors 802 and 804. Preferably, step 1304 occurs prior to or shortly after infusate begins to be delivered to the patient. Alternatively, the pressure sensing wire may be withdrawn to a position antegrade to the stenosis while recording, a process that allows the hemodynamic pressure gradient across the stenosis to be assessed at a known injected flow rate.

[0090] In step 1306, infusate, preferably having little or no oxygen content, is delivered to the patient. For example, an initial flow value of 10 ml / min may be selected. The pressure in the vessel is then measured in step 1308. In step 1320, a determination is made whether there is sufficient data to determine a linear relationship between pressure and infusate flow rate. If there is insufficient data, the method proceeds to step 1312, where the flow rate of the infusate is adjusted. The pressure in the vessel corresponding to the adjusted flow rate is measured in step 1308. The method then proceeds back to step 1310, and the cycle may continue until a determination is made that sufficient data has been acquired and no need for additional pressure measurements is required at other flow rates, as determined in step 1310. A regression of the accumulated data values ​​of flow and pressure may be performed in step 1314, and an equilibrium flow rate may be determined in step 1316. In step 1318, additional injection may be performed at the equilibrium flow rate, the FFR may be calculated as the ratio of the pressures measured at each end of the stenosis, and the stenosis resistance may be calculated as the ratio of the pressure gradient across the stenosis divided by the equilibrium flow rate.

[0091] In a preferred embodiment, the flow rate may progress in a stepwise manner across the parameter range, e.g., from 0 to 40 ml / min or more in incremental steps of 10 ml / min, although it will be understood that the steps need not be increased at the same rate and may, in fact, be adjusted arbitrarily. As shown above, the linearity of the injected flow-resulting pressure relationship can be used to calculate the equilibrium value using as few as two injection levels.

[0092] Those skilled in the art will recognize that method 1300 may be practiced with or without an occlusion balloon. It should be further appreciated that data obtained via method 1300 may be aggregated or shared across multiple patients or procedures to improve accuracy.

[0093] Referring now to FIG. 12, a block diagram of a system constructed in accordance with the present invention is described. For example, the system 1500 includes components that may be incorporated into the system 100 of FIG. 1 herein. The system 1500 includes a controller having a memory 1504. The controller may be a computer, and the memory may be a disk drive or flash memory. The controller 1502 is in electrical communication with a pump 1506, a steerable guidewire 1508, one or more pressure sensors 1510, and optionally other sensors 1512, such as a temperature sensor. The controller 1502 also communicates with an infusate reservoir 1514 and, if present, an inflation source 1516, which may be used to inflate one or more balloons. The pump 1506, the guidewire 1508, the pressure sensor 1510, the optional other sensors 1512, the infusate reservoir, and the inflation source 1516 are operatively coupled to an infusion catheter that is inserted into the patient.

[0094] The controller 1502 also communicates with a user interface 1520, a communication unit 1522, and a power supply 1524. The controller 1502 includes a processor that is programmed to perform regression analysis on accumulated data to calculate an equilibrium injection rate, as described above. The user interface 1520 may include a keyboard, a mouse device, a display screen, a touch screen, or other user interface devices. The communication unit 1522 may include an alarm, WiFi, Internet, cloud storage, and a telecommunications device. The power supply 1524 may include, or be switchable between, AC or DC power. It should be understood that the methods and / or algorithms of the present invention may be stored as programmed instructions or as a non-transitory computer readable medium accessible to the processor of the controller 1502, thereby enabling the programmed methods of the present invention, as described above, to be implemented within a computer control system.

[0095] It should be understood that the implementations described herein are illustrative and that the scope of the invention is not limited to those specific embodiments, and that many variations, modifications, additions, and improvements are possible. For example, functionality may be separated or combined in different blocks or described in different terminology in various embodiments of the disclosure. These and other variations, modifications, additions, and improvements may fall within the scope of the disclosure as defined in the following claims.

Claims

1. 1. A system for determining one or more vascular physiological parameters for a patient, the system comprising: a catheter having a lumen, the catheter configured to be advanced into an arterial blood vessel of the patient, the arterial blood vessel having antegrade blood flow, the lumen having a distal end; a pressure sensor configured to measure an arterial pressure in the arterial blood vessel; a reference pressure sensor configured to measure a reference arterial pressure at a location proximal to a distal end of the lumen; Controller and Equipped with The controller: delivering a fluid through the lumen into the arterial blood vessel at a first volumetric flow rate; obtaining a measurement of a first arterial pressure in the arterial blood vessel, the first arterial pressure corresponding to the first volumetric flow rate; delivering the fluid through the lumen into the arterial blood vessel at a second volumetric flow rate; obtaining a measurement of a second arterial pressure in the arterial blood vessel, the second arterial pressure corresponding to the second volumetric flow rate; and determining an equilibrium volumetric flow rate of the fluid at which the pressure proximate a distal end of the lumen corresponds to the reference arterial pressure based on the first volumetric flow rate, the first arterial pressure, the second volumetric flow rate, and the second arterial pressure; A system configured to:

2. The system of claim 1, wherein the controller is further configured to determine microvascular resistance based on the reference arterial pressure and the balanced volumetric flow rate.

3. 3. The system of claim 2, wherein the first arterial pressure corresponds to one of a first peak systolic pressure, a first peak diastolic pressure, a first RMS pressure, or a first mean pressure, and the second arterial pressure corresponds to one of a second peak systolic pressure, a second peak diastolic pressure, a second RMS pressure, or a second mean pressure.

4. The system of claim 1 , wherein the fluid contains little or no free oxygen.

5. The system of claim 1 , wherein the equilibrium volumetric flow rate is determined using regression analysis.

6. a stenosis is disposed within the arterial vessel; The controller: delivering the fluid through the lumen into the arterial blood vessel at the balanced volumetric flow rate; obtaining a third arterial pressure measurement proximal to the stenosis; and obtaining a fourth arterial pressure measurement distal to the stenosis; The system of claim 1 , further configured to:

7. The system of claim 6, wherein the controller is further configured to characterize the stenosis based on the third arterial pressure and the fourth arterial pressure.

8. The system of claim 6, wherein the controller is further configured to determine a stenosis resistance based on the third arterial pressure, the fourth arterial pressure, and the balanced volumetric flow rate.

9. The system of claim 6, wherein the controller is further configured to determine a blood flow reserve ratio based on a ratio of the fourth arterial pressure to the third arterial pressure.

10. The system of claim 1 , wherein the fluid is delivered from the catheter through an exit port at a distal end of the catheter and into the arterial blood vessel.

11. The system of claim 1 , wherein fluid is delivered from the catheter into the arterial blood vessel through a plurality of holes disposed at a distal end of the catheter.

12. The system of claim 1 , wherein the catheter is balloonless.

13. The system of claim 1 , wherein the reference arterial pressure is the pressure on a proximal segment of the catheter.

14. The system of claim 1 , wherein the reference arterial pressure is an aortic pressure.

15. 1. An apparatus for assessing a patient suffering from vascular stenosis and / or dysfunction, the apparatus comprising: a catheter having a distal region sized and shaped to be advanced into an arterial blood vessel, said catheter including a lumen for delivering a fluid into said arterial blood vessel; a pressure sensor disposed in the distal region of the catheter for measuring pressure; a reference pressure sensor configured to measure a reference pressure at a location proximal to the distal region; a controller operatively coupled to the reference pressure sensor and the pressure sensor, the controller comprising: delivering the fluid through the lumen into the arterial blood vessel at a first volumetric flow rate; measuring a first arterial pressure in the arterial blood vessel while the fluid is delivered at the first volumetric flow rate; delivering the fluid through the lumen into the arterial blood vessel at a second volumetric flow rate; measuring a second arterial pressure in the arterial blood vessel while the fluid is delivered at the second volumetric flow rate; determining an equilibrium volumetric flow rate at which said pressure corresponds to said reference pressure; a controller configured to An apparatus comprising:

16. The apparatus of claim 15 , wherein the controller is further configured to calculate microvasculature resistance by dividing the baseline pressure by the equilibrium volumetric flow rate.

17. 16. The apparatus of claim 15, wherein the fluid contains little or no available oxygen.

18. The apparatus of claim 15 , wherein the pressure sensor is disposed on the catheter.

19. The apparatus of claim 15 , wherein the pressure sensor is disposed on a guidewire coupled to the catheter.

20. The device of claim 15 , wherein the catheter is balloonless.

21. The apparatus of claim 15 , wherein the controller is further configured to determine the equilibrium volumetric flow rate using regression analysis.

22. The apparatus of claim 15 , wherein the controller is further configured to deliver the fluid at the equilibrium volumetric flow rate.

23. 23. The device of claim 22, wherein the pressure sensor is configured to be advanced from proximal to distal to the stenosis.

24. 23. The apparatus of claim 22, further comprising a second pressure sensor, the pressure sensor and the second pressure sensor configured to be positioned on opposite sides of the stenosis.

25. The device of claim 15 , wherein the catheter is configured to deliver the fluid through an exit port disposed in the distal region.

26. The device of claim 15 , wherein the catheter is configured to deliver the fluid through a plurality of holes disposed in the distal region.

27. The apparatus of claim 15 , wherein the reference pressure sensor is disposed on the catheter at a location proximal to the distal region.

28. The apparatus of claim 15 , wherein the reference pressure sensor is configured to be placed in an aorta of the patient.

29. 23. The apparatus of claim 22, further configured to measure a third arterial pressure and a fourth arterial pressure, the third arterial pressure being measured at a point proximal to a stenosis in the arterial blood vessel and the fourth arterial pressure being measured at a point distal to the stenosis.

30. 30. The apparatus of claim 29, wherein the controller is further configured to characterize the stenosis based on the third arterial pressure and the fourth arterial pressure.

31. 30. The apparatus of claim 29, wherein the controller is further configured to determine a stenosis resistance based on the third arterial pressure, the fourth arterial pressure, and the balanced volumetric flow rate.

32. 30. The apparatus of claim 29, wherein the controller is further configured to determine a fractional flow reserve based on a ratio of the fourth arterial pressure to the third arterial pressure.

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