Systems and methods for determining microvascular resistance reserve - Patents.com

Abstract

The present invention relates to a method for determining microvascular resistance reserve (MRR) in myocardium perfused by normal or stenosed coronary arteries of a human patient, the method comprising measuring blood flow Q through the coronary arteries while the patient is in a resting state. rest (1) measuring blood pressure P at a location proximal to the coronary artery or proximal to any stenosis, if present, during the patient's resting state or maximum hyperemia; a and measuring (2) the blood flow Q through the coronary artery during maximum hyperemia in the patient. max and (3) measuring the blood pressure P at a location distal to the coronary artery or distal to any stenosis, if present. d (4) measuring the microvascular resistance reserve MRR; and (5) determining the microvascular resistance reserve MRR. [Equation 1] and a step of calculating the image quality as JPEG2023531566000030.jpg10159.

Description

[Technical Field]

[0001] The present invention relates generally to the assessment of coronary circulation in the heart of a human patient, and more particularly to methods and systems for determining the microvascular resistance reserve and microvascular resistance of the coronary microcirculation in the heart. [Background technology]

[0002] The coronary circulation, i.e., the blood supply of the heart, consists of the so-called epicardial coronary arteries, which have diameters in the interval of about 0.5 to 5 millimeters and can be seen on a coronary angiogram, and the so-called coronary microcirculation or microvasculature, which consists of arterioles and capillaries, which have diameters less than 0.5 millimeters and cannot be seen on a coronary angiogram.

[0003] Diseases of the epicardial coronary arteries, such as stenosis or occlusion, which can cause angina or heart attack, can be successfully diagnosed and treated by multiple techniques. However, for all patients diagnosed with coronary artery disease, 25–50% suffer from symptoms caused not only by epicardial stenosis but also by microvascular disease. Unfortunately, reliable systems and techniques for assessing such complex diseases are not yet available. Instead, current methods are crude, inaccurate, operator-dependent, not quantitative, or do not distinguish between the epicardial arterial and microvascular contributions to disease. Without the possibility to distinguish between epicardial and microvascular contributions to disease, optimal diagnosis and treatment of patients with heart disease would clearly be hindered.

[0004] A paper by Xaplanteris et al. (Circ Cardiovasc Interv. 2018;11:e 006194. DOI:10.1161 / CIRCINTERVENTIONS.117.006194) shows how absolute microvascular resistance during maximal hyperemia can be derived from measurements of blood pressure and maximal blood flow. Knowledge of absolute microvascular resistance would solve some of the problems mentioned above, but so far, absolute microvascular resistance can only be assessed during maximal vasodilation of the microvasculature. Its use is further limited by the lack of a uniform normal value due to large variations depending on the amount of myocardial tissue perfused and large variations within normal, i.e., healthy, individuals.

[0005] It is therefore an object of the present invention to provide improved methods and systems for the assessment of microvascular coronary artery disease that will facilitate and improve the diagnosis and treatment of the microvascular coronary artery disease in question.It is another object of the present invention to provide improved methods and systems for assessing microvascular coronary artery disease in which epicardial coronary artery disease is also present. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Xaplanteris et al.,Circ Cardiovasc Interv.2018;11:e 006194.DOI:10.1161 / CIRCINTERVENTIONS.117.006194 Summary of the Invention

[0007] The above object is achieved by the present invention according to the independent claims. Preferred embodiments are set out in the dependent claims.

[0008] The method and system according to the present invention involves the calculation of microvascular resistance under resting conditions, which is not confounded by the presence of epicardial disease, and provides a new index called microvascular resistance reserve (MRR), which provides a clear measure of microvascular function or the severity of microvascular disease that is not confounded by the presence of epicardial disease. To obtain the MRR, measurements are taken under both resting and hyperemic conditions.

[0009] The terms "proximal" and "distal" are used herein, as well as similar or related terms such as "proximally," "distally," "proximal location," "proximal pressure," "distal location," and "distal pressure." These definitions are well known and generally accepted in the field of cardiology and in the cardiovascular science literature. In the case of coronary artery stenosis, whether focal or diffuse, and whether revealed or detected, for example, by coronary angiography or FFR measurement, the term "proximal" refers to the location proximal to the stenosis, and the term "distal" refers to the location distal to the stenosis. In the case of normal or near-normal coronary arteries, the term "proximal" refers to the initial portion of the artery, i.e., the location near the ostium, and the term "distal" refers to the location distal to the coronary artery. While FIG. 1 shows a schematic representation of a stenotic artery for purposes of illustrating the present invention, in the case of a normal coronary artery without stenosis, the description and scope of the present invention remain valid with the "proximal" and "distal" pressures defined above. Thus, whenever the phrase "at a location proximal to any stenosis" is used, it should be read as "proximal to the coronary artery" in the absence of an epicardial stenosis, i.e., in the case of a normal coronary artery. Whenever the phrase "at a location distal to any stenosis" is used, it should be read as "distal to the coronary artery" in the absence of an epicardial stenosis, i.e., in the case of a normal coronary artery, and "any" may be "a" or "the" or similar determination.

[0010] The pressure measured at a location proximal to the coronary artery or proximal to any stenosis, if present, is P a It is shown by P aWhen measured under resting conditions, P a,rest When measured under hyperemic conditions, it is called P a,hyper It is called.

[0011] The pressure measured at a location distal to the coronary artery or distal to any stenosis, if present, is P d It is shown by P d When measured under resting conditions, P d,rest When measured under hyperemic conditions, it is called P d,hyper It is called.

[0012] Microvascular resistance reserve (MRR) is defined as:

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[0013] All six aspects of the invention described below utilize resting microvascular resistance R that is not confounded by epicardial disease. micro,rest Based on the common inventive concept of micro,rest may also be referred to as true microvascular resistance at rest, since, if present, it is independent of epicardial disease.

[0014] In a first aspect, the present invention relates to a method for determining microvascular resistance reserve MRR in myocardium perfused by normal or stenotic coronary arteries of a human patient, the method comprising, while the patient is in a resting state: Blood flow through the coronary arteries Q rest measuring, during the patient's resting state or maximum hyperemia, Blood pressure P in the coronary artery proximal to any stenosis, if present a and during maximum hyperemia in the patient, Blood flow through the coronary arteries Q max measuring Blood pressure P distal to the coronary artery or distal to any stenosis, if present d,hyper measuring further comprising Microvascular resistance reserve (MRR) is a measure of microvascular resistance reserve.

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[0015] In one embodiment of the present invention, blood pressure (P) measured proximal to the coronary artery or proximal to any stenosis, if present, is measured. a ) includes measuring aortic blood pressure.

[0016] In a second aspect, the present invention relates to a system for determining microvascular resistance reserve MRR in myocardium perfused by normal or stenotic coronary arteries of a human patient, the system comprising: a processing unit; Blood flow through the coronary arteries while the patient is at rest, Q rest a first flow measurement system configured to measure While the patient is at rest or during maximal hyperemia, measure the blood pressure P in the coronary arteries proximal to any stenosis, if present. a a first pressure measurement device configured to measure Blood flow Q through the coronary arteries during the patient's maximum hyperemia max a second flow measurement system configured to measure During the patient's maximum hyperemia, measure the blood pressure P distal to the coronary artery or distal to any stenosis, if present. d,hyper a second pressure measurement device configured to measure Equipped with The processing unit receives the blood flow measurements Q from the first and second flow measurement systems. rest , Q max and obtain blood pressure measurements P from the first and second pressure measurement devices. a , P d The processing unit is configured to acquire the microvascular resistance reserve by

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[0017] As noted above, the first and second aspects of the present invention involve measuring blood pressure P at a location proximal to the coronary artery or proximal to any stenosis, if present, while the patient is either at rest or at maximum hyperemia. a The calculation of MRR involves measuring P a The value of P a,rest , i.e., P measured during resting state a In other words, when determining the MRR, the P measured during maximal hyperemia is a Measurements of P can only be used when techniques are used to induce a hyperemic state in the patient, so that aortic pressure is generally independent of the patient's state (rest / hyperemic). a Two different embodiments for measuring (resting or hyperemic) are described below.

[0018] In an embodiment of the first or second aspect of the invention, blood pressure at a location proximal to the coronary artery or proximal to any stenosis, if present, is measured while the patient is at rest to determine P a,rest In such embodiments, the microvascular resistance reserve is obtained by:

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[0019] P a,rest can be determined by any known invasive or non-invasive technique. a,rest A common invasive technique for measuring aortic blood pressure is by coronary (guide) catheterization. The simplest non-invasive technique involves measuring aortic blood pressure using a sphygmomanometer ("cuff measurement").

[0020] In an alternative embodiment of the first or second aspect of the invention, blood flow is measured using a technique such that aortic pressure is generally independent of the patient's state (rest / hyperemia), and blood pressure at a location proximal to the coronary arteries or proximal to any stenosis, if present, is instead measured during the patient's maximal hypertension to determine P a,hyper In such embodiments, the microvascular resistance reserve can be calculated as:

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[0021] In one embodiment, the microvascular resistance R micro,rest is R micro,rest =P a,rest / Q rest It is calculated as:

[0022] In an embodiment of the first or second aspect of the invention, Q rest , Q max blood flow measurements to obtain P d,hyper The pressure measurements to obtain P are taken at different times. For example, blood flow can be obtained during the first test, and P d,hyper can be obtained during a separate second examination, such as by invasive cardiac catheterization or non-invasive FFR determination (by CT) performed at a different time. d,hyper / P a,hyper The knowledge that is constant and independent of the instant at which it is measured is essential for the (separately evaluated) P d,hyperThis allows the combination of blood flow measurements (whether invasively by pressure wire or non-invasively by CT) with the respective blood flow measurements taken at different moments, which provides MMR. a can be measured during the same test as blood flow measurement with a sphygmomanometer ("cuff measurement").

[0023] The microvascular resistance reserve (MRR) defined above has the unique property of being specific to microvascular disease, independent of the presence or absence of epicardial disease.

[0024] In one embodiment of the present invention, the first flow measurement system and the second flow measurement system are the same flow measurement system.

[0025] In one embodiment, the system further comprises a display unit configured to receive the calculated microvascular resistance reserve value from the processing unit and to display said calculated value.

[0026] In one embodiment of the system, the first pressure measuring device is a pressure catheter or a guiding catheter. In another embodiment, the first pressure measuring device and / or the second pressure measuring device is a sensor-tipped guidewire.

[0027] Further, according to the present invention, the first flow measurement system and / or the second flow measurement system and / or the flow measurement device may be a system configured to measure blood flow (or a flow surrogate) by any invasive or non-invasive flow measurement technique. Invasive techniques may utilize, for example, continuous or bolus thermodilution, timed venous collection, electromagnetic flow measurement, conductance measurement, Doppler ultrasound or calibrated Doppler probe, thermal convection, thermal conduction, or epicardial ultrasound velocimetry. Non-invasive techniques for measuring blood flow (or a flow surrogate) may include (but are not limited to) computed tomography, magnetic resonance imaging, positron emission tomography, or echocardiography.

[0028] In one embodiment of the method according to the first aspect of the invention, Q rest , Pa , Q max , and P d,hyper The step of measuring is omitted and replaced by the following steps: While the patient is at rest, the blood flow through the coronary arteries, Q rest determining a While the patient is at rest, measure the blood pressure P in the coronary arteries proximal to any stenosis, if present. a,rest determining a Blood flow Q through the coronary arteries during the patient's maximum hyperemia max determining a During the patient's maximal hyperemia, measure the blood pressure P distal to the coronary artery or distal to any stenosis, if present. d,hyper determining MRR is

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[0029] In one embodiment of the system according to the second aspect of the invention, the first and second flow measurement systems and the first and second pressure measurement devices are not part of the system, and the system instead comprises an interface which may be integrally formed with a processing unit. rest , P a,rest , Q max , and P d,hyper and measuring the microvascular resistance reserve in response to at least one signal received via the interface including data indicative of

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[0030] The present invention also relates to a data processing device, a computer program product and a computer readable storage medium useful for carrying out the methods of the present invention to display the measured and calculated values ​​and, optionally, to guide a physician during the measurement and calculation of microvascular resistance reserve.

[0031] According to a third aspect of the present invention, there is provided a method for determining microvascular resistance reserve (MRR) in myocardium perfused by normal or stenotic coronary arteries of a human patient, the method comprising: determining a value of coronary flow reserve (CFR) of the patient's coronary arteries; determining a value of fractional flow reserve (FFR) of the patient's coronary arteries; and measuring a blood pressure value P during the patient's resting state. a,rest at a location proximal to the coronary artery or proximal to any stenosis, if present, and the patient's blood pressure during maximal hyperemia, P a,hyper at a location proximal to the coronary artery or proximal to any stenosis, if present, and the MRR is

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[0032] CFR, FFR, P a,rest and P a,hyper The step of determining the CFR, FFR, P does not necessarily involve making measurements; a,rest and / or P a,hyper It will be appreciated that the method of determining the temperature may simply involve obtaining one or more previously calculated or measured values ​​of:

[0033] In an embodiment, the step of determining the value of CFR comprises measuring the blood flow Q through the coronary arteries while the patient is in a resting state. rest and measuring the blood flow Q through the coronary artery during maximal hyperemia in the patient. max and measuring the CFR, where CFR=Q max / Q rest The step of determining the value of CFR is to calculate the blood flow Q max and Q rest The step of determining the value of CFR may include making at least one measurement using a non-invasive technique, such as computed tomography, magnetic resonance imaging, positron emission tomography, or echocardiography, to estimate the blood flow Q. Alternatively, the step of determining the value of CFR may involve measuring the blood flow Q by an invasive method, such as serial thermodilution. max and Q rest is.

[0034] In an embodiment, the patient's resting blood pressure value P is measured proximal to the coronary artery or proximal to any stenosis, if present. a,rest The step of determining the CFR may include measuring blood pressure substantially simultaneously with the step of determining the value of CFR. a,rest can be measured during the same test as the non-invasive flow measurement performed to determine CFR by sphygmomanometer ("cuff measurement").

[0035] In an embodiment, the step of determining the value of FFR comprises measuring the blood pressure P at a location proximal to the coronary artery or proximal to any stenosis, if present, during maximal hyperemia in the patient. a,hyper and blood pressure P distal to the coronary artery or distal to any stenosis, if present. d,hyper The FFR is calculated by measuring FFR=P d,hyper / P a,hyper The step of determining the value of FFR may include making at least one measurement using an invasive technique such as a pressure or guiding catheter or sensor-tipped guidewire, i.e., P a,hyper and P d,hyper Alternatively, the step of determining the value of FFR may include making at least one measurement using a non-invasive technique, such as computed tomography.

[0036] In an embodiment, the measurements taken to obtain the CFR value and the FFR value are taken at different times. For example, the CFR can be obtained during a first test, and the FFR can be obtained during a separate second test, such as an invasive cardiac catheterization performed at a different time or by non-invasive FFR determination (e.g., by CT). In such cases, the knowledge that the FFR is constant and does not depend on the moment at which it is measured allows for the combination of the (separately assessed) FFR (whether invasively by pressure wire or non-invasively by CT) with the respective flow measurements measured non-invasively at different moments, which provides MMR.

[0037] According to a fourth aspect of the present invention, a method for measuring resting state, R, in myocardium perfused by normal or stenotic coronary arteries of a human patient is provided. micro,rest A method for determining microvascular resistance during a patient's resting state is provided. The method comprises measuring blood flow Q through a coronary artery. rest and blood pressure P in the coronary artery proximal to any stenosis, if present. a,rest and measuring the microvascular resistance at rest, R micro,rest =P a,rest / Q rest It is calculated as: Q rest Measurement of P may be performed using non-invasive techniques such as computed tomography. a,rest Measurement of may be performed using non-invasive techniques such as a sphygmomanometer.

[0038] According to a fifth aspect of the present invention, there is provided a system for determining microvascular resistance reserve (MRR) in myocardium perfused by normal or stenotic coronary arteries of a human patient. The system comprises a processing unit and an interface, which may be integrally formed with the processing unit. The processing unit is configured to determine the coronary flow reserve (CFR) and fractional flow reserve (FFR) of the patient's coronary arteries, and to measure the patient's resting blood pressure (P) proximal to the coronary arteries or proximal to any stenosis, if present. a,rest , and the patient's maximal hyperemic blood pressure P at a location proximal to the coronary artery or proximal to any stenosis, if present. a,hyper and measuring the microvascular resistance reserve in response to at least one signal received via the interface, the signal further including data indicative of

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[0039] In other words, the processing unit determines: i) the coronary flow reserve (CFR) of the patient's coronary arteries; ii) the fractional flow reserve (FFR) of the patient's coronary arteries; iii) the patient's resting blood pressure P proximal to the coronary arteries or proximal to any stenosis, if present. a,rest, and iv) the patient's blood pressure during peak hyperemia, P, at a location proximal to the coronary artery or proximal to any stenosis, if present. a,hyper It is understood that these values ​​do not necessarily have to be measured by a measurement device that is part of the system, but on the contrary may be measured by one or more measurement devices directly or indirectly connected to the interface. Alternatively, the values ​​may be stored in a storage device connected to the interface. a,rest and / or P a,hyper may be a pre-calculated or measured value of

[0040] In an embodiment of the fifth aspect of the present invention, the system measures blood flow Q through the coronary arteries while the patient is in a resting state. rest Measure the blood flow Q through the coronary arteries during the patient's maximum hyperemia max The flow measurement device is connected directly or indirectly to an interface, and at least one signal received by the processing unit via the interface containing data indicative of the CFR is calculated as a Q from the flow measurement device. rest and Q max The processing unit includes the value of CFR=Q max / Q rest The flow measurement apparatus may comprise first and second flow measurement systems in the same way as described above with reference to the second aspect of the invention.

[0041] In an embodiment of the fifth aspect of the invention, the system measures blood pressure P proximal to the coronary artery or proximal to any stenosis, if present, during maximal hyperemia in the patient. a,hyper Measure the blood pressure P at a location distal to the coronary artery or any stenosis, if present, during the patient's maximal hyperemia. d,hyper The pressure measurement device is directly or indirectly connected to an interface, and at least one signal received by the processing unit via the interface containing data indicative of the FFR is indicative of the P from the flow measurement device. a,hyper and Pd,hyper The processing unit includes the value of FFR=P d,hyper / P a,hyper The pressure measurement device may comprise first and second pressure measurement devices, or embodiments thereof, in the same way as described above with reference to the second aspect of the invention.

[0042] According to a sixth aspect of the present invention, there is provided a method for measuring resting microvascular resistance R in myocardium perfused by normal or stenosed coronary arteries of a human patient. micro,rest A system is provided for determining blood flow Q through a coronary artery during a patient's resting state. The system comprises a processing unit and an interface, the processing unit being configured to determine blood flow Q through a coronary artery during a patient's resting state. rest and blood pressure P at a location proximal to the coronary artery or any stenosis if present while the patient is at rest. a,rest and measuring the resting state microvascular resistance R in response to at least one signal received via the interface including data indicative of micro,rest =P a,rest / Q rest The method is configured to determine the following:

[0043] In other words, the processing unit calculates i) the patient's resting blood pressure P at a location in the coronary artery proximal to or proximal to any stenosis, if present; a,rest , and ii) the blood flow through the coronary arteries while the patient is at rest, Q rest It will be appreciated that these values ​​do not necessarily have to be measured by a measurement device that is part of the system, but on the contrary may be measured by one or more measurement devices directly or indirectly connected to the interface. Alternatively, the values ​​may be stored in a storage device connected to the interface, such as a previously measured value P a,rest , and Q rest may be.

[0044] In an embodiment of the sixth aspect of the present invention, the system measures blood flow Q through the coronary arteries while the patient is in a resting state. restThe flow measurement device is connected directly or indirectly to the interface, and the at least one signal is a signal corresponding to Q rest The flow measurement device may comprise a first or second flow measurement system in the same way as described above with reference to the second aspect of the invention. Furthermore, the system may measure, while the patient is at rest, the blood pressure P at a location proximal to the coronary artery or proximal to any stenosis, if present. a,rest The pressure measuring device may be connected directly or indirectly to the interface, and at least one signal may be a signal representing P from the flow measuring device. a,rest The pressure measurement device may comprise a first or second pressure measurement device in the same way as described above with reference to the second aspect of the invention. In a particularly advantageous embodiment of the sixth aspect of the invention, the system comprises a Q rest and computed tomography, PET, or MRI systems to estimate P a,rest and a blood pressure monitor for measuring blood pressure.

[0045] The features of the above-described embodiments may be combined in any practically feasible manner to form embodiments having combinations of these features. Furthermore, all features and advantages of the embodiments described above with reference to the first, second, third, fourth, fifth and sixth aspects of the invention may be applied to corresponding embodiments of any of the other aspects of the invention.

[0046] The above and other aspects of the present invention will be explained in more detail using the accompanying drawings. [Brief explanation of the drawings]

[0047] [Figure 1] FIG. 1 is a schematic diagram of the coronary circulation. [Figure 2] 1 shows a flow chart of an embodiment of a method according to a first aspect of the present invention; [Figure 3] 4 shows a flow chart of an embodiment of the method according to the third aspect of the present invention. [Figure 4] 4 shows a flow chart of an embodiment of the method according to the third aspect of the present invention. [Figure 5] FIG. 2 shows a schematic diagram of a system according to a second aspect of the present invention. [Figure 6] FIG. 10 shows a schematic diagram of a system according to a fifth aspect of the present invention. [Figure 7] FIG. 10 shows a schematic diagram of a system according to a sixth embodiment of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0048] In Figure 1, letter A indicates the aorta, letter B indicates the epicardial artery, and letter C indicates the microcirculation. a is the pressure proximal to the stenosis, and P d is the pressure distal to the stenosis, and R epi is the resistance of the stenotic area. In a normal, non-stenotic blood vessel, R epi =0, P a =P d Then, while the patient is at rest, the microvascular resistance can be written as:

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[0049] In the presence of epicardial disease, R epi >0, and epicardial disease may be focal, but may also be diffuse. Microvascular resistance in this case can be written as follows while the patient is at rest:

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[0050] Resting blood flow (Q rest ) to keep it constant, R epi The existence of R micro,rest,N induces an equivalent compensatory decrease in R micro,rest,sten <R micro,rest,N (autoregulatory response of coronary circulation). Therefore, R micro,rest,sten can also be written as

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[0051] Pressure P, which is the pressure measured proximal to the stenosis a,rest can be measured preferably as aortic pressure, can be measured at the entrance of the coronary arteries, and then can be measured using a so-called guide catheter or pressure catheter, and Q rest is the measured resting blood flow, which can be measured using thermodilution techniques. Alternatively, blood flow can be measured or estimated using any other suitable invasive or non-invasive technique, as described below. Note further that equation (1) for calculating resting microvascular resistance is universally valid and does not depend on the presence or absence of epicardial disease.

[0052] The above formula was derived for the resting state. During the patient's hyperemic state, i.e., when microvascular resistance is minimal and blood flow is maximal, we calculated the normal non-stenotic vascular P a,hyper =P d,hyper and

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[0053] In the presence of epicardial disease, which can be focal or diffuse, additional resistance R epi is present, and during hyperemia, microvascular resistance is minimal and blood flow is maximal.

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[0054] Microvascular resistance reserve (MRR) is a novel quantity in the field of coronary artery medicine; despite its obvious utility, it has never before been measured and calculated in absolute terms. Microvascular resistance reserve (MRR) is defined as:

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[0055] It should be noted that the MRR defined above is a universally valid value of microvascular resistance reserve (MRR) and is independent of the presence or absence of epicardial disease. This latter property is a unique feature of this novel index.

[0056] Figure 2 shows a flow chart of one embodiment of the method according to the first aspect of the invention. The method comprises measuring blood flow Q through a coronary artery. rest 1. measuring blood pressure P in a coronary artery proximal to the coronary artery or proximal to any stenosis, if present, during the patient's resting state or maximum hyperemia; a The method further comprises step 2 measuring the blood flow Q through the coronary arteries during maximal hyperemia in the patient. max The method further includes step 3 of measuring a blood pressure P at a location distal to the coronary artery or distal to any stenosis, if present. d,hyper and step 4. measuring the microvascular resistance reserve.

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[0057] The pressure measurements required by this method are all well known to those skilled in the art and are performed, in particular, during measurements of fractional flow reserve (FFR), which is a standard technique in medical examinations of coronary arteries. During FFR measurements, the presence and location (if any) of a stenosis are determined. Typically, measurements distal to the stenosis (or distal to the coronary artery if no stenosis is present) are performed using a sensor-tipped guidewire. Such sensors are readily available, such as the PressureWire™ X Guidewire sold by Abbott. Proximal pressure can be measured using so-called pressure catheters or guiding catheters. However, it is also possible to measure proximal pressure using a sensor-tipped guidewire. It should be noted here that experience has shown that when blood flow is measured by thermodilution flowmetry both at rest and during hyperemia, and saline is continuously infused at different infusion rates, aortic pressure is generally independent of the patient's condition (i.e., whether the patient is in a hyperemic or resting state). Therefore, according to the present invention, proximal pressure can be measured during the patient's resting state or during hyperemic state. Therefore, the equation (3) derived above can be generalized as follows:

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[0058] P a If P varies between resting and hyperemic states (as may be the case with other means of inducing hyperemia, such as, but not limited to, adenosine injection or infusion), the pressure measured proximal to the stenosis should be compared to the resting P a (P a,rest (also called) and P d P during hyperemia d Let (P d,hyper (also referred to as ) is important. See equation (3). Those skilled in the art are further very familiar with methods for inducing a hyperemic state in a patient.

[0059] Flow measurements and corresponding flow measurement systems for performing such flow measurements can be performed, for example, using systems for measuring blood flow according to the continuous thermodilution technique, a technique well known to those skilled in the art and described, for example, in U.S. Patent No. 7,775,988 to Pijls. Catheters for such flow measurements are also readily available, such as the RayFlow™ multipurpose infusion catheter sold by HexaCath.

[0060] However, those skilled in the art are aware of many other techniques for measuring blood flow, both invasive and non-invasive. Such invasive techniques include bolus thermodilution, timed venous collection, electromagnetic flow measurement, conductance measurement, Doppler ultrasound or calibrated Doppler probes, thermal convection, thermal conduction, and epicardial ultrasonic flow velocity measurement. Most of these techniques are described, for example, in "Maximal Myocardial Perfusion as a Measure of the Functional Significance of Coronary Artery Disease," NHJ Pijls (1991), Cip-Gegevens Koninklijke Bibliotheek, den Haag, (ISBN 90-9003818-3). Examples of non-invasive flow measurement are techniques using computed tomography, magnetic resonance imaging, positron emission tomography, or echocardiography.

[0061] Typically, the system for measuring blood flow during a patient's resting state is the same as the system for measuring blood flow during a patient's hyperemic state. However, within the scope of the present invention, a first blood flow measurement system used for measuring blood flow during the resting state is different from a second blood flow measurement system used for measuring blood flow during the hyperemic state.

[0062] Q max and Q rest and P a and P d It is also within the scope of the present invention that the values ​​of the saturation and saturation can be measured at different times.

[0063] 3 shows a flow chart of one embodiment of a method according to the third aspect of the invention, which is an alternative method for determining MRR, but which, at least in theory, results in the same MRR value as the method according to the first aspect of the invention. This can be seen by rearranging equation (3) as follows: P a,rest / P d,hyper =(P a,rest / P a,hyper ).(P a,hyper / P d,hyper ) MRR=Q max / Q rest x(P a,rest / P a,hyper ).(P a,hyper / P d,hyper ) is obtained.

[0064] From this equation, MRR is the driving pressure P between the resting and hyperemic measurements. a (P a,rest / P a,hyper ) to compensate for the presence of any kind of epicardial disease. a,hyper / P d,hyper = 1 / FFR). This can be rewritten as follows: MRR=(CFR / FFR).(P a,rest / P a,hyper ) (4) Or P a If MRR remains constant between resting and hyperemia, then simply MRR = (CFR / FFR). Equation (4) gives the interrelationship between MRR, CFR, and FFR and is universally valid in coronary physiology. Furthermore, Equation (4) is independent of the technique used to obtain CFR and FFR.

[0065] The method of FIG. 3 includes steps 11 to determine a coronary flow reserve (CFR) value for the patient's coronary artery, 12 to determine a fractional flow reserve (FFR) value for the patient's coronary artery, and 13 to determine a resting blood pressure value P for the patient proximal to the coronary artery or proximal to any stenosis, if present. a,restand step 13 determining the patient's maximum hyperemic blood pressure value P at a location proximal to the coronary artery or proximal to any stenosis, if present. a,hyper The microvascular resistance reserve MRR is determined by an additional step 15 of calculating the microvascular resistance reserve according to equation (4).

[0066] Figure 4 shows a flow chart of one embodiment of the method according to the third aspect of the present invention. The method involves determining microvascular resistance as defined by equation (2). The method involves measuring blood flow Q through the coronary arteries while the patient is in a resting state. rest and step 21 measuring the blood pressure P at a location proximal to the coronary artery or proximal to any stenosis, if present. a,rest and measuring (22) the microvascular resistance at rest, R micro,rest =P a,rest / Q rest It is calculated as (23).

[0067] Figure 5 shows a schematic diagram of a system according to a second aspect of the invention. The system comprises a processing unit 31 and a measurement system 32 / 33 / 34 / 35 using the continuous thermodilution principle. The measurement system comprises a control unit 30a, a guide catheter 30b, an infusion catheter 30c and a sensor 30d arranged on the sensor guidewire. As mentioned above, such systems are known in the art and will not be described in further detail here. The sensor 30d is configured to measure temperature and pressure. In the position shown, the measurement system is connected to a Q rest , Q max , P d,hyper By relocating the sensor to a proximal position, Pa can also be measured. The measurement system thus constitutes a first and a second flow measurement system and a first and a second pressure measurement device in the sense of the second aspect of the invention. However, in other embodiments, P amay be measured by a separate measuring device (such as a guide catheter) or different types of measuring systems may be used together. The control unit 30a is electrically connected to a processing unit 31 via its interface 31′, which receives the blood flow measurements Q from the measuring system. rest , Q max and blood pressure measurement P a , P d The processing unit 31 can obtain

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[0068] 6 shows a schematic diagram of a system according to a fifth aspect of the present invention. The system comprises a processing unit 41 and an interface 42. The processing unit is configured to receive a blood pressure, P, during the patient's resting state, indicative of the patient's coronary arteries, the coronary flow reserve CFR, and the coronary flow reserve fraction FFR of the patient's coronary arteries, proximal to the coronary arteries or proximal to any stenosis, if present. a,rest , and the patient's maximal hyperemic blood pressure, P, at a location proximal to the coronary artery or proximal to any stenosis, if present. a,hyper and measuring the microvascular resistance reserve in response to at least one signal received via the interface including data further indicative of

number

[0069] Figure 7 shows a schematic diagram of a system according to a sixth aspect of the invention. The system comprises a processing unit 51 and an interface 52 connected thereto, said processing unit being adapted to measure blood flow Q through the coronary arteries during a patient's resting state. rest and blood pressure P proximal to the coronary artery or any stenosis if present while the patient is at rest. a,rest and measuring the resting state microvascular resistance R in response to at least one signal received via the interface including data indicative of micro,rest =P a,rest / Q rest A CT system 57 and a pressure measurement device 58 (sphygmomanometer) are connected to the interface to determine Q rest and P a,rest In this embodiment, no display is provided. Instead, an optional wireless communication module is shown connected to the processing unit for communicating the calculated microvascular resistance. R micro,rest In other embodiments, the processing unit configured to calculate σ may be part of a CT system. In other embodiments, system 57 may be a PET or MRI system.

[0070] As mentioned above, the system according to the invention comprises a processing unit which can acquire signals or other quantities, for example from the first and second flow measurement systems and the first and second pressure measurement devices, respectively, and converts these signals or other quantities into values ​​or numbers which can be at least temporarily stored and used to calculate the resting and minimum microvascular resistance and the microvascular resistance reserve (MRR) according to the invention. According to an embodiment, the system comprises a display unit which can display the measured and / or calculated values, preferably in real time.

[0071] As mentioned above, the embodiments of the present invention described above include processing units in which processing is performed by at least one processor. The present invention also extends to computer programs, particularly computer programs on or in a carrier, adapted to carry out the present invention. The program may be in the form of object code, such as source code, object code, code intermediate source, and partially compiled form, or may include software or firmware, or any other form suitable for use in carrying out the process according to the present invention. The program may be part of an operating system or a separate application. The carrier may be any entity or device capable of carrying a program. For example, the carrier may include a storage medium such as a flash memory, a ROM (Read Only Memory), e.g., a DVD (Digital Video / Versatile Disk), a CD (Compact Disc), or a semiconductor ROM, an EPROM (Erasable Programmable Read-Only Memory), or an EEPROM (Electrically Erasable Programmable Read-Only Memory), or a magnetic recording medium, e.g., a floppy disk or hard disk. Furthermore, the carrier may be a transmissible carrier, such as an electrical or optical signal, which may be conveyed via an electrical or optical cable, by radio or other means. When the program is embodied in a signal which may be conveyed directly by a cable or other device or means, the carrier may be constituted by such cable or device or means, or the carrier may be an integrated circuit in which the program is embedded, the integrated circuit being adapted for performing, or for use in the performance of, the relevant processes.In one or more embodiments, a computer program loadable into memory communicatively connected or coupled to at least one data processor, e.g., processing unit, may be provided, the computer program comprising software or hardware for performing a method according to any of the embodiments herein when the program is run on the at least one data processor. In one or more further embodiments, a processor-readable medium having recorded thereon a program that, when loaded into the at least one data processor, causes the at least one data processor, e.g., processing unit, to perform a method according to any of the embodiments herein.

[0072] Although the present invention has been described with reference to particular embodiments, which are also illustrated in the accompanying drawings, it will be apparent to those skilled in the art that many variations and modifications can be made within the scope of the invention as described herein and defined by reference to the claims.

Claims

1. A method for determining microvascular resistance reserve (MRR) in myocardium perfused by normal or stenosed coronary arteries of a human patient, said method comprising measuring blood flow (Q) through said coronary arteries during a resting state of said patient. ｒｅｓｔ (1) measuring the patient's blood pressure during rest or maximum hyperemia; Blood pressure P at a location proximal to the coronary artery or proximal to any stenosis, if present ａ During maximum hyperemia in the patient, The blood flow Q through the coronary artery ｍａｘ (3) measuring the A blood pressure P at a location distal to the coronary artery or distal to any stenosis, if present. ｄ，，ｈｙｐｅｒ (4) measuring Further comprising: The microvascular resistance reserve is [0010] and by the further step (5) of calculating method.

2. The blood pressure P is measured proximal to the coronary artery or proximal to any stenosis, if present. ａ 2. The method of claim 1, wherein the step of measuring comprises the step of measuring aortic blood pressure (2).

3. 3. The method of claim 1 or 2, wherein the step (2) of measuring the blood pressure proximal to the coronary artery or proximal to any stenosis, if present, is performed while the patient is at rest.

4. The patient's resting microvascular resistance R ｍｉｃｒｏ，ｒｅｓｔ R ｍｉｃｒｏ，ｒｅｓｔ =P ａ，ｒｅｓｔ / Q ｒｅｓｔ The method of claim 3 further comprising the step of calculating:

5. 1. A method for determining microvascular resistance reserve (MRR) in myocardium perfused by normal or stenosed coronary arteries of a human patient, comprising: determining (11) a value of coronary flow reserve (CFR) of said coronary artery of said patient; determining (12) a value of fractional flow reserve (FFR) of said coronary artery of said patient; a blood pressure value P of the patient in a resting state at a location proximal to the coronary artery or proximal to any stenosis, if present; ａ，ｒｅｓｔ (13) determining the patient's blood pressure value P during maximum hyperemia at a location proximal to the coronary artery or proximal to any stenosis, if present; ａ，ｈｙｐｅｒ and determining (14) Including, The microvascular resistance reserve (MRR) is [0025] and the method further comprising the step of calculating (15)

6. said step (11) of determining a value of CFR The blood flow Q through the coronary artery while the patient is at rest. ｒｅｓｔ and measuring The blood flow Q through the coronary artery during maximal hyperemia in the patient. ｍａｘ and measuring Including, In the formula, CFR is CFR=Q ｍａｘ / Q ｒｅｓｔ is determined by calculating The method according to claim 5.

7. 7. The method according to claim 5 or 6, wherein the step (11) of determining the value of CFR comprises making at least one measurement using a non-invasive technique such as computed tomography, magnetic resonance imaging, positron emission tomography or echocardiography.

8. a resting blood pressure value P of the patient proximal to the coronary artery or proximal to any stenosis, if present; ａ，ｒｅｓｔ 8. The method of claim 6 or 7, wherein the step of determining (13) comprises measuring blood pressure substantially simultaneously with the step of obtaining a value of CFR.

9. The step of determining an FFR value (12) comprises, during maximal hyperemia of the patient: The blood pressure P is measured proximal to the coronary artery or proximal to any stenosis, if present. ａ，ｈｙｐｅｒ and measuring A blood pressure P at a location distal to the coronary artery or distal to a stenosis, if present. ｄ，ｈｙｐｅｒ and measuring Including, FFR is FFR=P ｄ，ｈｙｐｅｒ / P ａ，ｈｙｐｅｒ It is calculated as 9. The method according to any one of claims 5 to 8.

10. 10. The method according to any one of claims 5 to 9, wherein the step (12) of determining the FFR value comprises taking at least one measurement using an invasive technique such as a pressure or guiding catheter or a sensor-tipped guidewire.

11. 10. The method according to any one of claims 5 to 9, wherein the step (12) of determining the FFR value comprises making at least one measurement using a non-invasive technique such as computed tomography.

12. 12. The method according to any one of claims 5 to 11, wherein the measurements taken to determine the value of CFR and to determine the value of FFR are taken at different times.

13. A step of determining a value of CFR (11), a step of determining a value of FFR (12), P ａ，ｒｅｓｔ determining (13) the value of P ａ，ｈｙｐｅｒ 12. The method according to claim 5, wherein at least one of the steps (14) of determining the value of comprises obtaining a pre-calculated or measured value.

14. Microvascular resistance R at rest in myocardium perfused by normal or stenosed coronary arteries in human patients ｍｉｃｒｏ，ｒｅｓｔ 11. A method for determining a patient's ability to perform a pulmonary function test, the method comprising, during a resting state of the patient: The blood flow Q through the coronary artery ｒｅｓｔ (21) measuring a blood pressure P proximal to said coronary artery or proximal to any stenosis, if present; ａ，ｒｅｓｔ measuring (22) Including, The microvascular resistance at rest is R ｍｉｃｒｏ，ｒｅｓｔ =P ａ，ｒｅｓｔ / Q ｒｅｓｔ (23) method.

15. Q ｒｅｓｔ The step (21) of measuring P is performed using a non-invasive technique such as computed tomography, magnetic resonance imaging or positron emission tomography, ａ，ｒｅｓｔ 15. The method of claim 14, wherein said step of measuring (22) is performed using a non-invasive technique, such as using a sphygmomanometer.

16. A processing unit comprising means for carrying out the method according to any one of claims 1 to 15.

17. A computer program product comprising instructions which, when executed by a computer, cause the computer to carry out the method according to any one of claims 1 to 15.

18. 1. A system for determining microvascular resistance reserve (MRR) in myocardium perfused by normal or stenosed coronary arteries of a human patient, comprising: A processing unit (31); The blood flow Q through the coronary arteries while the patient is at rest ｒｅｓｔ a first flow measurement system (32) configured to measure a blood pressure P 2 at a location proximal to said coronary artery or proximal to any stenosis, if present, during said patient's resting state or maximum hyperemia; ａ a first pressure measuring device (33) configured to measure The blood flow Q through the coronary artery during maximal hyperemia in the patient ｍａｘ a second flow measurement system (34) configured to measure During maximal hyperemia in the patient, a blood pressure P is measured distal to the coronary artery or distal to any stenosis, if present. ｄ，ｈｙｐｅｒ a second pressure measuring device (35) configured to measure Equipped with The processing unit (31) receives blood flow measurements Q from the first and second flow measurement systems. ｒｅｓｔ , Q ｍａｘ and obtaining blood pressure measurements P from the first and second pressure measuring devices. ａ , P ｄ，ｈｙｐｅｒ The processing unit is configured to obtain the microvascular resistance reserve. [0030] and further configured to calculate: system.

19. 20. The system of claim 18, wherein the first flow measurement system (33) and the second flow measurement system (34) are the same flow measurement system.

20. a display unit (36) configured to receive the calculated value of the microvascular resistance reserve from the processing unit and to display the calculated value; 20. The system of claim 18 or 19, further comprising:

21. 21. The system of any one of claims 18 to 20, wherein the first pressure measuring device (33) comprises a pressure catheter or a guiding catheter.

22. 21. The system of any one of claims 18 to 20, wherein the first pressure measuring device (33) and / or the second pressure measuring device (34) comprise a sensor tip guidewire.

23. 23. The system of any one of claims 18 to 22, wherein the first flow measurement system (34) and / or the second flow measurement system (35) are systems utilizing invasive or non-invasive flow or flow surrogate measurements.

24. A system for determining microvascular resistance reserve (MRR) in myocardium perfused by normal or stenosed coronary arteries of a human patient, comprising a processing unit (41) and an interface (42), said processing unit being adapted to determine a blood pressure P in the resting state of said patient in a location proximal to the coronary arteries or proximal to any stenosis, if present, indicative of coronary flow reserve (CFR) and fractional flow reserve (FFR) of said patient's coronary arteries. ａ，ｒｅｓｔ and the patient's blood pressure during maximum hyperemia P at a location proximal to the coronary artery or proximal to any stenosis, if present. ａ，ｈｙｐｅｒ measuring the microvascular resistance reserve in response to at least one signal received via the interface including data further indicative of [0045] The system is configured to determine:

25. Microvascular resistance R at rest in the myocardium perfused by normal or stenosed coronary arteries of human patients ｍｉｃｒｏ，ｒｅｓｔ 1. A system for determining blood flow Q through a coronary artery during a patient's resting state, the system comprising a processing unit (51) and an interface (52), the processing unit comprising: ｒｅｓｔ and the blood pressure P proximal to the coronary artery or proximal to any stenosis if present while said patient is in a resting state. ａ，ｒｅｓｔ and measuring the resting state microvascular resistance R in response to at least one signal received via the interface including data indicative of ｍｉｃｒｏ，ｒｅｓｔ =P ａ，ｒｅｓｔ / Q ｒｅｓｔ The system is configured to determine:

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