阅读说明：本技术 用于评估冠状动脉疾病的手段和设备 (Means and apparatus for assessing coronary artery disease ) 是由 杰伦.松克 卡洛斯.阿道夫.科勒特博托纳 于 2020-04-16 设计创作，主要内容包括：本发明涉及心脏病领域,尤其涉及冠状动脉血管的评估,尤其涉及确定阻塞或限制通过冠状动脉血管的血流的机制和模式。本发明提供了用于确定冠状动脉疾病状况的诊断方法和设备,具体用于确定冠状动脉疾病的功能性模式(局灶性或弥漫性)。(The present invention relates to the field of heart disease, in particular to the assessment of coronary vessels, and in particular to determining the mechanisms and patterns of blocking or restricting blood flow through coronary vessels. The present invention provides diagnostic methods and devices for determining the status of coronary artery disease, in particular for determining the functional pattern (focal or diffuse) of coronary artery disease.)

1. A computer-implemented method for quantifying a pattern of coronary artery functional disease in a coronary artery vessel from a patient under hyperemic conditions, the method comprising the steps of:

-obtaining a set of relative pressure values, obtained from:

-pressure values obtained at different locations along the coronary vessel between the coronary vessel ostium and the distal-most portion of the coronary vessel; relative to

-the pressure at the vascular orifice,

-mapping the set of relative pressure values along the coronary vessel length, and determining:

-contribution of the relative pressure drop of the functional disease relative to the relative pressure drop over the total length of the coronary vessel; and

-the extent of functional disease.

2. The method according to claim 1, wherein the method comprises the further step of:

-calculating a Functional Outcome Index (FOI) based on a combination of:

-the contribution of the pressure drop of the functional disease to the pressure drop over the total length of the coronary vessel; and

-the extent of said functional disorder.

3. The method of claim 1 or 2, wherein:

-the contribution of the pressure drop of the functional disease to the pressure drop over the total length of the coronary vessels corresponds to the ratio:

-relative pressure drop between proximal and distal edges of functional disorder, relative to

-the relative pressure drop between the coronary vessel orifice and the most distal end of the coronary vessel; and

-the extent of functional disease, corresponding to the ratio:

length of functional disease relative to

The total length of the coronary vessels.

4. The method of claim 3, wherein:

-the length of the functional disease, corresponding to:

-length of suspected vascular lesion;

-length of suspected vascular lesion with relative pressure drop; or

-the sum of the lengths of the segments of the coronary vessel having a relative pressure drop greater than or equal to a predetermined threshold, and/or

-the extent of functional disease, corresponding to:

-length of the suspected vessel lesion relative to the total length of the coronary vessel;

-the length of the suspected vascular lesion with a relative pressure drop, relative to the total length of the coronary vessel; or

-the sum of the lengths of the segments of the coronary vessels having a relative pressure drop greater than or equal to a predetermined threshold value, relative to the total length of the coronary vessels.

5. The method of claim 4, wherein the predetermined threshold is equal to a relative pressure drop of 0.0015 per millimeter of the length of the coronary vessel.

6. The method according to any one of the preceding claims, wherein the method comprises the steps of:

-obtaining a Fractional Flow Reserve (FFR) curve based on a plurality of FFR values obtained at different positions of the coronary vessel between the coronary vessel orifice and a distal-most portion of the coronary vessel,

-mapping the plurality of FFR values along a coronary vessel length, and determining:

-contribution of the FFR decrease in functional disease relative to the FFR decrease over the total length of coronary vessels; and

-the extent of said functional disorder.

7. A method according to claim 6 when dependent on claim 2, wherein the method comprises the steps of:

-calculating the Functional Outcome Index (FOI) from data from FFR curves such that FOI is an expression of at least one of the following functional patterns of coronary artery disease:

-focal coronary artery disease;

diffuse coronary artery disease.

8. The method according to claim 7, wherein the method comprises the steps of:

-calculating the functional result index (FOI) from data from FFR curves based on the following formula:

wherein Δ FFR_{Focus of disease}Is defined as the difference between the FFR value at the proximal edge and the distal edge of the functional disorder; Δ FFR_{Blood vessel}Is defined as the difference between the FFR value between the coronary vessel orifice and the distal-most portion of the coronary vessel; the length of the drop in FFR is defined as the sum of successive millimeters in which the drop in FFR is 0.0015; and total vessel length is the distance between the ostium of a coronary artery vessel and the most distal portion of the coronary artery vessel.

9. The method of claim 8, wherein when the value of FOI:

above 0.7, this is indicative of a functional pattern of focal coronary artery disease; and/or

Below 0.4, this indicates a functional pattern of diffuse coronary artery disease.

10. The method of any preceding claim, wherein the set of multiple relative pressure values is obtained by:

-manual or motorized retraction by means of a pressure line comprising at least one pressure sensor;

-by means of a pressure line comprising a plurality of built-in pressure sensors;

-FFR values derived from angiography along the length of coronary vessels; and/or

FFR values derived from CT angiography along the length of the coronary vessels.

11. A computer device for assessing coronary artery disease in a patient under hyperemic conditions, the computer device configured to generate an FFR curve based on a plurality of FFR values, the FFR values being relative pressure measurements from pressures obtained at different locations along a coronary vessel between a coronary vessel ostium and a distal-most portion of a coronary vessel relative to a pressure at the coronary vessel ostium, and wherein the computer device is further configured to map the plurality of FFR values along a coronary vessel length, and determine:

-contribution of the FFR decrease in functional disease relative to the FFR decrease over the total length of coronary vessels; and

-the extent of said functional disorder.

12. The computer device of claim 11, wherein the computer device comprises a computer algorithm configured to calculate a functional result index (FOI) based on a combination of:

-the contribution of the pressure drop of the functional disease to the pressure drop over the total length of the coronary vessel; and

-the extent of said functional disorder.

13. The computer device of any one of claims 11 to 12, wherein the computer device comprises a computer algorithm configured to calculate a Functional Outcome Index (FOI) based on the FFR curve and the correlation of the FFR value over the total length of the vessel, the computer output configured to display the FOI value such that the FOI value is an expression of at least one of the following functional patterns of coronary artery disease:

-focal coronary artery disease;

diffuse coronary artery disease.

14. The computer device of any of claims 11 to 13, wherein the computer device comprises a computer algorithm configured to calculate the functional result index (FOI) from data from an FFR curve based on the following formula:

wherein Δ FFR_{Focus of disease}Is defined as the difference between the FFR value at the proximal edge and the distal edge of the functional disorder; Δ FFR_{Blood vessel}Is defined as the difference between the FFR value between the coronary vessel orifice and the distal-most portion of the coronary vessel; the length of the drop in FFR is defined as the sum of successive millimeters in which the drop in FFR is 0.0015; and total vessel length is the distance between the ostium of a coronary artery vessel and the most distal portion of the coronary artery vessel.

15. The computer device of any of claims 11-14, wherein the computing device is further configured to co-register the relative pressure measurements with a location in a coronary vessel.

16. A system for assessing coronary artery disease in a patient under hyperemic conditions, comprising a computer device according to any one of claims 11 to 15, wherein the system further comprises at least one of the following in communication with the computer device and configured to generate a plurality of FFR values:

a conduit and a pressure line comprising at least one pressure sensor,

-a conduit and a pressure line coupled to a motorized device having a fixed withdrawal speed;

-a catheter and a pressure line comprising a plurality of built-in pressure sensors;

-a device configured to provide an angiographically derived FFR value along the length of a coronary vessel;

-a device configured to provide a CT angiographically derived FFR value along the length of a coronary vessel.

Technical Field

The present invention relates to the field of heart disease, in particular to the assessment of coronary vessels, and in particular to determining the mechanisms and patterns of blocking or restricting blood flow through coronary vessels. The present invention provides diagnostic methods and devices for determining the status of coronary artery disease, in particular for determining the functional pattern (focal or diffuse) of coronary artery disease.

Background

Since the early stages of percutaneous coronary intervention, physiological assessment of coronary artery disease has been encouraged.¹Over the past 20 years, randomized controlled trials have demonstrated the clinical benefit of invasive functional assessment in guiding myocardial revascularization clinical decisions in patients with stable coronary artery disease.^2,3In clinical practice, the hemodynamic significance of an epicardial coronary stenosis is assessed by means of a pressure ratio. Fractional Flow Reserve (FFR), assessed as the pressure ratio between distal coronary and aortic pressure during pharmacologically induced hyperemia, describes the maximum achievable blood flow in the coronary vessels.⁴FFR has been recommended for determining lesion significance and the appropriateness of revascularization according to the us and european guidelines.^5,6Treatment decision making is based on an FFR value that provides a vascular level metric surrogate for myocardial ischemia.

Pressure loss in the coronary arteries may result due to viscous friction and flow separation. The contribution of each of these components is described by bernoulli's equation and poisson's law and is highly dependent on the patient-specific coronary geometry. The reduction of luminal area regulated by lesion length reduces the pressure distal to the epicardial stenosis. In addition, focal features that affect laminar flow conditions can also lead to pressure drop.^7,8Along the normal crownArterioles, even during maximal microvascular vasodilation, show no pressure loss.⁹In contrast, early coronary atherosclerosis is usually associated with mild epicardial resistance of the coronary arteries, followed by a marked segmental stenosis in invasive coronary angiography. This can be identified by pressure measurements in the coronary arteries and this may lead to the development of myocardial ischemia.¹⁰Conventional coronary angiography is traditionally used to assess the stenotic significance and spatial patterns (i.e., focal or diffuse) of coronary artery disease. However, coronary angiography is not accurate in assessing the functional significance of coronary stenosis compared to FFR.¹¹In addition, intravascular imaging and coronary computed tomography studies have shown that coronary angiography underestimates the burden and spatial distribution of coronary atherosclerosis.^12,13Furthermore, with intravascular ultrasound, diffuse atherosclerosis is often observed in angiographically normal coronary reference segments of patients with stable coronary artery disease.¹⁴The atherosclerotic profile and its effect on luminal geometry has yet to be elucidated with respect to epicardial conductance along coronary vessels.

FFR withdrawal manipulation can be used to assess the distribution of epicardial conductance.⁴This technique reveals the contribution of focal and/or diffuse coronary artery disease (CAS) to the reduction of FFR along coronary vessels.

The assessment of the pattern of coronary artery disease (i.e., focal or diffuse) is one of the most compelling problems in interventional cardiology, and improved devices, systems and diagnostic methods are needed to assess the pattern of coronary artery disease. It is well known that coronary vessels with diffuse patterns of coronary artery disease do not respond well to stented percutaneous coronary interventions. In contrast, vessels with focal disease respond well to stented percutaneous coronary interventions. In particular, there is a need for diagnostic methods that can guide interventional cardiologists with treatment options in different patterns of coronary artery disease.

Disclosure of Invention

According to a first aspect of the present invention, there is provided a computer-implemented method for quantifying a pattern of coronary artery functional disease in a coronary artery vessel from a patient under hyperemic conditions, the method comprising the steps of:

-obtaining a set of relative pressure values, obtained from:

-pressure values obtained at different locations along the coronary vessel between the coronary vessel ostium and the distal-most portion of the coronary vessel; relative to

-the pressure at the vascular orifice,

-mapping the set of relative pressure values along the coronary vessel length, and determining:

-contribution of the relative pressure drop of the functional disease relative to the relative pressure drop over the total length of the coronary vessel; and

-the extent of functional disease.

According to an embodiment, a method is provided, wherein the method comprises the further steps of:

-calculating a Functional Outcome Index (FOI) based on a combination of:

-said contribution of pressure drop of functional disease to pressure drop over the total length of the coronary vessels;

and

-the extent of said functional disorder.

According to an embodiment, there is provided a method, wherein:

-said contribution of the pressure drop of the functional disease to the pressure drop over the total length of the coronary vessels corresponds to the ratio of:

-relative pressure drop between proximal and distal edges of functional disorder, relative to

-the relative pressure drop between the coronary vessel orifice and the most distal end of the coronary vessel; and-the extent of functional disease, corresponding to the ratio:

length of functional disease relative to

The total length of the coronary vessels.

According to an embodiment, there is provided a method, wherein:

-the length of the functional disease, corresponding to:

-length of suspected vascular lesion;

-length of suspected vascular lesion with relative pressure drop;

-the sum of the lengths of the segments of the coronary vessels having a relative pressure drop greater than or equal to a predetermined threshold value, relative to the total length of the coronary vessels; or

-the sum of the lengths of consecutive or non-consecutive segments of the coronary vessel having a relative pressure drop greater than or equal to a predetermined threshold, and/or

-the extent of functional disease, corresponding to:

-length of the suspected vessel lesion relative to the total length of the coronary vessel;

-the length of the suspected vascular lesion with a relative pressure drop, relative to the total length of the coronary vessel; or

-the sum of the lengths of the segments of the coronary vessels having a relative pressure drop greater than or equal to a predetermined threshold value, relative to the total length of the coronary vessels; or

-the sum of the lengths of the continuous or discontinuous sections of the coronary vessels having a relative pressure drop greater than or equal to a predetermined threshold value, relative to the total length of the coronary vessels.

According to one embodiment, a method is provided wherein the predetermined threshold is equal to a relative pressure drop of 0.0015 per millimeter of the length of the coronary vessel.

According to one embodiment, a method is provided, wherein the method comprises the steps of:

-obtaining a Fractional Flow Reserve (FFR) curve based on a plurality of FFR values obtained at different positions of the coronary vessel between the coronary vessel orifice and a distal-most portion of the coronary vessel,

-mapping the plurality of FFR values along a coronary vessel length, and determining:

-contribution of the FFR decrease in functional disease relative to the FFR decrease over the total length of coronary vessels; and

-the extent of said functional disorder.

According to one embodiment, a method is provided, wherein the method comprises the steps of:

-calculating the Functional Outcome Index (FOI) on data from FFR withdrawal curves such that FOI is an expression of at least one of the following functional patterns of coronary artery disease:

-focal functional coronary artery disease;

diffuse functional coronary artery disease.

According to one embodiment, a method is provided, wherein the method comprises the steps of:

-calculating the functional result index (FOI) from data from FFR curves based on the following formula:

wherein Δ FFR_{Focus of disease}Is defined as the difference between the FFR value at the proximal edge and the distal edge of the functional disorder; Δ FFR_{Blood vessel}Is defined as the difference between the FFR value between the coronary vessel orifice and the distal-most portion of the coronary vessel; the length of the drop in FFR is defined as the sum of successive millimeters in which the drop in FFR is 0.0015; and total vessel length is the distance between the ostium of a coronary artery vessel and the most distal portion of the coronary artery vessel.

According to one embodiment, a method is provided wherein, when the value of FOI:

above 0.7, this is indicative of a functional pattern of focal coronary artery disease; and/or

Below 0.4, this indicates a functional pattern of diffuse coronary artery disease.

According to one embodiment, a method is provided wherein the set of multiple relative pressure values is obtained by:

-manual or motorized retraction by means of a pressure line comprising at least one pressure sensor;

-by means of a pressure line comprising a plurality of built-in pressure sensors;

-FFR values derived from angiography along the length of coronary vessels; and/or

FFR values derived from CT angiography along the length of the coronary vessels.

According to a second aspect, there is provided a computer device for assessing coronary artery disease in a patient under hyperemic conditions, the computer device being configured to generate an FFR curve based on a plurality of FFR values, the FFR values being relative pressure measurements relative to the pressure at a coronary ostium from pressures obtained at different locations along a coronary vessel between the coronary ostium and a distal-most portion of the coronary vessel, and wherein the computer device is further configured to map the plurality of FFR values along a coronary vessel length, and to determine:

-contribution of the FFR decrease in functional disease relative to the FFR decrease over the total length of coronary vessels; and

-the extent of said functional disorder.

According to one embodiment, there is provided a computer device, wherein:

the computer device includes a computer algorithm configured to calculate a functional result index (FOI) based on a combination of:

-the contribution of the pressure drop of the functional disease to the pressure drop over the total length of the coronary vessel; and

-the extent of said functional disorder.

According to one embodiment, a computer device is provided, wherein the computer device comprises a computer algorithm configured to calculate a Functional Outcome Index (FOI) based on a correlation of the FFR curve and the FFR value over the total length of the vessel, the computer output being configured to display the FOI value such that the FOI value is an expression of at least one of the following functional patterns of coronary artery disease:

-focal functional coronary artery disease;

diffuse functional coronary artery disease.

According to one embodiment, a computer device is provided, wherein the computer device comprises a computer algorithm configured to calculate the functional result index (FOI) from data from an FFR curve based on the following formula:

wherein Δ FFR_{Focus of disease}Is defined as the difference between the FFR value at the proximal edge and the distal edge of the functional disorder; Δ FFR_{Blood vessel}Is defined as the difference between the FFR value between the coronary vessel orifice and the distal-most portion of the coronary vessel; the length of the drop in FFR is defined as the sum of successive millimeters in which the drop in FFR is 0.0015; and total vessel length is the distance between the ostium of a coronary artery vessel and the most distal portion of the coronary artery vessel.

According to one embodiment, a computer device is provided that is further configured to co-register (co-register) the relative pressure measurements with a location in a coronary vessel. According to a particular embodiment, the co-registration of the positions in the coronary vessels may be performed by means of angiography, however, according to alternative embodiments, the position embodiments may be derived from the measurement and/or registration of the displacement of the pressure lines with respect to the catheter, for example by means of a suitable sensor configured to determine the displacement and/or distance of the pressure lines and at least one sensor thereon with respect to the catheter, such as any suitable position sensor (e.g. a linear position sensor, a photoelectric displacement sensor, etc.). Or according to a further alternative embodiment, which allows to manually input the displacement and/or the relative position of the pressure line with respect to the catheter, or in other words how far or how long the pressure line and its corresponding at least one sensor are introduced into the blood vessel with respect to the orifice of the blood vessel, by means of a suitable visual scale present on the pressure line.

According to one embodiment, a system is provided, wherein the system comprises at least one of the following in communication with a computer device and configured to generate a plurality of FFR values:

a conduit and a pressure line comprising at least one pressure sensor,

-a conduit and a pressure line coupled to a motorized device having a fixed withdrawal speed;

-a catheter and a pressure line comprising a plurality of built-in pressure sensors;

-a device configured to provide an angiographically derived FFR value along the length of a coronary vessel;

-a device configured to provide a CT angiographically derived FFR value along the length of a coronary vessel.

Other embodiments of the system are possible in which the computer device implements embodiments of the computer-implemented method according to the first aspect and/or combinations thereof.

According to another aspect, there is provided a method for quantifying a pattern of coronary artery functional disease in a coronary vessel from a patient, comprising the steps of:

-obtaining pressure values at different locations along the coronary vessel between the coronary vessel ostium and the distal-most portion of the coronary vessel; and pressure at the vascular orifice;

-generating a set of relative pressure values by means of:

-pressure values obtained at different locations along the coronary vessel between the coronary vessel ostium and the distal-most portion of the coronary vessel; relative to

-the pressure at the vascular orifice,

-mapping the set of relative pressure values along the coronary vessel length, and determining:

-contribution of the relative pressure drop of the functional disease relative to the relative pressure drop over the total length of the coronary vessel; and

-the extent of functional disease.

Other embodiments of the method are possible in which the method implements embodiments of the computer-implemented method according to the first aspect and/or combinations thereof.

Furthermore, according to another aspect, a method is provided, the method further comprising the step of informing an interventional cardiologist of treatment options for coronary vessels based on the FOI value, wherein:

when the FOI value is higher than 0.7, this indicates the presence of focal lesions in the coronary vessels, and/or a percutaneous coronary intervention with stent implantation should be considered;

when the FOI value is in the range of 0.5 to 0.7, this indicates the presence of a combination of focal and/or diffuse lesions, and/or percutaneous coronary interventions with stent implantation may still be considered; and/or

When the FOI is less than 0.4, this indicates the presence of a diffuse lesion, and/or a treatment other than percutaneous coronary intervention with stent implantation should be considered, or percutaneous coronary intervention with stent implantation should not be considered.

According to one embodiment, we use manual or motorized coronary pressure withdrawal to characterize the physiologic pattern of Coronary Artery Disease (CAD) in a systematic way during persistent hyperemia in patients with stable coronary artery disease. Normalization of the coronary pressure-length relationship is achieved by motorized FFR retraction, which allows for accurate and reproducible tracking. We developed a new algorithm to calculate the Functional Outcome Index (FOI). This new parameter is based on the functional impact of anatomical lesions (anatomical lesions) on coronary artery disease. In other words, FOI is a continuous metric, where values near "1.0" represent focal physiologic coronary artery disease and values near "0" represent diffuse CAD. Thus, the FOI value has a direct impact on the treatment decisions of the interventional cardiologist. According to such embodiments, a Functional Outcome Index (FOI) is calculated from data from the FFR pullback curve based on the following formula:

wherein Δ FFR_{Focus of disease}Is defined as a functional diseaseThe difference between the FFR values at the proximal and distal edges of the disease; Δ FFR_{Blood vessel}Is defined as the difference between the FFR value between the coronary vessel orifice and the distal-most portion of the coronary vessel; the length of the drop in FFR is defined as the sum of successive millimeters in which the drop in FFR is 0.0015; and total vessel length is the distance between the ostium of a coronary artery vessel and the most distal portion of the coronary artery vessel. It is clear that in this wayVaries between 0 and 1, or in other words between 0% and 100%. It is still further clear that the ratioThe degree of functional disease of the defined coronary vessels also varies between 0 and 1, or in other words between 0% and 100%. Thus, it is clear that in the above formula, the two terms of sum combine to a value varying between 0 and 2, and therefore a division by 2 can be performed in order to obtain FOI values varying between 0 and 1 (or in other words, 0% to 100%).

According to another aspect, there is provided a diagnostic method for quantifying arterial disease in a coronary vessel from a patient, comprising the steps of:

i) generating a Fractional Flow Reserve (FFR) withdrawal curve based on a plurality of FFR values obtained between the vessel ostium and a distal-most portion of the vessel,

ii) calculating a Functional Outcome Index (FOI) from the data from the FFR curve based on formula (I):

wherein Δ FFR_{Focus of disease}Is defined as the difference between the FFR value at the proximal and distal lesion edges of the lesion; Δ FFR_{Blood vessel}Is defined as the difference between the FFR value between the vessel ostium and the most distal FFR measurement in the vessel; the length of the fall-off with FFR is definedIs the sum of consecutive millimeters in which the FFR drops by more than or equal to 0.0015; and the total vessel length is the distance between the vessel orifice and the most distal portion of the vessel.

According to one embodiment, a diagnostic method is provided in which a plurality of FFR values are obtained by motorized pullback.

According to one embodiment, a diagnostic method is provided in which a plurality of FFR values are obtained by a pressure line including a plurality of built-in pressure sensors.

According to an embodiment, a diagnostic method is provided, further comprising notifying an interventional cardiologist of treatment options for coronary vessels based on a FOI value, wherein when the FOI value is above 0.7, the presence of a focal lesion in the coronary vessels is indicated.

According to one embodiment, a diagnostic method is provided that advises an interventional cardiologist of non-intervention or intervention, wherein the intervention comprises angioplasty, stenting, drug, or a combination thereof.

According to another aspect, there is provided a system for assessing coronary artery disease in a patient under hyperemic conditions, comprising

i) A coronary catheter comprising a pressure sensor, said catheter further comprising a pressure line comprising at least one pressure sensor,

ii) a computing device in communication with the catheter and the pressure line, the computing device configured to generate an FFR curve based on a plurality of FFR values, the FFR values being relative pressure measurements from pressure obtained over a total length of the coronary vessel relative to pressure in the ostium,

iii) the computer device comprises a computer algorithm that calculates a Functional Outcome Index (FOI) based on the FFR withdrawal curve obtained in step ii) and the correlation of FFR values over the total length of the vessel, the computer output displaying a FOI value that informs the interventional cardiologist of treatment options based on the likelihood of the presence of focal or diffuse coronary artery disease in the coronary arteries.

According to one embodiment, a system is provided wherein the pressure line is coupled to a motorized device at a fixed withdrawal speed.

Drawings

FIG. 1 shows a schematic view of a: including the patient flow chart under study.

FIG. 2: FFR value distributions derived from withdrawal and distal vessel location. The left panel shows the distribution of FFR values derived from motorized pullback. The right panel depicts the distribution of far-end FFR values.

FIG. 3: reclassification between anatomical and physiological assessment of coronary artery disease patterns. The left pie chart presents the pattern and CAD classification based on coronary angiography (n-85 vessels). The pie on the right shows reclassification of CAD patterns evaluated using a motorized FFR pullback curve.

FIG. 4: fractional flow reserve, lesion gradient, and percent stenosis diameter. Gradient of FFR lesions stratified according to the anatomical severity of CAD (measured by percent stenosis diameter). In narrow diameter percentage<No significant difference in lesion FFR gradient was observed between 30%, 30% to 50% or greater than 50% of lesions.

FIG. 5: examples of cases of physiological coronary artery disease patterns and Functional Outcome Index (FOI). Three examples of cases describing physiological patterns of CAD. On the left panel, angiography shows a severe lesion of the middle LAD (white star) with a distal FFR of 0.68. This lesion resulted in a decrease in FFR, accounting for 86% of distal FFR. Only 20% of the vessels showed physiological lesions. FOI is 0.86 indicating the presence of physiological focal CAD. The middle panel shows the anatomical lesion of the middle LAD (white star) with a distal FFR of 0.78. This lesion resulted in a 33% decrease in vascular FFR, while 73% of the vessels showed physiological disease. FOI is 0.29 indicating the presence of physiological diffuse CAD. In the right panel, a severe lesion in the vascular ostium LAD (white star) was observed with a distal FFR of 0.62. This lesion accounts for 84% of the vessel FFR. However, in the proximal and middle LAD, mild stenosis produces a diffuse pressure drop and also affects the vessel FFR. The FOI was 0.57. LAD left anterior descending. CAD coronary artery disease. FFR fractional flow reserve. FOI functional outcome index.

FIG. 6: the functional outcome is exponentially distributed. The gray bars show the distribution of Functional Outcome Index (FOI) and the left y-axis shows the number of vessels. The boxplot shows median lesion FFR gradient divided by vessel FFR gradient stratified by FOI tertile (blue dashed line) (% FFR)_{Focus of disease})。％FFR_{Focus of disease}Significantly different between the tertiles (p)<0.001). The percentage range of vessels with functional disease is indicated by the black dashed line. The mean was plotted for each FOI tertile and there was a significant difference (p) between the FOI tertiles<0.001). Right y-axis shows% FFR_{Focus of disease}And% physiologic disease range.

Detailed Description

The present invention will be described with respect to particular embodiments and with reference to certain drawings but the invention is not limited thereto but only by the claims. Any reference signs in the claims shall not be construed as limiting the scope. The drawings described are only schematic and are non-limiting. In the drawings, the size of some of the elements may be exaggerated and not drawn on scale for illustrative purposes. Where the term "comprising" is used in the present description and claims, it does not exclude other elements or steps. Where an indefinite or definite article is used when referring to a singular noun e.g. "a" or "an", "the", this includes a plural of that noun unless something else is specifically stated. Furthermore, the terms first, second, third and the like in the description and in the claims, are used for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances and that the embodiments of the invention described herein are capable of operation in other sequences than described or illustrated herein. The following terms or definitions are provided solely to aid in the understanding of the present invention. Unless specifically defined herein, all terms used herein have the same meaning to one of ordinary skill in the art to which this invention belongs. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art (e.g., in molecular biology, interventional cardiology, fluid physics, biochemistry, and/or computational biology).

Randomized controlled trials have demonstrated the clinical benefit of invasive functional assessment in guiding clinical decisions for myocardial revascularization in patients with stable coronary artery disease. Currently, treatment decisions are based on only one FFR value, which provides a vascular level metric surrogate for myocardial ischemia. In the present invention, in patients with stable coronary artery disease, during persistent hyperemia, we used manual or motorized coronary pressure withdrawal to characterize the physiologic pattern of coronary artery disease. In our prospective, multicenter study of patients receiving coronary angiography for clinical indications, a withdrawal device adapted to clamp coronary pressure lines was set at a speed of 1 mm/sec. The pattern of coronary artery disease is judged to be focal, diffuse, or a combination of these two mechanisms based on coronary angiography and manual or motorized FFR withdrawal curves. Furthermore, by calculating a Functional Outcome Index (FOI), a quantitative assessment of the physiological pattern of coronary artery disease was established. FOI is a continuous measure, with values near 1.0 indicating focal physiological CAD and values near 0 indicating diffuse CAD.

Accordingly, the present invention provides a novel diagnostic method that incorporates a novel metric, namely the Functional Outcome Index (FOI). The FOI value takes into account the functional impact of anatomical lesions and the extent of physiological disease, distinguishing focal CAD from diffuse CAD.

Accordingly, the present invention provides in a first embodiment a method for assessing treatment options for a lesion present in a coronary vessel during continuous infusion of a hyperemic agent, the method comprising the steps of:

i) a coronary catheter comprising a pressure sensor is introduced into the ostium of a vessel of the left or right coronary artery, followed by a guide wire comprising at least one built-in pressure sensor,

ii) obtaining a set of relative pressure values obtained from pressure values obtained at different locations along the coronary vessel relative to the pressure present at a fixed location of the coronary vessel,

iii) mapping the set of relative pressure values along the coronary vessel length and determining the length of the vessel and the length of the suspected vascular lesion, or in other words, the length of the functional disorder. It is clear that the extent of functional disease thus corresponds to the ratio of the length of the functional disease relative to the total vessel length.

iv) optionally correlating the values obtained in step iii) with quantitative coronary angiography,

v) calculating a Functional Outcome Index (FOI) based on the combination of:

-the ratio of coronary pressure drop in the suspected lesion relative to the pressure drop in the entire blood vessel; and

degree of functional coronary artery disease, and

wherein FOI is the expression of a functional pattern of coronary artery disease,

vi) displaying the results of the FOI to aid in treatment decisions for revascularization of at least one lesion present in the coronary vessels.

It is clear that the pressure drop, or relative pressure drop, in a suspected lesion corresponds to the aggregate or sum of the pressure drops, or relative pressure drops, at all suspected lesion locations along the coronary vessel. In other words, in the case of a single, continuous suspected lesion, or in the case of multiple, continuous and/or discontinuous suspected lesions, the pressure drop and/or relative pressure drop between the proximal and distal edges is an aggregate or sum of the pressure drop and/or relative pressure drop of each lesion between its respective proximal and distal ends. Or in other words, it is clear that the relative pressure drop between the proximal and distal edges of the functional disorder corresponds to the difference between the relative pressure value at the distal end of the functional disorder and the relative pressure value at the proximal end of the functional disorder. It is further clear that according to a specific embodiment, a decrease in FFR of a functional disease or suspected lesion corresponds to an FFR at the distal end of the functional disease or suspected lesion minus an FFR at the proximal end of the functional disease or suspected lesion. Similarly, it is clear that the relative pressure drop between the coronary vessel orifice and the distal-most end of the coronary vessel corresponds to the difference, increment or gradient between the distal-most end relative pressure measurement of the vessel and the vessel orifice relative pressure measurement. Thus, according to a particular embodiment, this means the difference between FFR at the distal end of the vessel and FFR at the ostium of the vessel.

In yet another embodiment, the present invention provides a method for assessing treatment options for a lesion present in a coronary vessel during and/or after infusion (e.g., continuous infusion or any other suitable type of infusion) of a hyperemic agent, the method comprising the steps of:

i) introducing a coronary catheter comprising a pressure sensor into the ostium of a left or right coronary vessel, followed by a guidewire comprising at least one built-in pressure sensor,

ii) obtaining a set of relative pressure values obtained from pressure values obtained at different locations along the coronary vessel with respect to the pressure present at the fixed location of the coronary vessel,

iii) mapping the set of relative pressure values along the coronary vessel length and determining the length of the vessel and the length of the suspected vascular lesion,

iv) optionally correlating the values obtained in step iii) with quantitative coronary angiography,

v) calculating a Functional Outcome Index (FOI) based on: a ratio of coronary pressure drop in a suspected lesion relative to pressure drop in the entire blood vessel; and the extent of a suspected lesion, or in other words, the extent of a functional disease, and wherein FOI is the expression of a functional pattern coronary artery disease, or

The Functional Outcome Index (FOI) was calculated based on: a ratio of coronary pressure drop in a suspected lesion relative to pressure drop in the entire blood vessel; and the degree of functional coronary artery disease,

vi) displaying the results of the FOI to aid in treatment decisions for revascularization of at least one lesion present in coronary vessels,

vii) wherein when the FOI is less than 0.4, treatments other than stented percutaneous coronary intervention should be considered.

Thus, it is clear that, according to one embodiment, when FOI is below 0.4, this indicates a functional pattern of diffuse coronary artery disease. However, it is clear that alternative embodiments are possible, wherein e.g. when the FOI is below a suitable maximum threshold, e.g. below 0.3, below 0.2 or below 0.15, a functional pattern of diffuse coronary artery disease is indicated.

The expression "pressure drop in the entire blood vessel" refers to the pressure difference obtained between the pressure measured at the orifice of the coronary artery blood vessel and the pressure obtained at the most distal part of the coronary artery blood vessel.

In yet another embodiment, the present invention provides a method for assessing treatment options for a lesion present in a coronary vessel in a hyperemic state (e.g., at a bolus injection or during continuous infusion of a hyperemic agent), comprising the steps of:

i) introducing a coronary catheter comprising a pressure sensor into the ostium of a left or right coronary vessel, followed by a guidewire comprising at least one built-in pressure sensor,

ii) acquiring a set of relative pressure values obtained from pressure values obtained at different positions along the coronary vessel with respect to the pressure present at a fixed position of the coronary catheter, using a motorized distal device having a fixed withdrawal speed,

iii) mapping the set of relative pressure values along the coronary vessel length and determining the length of the vessel and the length of the suspected vascular lesion,

iv) optionally correlating the values obtained in step iii) with quantitative coronary angiography,

v) calculating a Functional Outcome Index (FOI) based on a combination of: a ratio of coronary pressure drop in the suspected lesion relative to pressure drop in the entire blood vessel and a degree of the suspected lesion; and wherein FOI is the expression of functional pattern coronary artery disease, or a Functional Outcome Index (FOI) is calculated based on a combination of: a ratio of coronary pressure drop in a suspected lesion relative to pressure drop in the entire blood vessel; and the degree of functional coronary artery disease,

vi) displaying the results of the FOI to aid in treatment decisions for revascularization of at least one lesion present in coronary vessels,

it is thus clear that the length of the vessel, also referred to as total vessel length, can be determined by determining the distance between and/or the difference between the positions mapped to the pressure values associated with the coronary vessel ostia and the most distal part of the coronary vessel.

In yet another embodiment, the invention provides a diagnostic method for quantifying arterial disease in a coronary vessel from a patient, comprising the steps of:

i) generating an FFR curve based on a plurality of FFR values obtained between the ostium and a distal-most portion of the blood vessel,

ii) calculating a Functional Outcome Index (FOI) from the data from the FFR curve based on the following formula:

wherein Δ FFR_{Focus of disease}Is defined as the difference between the FFR value at the proximal and distal lesion edges of the lesion; Δ FFR_{Blood vessel}Is defined as the difference between the FFR value between the FFR measurements of the vessel ostium and the distal-most portion in the vessel; the length of the drop in FFR is defined as the sum of successive millimeters in which the drop in FFR is 0.0015; and the total vessel length is the distance between the vessel orifice and the most distal portion of the vessel.

In the present invention, the term "guide wire comprising at least one pressure sensor" or "pressure line" is equivalent.

In one particular embodiment, a Fractional Flow Reserve (FFR) curve is obtained by a manual or motorized withdrawal device that is connected to a pressure line.

In yet another particular embodiment, a motorized retraction device is not required, but rather the FFR curve is obtained from a pressure line that includes a plurality of built-in pressure sensors. In particular, when the retraction is performed manually or by means of a motorized device, the FOI value does not change.

In a particular embodiment, the diagnostic method of the present invention provides a treatment recommendation to an interventional cardiologist based on a FOI value, wherein when the FOI value is above 0.7, above 0.8, or above 0.9, it indicates the presence of a focal lesion in a coronary vessel and benefits from percutaneous coronary intervention with stent implantation. In a particular embodiment, the diagnostic method of the invention provides a treatment recommendation to an interventional cardiologist based on the FOI value, wherein when the FOI value is preferably below 0.4, below 0.3 or below 0.2, below 0.15, this indicates the presence of a diffuse lesion in the coronary vessels and that it cannot benefit from percutaneous coronary intervention with stent implantation. It has also been found that treatment recommendations can be made to an interventional cardiologist based on FOI values (where when the FOI value is above 0.4 and below 0.7, for example in the range of 0.5 to 0.7, which indicates the presence of a combination of focal and diffuse lesions in the coronary vessels), i.e. there may still be benefit from percutaneous coronary intervention with stent implantation. However, when the FOI value is below 0.4, percutaneous coronary intervention with stent implantation would be of no benefit.

In a particular embodiment, the catheter is configured to obtain diagnostic information about coronary vessels. In this regard, the catheter may include one or more sensors, transducers, and/or other monitoring elements configured to obtain diagnostic information about the vessel. The diagnostic information includes one or more of pressure, flow (velocity), images (including images obtained using ultrasound (e.g., IVUS), Optical Coherence Tomography (OCT), thermal, and/or other imaging techniques), temperature, and/or combinations thereof. In some cases, the one or more sensors, transducers, and/or other monitoring elements are positioned less than 30cm, less than 10cm, less than 5cm, less than 3cm, less than 2cm, and/or less than 1cm from the distal tip of the catheter. In some cases, at least one of the one or more sensors, transducers, and/or other monitoring elements is positioned at the distal tip of the catheter. In another particular embodiment, the catheter includes at least one element configured to monitor pressure within a coronary vessel. The pressure monitoring element may take the form of a piezoresistive pressure sensor, a piezoelectric pressure sensor, a capacitive pressure sensor, an electromagnetic pressure sensor, an optical pressure sensor, and/or combinations thereof. In some cases, one or more features of the pressure monitoring element are implemented as a solid-state component fabricated using semiconductor and/or other suitable fabrication techniques.

In yet another embodiment, the catheter includes a pressure wire (or guidewire). Examples of commercially available guidewire products that include suitable pressure monitoring elements include, but are not limited to: prime WirePressure guide wire, PrimePressure guide wire andXT pressure and flow guidewires, both available from volcano corporation; and Pressure Wire^TMCertus guide Wire and Presure Wire^TMAeris guidewires, all available from st. jude Medical, Inc; or COMET available from Boston Scientific^TMFFR pressure guidewire. The pressure line is also configured to obtain diagnostic information about the coronary vessels. In some cases, the pressure line is configured to obtain the same diagnostic information as the catheter. In other cases, the pressure line is configured to obtain diagnostic information different from the catheter, which may include additional diagnostic information, less diagnostic information, and/or alternative diagnostic information. The diagnostic information obtained from the pressure lines includes one or more of pressure, flow (velocity), images (including images obtained using ultrasound (e.g., IVUS), OCT, thermal, and/or other imaging techniques), temperature, and/or combinations thereof.

Similar to the catheter, the pressure line also includes at least one element configured to monitor pressure within the vessel. The pressure monitoring element may take the form of a piezoresistive pressure sensor, a piezoelectric pressure sensor, a capacitive pressure sensor, an electromagnetic pressure sensor, an optical pressure sensor, and/or combinations thereof. In some cases, one or more features of the pressure monitoring element are implemented as a solid-state component fabricated using semiconductor and/or other suitable fabrication techniques. In particular embodiments, the pressure line may include a plurality of pressure sensors, such as at least 10, at least 20, at least 30, at least 40, at least 50, or more pressure sensors. It is clear that according to such an embodiment of the pressure line, a plurality of pressure sensors are provided at different positions along the length of the pressure line and are thus configured to determine a plurality of pressure measurements at different positions along the length of the coronary vessel, or in other words at different positions between the coronary vessel orifice and the distal end of the coronary vessel, even at rest, after being introduced into the coronary vessel up to the distal end of the coronary vessel.

In certain embodiments, the pressure line is configured to monitor pressure within the vessel while being moved through the lumen of the vessel. In some cases, the pressure line is configured to be moved through a lumen of a blood vessel and through a stenosis present in the blood vessel. In this regard, in some cases, the pressure line is positioned distal of the stenosis and moved (i.e., withdrawn) proximally through the stenosis to a location proximal of the stenosis. In some embodiments, the movement of the pressure line may be manually controlled by medical personnel (e.g., a surgeon's hand). In other preferred embodiments, movement of the pressure line is controlled by a mobile control device (e.g., a retraction device, such as Trak available from volcano corporationII or volcano R-100 devices). In this regard, in some instances, the movement control device controls the movement of the pressure line at a selectable and known rate (e.g., 5.0mm/s, 2.0mm/s, 1.0mm/s, 0.5mm/s, etc.). In some cases, the movement of the pressure line through the vessel is continuous with each withdrawal. In other cases, the pressure line is moved stepwise (i.e., repeatedly moved a fixed amount of distance and/or a fixed amount of time) through the vessel.

In yet another embodiment, the invention provides a system for assessing coronary artery disease in a patient under hyperemic conditions, the system comprising

i) A coronary catheter comprising a pressure sensor, said catheter further comprising a pressure line comprising at least one pressure sensor,

ii) a computing device in communication with the catheter and the pressure line, the computing device configured to generate an FFR curve based on the plurality of FFRs (the former being a relative pressure measurement of pressure obtained over the total length of the coronary vessel relative to pressure in the ostium of the vessel),

iii) the computer device comprises a computer algorithm that calculates a Functional Outcome Index (FOI) based on the FFR curve and the correlation of the FFR values obtained in step ii) over the length of the vessel, the computer output displaying the FOI value that informs the interventional cardiologist of treatment options based on the likelihood of the presence of focal or diffuse coronary artery disease in the coronary arteries.

In yet another embodiment, the invention provides a system for assessing coronary artery disease in a patient under hyperemic conditions, comprising

i) A coronary catheter comprising a pressure sensor, the catheter further comprising a pressure line comprising at least one pressure sensor, the pressure line coupled to a motorized device at a fixed withdrawal speed,

ii) a computing device in communication with the catheter and the pressure line, the computing device configured to generate an FFR curve based on relative pressure measurements of pressure obtained from the coronary vessel relative to pressure in the ostium, and the computing device further co-registering the relative pressure measurements with a location in the coronary vessel,

iii) the computer device comprises a computer algorithm that calculates a Functional Outcome Index (FOI) based on the FFR curve, and a computer output displays a FOI value that informs a cardiologist of treatment options based on a likelihood of a focal or diffuse coronary artery disease being present in the coronary artery.

In the present invention, the "system" is equivalent to the "apparatus" or the "device".

Computing device generally represents any device suitable for performing the processing and analysis techniques discussed in this disclosure. In some embodiments, a computing device includes a processor, random access memory, and a storage medium. In this regard, in some particular instances, the computing device is programmed to perform steps associated with the data acquisition and analysis described herein. Accordingly, it should be understood that any steps related to data acquisition, data processing, FOI calculation, instrument control, and/or other processing or control aspects of the present disclosure may be implemented by a computing device using corresponding instructions stored on or in a non-transitory computer-readable medium accessible to the computing device. In some cases, the computing device is a console device. In some cases, the computing device is portable (e.g., handheld, on a rolling cart, etc.). Further, it should be understood that in some cases, the computing device includes multiple computing devices. In this regard, it is specifically understood that the different processing and/or control aspects of the present disclosure may be implemented using multiple computing devices, individually or within predefined groupings. Any division and/or combination of the processing and/or control aspects described herein across multiple computing devices is within the scope of the present disclosure.

It should be understood that any communication path between the catheter and the computing device may be utilized, including physical connections (including electrical, optical, and/or fluid connections), wireless connections, and/or combinations thereof. In this regard, it is understood that in some cases, the connection is wireless. In some cases, the connection is a communication link over a network (e.g., an intranet, the internet, a telecommunications network, and/or other network). In this regard, it should be understood that in some instances, the computing device is located remotely from the operating area in which the catheter is used. Having the connection comprise a connection over a network may facilitate communication between the conduit and the remote computing device regardless of whether the computing device is in an adjacent room, adjacent building, or in a different state/country. Further, it should be understood that in some cases, the communication path between the catheter and the computing device is a secure connection. Further, it should be understood that in some cases, data communicated over one or more portions of the communication path between the catheter and the computing device is encrypted.

It should also be understood that FOI values obtained with respect to the characteristics of coronary artery disease (predicted as a diffuse, intermediate, or focal lesion) indicated by the FOI values may be compared or considered in addition to other representations of lesions or stenosis and/or vessels, such as IVUS (including virtual histology), OCT, ICE, thermal, infrared, flow, doppler flow, and/or other vessel data collection modalities, to provide a more complete and/or accurate understanding of vessel characteristics. For example, in some cases, information calculated or determined using one or more other vascular data collection modalities is validated with information about features of a lesion or stenosis and/or vessel indicated by the FOI value.

It is to be understood that although specific embodiments, specific configurations, and materials and/or molecules have been discussed herein for elements and methods according to the invention, various changes or modifications in form and detail may be made without departing from the scope and spirit of this invention. The following examples are provided to better illustrate particular embodiments and should not be considered limiting of the present application. This application is limited only by the claims.

Examples of the invention

1. Patient population

Between 11 months in 2017 and 1 month in 2019, two european centers received a total of 111 patients with 158 blood vessels. In 100 vessels (79 patients), a motorized FFR withdrawal analysis was feasible (fig. 1). The average age is 66 plus or minus 10 years, women account for 11 percent, and diabetics account for 29 percent. The target blood vessels are 66% of left anterior descending branch, 16% of left branch and 18% of right coronary artery. Clinical, angiographic and functional properties are shown in table 1. All patients received a motorized FFR withdrawal assessment. The mean withdrawal length was 97.9. + -. 19.6mm and the mean adenosine infusion time was 3.6. + -. 0.3 min. There were no adverse intraoperative events associated with motorized FFR withdrawal. Overall, 984.813 FFR values were used to generate the FFR pullback curve. The mean FFR value derived from withdrawal is 0.89 ± 0.09, and the mean far-end FFR is 0.83 ± 0.09. Fig. 2 presents the distribution of FFR values. Of the 37 vessels (37%), the most distal FFR was 0.80, 22 patients received PCI, 3 received CABG, and 12 received the best drug treatment.

Visual assessment of CAD patterns

Anatomical and functional CAD observations were made of 85 vessels. In 15 cases, the withdrawal curve was assessed as being free of physiological disease despite the presence of anatomical stenosis, and was excluded from the present analysis. Using coronary angiography alone, 63% of the vessels were classified as having focal CAD, 26% diffuse disease, and 11% a combination of focal and diffuse CAD. The inter-observer consistency of CAD models based on conventional angiography alone was moderate (Fleiss' Kappa coefficient 0.45; 95% CI 0.29 to 0.61). After evaluation of the FFR withdrawal curve, 53% of the vessels were identified as focal disease, 20% as diffuse disease and 27% as a combined pattern of pressure drop. The inter-observer agreement based on the physiological CAD model was significant (Fleiss' Kappa 0.76; CI 0.67 to 0.87). In identifying patients with anatomical focal disease, 26% were reclassified as diffuse or combined CAD patterns, while 13% of anatomical diffuse disease were reclassified as focal CAD (fig. 3).

Quantitative assessment of CAD patterns

Average FFR_{Focus of disease}61.7 + -25%, while the mean vascular length percentage with physiological disorders is 59.8 + -21%. Table 2 shows% FFR for physiological disorders layered in a physiological CAD model_{Focus of disease}And a length. The correlation between FFR pressure drop and percent diameter narrowing is weak (r 0.21, p 0.028; fig. 4). The average FOI was 0.61. + -. 0.17. The average FOI of the tertile fractions were 0.43. + -. 0.09, 0.61. + -. 0.04 and 0.78. + -. 0.08. FIG. 5 shows an example of a physiological disease pattern with calculated FOI, and FIG. 6 shows the FOI distribution and corresponding% FFR_{Focus of disease}And the extent of functional disease.

4. Continuous focus

A total of 25 vessels in the cohort presented anatomically defined, continuous lesions. By visual assessment of the FFR withdrawal curve, 40% of vessels with continuous lesions were judged as two focal decreases, 52% as a combination of focal and diffuse decreases, and 8% as diffuse CAD. When combined with successive lesionsWhen contributing,% FFR_{Focus of disease}Is 70.2 +/-20%. % FFR of proximal lesions_{Focus of disease}35.0 ± 20%, and 34.9 ± 19% of distant foci (p ═ 0.99). The percentage of vessel length without physiological disease was 46 ± 17%. The average FOI is 0.58 + -0.15 (range of 0.30-0.95). Including only the far-end FFR<Sensitivity analysis of the 0.80 vessels showed that the physiologic pattern distribution of coronary artery disease and FOI were similar.

5. Discussion of the related Art

5.1 summary of findings

The main findings of the present invention can be summarized as follows: 1) coronary angiography is inaccurate, and the mode and distribution of CAD cannot be evaluated; 2) 34% of vascular disease patterns were reclassified (i.e., focal, diffuse, or combined) using motorized FFR withdrawal as compared to conventional angiography; 3) the inclusion of functional ingredients increases inter-observer agreement regarding disease pattern recognition; 4) a new computer algorithm was developed to calculate the FOI. FOI distinguishes focal and diffuse CAD using quantitative measures based on the functional impact of anatomical lesions and the extent of physiological disease.

The present invention provides a characterization of CAD physiologic patterns by assessing the distribution of epicardial coronary artery resistance in a hyperemic state in patients with stable coronary artery disease. Using motorized FFR withdrawal, new insights into the mechanisms of pressure loss in stable CAD patients are described. Furthermore, co-registration with coronary angiography enables us to assess the relationship between lesion level anatomical and functional findings, confirming a moderate correlation between diameter stenosis and pressure gradients. Three physiological CAD patterns were observed, i.e. focal, diffuse or a combination of the two mechanisms.

5.2 coronary artery disease Pattern

The differences between the anatomical and physiological significance of coronary artery disease have been widely recognized¹¹. Furthermore, there is no consensus on the definition of diffuse CAD. Several authors proposed different descriptions of diffuse CAD based on the extent of atherosclerosis, vessel diameter, lesion number and appearance of distal runoff^9，16，17. This analysis extends our knowledge to the contribution of epicardial lesions to the total pressure gradient. In this study, 62% of the decrease in vascular FFR was associated with angiographically visible stenosis; in other words, almost 40% of the FFR drop is not associated with angiographic stenosis. In addition, physiological disease was observed over 60% of the vessel length, while percent lesion length was observed over 25% of the vessel length. This analysis recombines the intravascular ultrasound observation of diffuse coronary atherosclerosis with the physiological response in terms of pressure loss along the coronary vessels (physiological regression). Furthermore, these findings can be extrapolated to recent randomized clinical trials in the field of coronary artery physiology. In this study, the mean far-end FFR was 0.83. + -. 0.09, comparable to the values observed in Define Flair (0.83. + -. 0.09) and SWEDEDHEART (0.82. + -. 0.10)^18，19. In vessels evaluated as focal CAD using conventional angiography, one-fourth still showed diffuse physiological disease, while in vessels with anatomically diffuse disease, one-tenth was reclassified as focal CAD using motorized FFR withdrawal. Evaluation of FFR withdrawal curves reclassified 34% of the vascular CAD patterns. In addition, the use of coronary physiology increases inter-observer reproducibility associated with CAD patterns. Nevertheless, it should be appreciated that a differential assessment of the CAD pattern was observed in 19% of the vessels using a visual assessment of the FFR withdrawal curve.

5.3 implications of revascularization strategies

The distribution of coronary atherosclerosis (e.g., focal and diffuse) has been shown to impact clinical decisions of revascularization strategies. Patients with anatomical diffuse CAD are usually treated conservatively with optimal drug therapy, or referral to coronary artery bypass grafting.²⁰Interestingly, diffuse disease shows poor prognosis even in patients who undergo surgery. Diffuse physiologic disease in LAD is associated with higher left internal mammary artery graft occlusion rates compared to focal disease.¹⁷Furthermore, although in the distal blood vessel FFR<The clinical benefit of PCI was observed in 0.80 patients, but still three thirdsOne patient receiving PCI still had a poor FFR after PCI, which was associated with a major adverse cardiac event.^21,3In the case of focal physiologic CAD, focal percutaneous based therapies may be able to restore coronary physiology and relieve ischemia. However, for diffuse cases of CAD, the clinical benefit of PCI may be suspected.^21,22In patients receiving drug treatment, assessing lesion-associated gradients may also help in lesion-based risk stratification; high incremental focal FFR gradient (i.e.>0.06) has been identified as a hemodynamic predictor of plaque rupture and acute coronary syndrome.²³Upon contemporary risk stratification using clinical characteristics, luminal and atherosclerotic plaque composition, and the presence of ischemia, determining the FFR lesion gradients and the physiological pattern of CAD can further refine lesion-based risk stratification. Furthermore, personalized approaches to physiological diseases based on vascular and focal levels have the potential to improve clinical decision making and outcome.

In the present invention, a new physiological metric is developed to objectify the model of CAD. FOI focuses the physiological pattern of CAD to appear focal, diffuse, or combined. The FOI should be interpreted as a continuous measure and should not define the pattern of the CAD by dividing the data into three parts. The higher the FOI, the more focal CAD and the higher the potential gain in PCI epicardial conductance. The availability of quantitative measures to characterize CAD patterns in hyperemic states has enabled us to design a clinical trial to study the effectiveness of PCI with optimal drug treatment layered on a CAD physiologic pattern. This will further personalize the treatment strategy for CAD patients based on coronary artery physiology.

5.4 continuous lesions

Some authors define the presence of a continuous lesion as diffuse CAD. In the current cohort, 29% of the vessels appeared to be consecutive lesions. Visually, the FFR withdrawal curve visually depicts two focal decreases of 40%, one focal combination diffuse decrease of 52%, and 8% diffuse disease (no focal FFR decrease). FOI ranges from 0.30 to 0.95, describing variable physiological responses of successive lesions. Physiological interdependence in the coronary artery treeThe dependency, the so-called focal crosstalk, has been described in the hyperemic state.²⁴We observed that the functional contribution of proximal and distal lesions was similar in terms of incremental FFR percentage. No percent diameter stenosis or% FFR between proximal and distal lesions was found_{Focus of disease}There are differences. This finding may be the result of moderate angiographic disease (mean diameter stenosis percentage 45.9 ± 14.2%) observed in this population, which may not be sufficient to reduce coronary flow and improve pressure gradients in distal lesions.^{25 26 27}In the case of a continuous lesion, the true FFR gradient can be revealed by removing one lesion and re-evaluating the FFR. Kim et al found that treating lesions with maximal increase in FFR and reevaluating the functional components of the vessel to determine whether further treatment was required is a safe strategy.²⁸In addition, traditional statistical and machine learning methods have also been developed to predict functional outcomes in FFR in continuous lesions.

5.5 clinical meanings

The adoption of coronary artery physiology in clinical practice has increased after evidence of clinical benefit compared to anatomical guidance and drug treatment, as well as the development of non-congestive pressure ratios.²⁹As the field progresses, improvements in invasive techniques have the potential to further improve clinical decision making and patient selection for revascularization. Characterization of coronary artery disease patterns is a necessary step toward this direction to predict which patients benefit most from PCI, CABG, or drug treatment based on the distribution of epicardial resistance. The prediction of post-PCI functional outcome is an important issue and is a matter of intensive research using non-invasive and invasive methods.³⁰In view of the possibility of providing FFR values at arbitrary points of the coronary tree and thus characterizing CAD patterns, angiographically derived FFR and CT angiographically derived FFR have inherent advantages.^{31 32}Thus, it is clear that according to such embodiments, FFR values at different positions along the coronary vessel length may be obtained from the following generation and/or CT angiography derived FFR values: configured to provide or follow coronary vesselsLength, and/or angiographically derived FFR values at any desired point in the coronary tree. These tools must demonstrate the clinical benefits employed in clinical practice as part of the physiological assessment of CAD, improving the selection and ultimately the clinical outcome of patients with stable coronary artery disease.

5.6 conclusion

Coronary angiography does not allow accurate assessment of CAD patterns. The inclusion of functional ingredients reclassified 34% of vascular disease patterns (i.e. focal, diffuse or combined). A new metric, FOI, was developed based on the functional impact of anatomical lesions and the physiological extent of disease distinguishing focal and diffuse CAD.

Materials and methods

1. Design of research

Prospective, multicenter studies of patients receiving coronary angiography of clinical indications. Fractional flow reserve assessment is recommended for patients with moderate coronary lesions (defined as a narrowing of visual diameter between 30% and 70%). All patients underwent motorized FFR withdrawal. Patients presenting with acute coronary syndrome, past coronary artery bypass graft, significant valvular disease, severe obstructive pulmonary disease or bronchial asthma, coronary artery vascular access lesions, severe tortuosity or severe calcification were excluded. The study was approved by the research review board or ethical committee of each participating center.

2. Motorized FFR program

FFR measurements are made following the recommendations of fractional flow reserve measurement standardization files.¹⁵Pressure lines are placed at least 20mm distal of the most distal coronary stenosis in vessels over 2mm in diameter as assessed by visual inspection. The pressure line position was recorded using a contrast agent injection. Invasive coronary pressure was measured using the RadiAnalyzer Xpress (St Jude Medical, Minneapolis, USA) and the QUANTIEN Integrated FFR system (Abbott Vascular, Ill., USA). After intracoronary administration of nitrates, the drug is administered externallyThe peripheral or central vein was subjected to continuous intravenous adenosine infusion at a dose of 140 μ g/kg/h to obtain steady state hyperemia for at least 2 minutes. A retraction device (Volcano R100, san diego, usa) adapted to clamp a coronary pressure wire (PressureWire X, St Jude Medical, minneapolis, usa) is set at a speed of 1 mm/sec to retract the pressure wire up to the guide catheter tip during continuous pressure recording. The maximum withdrawal length of each vessel was 13 cm. If FFR drift is observed (>0.03), the FFR measurement is repeated.

3. Pressure tracking analysis

FFR values were extracted from the pressure trace every 10 microns. FFR is defined as the ratio of the moving averages of proximal and distal coronary pressure. Pressure tracking was examined to assess quality, curve artifact and congestion stability (supplementary appendix fig. 1). The absence of functional CAD is defined as distal vessel FFR>0.95. The CAD pattern was judged to be focal, diffuse, or a combination of the two mechanisms by visual inspection of the FFR withdrawal curve. In addition, the physiological pattern of CAD was also quantitatively classified based on (1) the contribution of epicardial lesion functionality relative to total vessel FFR (Δ lesion FFR/Δ vessel FFR) and (2) the length of the epicardial coronary segment with decreased FFR (mm) relative to total vessel length. These two ratios (i.e. lesion-related pressure drop (% FFR)_{Focus of disease}) And extent of functional disease) yields a Functional Outcome Index (FOI), which is a metric that describes CAD patterns (i.e., focal or diffuse) based on coronary artery physiology.

Wherein Δ FFR_{Focus of disease}Is defined as the difference between the FFR value at the proximal and distal lesion edges of the lesion; Δ FFR_{Blood vessel}Is defined as the difference between the FFR value between the vessel ostium and the most distal FFR measurement; the length with the FFR drop is defined as the sum of consecutive millimeters in which the FFR drop is 0.0015. FOI is a continuous measure, values close to 1.0 indicate focal physiologic coronary artery disease,values close to 0 indicate diffuse coronary artery disease. In cases with continuous lesions, the physiological contribution of each lesion was added to calculate Δ FFR_{Focus of disease}. The calculations employ automated and proprietary algorithms based on motorized FFR curves.

It is clear that other suitable values of the threshold value are possible for determining the length with FFR drop, then a specific value of 0.0015, wherein, for example, the length with FFR drop is defined as the sum of the adjacent millimeters for which the FFR drop ≧ said suitable threshold value. Or in other words, the length of the functional disorder, corresponds to the sum of the lengths of the segments of the coronary vessels having a relative pressure drop greater than or equal to a predetermined threshold, such as a relative pressure drop of 0.0015 per millimeter of the coronary vessel length, or any other suitable threshold.

4. Angiography assessment

Coronary angiography was collected and analyzed centrally by a separate core laboratory. The anatomical pattern of coronary artery disease is determined by visual inspection of the target vessel as focal, diffuse, or a combination of both mechanisms. A continuous lesion is defined as the presence of two or more stenoses with a visual diameter stenosis greater than 50% and a separation between the two stenoses of at least three times the diameter of a reference vessel¹⁶. Lesion length was detected by automated Quantitative Coronary Angiography (QCA) software. The length of the vessel from the vessel ostium to the location of the pressure line sensor is defined. Manually corrected QCA tracking was recorded. Quantitative coronary angiography analysis was performed using the CAAS workstation 8.1(Pie Medical Imaging, macterhirt, the netherlands). Co-registration of coronary angiography and FFR pullback is performed offline using anatomical landmarks recorded during imaging acquisition.

5. Statistical analysis

Continuous variables with a normal distribution are presented as mean plus/minus standard deviation, and non-normal distributed variables are presented as median [ interquartile range ]. The classification variables are presented as percentages. The consistency of the CAD patterns and the consistency between observers were evaluated using the Kappa of Fleiss. Quantitative variables were compared using analysis of variance (ANOVA). The correlation between variables was evaluated by Pearson moment coefficients. All analyses were performed in R (R statistical computing foundation, vienna, austria) and Data charts were created using Data charts 4.3 software (Visual Data Tool Inc.).

Table 1 baseline clinical, angiographic and physiological examinations.

In vessels with distal fractional flow reserve > 0.95. BMI Body mass index (Body mass index). FFR Fractional flow reserve (Fractional flow reserve). FOI functional outcome index. LAD Left anterior descending (Left antisense descending). LCX Left Circumflex artery (Left Circumflex artery). QCA Quantitative coronary angiography (Quantitative coronary angiography). RCA Right coronary artery (Right coronary artery). SD standard deviation (standard deviation).

TABLE 2 anatomical and functional characteristics layered according to coronary artery disease patterns.

The abbreviations are as in the above table.

Match drawing

Reference to the literature

Gruntzig AR, Senning A and Siegenghaler WE. Non-surgical dilation of coronary stenosis: percutaneous transluminal coronary angioplasty (coronary-artery transluminal angioplasty: percutaneous transluminal coronary artery surgery), New England journal of medicine (The New England and journal of medicine), 1979; 301: 61-8.

Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' T Veer M, Klauss V, Manoharan G, Engstrom T, Oldoroyd KG, Ver Lee PN, MacCarthy PA and Fearon WF. for guiding The comparison of Fractional flow reserve for percutaneous coronary intervention with angiography (Fractional flow reserve analysis for guiding perfusion coronary intervention) New England medicine (The New England and journal of medicine) 2009; 360: 213-24.

Xaplaniteris P, Fournier S, Pijls NHJ, Fearon WF, Barbato E, Tonino PAL, Engstrom T, Kaab S, Dambrink JH, igno fol G, Toth GG, Piroth Z, Witt N, Frobert O, Kala P, Link A, Jagic N, mats M, Mavromatis K, Samady H, Irimpen A, Oldroyd K, Campo G, Rothenbuhler M, Juni P and De Bruyne B. PCI Five-Year results with blood Flow Reserve score as guide (Five-Yeast outer with PCI Guided by Flow resonance). 379: 250-259.

Measuring fractional flow reserve to assess The functional severity of coronary stenosis (Measurement of fractional flow reserve of The functional-area stenoses), New England journal of medicine (The New energy and journal of medicine) 1996; 334: 1703-8.

Major updates of the diagnostic and management guidelines for Fihn SD, Blankenship JC, Alexander KP, Bittl JA, Byrne JG, Fletcher BJ, Fonarow GC, Lange RA, Levine GN, Maddox TM, Naidu SS, Ohman EM and Smith PK.2014 ACC/AHA/AATS/PCNA/SCAI/STS Stable ischemic cardiopathic patients: american Society of Cardiology/American Society of Heart guide working groups and American Society of Thoracic Surgery, Society of Carn and Cardiovascular prevention, Society of Cardiovascular Angiography and intervention and the Society of Thoracic Surgeons (2014ACC/AHA/AATS/PCNA/SCAI/STS focused update of the diagnostic for and management of patients with stable diagnostic Heart disease a report of the American Society of diagnosis/American Heart Association Task Force on activity Guidelines and the American Association for the clinical benefit of the patient Circulation and the clinical benefit of the patient Circulation 2014; 130: 1749-67.

Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA, Collet JP, Falk V, Head SJ, Juni P, Kastrati, Koolera, Kristensen SD, Niebauer J, Richter DJ, Seferovic PM, ribbon D, Stefanini GG, Windecker S, Yadav R and Zembala MO.2018 ESC/EACTS myocardial revascularization guide (2018ESC/EACTS Guidelines on myocarpial revascularization) European Heart journal (European heart journal). 2019; 40: 87-165.

Pressure-flow characteristics of unseated canine coronary stenosis during vascular quiescence and dilatation of the Gould KL. coronary artery (Pressure-flow characteristics of coronary stents in unseated dogs at rest and during coronary stenosis), cycling study (Circulation research) 1978; 43: 242-53.

Physiologically guided treatment of Modi BN, De Silva K, Rajani R, Curzen N and perer d. Review (physical-Guided Management of Serial Coronary array Disease: A Review). JAMA cardiology (JAMA cardiology). 2018; 3: 432-438.

De Bruyne B, Hersbach F, pijs NH, Bartunek J, Bech JW, heydrickx GR, Gould KL and wijs w. diffuse atherosclerosis but coronary angiography "Normal" patients with epicardial coronary resistance abnormalities (Abnormal coronary artery resistance in patients with arterial disease resistance but with differential coronary artery angiography) Circulation (Circulation) 2001; 104: 2401-6.

Frequency and clinical significance of hydrodynamically significant diffuse coronary artery disease with graded, longitudinal, basal-apical myocardial perfusion abnormalities by invasive positron emission tomography (Frequency and clinical abnormalities of hydrodynamic diffuse coronary artery disease as graduations, longitudinal, basal-apical myocardial perfusion abnormalities) cycles (Circulation) 2000; 101: 1931-9.

Toningo PA, Fearon WF, De Bruyne B, Oldroyd KG, Leesar MA, Ver Lee PN, Maccarthy PA, Van't Veer M and Pijs NH. angiography of coronary stenosis in FAME studies with functional severity comparison, blood flow reserve score in multivessel assessment with angiography comparison (anatomical functional specificity of coronary artery stenosis in multiple vessel assessment.) Journal of the American society of Cardiology (Journal of the American College of Cardiology) 2010; 55: 2816-21.

Butler J, Shapiro M, Reiber J, Sheth T, Ferencik M, Kurtz EG, Nichols J, Pena a, Cury RC, Brady TJ and Hoffmann u, scope and distribution of coronary artery disease: a comparative study of invasive and non-invasive angiography and computer angiography (extend and distribution of coronary area: a comprehensive study of innovative negative positive and negative positive regional analysis) US Heart journal (American heart journal) 2007; 153: 378-84.

The limitations of Mintz GS, Popma JJ, Pichard AD, Kent KM, Satler LF, chung YC, defelco RA and Leon MB. coronary angiography in assessing coronary plaque distribution: a systematic study of eccentricity of target lesions among 1446lesions (Limitations of anatomical in the assessment of plan in the coronary area: a systematic study of target lesion in 1446 lesions.) Loop (Circulation) 1996; 93: 924-31.

Atherosclerosis in "normal" coronary reference segments of angiography "Mintz GS, Painter JA, Picard AD, Kent KM, Satler LF, Popma JJ, chung YC, Bucher TA, Sokolowwicz LE and Leon MB.: an intravascular ultrasound study of clinical relevance (intravascular ultrasound in clinical "normal" coronary image reference sections: an intravascular ultrasound study with clinical studies. Journal of the American society of Cardiology 1995; 25: 1479-85.

Toth GG, Johnson NP, Jeremias A, Pellicano M, VrandkX P, Fearon WF, Barbato E, Kern MJ, Pijss NH, and De Bruyne B, Standardization of Fractional Flow Reserve Measurements (Standardization of Fractional Flow Reserve Measurements) J.American Heart Association (Journal of the American College of Cardiology) 2016; 68: 742-53.

Sinanos G, Morel MA, Kappetein AP, mountain MC, Colombo A, Dawkins K, Van den Brand M, Van Dyck N, Russell ME, Mohr FW and Serrouys PW. grammar scores: angiography tool to grade The complexity of coronary artery disease (The SYNTAX Score: an anatomical tool grading The complexity of coronary artery disease). The EuroPCR journal (EuroIntervision: journal of EuroPCR in college Interventional Cardiology with the world Group on International Cardiology of the European Society of Cardiology) 2005; 1: 219-27.

Shiono Y, Kubo T, Honda K, Katayama Y, Aoki H, Satogami K, Kashiyama K, Taruya a, Nishiguchi T, Kuroi a, Orii M, Kameyama T, Yamano T, Yamaguchi T, Matsuo Y, Ino Y, Tanaka a, Hozumi T, Nishimura Y, Okamura Y and akaakaakaka T. the effect of functional local patency and diffuse coronary artery disease on bypass graft rate (Impact of functional vertical coronary artery disease area array type.) journal of International cardiology 2016; 222: 16-21.

Gotberg M, Christiansen EH, Gudmundsdottir IJ, Sandhall L, Danielewicz M, Jakobsen L, Olsson SE, Ohagen P, Olsson H, OmerovicE, Calais F, Lindroos P, Maeng M, Todt, Venetsanos D, James SK, Karegren A, Nilsson M, Carlsson J, Hauer D, Jensen J, Karlson AC, Panayi G, Erling D and Frobert O. used to Guide The Ratio of The Instantaneous Wave-free Ratio of PCI to The blood Flow Reserve fraction (instant Wave-free Ratio of Flow Reserve Guide) New English journal of medicine (The New England, and 2017; 376: 1813-1823.

Davies JE, Sen S, Dehbi HM, Al-Lame R, Petraco R, Nijrer SS, Bhindi R, Lehman SJ, Walters D, Sapontis J, Janssens L, Vrints CJ, Khasaba, Lane M, Van Belle E, Krackhardt F, Bojara W, going O, Harle T, Indolfi C, Niccoli G, Ribichini F, Tanaka N, Yokoi H, Takashima H, Kikuta Y, Erglis A, Vinhas H, Canas Silva P, Baptista SB, Alghamdi A, Heldylig F, KooBK, Nam, Shin ES, Doh JH, Brugetes, Alegria-Sahabita E, Sahabitant J, Shin J, Markura J, Makura K, Makura J, Makura, Ma-K, Makura, Ma-K, and Ma-K PCI), The New England journal of medicine (The New England journal of medicine) 2017; 376: 1824-1834.

Coronary artery bypass surgery for diffuse advanced coronary artery disease, dourad LOC, Bittencourt MS, Pereira AC, Poppi NT, Dallan LAO, Krieger JE, Cesar LAM, and Gowdak lhw: 1 Year Clinical and Angiographic findings (Coronary Artery Bypass Surgery in Diffuse Advanced Coronary Artery diseases: 1-Yeast Clinical and cardiovascular problems.) Thoracic and cardiovascular surgeons (The Thoracic and cardiovascular Surgery) 2018; 66: 477-482.

Piroth Z, Toth GG, Tonino PAL, Barbato E, Aghlmani S, Curzen N, ignofol G, Pijs NHJ, Fearon WF, Juni P and De Bruyne B.prognostic Value of Fractional Flow Reserve Measured Immediately After Implantation of a Drug Eluting Stent (diagnostic Value of Fractional Flow responsive Measured After Implantation-Cardiovascular Drug drive-estimated Stent Implantation) circulating Cardiovascular interventions (Circulation Cardiovascular interventions) 2017; 10.

FFR outcome after PCI is suboptimal in long diffuse coronary artery disease (FFR residual post PCI is subalpital in long diffuse coronary artery disease) european intervention: the EuroPCR journal (EuroIntervision: journal of EuroPCR in college Interventional Cardiology with the world Group on International Cardiology of the European Society of Cardiology) 2016; 12: 1473-1480.

Lee JM, Cho G, Koo BK, Hwang D, Park J, Zhang J, Kim KJ, Tong Y, Kim HJ, Grady L, Doh JH, Nam CW, Shin ES, Cho YS, Choi SY, Chun EJ, Cho JH, Norgaard BL, Christiansen EH, Niemenn K, Otake H, Penika M, de Bruyne B, Kubo T, Akasaka T, Narula J, Douglas PS, Taylor CA and Kim HS. use Coronary computer tomography and Computational Fluid mechanics to identify High Risk Plaques that may lead to Acute Coronary Syndrome (Identification of High-Risk plaque diagnosis synthetic general use) by Using Cardiovascular diagnosis, Inc. 8.

Effect of downstream coronary stenosis on left main coronary artery disease fractional flow reserve assessment of Fearon WF, Yong AS, inders G, Toth GG, Dao C, Daniels DV, Pijls NHJ and De Bruyne b: human validation (The impact of downstream Cardiovascular disease on fractional flow responsive area disease: human identification). JACC Cardiovascular intervention (JACC Cardiovascular interventions) 2015; 8: 398-403.

Assessment of a coronary pressure measurement of continuous stenotic hemodynamic significance in coronary artery, Pijls NH, De Bruyne B, Bech GJ, liostro F, Heyndrickx GR, Bonnier HJ and Koolen jj: human body verification (coherent pressure measurement to the modelling information of serial with one nucleotide array) loop (Circulation) 2000; 102: 2371-7.

De Bruyne B, Pijls NH, Heyndrickx GR, Hodeige D, Kirkeeide R and Gould KL. to assess the fraction of flow reserve resulting from the pressure of continuous epicardial stenosis: theoretical basis and animal validation (Pressure-derived fractional flow reserve to assessment of serial environmental tests. Circulation. 2000; 101: 1840-7.

Optimized use of Modi BN, Ryan M, Chattersingh a, Eruslanova K, Ellis H, gaddem N, Lee J, Clapp B, choweinciczyk P and Perera d. fractional flow reserve in the assessment of a series of coronary heart diseases: 3D print Experimental Study With Clinical Validation (Optimal Application of Fractional Flow Reserve to Association Serial Central Coronary area: A3D-Printed Experimental Study With Clinical Validation. Journal of the American Heart Association. 2018; 7: e010279.

clinical and physiological outcomes in patients with continuous stenosis of a single coronary artery guided by percutaneous coronary intervention (Clinical and physiological issues of fractional coronary intervention) JACC Cardiovascular intervention (JACC Cardiovascular interventions), 2012, by Kim HL, Koo BK, Nam CW, Doh JH, Kim JH, Yang HM, Park KW, Lee HY, Kang HJ, Cho YS, Youn TJ, Kim SH, Chae IH, Choi DJ, Kim HS, Oh BH, and Park YB. blood flow reserve fractions; 5: 1013-8.

Future development of Instantaneous Wave-Free ratios to Flow Reserve fraction of Gotberg M, Cook CM, Sen S, Nijjer S, Escan J and Davies JE. (The evolution Future of instant Wave-Free Ratio and Fractional Flow Reserve) Journal of The American society for Cardiology (Journal of The American College of medicine) 2017; 70: 1379-1402.

Gosling RD, Morris PD, Lawford PV, Hose DR and Gunn JP. personalized fractional flow reserve: a new Concept for optimizing Myocardial Revascularization (Novel sectional Flow Reserve: Novel concentrate to optimal Myocardial Revascularization). The European journal of PCR in Cardiology with the Working Group of the Working Group on International Cardiology of the European Society, 2018.

The effect of Coronary Remodeling on Fractional Flow Reserve (Impact of Coronary remodelling on Fractional Flow Reserve) of Collet C, Katagiri Y, Miyazaki Y, Asano T, Sonck J, van gemens RJ, Andreini D, Bittencourt MS, Kitslaar P, tenekciouglu E, Tijssen JGP, Piek JJ, de Winter RJ, Cosyns B, Rogers C, Zarins CK, Taylor C, onyma Y and serrouys PW. [ Circulation ]. 2018; 137: 747-749.

Diagnostic performance of fractional flow reserve obtained from Collet C, oncoma Y, Sonck J, Asano T, Vandeloo B, Kornowski R, Tu S, Westra J, Holm NR, Xu B, De Winter RJ, Tijssen JG, Miyazaki Y, Katagiri Y, Tenekecioglu E, Modolo R, chicoreon P, costyns B, zoors D, Roosens B, Lochy S, arghaca JF, van Rosendael a, Bax J, Reiber JHC, Escaned J, De Bruyne, Wijns W and serrouys PW. angiography: system overview and Bayesian meta-analysis (a systematic review and Bayesian meta-analysis.) European journal of the Heart (European heart journal) 2018; 39: 3314-3321.