Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/68—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient
  • A61B5/6846—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive
  • A61B5/6847—Arrangements of detecting, measuring or recording means, e.g. sensors, in relation to patient specially adapted to be brought in contact with an internal body part, i.e. invasive mounted on an invasive device
  • A61B5/6851—Guide wires
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
  • A61B5/021—Measuring pressure in heart or blood vessels
  • A61B5/0215—Measuring pressure in heart or blood vessels by means inserted into the body
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
  • A61B5/00—Measuring for diagnostic purposes; Identification of persons
  • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
  • A61B5/026—Measuring blood flow

Definitions

• Vascular diseases are often manifested by reduced blood flow due to atherosclerotic occlusion of vessels
• occlusion of the coronary arteries supplying blood to the heart muscle is a major cause of heart disease
• Numerous methods are currently available for treating various lesion types Some of these methods are given herein below, sequenced from softer to heavier, relating to their ability to open calcified lesions, per cutaneous transluminal angioplasty (PTCA), Cutting balloon angioplasty, directional coronary atherectomy (DCA), rotational coronary atherectomy (RCA), Ultrasonic breaking catheter angioplasty, transluminal extraction catheter (TEC) atherectomy Rotablator atherectomy, and excimer laser angioplasty (ELCA )
• PTCA cutaneous transluminal angioplasty
• DCA directional coronary atherectomy
• RCA rotational coronary atherectomy
• Ultrasonic breaking catheter angioplasty transluminal extraction catheter
• TEC transluminal extraction catheter
• Rotablator atherectomy and exci
• Lesion geometry is evaluated by angiography, qualitative coronary angiography (QCA), or by intravascular ultrasound (IVUS) These measurements allow calculation of the percent diameter stenosis (angiography or QCA) or percent area stenosis (IVUS) This information is used to estimate stenosis severity, but during the last years clinicians have realized that direct physical information about pressure and flow is necessary for complete evaluation of coronary artery disease Physiological measurements such as pressure gradient have been clinically used as an indicator for lesion severity However, previous attempts to relate the pressure gradient across the stenosis to its functional significance have been disappointing The decrease in the pressure gradient after PTCA has been used to assess the success of the treatment, with poor correlation.
• the coronary flow velocity reserve (CFVR) is defined as the ratio of hyperemic to baseline flow velocity
• the fractional flow reserve (FFR) is defined as the ratio of distal (to stenosis) pressure (Pd) to aortic pressure (Pa) during hyperemia
• Pd distal
• Pa aortic pressure
• Hyperemic conditions are obtained by administration of vasodilators (e g papave ⁇ ne, adenosine)
• vasodilators e g papave ⁇ ne, adenosine
• Clinical studies have demonstrated that in most cases, lesions with CFVR ⁇ 2 must be treated using one of the above mentioned methods, whereas for patients with CFVR > 2, angioplasty may be avoided Similarly, in most cases angioplasty may be avoided if FFR > 0 75 Coronary flow occurs essentially during diastole while systolic contribution to total coronary flow is smaller
• the FFR and CFVR are independent but complementary indicators The first characterize the specific lesion whereas the second is a more global parameter, characterizing the lesioned vessel (lesion and distal bed)
• Clinical studies show that for approximately 75% of the patients CFR and FFR lead to the same conclusion regarding the lesion significance At the same time, for 25% of the patients, the conclusions regarding lesion significance were different This means that simultaneous determination of coronary flow reserve and fractional flow reserve is highly important and gives the clinician the additional and more complete information regarding the lesion severity
• This invention provides a method for calculating the flow-based clinical characteristics, coronary flow reserve (CFR) and diasto c to systolic velocity ratio (DSVR), in addition to the FFR, using pressure measurements across a stenosis
• CFR 0 coronary flow reserve in the same vessel without stenosis
• DSVR diasto c to systolic velocity ratio
• the present invention relates generally to a sensor apparatus for determination of characteristics in a tubular conduit, such as a blood vessel or the urethra, having at least one pressure sensor adapted to measure pressure across an obstruction
• This invention provides, a processor unit operatively connected to the at least one sensor, and a program for controlling the processor unit
• the processor unit is operative with the program to receive signals from the sensor, identify changes in the sensor signal, detect characteristics of the tubular conduit, the characteristics of the tubular conduit being derived from changes in the sensor signal, and recognize and assign a label to the characteristic of said tubular conduit
• This invention provides a system which includes the Automatic Similar Transmission method
• the characteristics that may be determined include a flow ratio in a blood vessel, a coronary flow reserve in a blood vessel diastole to systole velocity ratio in a blood vessel, coronary flow reserve together with fractional flow reserve in the same blood vessel without stenosis and analysis of their correlation for estimation of vascular bed conditions, coronary flow reserve together with fractional flow reserve in the same blood vessel without stenosis for estimation of vasodilatation effectiveness
• this invention provides the determination of a hemodynamic condition of the artery by determining the vascular bed index (VBI 0 ) which is equal to the ratio of mean shear to mean pressure
• VBI 0 vascular bed index
• the present invention provides a methods of determining/detecting microvascular disease due to the abnormal ratio of FFR to CFR based on either or proximal and/or distal pressure
• the method may be in combination with a balloon procedure
• the methods described provide for post PTCA evaluation (prior to stenting), determination or validation of dilatation success by subsequent CFR increase after PTCA, and indication of whether a stent is neded
• the methods and systems provided herein indicate high probability of microvascular disease, due to the abnormal ratio of FFR to CFR
• Post Stenting in combination with a deflated balloon allows the estimation of CFR of the vessel
• only a distal pressure measurement will allow the CFR calculation
• this invention provides determining CFR and FFR directly from intraarterial pressure measurements, thus the simultaneous CFR and FFR measurements permit one to obtain additional information about the vascular bed
• the present invention provides the hemodynamical parameters in estimating the severity of stenotic blood vessels in an attempt to increase the reliability of these parameters
• Fig 1 is a schematic isometric view of a system for determining blood vessel hemodynamic parameters, constructed and operative in accordance with a preferred embodiment of the present invention
• Fig 1 a are schematics isometric view of a system for determining blood vessel hemodynamic parameters, constructed and operative in accordance with another preferred embodiment of the present invention
• Fig 1 b are schematics isometric view of a system for determining blood vessel hemodynamic parameters, constructed and operative in accordance with another preferred embodiment of the present invention
• Fig 2 is a schematic functional block diagram illustrating the details of the system 1 of Fig 1 ,
• Fig 2 a is a schematic functional block diagram illustrating the details of the system 1 a of Fig 1 a,
• Fig 3 is a schematic isometric view of a part of system 1 or 1 a of Fig 1 or 1 a, constructed and operative in accordance with another preferred embodiment of the present invention
• Fig 4 is a schematic isometric view of an in-vitro system, constructed and operative in accordance with a preferred embodiment of the present invention
• Fig 5 is a schematic detailed illustration of the in-vitro tubing system 51 of Fig 4
• Fig 6 is a detailed schematic illustration of the experimental section 44 of Fig 5 and the positioning of the pressure sensors within a the latex tube during the operation of the system of Figs 4 and 5
• Fig 7 is a schematic cross section illustrating an artery with a stenosis and points A and B designating pressure measurement points
• Fig 8 is a schematic cross section of a blood vessel, illustrating the positioning of the two pressure sensors used in Method 1
• Fig 9 is a schematic cross section of a blood vessel, illustrating the positioning of the pressure sensors used in Method 2
• Fig 10 presents an example of pressure data used by Method 3 to determined hemodynamic coefficients
• Fig 1 1 presents the result of the calculation performed on the data shown
• Fig 12 is a schematic cross section of a blood vessel, illustrating the positioning of the pressure sensors used in Method 3
• Fig 13 presents the positioning of pressure sensors and stenosis inside the latex test tube of the in-vitro system of Figs 4-6 This configuration was used to validate Method 1 , the transfer function method
• Fig 14 illustrates a calculated pressure pulse by Method 1 , with the actual pressure pulse measured at that point
• Fig 15 illustrates an artery with a stenosis, a fluid filled pressure catheter and a pressure wire
• Points A and B designate measurements points
• Fig 16 presents pressure and ECG data, measured on human at rest condition, used by Method 4
• Fig 17 presents the ECG signals, at rest, after time transformation The transformation is done using Method 2
• Fig 18 presents the fluid filled catheter pressure signals at rest and after synchronization of the pulses
• Fig 19 presents the synchronized pressure signals representing the pressure proximal and distal to the stenosis
• Fig 20 presents ECG and pressure signals measured at point A during rest and at point B during vasodilatation state
• Fig 21 presents ECG signals, at rest (point A) and during vasodilatation (point B), after synchronization, applying the transformation of Method 2
• Fig 22 presents the fluid filled catheter pressure signals, at rest (point A) and during vasodilatation (point B), after synchronization of the pulses
• Fig 23 presents the guide wire pressure signals, at rest (point A) and during vasodilatation (point B), after synchronization of the pulses
• Fig 24 presents the distribution of a set of synchronized and transformed pressure signals measured at rest and during vasodilatation, used for determining mean values of hemodynamic coefficients
• Fig 25 presents the calculated values of the non-dimensional flow using the data shown in Fig 24
• Fig 26 presents the calculated values of CFR and FFR for each pulse
• Fig 27 presents the mean values over number of heartbeats of pressure at point A and point B at rest and vasodilation conditions
• Fig 28 presents the calculated values of the non-dimensional flow using the data described in Fig 27
• Fig 29 presents human data of ECG signals and pressure measurements during rest and vasodilatation These data are used to calculate hemodynamic parameters using synchronization by ECG signals
• Fig 30 presents synchronized pressure signals during rest and vasodilatation
• Fig 31 presents non-dimensional flow curves calculated from the synchronized curves of Fig 30
• Fig 32 presents the mean values of the synchronized pressure signals shown in Fig 30
• Fig 33 presents the calculated mean non-dimensional flow used to determine hemodynamic parameters
• Fig 34 illustrates the positioning of the pressure sensors and measurements location when using the method of synchronization by max pressure signal
• Fig 35 illustrates the pressure measurement points inside a non-lesioned blood vessel
• Fig 36 illustrates a balloon artificial obstruction inside a non-lesioned blood vessel and pressure measurement distal to the balloon
• Fig 45 illustrating a cross section of an artery 30 having an arterial walll 32 and a stenosis 34 Two points A and D upstream and downstream of the stenosis define a section of the artery
• the hemodynamic parameter FFR, along this section, is of interest
• the pressure gradient in a blood vessel without stenosis is small (pressure difference between two points 5cm apart is less then 1 mm Hg)
• the accuracy of the devices for pressure measurement, which are used in medicine for intracoronary pressure measurements does not allow accurate determination of such small pressure differences Therefore, one cannot make an accurate calculation of flow using these existing pressure measurement devices in a healthy non-stenosed vessel
• the situation is different if an obstruction exists in the blood vessel (stenosis or some artificial obstruction)
• the pressure difference across such an obstruction may reach 40-50 mmHg at rest and 60-70 mmHg during hyperemia
• This significant pressure difference may be measured with high accuracy and may be used for calculations of coronary flow reserve (CFR), using the methods and system presented herein
• This calculated CFR might be slightly different then the coronary flow velocity reserve (CFVR) as measured by the Flow wire
• the difference may arise from changes in the velocity profiles Limiting to the available technologies, accurate results may be achieved if the pressure difference across the stenosis at rest is more then 4
• the present invention provides methods and a system for calculation of CFR and FFR from on line intra-art pressure measurements
• Intracoronary pressure measurements were made in patients undergoing diagnostic angiography with findings of lesions of questionable clinical significance (intermediate lesions of 50-70% visual stenoses severity)
• Basal pressure measurements proximal, distal and during trans-lesional pull back were made with the methods and systems provided herein
• Patients were given intracoronary adenosine to achieve maximal vasodilatation and measurements were taken
• K is a constant determined solely by the stenosis diameter
• the coronary flow reserve is defined as the ratio of the mean hyperemic flow to the mean flow at rest and may be calculated if the pressure difference across the stenosis is known during rest and hyperemia.
• the coronary flow reserve may be calculated if the pressure difference across the stenosis is known during rest and hyperemia.
• Equations (2) and (3) are valid only for short stenosis.
• the pressure difference across the stenosis may be expressed as (Young
• equations (2) and (3) may be used If ⁇ p across the stenosis is more then 4 mmHg, the accuracy of CFR calculation will reach (10%)
• CFR 0 is the coronary flow reserve of a healthy vascular bed without stenosis i o Using the following notations
• Q v mean flow over a heartbeat in a stenotic vessel during hyperemia
• Q N mean flow over a heartbeat in the same non-stenotic vessel at rest
• Q N V - mean flow over a heartbeat in the same non-stenotic vessel during hyperemia (vasodilatation)
• CFR and FFR are known, then the coronary flow reserve (CFRO) in the same vessel, in case of healthy vascular bed, may be derived
• CFR 0 indicates a non healthy vascular bed
• Too low value of CFR for given FFR indicates either downstream flow restriction (additional stenosis) or insufficient infusion of vasodilator
• Too high value of CFR for given FFR indicates vascular bed disease
• the last equation may be used for determination of coronary flow reserve by positioning an artificial obstruction in a blood vessel, as presented herein below
• calculating CFR and FFR may be accomplished by dividing into pulses the proximal and distal pressure Dividing the pulses are known to those skilled in the art For example, one use an ECG signal or only using a pressure signal
• the Automatic Similar Transformation (AST) Method the steps of which are described in Figure 43
• the systems provided herein include the AST method
• mean pressure pulse P mean ( ⁇ ) is calculated, using averaging over all pulses for a give ⁇
• Six pressure signals result mean proximal fluid filled pressure Fp( ⁇ ), mean proximal pressure, measured by pressure transducer Pp( ⁇ ), mean fluid filled pressure Fd( ⁇ ) and mean pressure transducer pressure Pd( ⁇ ) both measured at rest when pressure transducer is distal to stenosis mean fluid filled pressure Fv( ⁇ ) and mean pressure transducer pressure Pv( ⁇ ) both measured during vasolidation when pressure transducer is distal to stenosis
• Pressure signals Pd( ⁇ ) and Pv( ⁇ ) are corrected to the changes in aortic pressure
• step 5 The steps of step 5 applied to every n-th pulse P 3n (1200) remaining after stage 2 Then CFR n for this pulse is calculated using equation
• the mean velocity u may be calculated by Young&Tsai equation (without linear term)
• FFR can be used to estimate % stenosis
• Figs 1 , 1 a, 1 b 2 and 2 a present a schematic isometric view of a system for determining blood vessel (lesion regions and non-lesioned regions) clinical hemodynamic characteristics CFR , DSVR and FFR
• the system is constructed and operative in accordance with two embodiment of the present invention (1 and 1 a)
• Fig 2 and 2 a are schematic functional block diagrams illustrating the details of the system 1 of Fig 1 and i o system 1 a of Fig 1 a
• the systems 1 , 1 a, and 1 b include a pressure sensor catheter or guide wire 4 inserted into the vessel directly or via a catheter lumen 3 for measuring the pressure inside a blood vessel
• the lumen catheter may be a guiding catheter (e g 8F Archer coronary guiding catheter from Medtronic Interventional Vascular,
• any other hollow catheter System 1 and systems 1 a and 1 b may include one (4) or more (i e Fig 3) pressure sensors on guide wire and also a fluid filled (FF) pressure transducer 31
• the pressure sensor 4 can be the 3F one pressure sensor model SPC-330A or dual pressure catheter SPC-721 commercially available from Millar Instruments Ine , TX, U S A , or any other pressure catheter suitable for diagnostic 25 or combined diagnostic / treatment purposes such as the 0 014 guidewire mounted pressure sensor product number 12000 from Radi Medical Systems, Upsala, Sweden, or Cardiomet ⁇ cs WaveWire pressure guidewire from Cardiometrics Ine an Endsonics company of CA U S A
• the systems 1 , 1 a and 1 b also include a signal conditioner 23 such as a
• the signal conditioner 23 is suitably connected to the pressure sensor 4 for amplifying the signals of the pressure sensor
• the system 1 further includes an analog to digital (A/D) converter 28 (i e Nl E Series 5 Multifunction I/O model PCI-MIO-16XE-10 commercially available by National Instruments, Austin, TX) connected to the signal conditioner 23 and to the FF pressure transducer 31 for receiving the analog signals therefrom
• A/D analog to digital
• the signal conditioner 23 may be integrated in the data acquisition card of the computer 20, or may also be omitted altogether, depending on the specific type of pressure i o sensors used
• the system 1 a of Fig 1 a also includes a standard cardiac cathetenzation system 22, such as Nihon Kohden Model RMC-1 100, commercially available from Nihon Kohden Corporation, Tokyo, Japan
• the signal conditioner 23 and the FF pressure transducer 31 are directly connected to the monitoring system 22
• the signal conditioner 23 and the FF pressure transducer 31 are directly connected to the monitoring system 22
• the signal conditioner 23 and the FF pressure transducer 31 are directly connected to the monitoring system 22.
• the system 1 a further includes an analog to digital (A/D) converter 28 connected to the output of the monitoring system 22 through a shielded I/O connector box 27, such as Nl SCB-68 or BNC-2090 commercially available from National Instruments, Austin, TX
• the systems 1 and 1 a also include a signal analyzer 25 connected to the
• the signal analyzer 25 includes a computer 20 and optionally a display 21 connected to the computer 20 for displaying text numbers and graphs representing the results of the calculations performed by the computer 20 and a
• the A/D converter 28 can be a separate unit or can be integrated in a data acquisition card installed in the computer 20 (not shown)
• the computer 20 processes the pressure data, sensed by the pressure sensors 4 and acquired by the A/D converter 28 or the data acquisition card (not shown)
• the system 1 b includes a single hardware box 29 containing all signal conditioning, calculations, archiving options and digital display and output to a printer 26
• Fig 5 5 is a schematic diagram representing an in-vitro experimental apparatus constructed and operative for determining flow characteristics in simulated non-lesioned and lesioned blood vessels, in accordance with an embodiment of the present invention
• Fig 2 is a schematic functional block diagram illustrating the functional details of a system including the apparatus of Fig 5 and apparatus for i o data acquisition, analysis and display
• the fluidics system 51 of Fig 5 is a recirculating system for providing pulsatile flow
• the system 51 includes a pulsatile pump 42 (model 1421A pulsatile blood pump, commercially available from Harvard Apparatus, Ine , Ma, U S A )
• the pump 42 allows control over rate, stroke volume and systole / diastole ratio
• the pulsatile pump 42 allows control over rate, stroke volume and systole / diastole ratio
• the system 51 further includes a flexible tube 43 immersed in a water bath 44, to compensate for gravitational effects
• the flexible tube 43 is made from Latex and has a length of 120 cm
• the flexible tube 43 simulates an artery
• a bypass tube 45 allows flow control in the system and simulates flow partition between blood vessels
• a Windkessel compliance chamber 46 is located proximal to the flexible tube 43 to control the pressure signal characteristics
• the system 51 of Fig 5 further includes an artificial stenosis made of a tube section 55, inserted within the flexible tube 43
• the tube section 55 is made from a piece of Teflon tubing
• the internal diameter 52 (not shown) of the artificial stenosis 55 may be varied by using artificial stenosis sections fabricated separately and having various internal diameter
• Fig 6 is a schematic cross sectional view illustrating a part of the fluidics system 51 in detail
• Pressure is measured along 5 the flexible tube 43 using a pressure measurement system including MIKRO-TIP pressure catheters 57,58 and 59, SPC-320, SPC-721 or SPR-524 pressure catheter, connected to a model TCB-500 control unit, commercially available from Millar Instruments Ine , TX, U S A
• the catheters 57,58 and 59 are inserted into the flexible tube 43 via the connector 10, connected at the end of the flexible tube i o 43
• the catheters 57,58 and 59 include pressure sensors 24A, 24B and 24C, respectively, for pressure measurements
• a fluid filled pressure transducer 31 is connected to the system 51 via the end of the guiding catheter 3, inserted into the flexible tube 43 via the connector 9
• the fluid filled pressure transducer 31 is connected to the system 51 , when additional pressure readings are needed, or in
• the system 51 of Fig 5 also includes a flowmeter 1 1 connected distal to the flexible tube 43 and a flowmeter 12 connected to the bypass tube 45
• the flowmeters 1 1 and 12 are suitably connected to the A/D converter 28
• the flowmeters 1 1 and 12 are model 1 1 1 turbine flow meters, commercially available
• the system 41 includes the system 51
• the system 41 also includes a signal conditioner 23 of the type sold as model TCB-500 control unit commercially available from Millar Instruments
• the signal conditioner 23 is suitably connected to the pressure sensors 24A, 24B and/or 24C
• the system 41 further includes an analog to digital converter 28 (E series Instruments multifunction I/O board 28 model PC-MIO-16E-4, commercially available from National Ine , TX, U S A ) connected to the signal conditioner 23 for receiving the conditioned analog signals therefrom
• the system 41 also includes a signal analyzer 25 connected to the A/D converter
• the signal analyzer 25 includes a computer (Pentium 586) 20, a display 21 connected to the computer 20 for displaying text numbers and graphs representing the results of the calculations performed by the computer 20
• a printer 26 is suitably connected to the computer 20 for providing hard copy of the results for 5 documentation and archiving
• the computer 20 processes the pressure data which is sensed by the pressure sensors 24A, 24B and 24C and acquired by the A/D converter 28 and generates textual, numerical and graphic data that is displayed on the display 21
• the I/O board was controlled by a Labview graphical programming software, i o commercially available from National Instruments Ine , TX, U S A 10 sec interval of pressure and flow data were sampled at 5000Hz, displayed during the experiments on the monitor and stored on hard disk Analysis was performed offline using Matlab version 5 software, commercially available from The MathWorks, Ine , MA, U S A
• the system uses various methods to determine the hemodynamic parameters defined herein above CFR, DSVR, and FFR All the methods are based on measurement or calculation of the pressure gradient (pressure drop) between two points along a blood vessel or tubular conduit These two points may be located proximal and distal to a stenosis an aneurysm or a section of the vessel
• the artery 30 may also include a stenosis 34, obstructing the blood flow Points A and B are located proximal and distal to the stenosis
• the pressure over time, P A (t) and P B (t) enable the calculation of the above mentioned parameters
• CFR CALCULATION In order to estimate the CFR value, pressure measurements are performed with the patient in REST and HYPEREMIA conditions CFR parameter is calculated using the following equation
• the method of CFR calculation uses the pressure difference across the stenosis over a full heartbeat
• the methods provided herein provide for the calculation of CFR as the ration of the flow diastolic maximum during vasolidation and at rest (Figure 40)
• the ratio of flows during vasolidation and rest is almost constant during systole
• CFR may be calculated as a ratio of maximal flows at rest and during vasolidation
• the flow is proportional to the square root of the pressure difference across a stenosis, yielding the following equation
• diastole DSVR parameter is calculated by using the following equation
• FIG 8 illustrating a cross section of an artery 30 having an arterial wall 32 and stenosis 34
• Two points, A and B proximal and distal to the stenosis define a section of the artery
• the hemodynamic parameters CFR, DSVR, and FFR, along this section are of interest
• a guiding catheter 3 (or diagnostic catheter, or any other hollowed catheter) is inserted into the blood vessel of interest
• Both pressure sensors are connected to signal conditioners 23A and 23B, of the kind described in Figs 1 , 1 a and 2, 2 a
• Step 1 Simultaneous measurement of pressure is performed by the two pressure sensors, yielding Pr t) and Pr B (t) The measurement is performed while the patient
• Step 2 Simultaneous measurement of pressures is performed again, by the two pressure sensors, yielding Pv A (t) and Pv B (t) The measurement is performed while the patient is under the effect of vasodilation dragues
• FIG 9 illustrating a cross section of an artery 30 with an arterial wall 32 and a stenosis 34
• Two points A and B upstream and downstream of the stenosis define a section of the artery
• the hemodynamic parameters CFR, DSVR, and FFR, of this section are of interest
• a guiding catheter 3 (or diagnostic catheter, or any other hollowed catheter) is inserted into the blood vessel of interest
• the tip of the catheter is positioned at point A, at the proximal section of the vessel
• a pressure fluid filled transducer 31 is connected to the external end of the catheter (point C) and measures the pressure at that point
• a single guide wire (6) having a pressure sensor at its tip (4B) is inserted trough the guiding catheter and positioned so that the pressure sensor 4B is located at point B
• the pressure sensor is connected to a signal conditioner 23 as described in Figs 1 ,1 a and 2,2 a
• Step 1 Simultaneous measurement of pressure is performed by the two pressure sensors, yielding Pr c (t) and Pr B (t) The measurement is performed while the patient is at rest
• Step 2 Simultaneous measurement of the pressure is repeated, yielding Pv c (t) and Pv B (t) The measurement is performed while the patient is at vasodilatation condition
• P A is considered to be equal to P c , (P A ⁇ P C ) All 3 parameters (CFR, DSVR, and FFR) are calculated using the equations described herein above
• Fig 10 illustrating the data acquired on paper (velocity of 25 mm/sec)
• the data was digitized using a computer software
• Graph 61 illustrates pressure data versus time during rest Curves Per and Pbr describe the pressure at points C and B, respectively
• Graph 62 illustrates pressure data versus time during vasodilatation Curves Pcv and Pbv describe the pressure at points C and B, respectively Due to the high pressure gradient across the stenosis (more than 10 mmHg at rest condition), the pressure measured by the fluid filled manometer (Pc) may be used instead of pressure data at point A
• the system was run in two different modes to simulate rest and vasodilatation conditions These modes were obtained by changing three variables of the in-vitro system including the pump flow, the bypass opening and closure, and the height of the output reservoir Yielding various flow levels through the stenosis, with stable physiologic input pressure, simulating the aortic pressure Flowmeter 1 1 data and pressure data from both sensors were obtained in each system mode Applying the analysis described in Method 2 to this data yields the FFR and CFR values
• Fig 12 illustrating a cross section of an artery 30 having an arterial wall 32 and a stenosis 34
• Two points, A and B, proximal and distal to the stenosis define a section of the artery
• the parameters CFR, DSVR, and FFR of this section are of interest
• a guiding catheter 3 (or diagnostic catheter, or any other hollowed catheter) is inserted into the blood vessel of interest 30
• An external fluid filled pressure transducer 31 is connected to the guiding catheter ostium (proximal end), measuring the pressure at point C (referred as fluid field pressure)
• One guide wire 6, having a pressure sensor at its tip 4 is inserted through the guiding catheter and positioned so that the pressure sensor 4 is located at point
• the pressure sensor 4 is connected to system 23 described in Figs 1 , 1 a and 2, 2 a Then, the pressure sensor 4 is moved to point B for further measurements
• Step 1 The pressure sensor 4 is located proximal to the stenosis, at point A
• Step 2 Simultaneous measurement of pressure by the two pressure sensors, 4 and 31 are obtained, yielding Pr A (t) and Pr-(t)
• the measurements are performed while the patient is at rest
• the pressure sensor 4 is moved to point B, distal to the stenosis
• Step 3 Simultaneous measurement of pressure is performed by the two pressure sensors, 4 and 31 Data of pressure versus time Pr B (t) and Pr c (t) is obtained
• Step 4 Inducing vasodilatation
• Step 5 Simultaneous measurement of pressure is performed by pressure sensors 4 and 31 , yielding Pv B (t) and Pv c (t) The measurements are performed during vasodilatation condition
• Step 6 Pressure sensor 4 is moved backward to point A , proximal to stenosis
• Step 7 Simultaneous measurement of pressure is performed by the pressure sensors 4 and 31 , yielding Pv A (t) and Pv c (t) is obtained
• Step 3 Perform FAST FOURIER TRANSFORM (FFT) on X1 (t) and Y1 (t)
• Fx FFT(X1 )
• Fy FFT(Y1 )
• Tea Pr A 3 CONV (Tea, Pr c 3) i o
• the simultaneous pressure proximal and distal to the stenosis is known (Pr A 3 and Pr B 3)
• the same procedure is used to determine the simultaneous pressure, proximal and distal to the stenosis during vasodilatation (Pv A 5 and Pv B 5)
• the calculation of the parameters CFR, DSVR, and FFR is performed using the equation mentioned herein above
• the system included a Latex test tube with a smooth stenosis model, 2cm long, with an internal diameter of 2 mm
• the stenosis was located 35 8 cm from the left bath edge Cordis 8F MPA-I was located within the connector 9
• One pressure transducer was located along the latex tube
• Another pressure transducer was located within the guiding catheter to simulate 25 fluid filled pressure readings
• the graph designated 66 is the 5 calculated pressure at point P
• the graph designated 67 is the actual pressure measurement at point P, as measured by the sensor 24D during the same heartbeat Almost perfect match exists between the two curves (66 and 67)
• Optimal Overlap Method i o
• the idea of the Optimal Overlap method is based on the observation that fluid filled pressure wave pulse P c (t) is mathematically similar to P A (t) but a delayed version of the latter
• the best stretching coefficient ⁇ and the best delay ⁇ t, for which the function ⁇ P 2 (T + ⁇ t) is globally close to the foot of P A (t) is determined
• the reason for the appearance of the stretch coefficient is a possible change in
• i be the index of N successive samples in the foot of the same heart beat (that 20 is from onset of systole to, say 80%, of the maximum of the pressure wave P A (t)) and t the corresponding sample times
• Fig 12 illustrating a cross section of an artery 30 having an arterial wall 32 and a stenosis 34
• Two points A and B upstream and downstream of the stenosis define a section of the artery
• the hemodynamic parameters CFR, DSVR, and FFR, along this section are of interest
• a guiding catheter 3 (or diagnostic catheter) is inserted into the blood vessel of interest
• An external fluid filled pressure transducer 31 is connected to the guiding catheter entrance (proximal end) measuring the pressure at point C (fluid filled pressure)
• a guide wire 6 having a pressure sensor at its tip 4 is inserted through the guiding catheter and positioned so that the pressure sensor 4 is located at point A downstream the stenosis
• Both pressure sensors 4 and 31 are connected to the system 23 described in Fig 1 ,1 a and 2,2 a
• Step 1 Simultaneous pressure and ECG measurements are performed Pressure are measured by two pressure sensors 4 and 31 Data of pressure versus time Pr A (t) and Pr c (t) and ECG are acquired, while the patient is at rest condition Step 2 Pressure sensor 4 is moved to point B, distal to stenosis Step 3 Simultaneous measurements of pressure and ECG are repeated, yielding data of pressure versus time Pr B (t) and Pr r (t) and ECG Step 4 Induce vasodilatation
• Step 5 Simultaneous measurement of ECG and pressure is repeated yielding data of pressure versus time Pv B (t) and Pv c (t), and ECG The measurements are performed while the patient is at vasodilatation condition Step 6 (optional) Pressure sensor 4 is pulled back to point A proximal to stenosis while simultaneous measurements of pressure and ECG are performed Data of pressure versus time Pv A (t) and Pv c (t) and ECG chart are obtained
• FIG 15 Aortic pressure was measured with a fluid filled manometer (not shown) connected to the guiding catheter 93 Pressure in the LAD artery was measured using a Radi pressure wire 91 at point A upstream of the stenosis 92 Then, the pressure wire 91 was moved to measure the pressure at point B downstream of the stenosis Measurements at point A were made during rest, and at point B and C, during rest and during intracoronary adenosine injection (vasodilatation condition) Pressure signals from the fluid filled manometer, Radi guidewire pressure sensor 91 and ECG were simultaneously recorded and stored with sampling rate of 1 kHz
• the Optimal Method is used to move the section assigned 76-76a of the 5 ECG signal 76 (measured when pressure sensor 91 is at point B) to the section 75-75a of the ECG signal 75 (measured when Radi pressure wire is at point A)
• Linear time transformation is applied to the signal 76, in order to match the time length of the signals 75-75a and 76-76a
• Fig 17 where the Curve 76t is the transformed ECG curve 76 i o
• the same time transformation (moving and stretching) is applied to the data measured by the fluid filled pressure transducer and Radi pressure wire
• Figs 18 and 19 Fig 18 illustrates the measured fluid filled pressure, curve 71
• Fig 19 describes the measured pressure at point A, curve 72, and the
• the mean values, as measured by the fluid filled manometer when Radi pressure wire is at point A or B are different
• the pressure measured at point B by Radi pressure wire is corrected according to the observed difference of the mean fluid filled pressure signals
• the mean pressure correction turns the
• Fig 20 illustrating the pressure and ECG signals corresponding to vasodilatation condition
• Curve 81 is the fluid filled pressure
• Curve 82 is the Radi pressure
• the suggested method of FFR calculation is more accurate then the standard method due to the fact that pressure data at point A is used instead of pressure data measured by fluid filled manometer
• Fig 24 illustrates synchronized and transformed pressure data at point A during rest (curves set 90), at point B during rest (curves set 91 ) and at point B during vasodilatation (curves set 92)
• Fig 25 illustrates the derived non-dimensional flow during rest (curves set 94) and during vasodilatation (curves set 93)
• the example is based on human pressure data measured in the LAD artery, using a standard fluid filled pressure transducer, Radi pressure wire by Radi Medical Systems AB, Uppsala, Sweden and doppler flow wire by Endosonics Data of ECG, pressures measured by Radi guide wire and fluid filled manometer were 5 recorded and printed simultaneously These data were scanned and digitized for computerized analysis Some fragments of the digitized pressure and ECG curves, are shown on Fig 29
• the graph designated 106 describes pressure and ECG curves measured at rest while the Radi pressure sensor is located proximal to the stenosis (point A) i o
• the graph designated 107 describes pressure and ECG curves measured at rest while the Radi pressure sensor is located distal to the stenosis (point B)
• the graph designated 108 describes pressure and ECG curves measured during vasodilatation while the Radi pressure sensor is located distal to the stenosis (point B)
• Curve 101 in graphs 106, 107, 108 illustrate
• Fig 30 illustrates three sets of pressure signals after ECG synchronization 1 Curves set 109 is the pressure signals measured at rest and proximal to the stenosis (point A) 2 Curves set 1 10 is the pressure signals measured at rest and distal to the stenosis (point B) 3
• Curves set 1 1 1 is the pressure signals measured during vasodilatation and distal to the stenosis (point B)
• Fig 32 illustrates the mean values of each set of the pressure curves shown in Fig 30, where Curve 1 12 is the mean value of the pressure signals measured at rest proximal to the stenosis (point A) Curve 1 13 is the mean value of the pressure signals measured at rest distal to the stenosis (point B), and Curve 1 14 is the mean value of the pressure signals measured during vasodilatation distal to the stenosis (point B)
• Fig 31 illustrates the non dimensional flow curves calculated from the curves of Fig 30
• the set of curves 1 15 describe the non dimensional flow during rest
• the set of curves 1 16 describe the non dimensional flow during vasodilatation
• Fig 33 describes the calculated mean non dimensional flow, where Curve 1 17 is the mean non dimensional flow at rest, and Curve 1 18 is the mean non dimensional flow during vasodilatation
• FIG 12 illustrating a cross section of an artery 30 having an arterial wall 32 and a stenosis 34
• Two points A and B upstream and downstream of the stenosis define a section of the artery
• the hemodynamic parameters CFR, DSVR, and FFR along the section are of interest
• a guiding catheter 3 (or diagnostic catheter) is inserted into the blood vessel of interest
• An external fluid filled pressure transducer 31 is connected to the guiding catherter entrance (proximal end) measuring the pressure at point C (fluid filled pressure)
• a guiding wire 6 having a pressure sensor at its tip 4 is inserted through the guiding catheter and positioned so that the pressure sensor 4 is located at point A downstream of the stenosis
• Both pressure sensors 4 and 31 are connected to the system 23 described in Figure 1 , 1 a, 1 b , 2, and 2 a Simultaneous ECG data is collected using standard instrumentation available at all times in all cathete ⁇ zation procedures
• Step 1 Simultaneous pressure and ECG measurements are performed
• the pressure transducer 4 is at point B Data of pressure versus time P RSt) and P RC( and ECG are acquired, while the patient is at rest condition
• Step 2 Induce vasolidation
• Step 3 Simultaneous measurements of pressure and ECG are repeated, yielding data of pressure verses time P RS(I) and P RC(t) and ECG The measurements are performed while the patient is at vasolidation condition Step 4 Pullback the pressure tansducer 4 to point A Step 5 Simultaneous measurement of ECG and pressure is repeated, yielding data of pressure versus time P ⁇ , and P C(I and ECG
• Fig 34 illustrating a cross section of an artery 30 having an arterial wall 32 and a stenosis 34
• the parameters CFR, FFR, and DSVR of this section are of interest
• a guiding catheter 3 (or diagnostic catheter, or any other hollowed catheter) is inserted into the blood vessel of interest
• the guide wire 6, having a pressure sensor at its tip 4 is inserted trough the guiding catheter and positioned so that the pressure sensor 4 is located at point A, proximal to the stenosis
• the pressure sensor 4 is connected to the system 23 described in Figs 1 ,1 a and 2,2 a
• Step 1 Measurement of pressure is performed by the pressure sensor 4, yielding Pr A (t) The measurement is performed while the patient is at rest condition
• Step 2 The pressure sensor 4 is moved upstream to point B .distal to stenosis Step 3: Measurement of pressure is performed by the pressure sensor 4, yielding
• Step 4 Induce vasodilatation Step 5 Measurement of pressure is performed by the pressure sensor 4, yielding Pv B (t) The measurement is performed during vasodilatation Step 6(opt ⁇ onal) Pressure sensor 4 is moved backward to point A, proximal to the stenosis, yielding Pv A (t) This step is optional The alternative is to rely on the 5 assumption that the pressure at point A during vasodilatation is equal to the pressure at point A during rest
• Optimal Overlap method is used to synchronize the pressure pulses i o measured at points A and B. Synchronization is achieved by moving the pressure signal measured at point B, so that its maximum value fits the maximum value of the other pressure signal (measured at point A) Now, simultaneous pressure data, proximal and distal to the stenosis, are available, and the hemodynamic parameters are calculated.
• a method for the determination of the hemodynamic parameters in a 25 non-obstructed vessel using a standard balloon, inserted into the blood vessel of interest Inflating the balloon induces an artificial obstruction
• the inflated balloon should not significantly impede the flow
• a minimal pressure gradient of about 4 mmHg in rest is required Pressures across the induced stenosis are obtained, and calculation of the hemodynamic Parameters are performed using one of the methods mentioned herein above
• the CFR 0 is then calculated according to the equations described herein above
• Fig 35 illustrating a cross section of an artery 30 having an arterial wall 32
• the parameter CFRo, of this section is of interest
• a guiding catheter 3 (or diagnostic catheter, or any other hollowed catheter) is inserted into the blood vessel of interest
• An external fluid filled pressure transducer 31 is connected to the guiding catheter ostium (proximal end) measuring the pressure at point C (fluid filled pressure)
• a guide wire 6, having a pressure sensor 4 at its tip is inserted through the guiding catheter and positioned so that the pressure sensor 4 is located at point
• Pressure sensor 4 is connected to system 23 described in Figs 1 ,1 a and 2,2 a
• a balloon catheter is then inserted into the blood vessel of interest 30 (not shown)
• Step 1 Simultaneous measurement of pressure is performed by the pressure sensors 4 and 31 , yielding Pr A (t) and Pr c (t) The measurements are performed while the patient is at rest condition Step 2 Reference is made to Fig 36 The pressure sensor 4 is moved to point B
• the balloon catheter 120 is inserted into the blood vessel 30 and positioned so that the balloon is located between points A and B At this stage the balloon 121 is inflated
• Step 3 Simultaneous measurement of pressure is performed by the pressure sensors 4 and 31 , yielding Pr B (t) and Pr c (t)
• Step 5 Simultaneous measurement of pressure is performed by pressure sensors
• the hemodynamic conditions of a healthy artery may be characterized by CFRo and the vascular bed index VBIo, where the index 0 refers to healthy vessels
• VBIo vascular bed index
• the new parameter VBIo that is introduced in the present study, is equal to the ratio of mean shear to mean pressure
• a numerical model of the blood flow in a vessel with a blunt stenosis and autoregulated vascular bed is used The exact autoregulation mechanism is unknown Therefore, two different possible autoregulation conditions were tested (i) constant wall shear stress and (n) constant flow The model is based on the comparison of flow in healthy and stenotic vessels
• METHOD 8 FFR calculation using moving pressure transducer.
• Fig 45 illustrating a cross section of an artery 30 having an arterial walll 32 and a stenosis 34
• Two points A and D upstream and downstream of the stenosis define a section of the artery
• the hemodynamic parameter FFR, along this section, is of interest
• Standard FFR measuiements proximal pressure P is measured by fluid fllled manometer distal pressure P ( is measured by Pressure Wire
• the pressure measured by fluid filled manometer may be different from aortic pressure due to improper height of the fluid filled pressure transducer This height must be adjusted when Pressure Wire transducer is put at the end of the guiding catheter
• the present system may easily require calibration between the two pressure sensors
• the same transducer is used to measure the pressure at the proximal and distal points.
• the Pressure Wire is put proximal to the stenosis.
• the Fluid filled pressure P, a and proximal pressure P a measured by Pressure Wire are 5 measured at point A and, subsequently, saved in the computer memory. Measurements are as follows: 1 measurement is performed at point A for about 10 seconds having about 12 pulses. Then move the transducer to point D and measure again for 10 seconds having about 12 pulses.
• the Pressure Wire is moved distal to the stenosis to point D.
• the Fluid filled pressure P ld and distal i o pressure P d measured by Pressure Wire during hyperemia are measured and, subsequently, saved in the computer memory. Then FFR is calculated using mean values of Pd and Pa measured by Pressure Wire.
• the pressure measured by Fluid Filled catheter is used only for correction in the change of the hemodynamic conditions.
• the maximum hyperemia is determined by calculating FFR for every heart beat.
• the following graph presents the two main parameters that affect the algorithm range of operation, and combines them in order to schematically present the active range of the algorithm.
• the invention also provides for various VB diseases: intrinsic, vasomotor aspects.
• the system provided herein which includes the Automatic Similar Transformation method was connected to a Siemens Cathcor cathlab monitor for acquisition of the aortirial pressure wave, the Radi pressure wave and the ECG.
• the ECG signal output included a triggering signal which processed ECG.
• the system included pressure wires and pressure wire interface box and a fluoroscopy system. The velocity signal was directly sampled and used the analogous output of the Endosonics FlowMap system and flow wires.
• Table 2 D.H.-. RCA 80-90% stenosis.
• Table 3 W.G. - CIRC 70-90% stenosis.
• Table 4 T. LAD 90% stenosis.
• HPG- ⁇ P vaS0 mean pressure gradient across stenosis during vasolidation
• AST Automatic Similar Transformation
• the animal was anesthetized, the chest opened and the heart exposed The LCX was then dissected to allow introduction of the pe ⁇ vascular flowprobe and the balloon occluder The animal was cathete ⁇ zed via the carotid, and a pressure wire was introduced Proximal and distal measurements were collected for each level of stenosis Vasodilatation response was induced using IC Papave ⁇ ne 4mg In the first two animals the vasodilatation dose for max hyperemic response was studied using a total occlusion technique A series of occlusions was introduced by slowly inflating the balloon occluder, or by using a snare. In each level of occlusion the required measurements were obtained. At each level of stenosis, the percent stenosis was estimated from a rentgen picture.
• the animals used were very stable and in a good physiological condition throughout the procedure.
• the target vessel was the LCX, where a straight section with no branches was easier to find. 5-6 levels of stenosis were induced in each animal. The level of stenosis was estimated after each measurement by a Rentgen picture.
• Vasodilator effect Vasodilatation was achieved by intracoronary Papaverine injection. The response to Papaverine was immediate, reaching the max hyperemia after about 45 sec. The data is presented in Table 6 and Figures 37 and 38. All together, 22 stenoses were studied, all shown in Figure 37. Very good correlation is observed between Automatic Similar Transformation (AST) method calculated parameters (CFR-AST) and the flow based CFR using the alleged gold standard CardioMed flowmeter (A-CFR). As expected, low correlation is observed only in few cases of very light stenosis (25%), where the pressure gradient reaches the low limit of the method. In Figure 38,21 of 22 values are presented and regressed. Only one point is excluded, representing a stenosis ⁇ 25%.
• Table 6 AST-CFR/FFR calculated values compared to flow based CFR and FF pressure.
• the measured hyperemic velocity corresponds to the measured hyperemic pressure gradient for a 52% stenosis, as shown in Table 10:
• the baseline velocity measured by the FlowWire is too low for the measured pressure.
• the HAPV (55 cm/s) and BAPV (27 cm/s) values were used instead of 50 cm/s and 30 cm/s as measured by Flow wire and obtain a CFR equal to 2.0 instead of 1 .7.
• PCI percutaneous coronary intervention
• PC1 currently is guided by anatomic rather than flow assessment of lesion severity.
• Physiologic parameters such as Coronary Flow Reserve (CFR) and Fractional Flow reserve (FFR) more accurately describe the severity of flow reduction but are cumbersome to measure clinically.
• CFR Coronary Flow Reserve
• FFR Fractional Flow reserve
• the System which includes the AST as described above, was connected to an Astro-Med cathlab monitor for acquisition of the arterial pressure wave and the ECG.
• a modified Radi Pressure Wire Interface Box was used to allow high frequency data acquisition.
• the pressure signal was directly sampled by the AST System.
• a Fluoroscopy system of the animal lab was used and a Transconic ultrasonic flowmeter (Model T206) with pehvascular flowprobes (2,3, and 4 mm). The flow signal was directly sampled by the AST System.
• the pigs were anesthetized, the chest opened and the heart exposed.
• the LAD was then dissected in two separate sites to allow introduction of the pehvascular flowprobe and the balloon occluder.
• One the preparation stage is over reference measurements are obtained.
• a series of occlusions is introduced by slowly inflating the balloon occluder. In each level of occlusion the required measurements for CFR/FFR calculations are obtained.
• Vasolidation was achieved eitehr by intracoronary Adenosine or intracoronary Papaverine injections.
• the effect of Papaverine is long (>3 min) but not different then the short effect of the Adenosine. Maximal hyperemia is achieved by both. When no effect was observed it was due to the compensatory vasolidation of the distal bed. The results are presented in Table 14 and Figure 39.
• BPG Base Pressure Gradient across stenosis at rest.
• HPG Pressure gradient across stenosis at vasolidation.
• intraluminal pressured derived coronary flow indices correlate closely with indices derived from Doppler flow data. Derivation of these indices from pressure is simpler and more reliable as this method is independent of velocity profiles which may be individually variable.
• the vascular bed index is the same for mother and daughter arteries, if the ratio of the diameters of these arteries follows Murray's law (the Murray law discussed in the paper Kassab G S , Fung Y B The pattern of coronary arteriolar bifurcations and the uniform shear hypothesis ) The VBI using human data obtained was calculated

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