WO2000053081A1 - A method and system for pressure based measurements of cfr and additional clinical hemodynamic parameters - Google Patents

Abstract

The present invention relates to intravascular pressure measurement based devices and methods determining clinical parameters related to stenosis severity for improved clinical diagnosis and treatment of cardiovascular disease in blood vessels or tubular conduits. More specifically, the invention provides methods for the determination of the clinically significant well known Coronary Flow Reserve (CFR) parameter-previously acquired by velocity measurement devices. In addition Coronary Flow Reserve in the same vessel without stenosis may be estimated and uses to select the necessary medical treatment. Additional pressure based clinical parameters, Diastole to Systole Velocity Ratio (DSVR) and Fractional Flow Reserve (FFR) in stenotic blood vessel during intervention (using only pressure measurements across stenosis) may also be calculated simultaneously, with the same set of interventional devices. Correlation of CFR with these parameters (e.g. FFR) may be further used to estimate the stenosis severity, downstream stenosis and the condition of the vascular bed or conditions related to aneurysms. It is known that there is a correlation between CFR and FFR for healthy vascular bed. Too low value of CFR for given FFR indicates either downstream flow restriction or insufficient infusion of vasodilator. Too high value of CFR for given FFR indicates vascular bed disease.

Description

A METHOD AND SYSTEM FOR PRESSURE BASED MEASUREMENTS OF CFR AND ADDITIONAL CLINICAL HEMODYNAMIC PARAMETERS

FIELD OF INVENTION

The present invention relates to the field of medical diagnostic and therapeutic devices in general and to a system for intravascular characterization of blood vessel lesions and vascular bed

BACKGROUND OF THE INVENTION Vascular diseases are often manifested by reduced blood flow due to atherosclerotic occlusion of vessels For example, 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 ) Often, stents are placed within the lesion so as to prevent re-closure of the vessel (also known as recoil)

Lesion characteristics, together with vessel condition proximal and distal to the lesion and vascular bed condition are used to determine the medically and economically optimal treatment method or combination of methods of choice Geometry, pressure and flow are three variables often measured in the cardiovascular system These measurements are performed prior, during and after the treatment, providing diagnostic and therapeutic data The measurement prior to the treatment allows careful treatment selection Measurements during and after the treatment enable evaluation of the treatment efficacy Recent progress in probe miniaturization opened a whole new range of pressure and flow measurements that have been previously impossible to perform

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. Other parameters have been defined and proven more effective as indicators for lesion severity 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 Hyperemic conditions are obtained by administration of vasodilators (e g papaveπne, 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 A notable difference between diastolic to systolic velocity ratio (DSVR) was observed between normal and stenotic arteries A cut-off value of 1 7 was proposed to distinguish between significant and non-significant lesions

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 (Di Mario et al , Catherization and Cardiac Diagnosis 38, 189-201 ,1996) 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

Major technical progress has been made lately with respect to pressure and velocity monitoring guide wires For example, 0 014" Pressure Wire™ (Radi Medical System, Uppsala, Sweden) is now available for intracoronary pressure measurements However, for light stenosis, these measurements may be performed using diagnostic low profile catheters, Millar pressure transducer catheters (available by Millar Instruments, Ine , Houston, Texas, U S A ) or any other intravascular pressure equipment

A 0 014 Doppler Flow wire (Cardiometπcs Ine , Mountain View, CA) is now available for intracoronary velocity measurements Both wires may be advanced into distal parts of the coronary tree without significantly impeding the flow Simultaneous measurements of FFR and CFVR require the use of both wires Such a procedure is complicated, expensive and was used only for research purposes Therefore, clinicians use either velocity measurements to calculate coronary flow velocity reserve (CFVR) or pressure measurements to calculate fractional flow reserve (FFR) Furthermore, working with the Flow wire is sensitive to the location of the tip within the vessel cross section The wire tip will measure accurately if located along the longitudinal axis However, significant errors will appear once the wire is within the boundary layer Therefore, manipulating the Flow wire requires high expertise and a lot of experience Fortunately, these limitations are not relevant to the pressure wire measurements, yielding accurate data with simple handling SUMMARY OF THE INVENTION

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 In addition coronary flow reserve in the same vessel without stenosis (CFR₀) may be estimated as well as aneurysms FFR, CFR, CFR₀ and DSVR are simultaneously calculated for a complete characterization of the vessel of interest . Further, 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

Further, this invention provides the determination of a hemodynamic condition of the artery by determining the vascular bed index (VBI₀) which is equal to the ratio of mean shear to mean pressure The invention provides a system and methods for determining the vascular bed index Further, 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 Also, 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 Further, Post Stenting in combination with a deflated balloon allows the estimation of CFR of the vessel Thus, in one embodiment of the invention only a distal pressure measurement will allow the CFR calculation

Lastly, 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

BRIEF DESCRIPTION OF THE DRAWINGS The present invention will be understood and appreciated more fully from the following detailed description taken in conjunction with the appended drawings in which like components are designated by like reference numerals 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 37 In-vivo canine data of CFR -F which uses the Automatic Similar Transformation method and CFR flow

Fig 38 In-vivo canine data of CFR -F which uses the Automatic Similar Transformation method and CFR flow

Fig 39 In-vivo pig data of CFR -F which uses the Automatic Similar Transformation method and CFR flow

Fig 40 Results of flow calculation using only pressure measurements across stenosis Fig 41 Results of flow calculation using only pressure measurements across stenosis

Fig 42 Results of VBI calculation based on human data

Fig 43 Block diagram of Automatic Similar Transformation (AST) Method Fig 44 In-vivo human data of CFR which uses the AST Method

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

DETAILED DESCRIPTION OF THE INVENTION

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 mmHg However, using advanced methods of analysis, will allow to reduce this limitation to about 0 5 mmHg As provided herein, the methods and systems described allow the calculation of both coronary flow indices, CFR and FFR directly from intrarterial pressure measurements The pressure derived flow indices correlated with and accurately predicted actual flow measurements By applying the methods percutaneous coronary interventions (PCI) decisions may be accurately made so as to achieve reduction in flow limiting ischemia The results presented herein based on both a Computational Fluid Dynamic (CFD) simulation and confirmance by in-vivo experiments demonstrated that the methods and systems provided herein, at all levels of stenosis severity, pressure measurements derived indices of CFR and FFR had superior correlation with actual flow indices

Further, the present invention provides methods and a system for calculation of CFR and FFR from on line intra-artenal 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

In the work of Wong M , V ayaraghavan G , Bae J H Shah P M " In Vitro Study of Pressure-Velocity Relation Across Stenotic Orifices, published in the American Journal of cardiology, v 56, pp 465-469 pressure - flow relation across stenotic orifices was investigated in pulsatile in-vitro model They had shown that for short stenosis the pressure - flow relation is independent of the orifice size, for a wide pressure range The relation is quadratic and crosses zero This means, that in short stenosis, the pressure gradient across the stenosis (Δp is a quadratic function of flow (Q) Δp = K Q² (1 )

Where K is a constant determined solely by the stenosis diameter If pressure measurements are obtained simultaneously upstream of the stenosis and downstream of the stenosis during rest and during hyperemia, then flow at rest across the stenosis may be calculated using the equation

And the hyperemic flow may be found using the equation

K) (3)

Where Δp_resl , Q_rest and Δp_hyper , Q_hyper are the pressure differences across

J e stenosis and flow during rest and hyperemia respectively. The coronary flow reserve (CFR) 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.

liR

Assuming the stenosis geometry is similar during rest and hyperemia, then K in equations (2) and (3) cancels out

Therefore, the coronary flow reserve (CFR) 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. In the case of an arbitrary stenosis, the pressure difference across the stenosis may be expressed as (Young

π D F Tsai F Y Flow characteristics in model of arterial stenosis - II Unsteady flow J Biomechanics, 1973 vol 6, pp 547-559)

Δp =K₁Q+K₂Q² +K₃dQ/dt

5 In the physiological range, the first and last components of this equation are small With accuracy of 1 mmHg, equations (2) and (3) may be used If Δp across the stenosis is more then 4 mmHg, the accuracy of CFR calculation will reach (10%)

CFR₀ is the coronary flow reserve of a healthy vascular bed without stenosis i o Using the following notations

Q mean flow over a heartbeat in a stenotic vessel at rest,

Q^v mean flow over a heartbeat in a stenotic vessel during hyperemia

(vasodilatation),

Q _N mean flow over a heartbeat in the same non-stenotic vessel at rest, 15 Q_NV - mean flow over a heartbeat in the same non-stenotic vessel during hyperemia (vasodilatation),

Pa Aortic pressure

Pd Mean distal pressure at rest Then,

2 0

O^v

CFR = CFR _a = FFR = -- :

Q Q,

25 and,

CFR . ₌ ^Q ^ . _CFR ^Q

Q Q Q FFR Q _N The vascular bed autoregulation tends to compensate hydraulic resistance of the stenosis, so at rest Q = Q_N, hence CFRo =CFR / FFR

If CFR and FFR are known, then the coronary flow reserve (CFRO) in the same vessel, in case of healthy vascular bed, may be derived A too high or too low value of CFR₀ 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

In the preferred embodiment, 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 In one embodiment, the systems provided herein include the AST method

In the AST method, every pulse p(t) 0<t1 <t2 is mapped to the time interval [01 ] using the following transformation P(τ)=P((τ-t1 )/(t-t2))) 0<τ<1 Then mean pressure pulse P _mean (τ) is calculated, using averaging over all pulses for a give τ Six pressure signals result mean proximal fluid filled pressure Fp(τ), mean proximal pressure, measured by pressure transducer Pp(τ), mean fluid filled pressure Fd(τ) and mean pressure transducer pressure Pd(τ) both measured at rest when pressure transducer is distal to stenosis mean fluid filled pressure Fv(τ) and mean pressure transducer pressure Pv(τ) both measured during vasolidation when pressure transducer is distal to stenosis Pressure signals Pd(τ) and Pv(τ) are corrected to the changes in aortic pressure

Pd(τ)=Pd(τ) ^*mean(Fp(τ) )/mean(Fd(τ) )),

Pv(τ)=Pv(τ) ^*mean(Fp(τ) )/mean(Fv(τ) )), Now pressure Pp(τ), Pd(τ), and Pv(τ) are used to calculate CFR, FFR, and DSVR In the pulse detection using only pressure signal the pulse detection is based on the pressure signal measured by moving pressure transducer The pulse detection method consists from following stages

1 FFT (fast Fourier transform) of the measured pressure signal in proximal point at rest (P.(t)), in distal point at rest (P₂(t)) and in distal point during vasodilatation (P (t))

2 The frequency corresponding to the maximum value of the Fourier coefficients in the interval (0 5 - 10 Hz) is used as the pulse frequency c , (for P, series), ω₂ (for P₂ series), o>₃ (for P₃ series). 3 For every pressure series P, pressure the times of every pulse maximums t_ιm are found using following steps a First maximum must be found in the interval 0<t< c ^*f, were f is the sampling rate b The pressure maximum number k is looking for in the interval (t_{m k 1}+0 5^*c .^*f, t_{m k 1} +1 5^*o ^*f)

4 Finding time T_{m (}, when pressure reach minimum in the time interval (t_{m k} ,, t_m Points T_{m k} are points of the beginning of the pulse number k (hence end of the pulse k-1 ) The measured pressure signal is now divided into pulses For pulse selection, the following steps are taken

1 For every pulse calculate length' Ip of the fluid filled (P_f) and pressure (P_r) signal using equation Ip = mean(P²)-mean(P)^*mean(P), where mean is calculated over one heartbeat P means P_f or P_r

2 Only pulses with lp_f/lp>thesh are considered (here Ip, and Ip are the length of fluid filled and pressure pulses respectively, tresh is a number (in software realization tresh=0 1 )) This allows throwing away pulses with drug admission Every pulse is mapped to time interval (0,1 ) with sampling rate 200Hz as in the previous version of the algorithm Mean pulses P_1m and P_2m at rest are calculated from pressure series

P-,(t) and P₂(t) as in the previous algorithm (for example P_1m(k)=mean(P₁(k)), 1 <k<200 tιme point number for interpolated pulse Mean value is calculated over all pulses remaining after stage

2) Due to difference of the pulse shape before and after stenosis the position of the pulse minimum may be different relative to the systole beginning To compensate, the following cycle pressure steps are taken

a Double pulse P_2m P_{2m double}(1 400)=[ P_2m (1 200), P_2m (1 200)] b Calculate

c Find k_mιn, the value of k when s(k) reach minimum Instead P_2m use P__ =P_{2 ll d0Ub},_e(k_{m n} k„_n+200) The steps of step 5 applied to every n-th pulse P _n(1 200) remaining after stage 2 Then CFR_n for this pulse is calculated using equation

c rR = (∑^P (/) - /i (/) '∑-/7 / ) - /^> ( )

The pulse n_maλ when CFR_n reach maximum must be found Mean pulse during vasodilatation P₃ - is calculated as mean for 5 pulses n_max-2 n_max+2 Then CFR and FFR are calculated 9 d Double pulse P₂ - P_2Tldouble(1400)=[ P_2ll (1200) P_2m (1200)] e Calculate

i(λ)= ∑(P , „ ( +ι)-P_t (/))

f Find k_mn, the value of k when s(k) reach minimum Instead P_2m

^USe P2m~P2mdouble(kτιπ ^,- + 200)

10 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

CFR = (∑^P (/)-/^> (ι)/∑ ^> (ι)-P_t (X)

I I

11 The pulse n_max when CFR_n reach maximum must be found Mean pulse during vasodilatation P_3τι is calculated as mean for 5 pulses n_^a-,-2 n-_nax+2 Then CFR and FFR are calculated

In another embodiment CFR may be calculated based on the difference across the stenosis may be estimated from the volume flow rate 0(t) the minimal stenosis cross-sectional area I and the healthy vessel cross-sectional area A using the Young-Tsai (Young D F Tsai F Y A flow characteristics in model of arterial stenosis A B II Unsteady flow J Biomechanics 1973 vol 6 pp 547-559) equation upon one-heart beat (u=Q/A₀)

Δ/^J = A // +λ // (1)

k =4 u k /{τ D ) Λ „ = ^"-2 ' I ' (0 83 ' / + I M * D )/(/) I )

u mean velocity CQ=1 1 AO cross-sectional area of a vessel

DO cross-sectional diameter of a vessel p blood density μ blood viscosity LS stenosis length

If mean(u²)=b»mean(u)², then (HPG-hyperemic pressure gradient, BPG -

baseline pressure gradient) BPG =K1 ^*b^*(Q/A₀)² HPG =K1 ^*b^*(Q_v/A₀)², Q, Q_v - flow at rest and during vasodilatation respectively, then HPG/BPG= (Q_v /Q)²

CFR= Q_v /Q, hence CFR=sqrt(HPG/BPG) In another embodiment flow was calculated using only pressure measurements across a stenosis The flow (ml/min) in rest and after vasodilatation is determined based on measured FFR The following relation between FFR and % stenosis was determined

st nosis ) 8861 + 0 0641 FFR - 0 67^ / ER

(3)

If the % stenosis is known, then the mean velocity u may be calculated by Young&Tsai equation (without linear term) The flow Q may be calculated if the diameter d of the vessel is known (Q=u^*πd /4) FFR can be used to estimate % stenosis As shown in Figure 40 hyperemic flow and flow at rest for all 4 dogs are presented The hyperemic results are acceptable for all dogs (correlation coefficient R=0 94) The correlation coefficient at rest is relatively low (R=0 77) mainly due the fourth dog Correlation between measured and calculated flow for first 3 dogs is better, as may be seen from fig 41 a and 41 -b (R=0 88 at rest and R=0 95 during vasodilatation)

Reference is now made to Figs 1 , 1 a, 1 b 2 and 2 a Figs 1 , 1 a and 1 b 5 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,

15 Minneapolis, U S A ) or a diagnostic catheter (e g Siteseer diagnostic catheter, from Bard Cardiology, U S A ), a balloon catheter (e g Supreme fast exchange PTCA catheter, by Biotronik GMBH & Co, U S A ) or 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

20 (standard catheteπzation lab equipment), connected via the end of the guiding catheter 3 for measuring the pressure inside a blood vessel In an exemplary embodiment 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 Cardiometπcs 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

30 model TCB-500 control unit commercially available from Millar Instruments, or Radi Pressure Wire Interface Type PWI 10, Radi Medical Systems, Upsala, or other suitable signal conditioner 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 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

15 ECG is also available from the monitor using standard equipment and procedures 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

20 The systems 1 and 1 a also include a signal analyzer 25 connected to the

A/D converter 28 for receiving the digitized conditioned pressure signals from the A/D converter 28 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

25 printer 26 suitably connected to the computer 20 for providing hard copy of the results for documentation and archiving 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

30 shown) and generates textual, numerical and/or graphic data that is displayed on the display 21 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

Reference is now made to Figs 4, 5 and 6 for purposes of illustration 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

15 pump 42 re-circulates distilled water from a water reservoir 15 to a water reservoir 14

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 The flexible

2 o tube 43 is connected to the pulsatile pump 42 and to other system components by Teflon tubes All the tubes in system 51 have 4 mm internal diameter 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 A Windkessel

25 compliance chamber 47 and a flow control valve 48 are located distal to the flexible tube 43 to simulate the impedance of the vascular bed 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

Reference is now made to Fig 6, which 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

15 place of an intravascular pressure transducer, according to the defined experiment

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

20 from McMillan Company, TX, U S A

Reference is now made to Fig 4 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

25 for amplifying the pressure signals 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

30 28 for receiving the digitized conditioned pressure signals from the A/D converter 28 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

15 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

20 where the wall characteristics are of interest

The methods described herein below are more efficient and accurate than the existing tools and methods First the possibility to obtain multiple parameters in one procedure with one set of equipment allows the physician to gain a more comprehensive estimation of the vascular bed condition Second, the pressure

25 based CFR estimation presented herein is more accurate and robust than the velocity based CFR The reasons for this include the change in the velocity prof lie between rest and vasodilatation conditions, the errors introduced due to mal- positioning of the sensor within the vessel cross-section and also patient breathing and motion Lastly, the methods presented here are less sensitive to instability

30 (drift or jump) of the pressure transducers, and when instability is identified, correcting procedure is short and presents no further risk to the patient (no need to re-cross the lesion)

Reference is now made to Fig 7 describing a section of blood vessel 30 having an arterial wall 32 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

Depending on the parameter of interest, measurements of the pressure gradient across the stenosis or aneurysm during various physiological conditions are needed

1 REST condition The patient is in normal condition, without any effect of dragues causing changes in blood pressure or flow rate

2 HYPEREMIA / VASODILATATION condition The patient is under the influence of dragues causing dilatation of the vascular bed, resulting in an increase blood flow rate

3 SYSTOLE

4 DIASTOLE

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

} J Pv , - Λ , ) dt _o _____

CFR

where

Pv_A and Pv_B Pressure during hyperemia at points A and B respectively Pr and Pr Pressure at rest at points A and B respectively t Time

T Time of one heart beat

CFR CALCULATION using maximal diastolic flow maximum

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) As shown in Figure 1 1 , the ratio of flows during vasolidation and rest is almost constant during systole Hence, as provided herein, 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

This method of CFR calculation is beneficial foi stenosis with small mean pressure gradient at rest The maximal diastolic flow may be 1 5 - 2 times higher then the mean flow Therefore, the maximal flow pressure gradient at rest is 2-4 times higher than the mean pressure gradient As a result, good estimation of the CRR may be achieved even for pressure gradient at rest of 1 -2 mmHg or less This reduces a limitation is calculating the CFR parameter in cases where the pressure gradient across the stenosis is very low Consequently, allowing the calculation of the CFR parameter in most cases Accordingly, the present invention provides a method which incorporates calculating CFR using flow integral or using maximal diastolic flow as hereinabove described

DSVR CALCULATION In order to estimate DSVR, pressure data is required at REST condition only The pressure gradient between points A and B during diastole and during systole are calculated separately Therefore, simultaneous pressure data

_ _at points A and B are required during systole and diastole DSVR parameter is calculated by using the following equation

J( Prd_A - Prd_B ) dt diastole

DSVR =

syslolθ

Prd_A pressure at point A at rest during diastole Prd_B pressure at point B at rest during diastole

Prs_A pressure at point A at rest during systole

Prs_B pressure at point B at rest during systole

FFR CALCULATION In order to estimate FFR, pressure data during HYPEREMIA condition is required

FFR parameter is calculated using the following equation

Pv_B FFR = Pv_A where

Pv_B Mean pressure at point B during hyperemia Pv Mean pressure at point A during hyperemia

METHOD 1 : SIMULTANEOUS TWO SITES PRESSURE MEASUREMENTS

Reference is now made to 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 Two guide wires 6 and 7, each having a pressure sensor at the tip 4A or 4B, are inserted through the guiding catheter and positioned so that one pressure sensor (4A) is located at point A, proximal to the stenosis, and the second pressure sensor (4B) is located at point B, distal to the stenosis Both pressure sensors are connected to signal conditioners 23A and 23B, of the kind described in Figs 1 , 1 a and 2, 2 a

DATA ACQUISITION The following steps are performed to obtain the required data

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

DATA ANALYSIS

All 3 parameters (CFR, DSVR, and FFR) are calculated using the equations mentioned herein above METHOD 2: SIMULTANEOUS TWO SITES PRESSURE MEASUREMENT USING A FLUID FILLED PRESSURE TRANSDUCER

Reference is now made to 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

The pressure gradient between points A and C (P_A-P_C) are known to be small Therefore, it is assumed that P_A ( P_c In cases of severe or moderate stenosis, the pressure gradient is P_B-P_{C >} 10 mmHg The pressure difference P_A-P_C is negligible (comparing to P_B-P_C ) Therefore, the assumption that P_A-P_C does not affect the coefficients (CFR, DSVR and FFR) calculated values In cases of light stenosis the use of this method is not recommended

In another embodiment the pressure measured by the Pressure Wire, the mean fluid filled pressure pulse ff_m is corrected in accordance with the floowing equation for every pulse the correct pressure P measured by the Pressure Wire multiplicatively is Pc(t)=P(t)^*ff(t)/ff_m(t) Here Pc(t)corrected pressure, ff(t) pressure measured by fluid filled manometer

DATA ACQUISITION

The following steps are performed to obtain the required data 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

DATA ANALYSIS

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

CLINICAL EXAMPLE

Human test data are used to demonstrate the implementation of this method Pressure measurements were performed during rest and vasodilatation conditions The pressure was measured proximal to the stenosis (point A of Fig 9) using a fluid filled pressure sensor, and distal to the stenosis (point B of Fig 9) using Radi pressure wire

Reference is now made to 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

Reference is now made to Fig 1 1 which illustrates the calculated non-dimensional flow ratio versus time Then, the parameters CFR and FFR are calculated FFR = 0 46 and CFR = 1 48 IN-VITRO EXAMPLE

In vitro experiment was performed, using the in-vitro test system described in Figs 4, 5 and 6 The experimental section included an artificial stenosis (90% area reduction) Two pressure sensors (Millar SPC-524) were located, one 2 cm proximal to the stenosis and the second 2 cm distal to stenosis The system was running with a glycerin water solution to simulate blood viscosity

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

The results are presented in Table 1 , where the cases refer to different levels of flow through the system

A high correlation is observed between CFR value derived from actual flow measurements and from pressure measurements METHOD 3: NON-SIMULTANEOUS PRESSURE MEASUREMENTS WITH FLUID FILLED PRESSURE SYNCHRONIZATION

Reference is now made to 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

A proximal to the stenosis 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

DATA ACQUISITION

The following steps are performed to obtain the required data 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

DATA ANALYSIS To calculate hemodynamic parameters, simultaneous pressures at points

A and B are required Two independent methods where developed, synchronizing the pressure data at rest and vasodilatation conditions Once all pressures signals are available, the parameters CFR, DSVR, FFR are calculated using the equations mentioned herein above

Pressure Transfer Function

The measurements described previously are used to determine the transfer function of pressure between points C and A (Tea) using data acquired in step 1 Alternatively, transfer function between points C and B (Tcb) can be calculated, using data acquired at step 3 Once the transfer functions are known, pressure data at point A (or B) can be calculated from the known pressure at point C

Input

Data acquired at step 1 Pr_A1 (t) , Pr_c1 (t) Data acquired at step 3 Pr_B3(t) , Pr_c3(t)

Steps

Step 1 : Shift the pressure signal Pr_c1 (t) to yield a new pressure signal X1 (t) with mιn [X1 (t)] = 0, X1 (t) = Pr_c1 (t) - mm [Pr_c1 (t)]

Step 2: Shift the pressure signal Pr_A1 (t) to yield a new pressure signal Y1 (t) with mιn [Y1 (t)] = 0, Y1 (t) = Pr_A1 (t) - mιn[Pr_A1 (t)]

Step 3: Perform FAST FOURIER TRANSFORM (FFT) on X1 (t) and Y1 (t) Fx = FFT(X1 ) Fy = FFT(Y1 )

Step 4: Calculate the transfer function (H) in Fourier space H = Fy / Fx 5 Step 5 Calculate transfer function (Tea) in time space using INVERSE FAST FOURIER TRANSFORM (IFFT) Tca(t) = IFFT(H)

Step 6: Calculate pressure at point A, Pr_A3(t), from the known pressure at point C, Pr_c3(t), using convolution with the transfer function Tea Pr_A3 = CONV (Tea, Pr_c3) i o Now, the simultaneous pressure proximal and distal to the stenosis is known (Pr_A3 and Pr_B3) The same procedure is used to determine the simultaneous pressure, proximal and distal to the stenosis during vasodilatation (Pv_A5 and Pv_B5) The calculation of the parameters CFR, DSVR, and FFR is performed using the equation mentioned herein above

15

IN VITRO EXAMPLE

In vitro experiment was performed to validate the transfer function Method 1 , using the in-vitro test system described in Figs 4 5 and 6 The system was set

20 to 51 strokes/mm and 9 cc/stroke 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

Reference is now made to Fig 13, illustrating the positioning of the pressure sensors 24P and 24S, and the artificial stenosis 55, within the latex test tube, 43 The method 1 is applied to the pressure data at points S and P, to calculate the transfer function between these points, Tsp Then, the pressure at point D was

30 calculated using the pressure measured at point P, at a different time, and applying the calculated transfer function This calculated pressure value was compared with the actual pressure at point D as was measured by the sensor 24D during the same heartbeat

The results are described in Fig 14 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 Thus the best stretching coefficient β and the best delay Δt, for which the function β P₂(T +Δt) 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

15 pressure between measurements Mathematically, a minimum distance in L₂ norm, or equivalently a least square criterion is required Thus, the least square optimal overlap methods can be formulated as follows

Let 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

METHOD 4 : NON-SIMULTANEOUS PRESSURE MEASUREMENTS WITH ECG SIGNALS SYNCHRONIZATION

25

Reference is now made to 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

^"Simultaneous ECG data is collected using standard available, at all times, in all cathetenzation procedures

DATA ACQUISITION

The following steps are performed to obtain the required data

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

DATA ANALYSIS

To calculate hemodynamic parameters simultaneous pressure at points A and B during rest and vasodilatation are required The pressures at points A and B during rest are measured, but non-simultaneously Time synchronization is performed using the idea that the ECG signals are stable while measuring pressure at points A or B Therefore, synchronizing the ECG signals, results in synchronization of the pressure signals at points A and B Synchronization is achieved by applying Method 2, with the ECG signals used instead of the fluid filled pressure signals For the vasodilatation condition, it is possible to measure pressure only at point B (downstream) The enlargement of the vessel wall during vasodilatation is negligible proximal to the stenosis, at point A Therefore, it can be assumed that Pv_A = Pr_A, and step 6 of this method may be skipped The simultaneous pressures at point A and B during vasodilatation is calculated Then, the parameters CFR, DSVR and FFR are derived using the equations mentioned herein above

CLINICAL TEST EXAMPLE 1

Data of pressure measurements of a 70 years old woman were used for estimation of CFR, DSVR and FFR The patient had two lesions in the mid and distal sections of the LAD

Reference is now made to 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

Data analysis included the calculation of CFR, DSVR and FFR using ECG synchronization Reference is now made to Fig 16, illustrating the pressure and ECG signals measured at rest (Radi pressure wire is located at point A and subsequently at point B) Curve 71 is the fluid filled pressure and Curve 72 is the pressure measured by sensor 91 , when the Radi pressure wire is at point A Curve 73 is the fluid filled pressure and Curve 74 is the Radi pressure measured at point B Curve 75 is the ECG signal measured when Radi pressure wire is at point A Curve 76 is the ECG signal measured when Radi pressure wire is at point B

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 The result of this transformation is shown in 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 The results of this transformation are shown in Figs 18 and 19 Fig 18 illustrates the measured fluid filled pressure, curve 71 , and the transformed fluid fllled pressure curve 73t Fig 19 describes the measured pressure at point A, curve 72, and the

15 transformed pressure of point B, curve 74t

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

20 calculation of the hemodynamic parameters using a moving pressure transducer more accurate, because it allows to exclude changes in the aortic pressure between measurements at points A and B Now the pressure measured at point A and the corrected pressure at point B (curves 72 and 74t on Fig 19) are used to calculate the non dimensional flow at rest The mean value of the non dimensional

25 flow is equal here to 1 8

Reference is now made to Fig 20, illustrating the pressure and ECG signals corresponding to vasodilatation condition The pressure upstream the stenosis (point A) during vasodilatation, is assumed to be equal in rest and vasodilatation conditions Curve 81 is the fluid filled pressure and Curve 82 is the Radi pressure,

30 measured when Radi pressure sensor 91 is at point A and during rest Curve 83 is the fluid fllled pressure and Curve 84 is the sensor 91 pressure, both measured when Radi pressure wire is at point B and during vasodilatation Curve 85 is the ECG signal measured when Radi pressure wire is at point A, at rest Curve 86 is the ECG signal measured when Radi pressure wire is at point B, during vasodilatation

The time transformation (moving and stretching) described herein above, is applied to the ECG measurements performed when Radi pressure wire is at point A at rest, and at point B during vasodilatation The moved and stretched ECG signal (curve 86t) and the ECG signal 85 are shown in Fig 21 The above analysis for data during vasodilatation is applied The results of the transformation are shown in Figs 22 and 23 Fig 22 illustrates the measured fluid filled pressure curve (81 ) and also the transformed fluid filled pressure curve (83t) Fig 23 describes the measured pressure curve at point A (82) and the transformed pressure curve of point B (84t) The mean value of the non dimensional flow during vasodilatation is 2 8 Now, the parameters of interest are calculated

FFR is calculated using the mean value of pressure measured at point A and the mean value of corrected pressure measured at point B, both during vasodilatation (shown in Fig 23), resulting in FFR=0 85 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

CFR is calculated as the ratio of the non dimensional flows during vasodilatation and rest CFR = 2 8 / 1 8 = 1 55

The procedure as described above, may be applied to a set of heartbeats 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)

CFR and FFR values as calculated for each pulse are shown in Fig 26 The mean value of CFR is 1 63, and the mean value of FFR is 0 85 A different analysis approach is to calculate the mean value of pressure (over multiple heartbeats), for every normalized (non-dimensional) time Fig 27 presents the pressure mean value at points A and B during rest (curves 95 and 96), and pressure at point B during vasodilatation (curve 97) Non-dimensional flow is calculated using these mean values, shown in Fig 28 Curve 98 is the calculated non dimensional flow during vasodilatation Curve 99 is the non dimensional flow during rest

CFR and FFR calculated this way are CFR= 1 61 and FFR= 0 87 These values are highly correlated to the values received above The data as shown in Fig 27 enables estimation of the third parameter mentioned above, the diastole to systole velocity ratio (DSVR) In this case DSVR=1 3

The parameters of interest were calculated for the same set of raw data using other methods proposed herein Using Method 2, Optimal Overlap Method CFR=1 92 , FFR=0 78 Using Method 5, synchronization by max pressure signal CFR=1 46 , FFR=0 81 , DSVR=1 15

CLINICAL TEST EXAMPLE 2

This example demonstrates the use of pressure data for CFR and FFR calculation using Method 4, ECG based signal synchronization The data includes blood flow measurements using the Flow wire by Endosonics, enabling the validation of the pressure based methods presented in this patent for derivation of CFR, FFR and DSVR It is shown that highly correlated values were derived for these parameters, using both methods

DATA ACQUISITION

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 illustrates the fluid filled manometer

15 measurement Curve 102 in graphs 106, 107, 108 illustrates the pressure measurement measured by the Radi pressure sensor Curve 103 in graphs 106, 107, 108 illustrates the ECG measurement Note that only the main peak of the ECG signal was digitized These data were used for CFR calculation DATA ANALYSIS

20 Method 4 was applied to calculate CFR Results of calculations are shown in Figs 30, 31 , 32 33 Reference is now made to Fig 30 which 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

25 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

From Fig 31 one may see, a major dispersion of the calculated flow during systole Flow calculated for various heartbeats during diastole is consistent The mean value of CFR (averaged over all heartbeats) is CFRm = 1 56 The mean value of FFR (averaged over all heartbeats) is FFRm = 0 79 In practice, CFR is usually determined as a ratio of the peak distal velocities In this case, the ratio of the flow at points M and N as marked in Fig 32 is CFRv = 1 86 Using the blood flow measurements during rest and during vasodilatation, CFR and FFR are calculated CFR = 1 8 and FFR = 0 75 The results using pressure measurements or flow rate measurements are highly correlated

METHOD 4A: PULLBACK PRESSURE MEASUREMENTS WITH ECG SIGNALS SYNCHRONIZATION

Reference is now made to Figure 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 catheteπzation procedures

DATA ACQUISITION The following steps are performed to obtain the required data

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

DATA ANALYSIS

To calculate hemodynamic parameters, simultaneous pressure at points A and B at rest and during vasolidation are required The pressures at points A and B during rest and vasolidation are measured but non-simultaneously Time synchronization is performed using the method that ECG signals are stable while measuring pressure points at A or B Therefore, synchronization of the ECG signals results in synchronization of the pressure signals at points A and B Synchronization is achieved by applying the method relating to Method 2, with the Ecg signals used instead of the fluid filled pressure signals For the vasolidation condition, it is possible to measure pressure only at point B (downstream) since P_VA = P_RA Then, the parameters CFR, DSVR, and FFR are derived using the equations mentions hereinabove This method is more robust to changes in pressure accuracy due to drifting effects as the proximal and distal pressure measurements are taken in a short time

METHOD 5: SYNCHRONIZATION BY MAX. PRESSURE SIGNAL CLINICAL SYSTEM

Reference is now made to Fig 34, illustrating a cross section of an artery 30 having an arterial wall 32 and a stenosis 34 The points A and B .proximal and distal to the stenosis, define a section of the artery 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

DATA ACQUISITION

The following steps are performed to obtain the required data 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

Pr_B(t)

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(optιonal) 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

DATA ANALYSIS

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.

15

Using the human test data described in Example 1 of Method 4 the following values are calculated

CFR = 1 46 FFR = 0 81 20 DSVR = 1 15

METHOD 6: INFLATED BALLOON CFR₀ CALCULATIONS

A method is described 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 However, 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 CFR₀ is then calculated according to the equations described herein above

Reference is now made to Fig 35, illustrating a cross section of an artery 30 having an arterial wall 32 The points A and B, define a non-lesioned section of the artery 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 A 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)

DATA ACQUISITION

The following steps are performed to obtain the required data

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 4 Induce 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 DATA ANALYSIS

CFR and FFR are calculated for the balloon obstructed vessel using the procedure described in Method 2 However, all other methods (mentioned herein above) of clinical system for pressure measurements and calculation can be used together with balloon artificial obstruction

After CFR and FFR (for the balloon obstruction) are calculated, the mean values of the pressure gradient during rest (P_Arest-P_Brest) and during vasodilatation (P_Arest-P_Bvaso) are calculated Then CFRo for the vessel without the obstruction, is calculated using the equation mentioned herein above

METHOD 7: CFD MODELING OF THE FLOW IN THE CORONARY ARTERY WITH STENOSIS. CFR AND FFR PARAMETERS.

Medical specialist estimate stenosis severity using either simple geometrical parameters, such as percent diameter stenosis, or hemodynamically based parameters such as the fractional flow reserve (FFR) or coronary flow reserve (CFR) As shown herein, the relationship between actual hemodynamic conditions and the above mentioned parameters of stenosis severity are established A numerical model of the blood flow in a vessel is used with a blunt stenosis and autoregulated vascular bed to simulate a stenosed blood vessel A key point to realistic simulations is to model properly the arterial autoregulation The present numerical model is based on the comparison 0 1 the flow in healthy and stenotic vessels The calculated values of CFR and FFR are in the physiological range

Results 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 The new parameter VBIo, that is introduced in the present study, is equal to the ratio of mean shear to mean pressure Instead of conducting hard to perform in-vivo experiments, in the first stage of the study 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

Conclusions Based on the results, the constant flow model of vascular bed autoregulation suggested in the present study allows using CFD to analyze different situations in clinical practice in an attempt to correlate between common hemodynamic parameters and the severity of stenosis

METHOD 8: FFR calculation using moving pressure transducer.

Reference is now made to 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

FFR is a ratio of distal (P_d) to proximal (P,) pressure (FFR=P₍ P_a)

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 Thus, it will be appreciated that the present system may easily require calibration between the two pressure sensors

DATA ACQUISITION The steps performed to obtain the required data will now be discussed. In the preferred method, 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.

15 In the preferred method, the maximum hyperemia is determined by calculating FFR for every heart beat. An advantage of the present method is that automatic recognition of the intracoronary adenosine or papavehne injection and maximal hyperemia. Another advantage is that the transducer is less sensitive of the transducer to drifts. Thus, the present invention provides a means for reducing

20 sensitivity to drifts.

DATA ANALYSIS

Data analysis is performed using the AST to determine FFR as hereinabove described..

25

CLINICAL TEST EXAMPLE

Table 1 : CFR/FFR algorithm vs. traditional common practice tools.

+ small pressure difference ++ moderate pressure difference +++ high pressure difference

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.

EXAMPLE 1 : IN-VIVO CFR-FFR MEASUREMENTS IN HUMAN

SUBJECTS

Studies on human patients were conducted provided the results set forth in Figure 44 and Tables 2-5. 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.

Protocol: The patients studied with single lesion, double lesions, intermediate lesions. All the patients were symptomatic. CFR/FFR were measured using the pressure wires and flow wire simultaneously. Data analysis for comparison of pressure based and velocity based CFR estimation was done off-line.

Table 2: D.H.-. RCA 80-90% stenosis.

Table 3: W.G. - CIRC 70-90% stenosis.

File , CFR FFR BPG HPG Comment

12 44 16 1 .08 0.55 32.3 33.9 Vaso 1 i

12_52_ 27 1 .12 0.49 33.0 39.5 Vaso 2

13_00_ _52 4.0 0.89 0.39 7.8 After balloon - old proximal pressure

13_00_ _52 3.0 0.87 1 3 10 1 After balloon - new proximal pressure

Table 4: T. LAD 90% stenosis.

File CFR ! FFR BPG HPG I Comment

10 37 21 1 .04 0.68 37.3 40.3 ^! Vaso 1

10 50 00 1 .2 ! 0.59 33.4 45.2 ! Vaso 2

10 50 00 3.2 ' 0.98 -0.7 1 .7 After balloon Table 5: CLINIAL DATA REPORT: CFR AND FFR CALCULATIONS

CFR # automatic CFR calculation by the Endosonics system CFR ^* CFR calculated based on flow raw data

BPG- ΔP_res„ mean pressure gradient across stenosis at rest

HPG- ΔP_vaS0, mean pressure gradient across stenosis during vasolidation

Results The results demonstrate that good correlation was found between the CFR-Automatic Similar Transformation (AST) method for CFR/FFR estimation to the velocity based CFR estimation In some case the CFR calculated based on velocity raw data actually resulted in a higher correlation, indicating problematic automatic CFR calculation of the Endosonics system The vasodilator/ effect was achieved by intracoronary Adenosine injection

EXAMPLE 2: IN-VIVO CFR-FFR MEASUREMENTS IN CANINES

Animal studies with 4 canines (20-25 Kg), were performed in a hospital in Japan The in-vivo studies set up included The Automatic Similar Transformation (AST) System connecting to a Nihon Kohden RM-6000 monitor for acquisition of the arterial pressure wave, a pressure signal, ECG and flow signal (fluoroscopy system which included a CardioMed CM2000 transit time and doppler flowmeter peπvascular handle flowprobes (3 mm)) The flow signal was presented on the monitor screen and sampled by the System which includes the AST method In these studies a FloWire was not used

Protocol The animal was anesthetized, the chest opened and the heart exposed The LCX was then dissected to allow introduction of the peπvascular flowprobe and the balloon occluder The animal was catheteπzed 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 Papaveπne 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.

Results: 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.

Case # 0 //o Values AST Values

Stenosis FFR CFR FFR ; CFR

Dog 1 / 50% 0.84 4 , 0.77 ' 4.2 25Kg

i 75% 0.64 2.6 ¹ 0.64 : 2.4

Discussion The significant difference (15-20 mm Hg) between the pressures measured by the fluid filled manometer and the Radi at the proximal point makes a direct estimation of the pressure gradient across the stenosis difficult For this reason, the pressure difference was computed taking into account the change in aortic pressure The mean pressure difference across the stenosis, denoted AP, is approximately 3 mm Hg 2 The pressure difference across the stenosis, Ap(t), may be estimated from the volume flow rate (in short flow) Q(t), the minimal stenosis cross-sectional area A, and the (healthy) vessel cross- sectional area A independent of geometry and can be approximated as 1 52 The coefficient (L,- length of the stenosis, D, and DO - diameters corresponding to the areas A, and Ao, respectively) Unfortunately, the functionof Q(t) is not known For estimation of the Q2 term it is assumed that Q(t) may be approximated as Q(l+sιn(27πt)), where Q is a constant Q² = 1 5Q² equal to mean flow The stenosis length Ls as well as Au are unknown However as the linear Poiseuille term ((the first term in Eq (2)) is small for typical stenosis, the representative values for the unknown parameters are taken Ls=2cm, Do=4mm Finally, it is assumed that blood viscositv u=0 O04 again due to the smallness of the Poiseuille term, the exact value of p is not important)

For definiteness two cases were examined, 1 ) 50% diameter stenosis, i e , A₀/A_s =4 and 2) 60% stenoisis When there is 50% diameter stenosis, it was estimated that ΔP for various flow velocities u (Q = u^*A₀)

Table 7 50% diameter stenosis

Table 8 60% diameter stenosis, h/,4, =6 25

In the above Japan results the following pressure differences across stenosis were measured ΔPrest=3 4mm Hg, ΔPvaso= 19 7 mm Hg As shown in Table 7 (50% stenosis') that corresponding to a value of ΔPrest=3,4mm Hg there corresponds a value of velocity at rest Urest=l2cm/s and to ΔPvaso=19 7 mm there corresponds a value of velocity during vasodilatation Uvaso=40cm/s Therefore, CFR=40/12=3 3 Similarly, using Table 8 (60% stenosis) Urest=6cm/s, Uvaso=20cm/s and again CFR=20/6=3 3

During the experiment the velocity measured by the FlowWire in the above experiment was about 6 cm/s at rest and about 40 cm/s during vasodilatation The measured percent stenosis was 50% In this case, the velocity at rest is half the calculated velocity using pressure differences (Urest=l2cm/s) A possible explanation for this discrepancy is due to the misalignment of the FlowWire in the vessel

The above results of the FlowWire measurements confirm the proposition that baseline flows both in the stenosed and healthy vessel are the same Baseline flows before and after PTCA were 18 cm/s and hyperemic flow changed from 24 cm/s to 63 cm/s FFR=0 55-0 59 hence CFR/FFR = 2 26 - 2 42 CFR after PTCA equal to 63/24=2 62 The discrepancy is within 10%

Simultaneous CFR and FFR measurements permit one to obtain additional information about the vascular bed For example, in cases 4, 5 and 6 As in the previous report, one may use the Young and Tsai equation to calculate the flow in the stenosed blood vessel In case 4, the stenosis parameters are in this case 50% diameter stenosis, BAPV=l6cm/s, HAPV=44cm s, BPG=12 mm Hg, HPG=33 mm Hg , FFR=0 59- 0 63 Due to change in aortic pressure during vasodilatation the HPG is calculated using the mean aortic pressure measured at rest and FFR, as well. It was assumed that stenosis has a length of L=2cm, artery diameter 3.0 mm, blood viscosity 0.0035. The results or the calculations are presented in Table. 9

Table 9. Calculations for LDA 50% diameter stenosis

From Table 9, that the measured velocities are small for a 50% stenosis. In this case, the CFR, which corresponds to the measured pressure gradients at rest and during vasodilatation is equal to 50/25=2.0 (which is the value computed using the methods described herein AST-CFR).

The measured hyperemic velocity corresponds to the measured hyperemic pressure gradient for a 52% stenosis, as shown in Table 10:

Table 10. Calculations for LDA 52% diameter stenosis

As demonstrated in Table 10 the baseline: velocity measured by the FlowWire is too low for the measured pressure. The baseline velocity corresponding to the base pressure gradient is 22 cm/s and CFR is again 44/22=2.0. The ratio CFR/FFR=2.0/0.63=3.2 3 is reasonable and doesn't seem to point to any problem with the vascular bed.

In case 5, LDA stenosis, its parameters are: 50% diameter stenosis, BAPV=IOcm/s, HAPV=34cm/s, BPG=12 mm Hg, HPG=34 mm Hg., FFR=0.66. Due to change in aortic pressure during vasodilatation, the HPG is calculated using mean aortic pressure, measured at rest As in the previous case, stenosis length L=2cm, artery diameter 3 mm, blood viscosity 0 0035 Results or the calculations are presented in Table 1 1

Table 1 1 Calculations for LDA 50% diameter stenosis

The flow velocity at rest measured by FlowWire is too low for the measured pressure gradient, in this case also The corresponding CFR=37/18=2 is close to the value 1 8 supplied by the AST-CFR method The ratio CFR/FFR=2/0 66=3 is reasonable and doesn't seem to point to any problem with the vascular bed

Case 6, RCA stenosis Its parameters are 25% diameter stenosis, BAPV=3 Ocm/s, HAPV=50cmls, BPG=5 7 mm Hg, HPG= 15 9 mm Hg , FFR=0 83 Due to change in aortic pressure during vasodilatation the HPG is calculated using mean aortic pressure, measured at rest Stenosis is L-2cm, artery diameter 3 mm and blood viscosity at 0 0035 Results are presented in Table 12

Table 12 Calculations for RCA 25% diameter stenosis

The percent stenosis is too low for the measured velocities and the pressure gradients The CRR corresponding to the measured pressure gradient is 130/60=2 17 This value again is in good agreement with the AST-CFR method The following results were obtained were stenosis is 40% Table 13. Calculations for LDA 40% diameter stenosis

In this case the CFR corresponding to the pressure gradient is 55/27=2.0, 10% less then the value calculated by the AST-CFR method. However, in this case where even a small error in the measured velocity or pressure gradient yields a 10-20% error in CFR. For example, in case 6, 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. The ratio CFR/FFR lies between 2.0/0.83=2.4 and 2.2/0.83=2.65. These values are near the lower bound of values CFR/FFR for normal vascular bed. Thus, there is a systematic error in the Flow Wire velocity measurements at velocities lower than 15-20 cm/s.

Conclusion: The above results demonstrate that the AST-CFR method is an accurate and more precise measurement of stenosis.

EXAMPLE 3: IN-VIVO CFR-FFR MEASUREMENTS IN SWINE

The goal of percutaneous coronary intervention (PCI) is to reduce flow-limiting arterial obstruction. 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. As demonstrated herein, the methods of this invention, allow calculation of CFR and FFR directly from intraarterial pressure measurements.

Methods: In anesthetized pigs (30kg,) following throacotomy an occluder and ultrasonic flow probe (distal, Transonics) were placed around the LAD. A solid state pressure guide wire (RADI Medical) and doppler flow wire (Endosonics) were placed in the LAD. Stenoses were established (30 - 70%)(n=IZ) and baseline and post-adenosine intracoronary pressure and flow measurements were made proximal, distal and during trans-lesional pullback. CFR and FFR were derived in real time from pressure via algorithm, and from actual measuredl flows. In 9 patients pressure and flow wires were placed proximal and distal to isolated coronary lesion (50 - 90 %), adenosine was administered and CFR and FFR were similarly derived.

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.

Animal Preparation: 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. Then 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 Effect: 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.

In all pigs a close correlation was observed for pressure derived CFR (CFR_P ) and FFR versus CFR (CFR_F) and FFR derived from actual flow determination (CFR_P=1 .03, CFR_F=0.095, R=0.89). In the human subject the CFR and FFR correlated closely with flow velocity derived CFR and FFR (CFR_P=1.06, CFR_F=0.100, R=0.85).

Therefore, 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.

EXAMPLE 4: IN-VIVO RESULTS OBTAINED BASED ON THE

AUTOMATIC SIMILAR TRANSFORMATION METHODS

The following results were obtained using the automatic similar transformation (AST) method described above.

Dog I -

EXAMPLE 5: VBI VERIFICATION

The vascular bed index is defined as VBI=( 4μQ)/(Pπd³)=( μu )/(Pd), where P -pressure, d- artery diameter, μ - dynamic viscosity 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

The results are present in Fig 43a-d There is a strong correlation between VBI and mean flow velocity at rest with correlation coefficient R=0 926 (Fig 42a ) The mean value of the VBI=1 7» 10⁵ The VBI is independent of the CFR, FFR and the ratio CFR/FFR (Fig 42b-d ) Hence, the VBI reflects another, then CFR and FFR, features of the vascular bed The low values of VBI indicate "slow flow" cases EXAMPLE 6: VERIFICATION OF CFRO (the ratio CFR/FFR)

The calculated values of the CFR/FFR ratio are compared with in vivo test results. The results are presented and summarized in the following Table 15:

*CFR and FFR are calculated using the Automatic Similar Transformation method

Standard deviation of the CFR/FFR for every dog is also presented in the Table 15. The results for first 3 dogs confirm that CFR/FFR ratio is independent from % stenosis. In the Dog4 case the standard deviation is high. It is explained by the large disperse of ratio values.

Claims

What is claimed is:

1. A method for determination of flow ratio in blood vessel, said method comprising the steps of providing an apparatus adapted to measure pressure across a blood vessel obstruction.

2. The method of claim 1 for determination of coronary flow reserve in stenotic vessel including the steps of measuring pressure distal and proximal to said obstruction with said apparatus.

3. The method of claim 1 for determination of coronary flow reserve in a stenotic vessel including the steps of measuring aortic pressure and pressure distal to said obstruction, simultaneously by said apparatus having a fluid filled manometer and a pressure transducer, respectively.

4. The method of claim 1 for determination of coronary flow reserve in a stenotic vessel including the steps of: measuring aortic pressure with said apparatus having a fluid filled manometer; and measuring pressure across said obstruction with said apparatus having a moving pressure transducer.

5. The method of claim 1 for determination of coronary flow reserve in a stenotic vessel including the steps of: measuring aortic pressure with said apparatus having a fluid filled manometer; measuring pressure across said obstruction with said apparatus having a moving pressure transducer; and synchronizing said pressure measurements with said apparatus having an ECG.

6. The method of claim 1 for determination of coronary flow reserve in a stenotic vessel including the steps of: measuring pressure across said obstruction with said apparatus having a moving pressure transducer; and synchronizing said pressure measurements with said apparatus having an ECG.

7. The method of claim 1 for determination of coronary flow reserve in a stenotic vessel including the steps of: measuring aortic pressure with said apparatus having a fluid filled manometer; measuring pressure across said obstruction with said apparatus having a moving pressure transducer; and synchronizing said pressure measurements with said moving pressure transducer.

8. The method of claim 1 for determination of coronary flow reserve in a stenotic vessel including the steps of: vessel including the steps of: measuring aortic pressure with said apparatus having a fluid filled manometer; measuring pressure across said obstruction with said apparatus having a moving pressure transducer; and synchronizing said pressure measurements with said fluid filled manometer.

9. A method for determination of coronary flow reserve in a blood vessel including the steps of: providing an apparatus adapted to measure pressure across an artificial obstruction.

10. The method of claim 9 for determination of coronary flow reserve in a blood vessel including the steps of: providing said artificial obstruction; and measuring pressures across said artificial obstruction wherein an aortic pressure and a pressure distal to said obstruction, are simultaneously measured by said apparatus having a fluid filled manometer and a pressure transducer, respectively.

11. The method of claim 9 for determination of coronary flow reserve in a blood vessel including the steps of: providing said artificial obstruction; measuring an aortic pressure with said apparatus having a fluid filled manometer for the aortic pressure; and measuring pressure across the obstruction with said apparatus having a moving pressure transducer.

12. The method of claim 9 for determination of coronary flow reserve in a blood vessel including the steps of: providing said artificial obstruction; measuring an aortic pressure with said apparatus having a fluid filled manometer for the aortic pressure; measuring pressure across the obstruction with said apparatus having a moving pressure transduce; and synchronizing said pressure signals with said apparatus having an ECG.

13. The method of claim 9 for determination of coronary flow reserve in a blood vessel including the steps of: providing said artificial obstruction; measuring an aortic pressure with said apparatus having a fluid filled manometer for the aortic pressure; measuring pressure across the obstruction with said apparatus having a moving pressure transduce; and synchronizing said pressure signals with said moving pressure transducer.

14. The method of claim 9 for determination of coronary flow reserve in a blood vessel including the steps of: providing said artificial obstruction; measuring an aortic pressure with said apparatus having a fluid filled manometer for the aortic pressure; measuring pressure across the obstruction with said apparatus having a moving pressure transduce; and synchronizing said pressure signals with said fluid filled manometer.

15. A method for determination of diastole to systole velocity ratio in a stenotic vessel including the steps of: providing an apparatus adapted to measure pressure distal and proximal to a stenosis.

16. The method of claim 15 for determination of diastole to systole velocity ratio in a stenotic vessel including the steps of: measuring aortic pressure with said apparatus having a fluid filled manometer; and measuring pressure across said stenosis with said apparatus having a moving pressure transducer.

17. The method of claim 15 for determination of diastole to systole velocity ratio in a stenotic vessel including the steps of: measuring aortic pressure with said apparatus having a fluid filled manometer; measuring pressure across said stenosis with said apparatus having a moving pressure transducer; and synchronizing said pressure measurements with said apparatus having an ECG.

18. The method of claim 15 for determination of diastole to systole velocity ratio in a stenotic vessel including the steps of: measuring aortic pressure with said apparatus having a fluid filled manometer; measuring pressure across said stenosis with said apparatus having a moving pressure transducer; and synchronizing said pressure measurements with said moving pressure transducer.

19. The method of claim 15 for determination of diastole to systole velocity ratio in a stenotic vessel including the steps of: measuring aortic pressure with said apparatus having a fluid filled manometer; measuring pressure across said stenosis with said apparatus having a moving pressure transducer; and synchronizing said pressure measurements with said fluid filled manometer.

20. The method of claim 1 wherein said obstruction is a natural stenosis.

21. The method of claim 1 wherein said obstruction is an artificial balloon obstruction.

22. A sensor apparatus for determination of flow ratio in blood vessel comprising: at least one pressure sensor adapted to measure pressure across an obstruction.

23. The sensor apparatus of claim 22 for determination of coronary flow reserve in stenotic vessel wherein said at least one pressure sensor includes a plurality of pressure sensors adapted to measure pressure distal and proximal to said obstruction.

24. The sensor apparatus of claim 22 for determination of coronary flow reserve in a stenotic vessel wherein said at least one pressure sensor includes a fluid filled manometer and a pressure transducer adapted to simultaneously measure aortic pressure and pressure distal to said obstruction, respectively.

25. The sensor apparatus of claim 22 for determination of coronary flow reserve in a stenotic vessel wherein said at least one pressure sensor includes a fluid filled manometer adapted to measure aortic pressure and a pressure transducer adapted to measure pressure across to said obstruction.

26. The sensor apparatus of claim 22 for determination of coronary flow reserve in a stenotic vessel including: said at least one pressure sensor includes: a fluid filled manometer adapted to measure aortic pressure; and a pressure transducer adapted to measure pressure across to said obstruction; and an ECG cooperatively connected to said sensors for synchronization of the pressure signals.

27. The sensor apparatus of claim 22 for determination of coronary flow reserve in a stenotic vessel including: said at least one pressure sensor includes: a moving pressure transducer adapted to measure pressure across said obstruction; and an ECG cooperatively connected to said sensors for synchronization of the pressure signals.

28. The sensor apparatus of claim 22 for determination of coronary flow reserve in a stenotic vessel including: said at least one pressure sensor includes: a fluid filled manometer adapted to measure aortic pressure; and a pressure transducer adapted to measure pressure across to said obstruction; wherein said moving pressure transducer pressure measurements are used for synchronization of said pressure measurements.

29. The sensor apparatus of claim 22 for determination of coronary flow reserve in a stenotic vessel including: said at least one pressure sensor includes: a fluid filled manometer adapted to measure aortic pressure; and a pressure transducer adapted to measure pressure across to said obstruction; wherein said fluid filled manometer pressure measurements are used for synchronization of said pressure measurements.

30. A sensor apparatus for determination of coronary flow reserve in a blood vessel comprising: at least one pressure sensor adapted to measure pressure across an obstruction.

31. The sensor apparatus according to claim 29 for determination of coronary flow reserve in a tubular conduit or blood vessel wherein said at least one pressure sensor includes a fluid filled manometer and a pressure transducer adapted to simultaneously measure aortic pressure and pressure distal to said obstruction, respectively.

32. The sensor apparatus according to claim 30 for determination of coronary flow reserve in a blood vessel including: an artificial obstruction; said at least one pressure sensor includes: a fluid filled manometer adapted to measure aortic pressure; and a pressure transducer adapted to measure pressure across to said obstruction.

33. The sensor apparatus according to claim 30 for determination of coronary flow reserve in a blood vessel including: an artificial obstruction; said at least one pressure sensor includes: a fluid filled manometer adapted to measure aortic pressure; and a pressure transducer adapted to measure pressure across to said obstruction; and an ECG for synchronization of said pressure measurements.

34. The sensor apparatus according to claim 30 for determination of coronary flow reserve in a blood vessel including: an artificial obstruction; said at least one pressure sensor includes: a fluid filled manometer adapted to measure aortic pressure; and a pressure transducer adapted to measure pressure across to said obstruction; and wherein said moving pressure transducer pressure measurements are used for synchronization of said pressure measurements.

35. The sensor apparatus according to claim 30 for determination of coronary flow reserve in a blood vessel including: an artificial obstruction; said at least one pressure sensor includes: a fluid filled manometer adapted to measure aortic pressure; and a pressure transducer adapted to measure pressure across to said obstruction; and wherein said fluid filled manometer pressure measurements are used for synchronization of said pressure measurements.

36. A sensor apparatus for determination of diastole to systole velocity ratio in a stenotic vessel comprising: a plurality of pressure sensors adapted to measure pressure distal and proximal to a stenosis.

37. The sensor apparatus according to claim 30 for determination of diastole to systole velocity ratio in a stenotic vessel including: said plurality of sensors including: a fluid filled manometer adapted for aortic pressure measurements; and a moving pressure transducer adapted for pressure measurements across said stenosis.

38. The sensor apparatus according to claim 36 for determination of diastole to systole velocity ratio in a stenotic vessel including: said plurality of sensors including: a fluid filled manometer adapted for aortic pressure measurements; and a moving pressure transducer adapted for pressure measurements across said stenosis; and an ECG for synchronization of pressure signals.

39. The sensor apparatus according to claim 36 for determination of diastole to systole velocity ratio in a stenotic vessel including: said plurality of sensors including: a fluid filled manometer adapted for aortic pressure measurements; and a moving pressure transducer adapted for pressure measurements across said stenosis; and wherein said moving pressure transducer pressure measurements are used for synchronization of said pressure measurements.

40. The sensor apparatus according to claim 36 for determination of diastole to systole velocity ratio in a stenotic vessel including: said plurality of sensors including: a fluid filled manometer adapted for aortic pressure measurements; and a moving pressure transducer adapted for pressure measurements across said stenosis; and wherein said fluid filled manometer pressure measurements are used for synchronization of said pressure measurements.

41. A sensor system comprising: at least one sensor adapted to measure pressure in a tubular conduit across an obstruction.

42. The sensor system according to claim 40 including: means for determining a flow ratio in a blood vessel.

43. The sensor system according to claim 41 including: means for determining coronary flow reserve in a blood vessel.

44. The sensor system according to claim 41 including: means for determining diastole to systole velocity ratio in a stenotic vessel.

45. The sensor system according to claim 41 including: means for determining coronary flow reserve together with fractional flow reserve in the same blood vessel or tubular conduit without stenosis and analysis of their correlation.

46. The sensor system according to claim 41 including: means for determining 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 or an aneurysm.

47. The sensor system according to claim 41 including: means for determining coronary flow reserve together with fractional flow reserve in the same blood vessel without stenosis for estimation of vasodilatation effectiveness.

48. The sensor system according to claim 41 including said sensor being operative to generate a signal; a processor unit operatively connected to said at least one sensor; a program for controlling the processor unit; said processor unit operative with said program to: receive said sensor signal; identify changes in said sensor signal; detect characteristics of said tubular conduit, said characteristics of said tubular conduit being derived from changes in said sensor signal; and recognize and assign a label to said characteristic of said tubular conduit.

49. The sensor system according to claim 48 wherein said processor unit is operative with said program to determine a flow ratio in a blood vessel.

50. The sensor system according to claim 48 wherein said processor unit is operative with said program to determine coronary flow reserve in a blood vessel.

51. The sensor system according to claim 48 wherein said processor unit is operative with said program to determine diastole to systole velocity ratio in a stenotic vessel.

52. The sensor system according to claim 48 wherein said processor unit is operative with said program to determine coronary flow reserve together with fractional flow reserve in the same blood vessel without stenosis and analysis of their correlation.

53. The sensor system according to claim 48 wherein said processor unit is operative with said program to determine 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.

54. The sensor system according to claim 48 wherein said processor unit is operative with said program to determine coronary flow reserve together with fractional flow reserve in the same blood vessel without stenosis for estimation of vasodilatation effectiveness.

55. The sensor system according to claim 48 wherein said processor unit is operative with said program to: determine a flow ratio in a blood vessel; determine coronary flow reserve in a blood vessel; determine diastole to systole velocity ratio in a stenotic vessel; determine 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; determine coronary flow reserve together with fractional flow reserve in the same blood vessel without stenosis for estimation of vasodilatation effectiveness.

56. The sensor system of claim 48 wherein said at least one pressure sensor includes a plurality of pressure sensors adapted to measure pressure distal and proximal to said obstruction.

57. The sensor apparatus of claim 48 wherein said at least one pressure sensor includes a fluid filled manometer and a pressure transducer adapted to simultaneously measure aortic pressure and pressure distal to said obstruction, respectively.

58. The sensor apparatus of claim 48 wherein said at least one pressure sensor includes a fluid filled manometer adapted to measure aortic pressure and a pressure transducer adapted to measure pressure across to said obstruction.

59. The sensor apparatus of claim 48 including: said at least one pressure sensor includes: a fluid filled manometer adapted to measure aortic pressure; and a pressure transducer adapted to measure pressure across to said obstruction; and an ECG cooperatively connected to said sensors for synchronization of the pressure signals.

60. The sensor apparatus of claim 48 including: said at least one pressure sensor includes: a moving pressure transducer adapted to measure pressure across said obstruction; and an ECG cooperatively connected to said sensors for synchronization of the pressure signals.

61. The sensor apparatus of claim 48 including: said at least one pressure sensor includes: a fluid filled manometer adapted to measure aortic pressure; and a pressure transducer adapted to measure pressure across to said obstruction; wherein said moving pressure transducer pressure measurements are used for synchronization of said pressure measurements.

62. The sensor apparatus of claim 48 including: said at least one pressure sensor includes: a fluid filled manometer adapted to measure aortic pressure; and a pressure transducer adapted to measure pressure across to said obstruction; wherein said fluid filled manometer pressure measurements are used for synchronization of said pressure measurements.

63. The sensor system according to claim 48 wherein said sensor is moveable between proximal and distal ends of said obstruction and said tubular conduit is a blood vessel; said processor unit is operative with said program to: receive a first sensor signal when said sensor is at said proximal end and said blood vessel is at rest; receive a second sensor signal when said sensor is at said distal end and said blood vessel is at rest; receive a third sensor signal when said sensor is at said distal end and during vasodilation of said blood vessel.

64. The sensor system according to claim 63 wherein said processor unit is further operative with said program to: determine the amplitude and phase of said first, second and third sensor signals as a function of frequency.

65. The sensor system according to claim 64 wherein said processor with said program determines said amplitude and phase of said sensor signals by a fast Fourier transform.

66. The sensor system according to claim 64 wherein said processor with said program is operative to: determine a frequency for calculating said amplitude and phase of said first, second and third sensor signals.

67. The sensor system according to claim 64 wherein said processor with said program is operative to: determine a time in which a maximum value of said first, second and third sensor signals occurs.

68. The sensor system according to claim 67 wherein said processor with said program is operative to: determine a time in which a minimum value of said first, second and third sensor signals occurs.

69. The sensor system according to claim 68 wherein said processor with said program is operative to: exclude from said sensor signals, sensor signals that are representative of a pressure pulses influenced by drug admissions.

70. The sensor system according to claim 69 wherein said processor with said program is operative to: determine coronary flow reserve from said sensor signals.

71. The sensor system according to claim 69 wherein said processor with said program is operative to: determine fractional flow reserve from said sensor signals.

72. A method for determination of fractional flow ratio in a blood vessel, said method comprising the steps of providing an apparatus adapted to measure pressure across a blood vessel obstruction.

73. The method of claim 72 for determination of fractional flow reserve in stenotic vessel including the steps of measuring pressure distal and proximal to said obstruction with said apparatus.

74. The method of claim 72 for determination of fractional flow reserve in a stenotic vessel including the step of measuring pressure across said obstruction with said apparatus having a moving pressure transducer.

75. The method of claim 73 for determination of fractional flow reserve in a stenotic vessel including the steps of measuring pressure across said obstruction with said apparatus having a moving pressure transducer; and synchronizing said pressure measurements with said apparatus having an ECG.

76. The method of claim 73 for determination of fractional flow reserve in a stenotic vessel including the steps of: measuring pressure across said obstruction with said apparatus having a moving pressure transducer; and synchronizing said pressure measurements with said apparatus having an ECG.

77. The method according to any of steps 72-74 including repeating said measuring steps across said obstruction.

78. The method according to claim 77 including the step of calculating mean values representing a plurality of said measuring steps proximal and distal to said obstruction.

79. The method according to claim 78 including the step of determining a ratio of said proximal mean value and distal mean value.