Method and system for measuring pulse wave velocity - Patents.com

Abstract

The present invention relates to a method and system for measuring pulse wave velocity (PWV) using pulse arrival time (PAT) and carotid-femoral distance, as well as patient age.

Description

[Technical field]

[0001] The present invention relates to a method and system for measuring Pulse Wave Velocity (PWV) that not only uses Pulse Arrival Time (PAT) and Carotid-Femoral Distance, but also takes into account the age of the patient. [Background technology]

[0002] prior art Mortality due to cardiovascular disease is one of the leading causes of death worldwide. Assessment of large arterial stiffness is an early and independent predictor of cardiovascular events. In fact, arterial aging is characterized by a decrease in elasticity, which is specific to large diameter arteries.

[0003] The best parameter for assessing this arterial stiffness is the measurement of carotid-femoral pulse wave velocity (herein referred to as PWVcf or PWV). PWVcf corresponds to the propagation velocity of the pulse wave from the carotid to the femoral artery, i.e., the time it takes for the pulse wave to travel from a point in the carotid to a point in the femoral artery.

[0004] Thus, patients with flexible arteries, i.e., younger patients at low cardiovascular risk, have a small PWVcf (6 m / sec), whereas patients with stiffer arteries, i.e., older patients at higher cardiovascular risk, have a large PWVcf (15 m / sec).

[0005] Therefore, assessing arterial stiffness based on PWVcf has become a high-priority therapeutic target, as demonstrated by its inclusion in the European recommendations for the management of hypertension.10 However, despite unanimous recognition by the academic community that this measurement is important, PWVcf has not been widely adopted in routine clinical practice.

[0006] There are at least two reasons for this low physician adoption rate.

[0007] The first reason is that the measurements are relatively difficult to perform. Indeed, in clinical practice, measurements are currently performed basically by imaging (MRI), by ultrasound techniques (combination of Doppler examination of the carotid and femoral arteries) or, finally, by combined tonometry (e.g., SphygmoCor, Complior). This entails specific equipment associated with training, expertise, and learning of techniques to collect and utilize the data. Concerning the measurement of PWV by MRI, one of three methods is commonly implemented (propagation time analysis, flow-area, and cross-correlation). All three methods must be performed in a radiology center with an MRI capable of performing complex imaging sequences (phase contrast MRI), which are time-consuming (45-60 min) and expensive. For all these reasons, MRI cannot be used as a preferred technique for mass screening and examination of individuals.

[0008] Both ultrasound and tonometry techniques are based on the following formula: PWVcf = carotid-femoral distance / carotid-femoral wave transit time. First, the carotid-femoral distance is measured with a tape measure. Then, the carotid-femoral wave transit time is measured by simultaneously recording the carotid and femoral signals over several beats. These carotid and femoral signals can be measured by various techniques, namely Doppler, tonometry, oscillometry, or a combination of both (using a tonometer placed on the carotid artery and a pressure cuff worn on the upper thigh to capture the femoral artery blood pressure signal, the two signals are also synchronized over several beats). Therefore, to obtain PWVcf measurements using these methods, an ultrasound scanner or a specialized device (Sphygmocor XCEL) and a skilled technician are required. Therefore, just like MRI techniques, and for the same reasons, but to a lesser extent, ultrasound or tonometry-based measurements are not suitable for large-scale screening of high-risk populations.

[0009] The second reason is that the values ​​obtained are relatively difficult to interpret.

[0010] In fact, the collected PWV values ​​should be analyzed by taking into account the anthropometric data of the patient, including the value of the blood pressure at the time of the examination as well as the patient's age. In fact, the Bramwell-Hill formula shows a direct relationship between PWV and arterial distensibility (defined as the change in the diameter of the arterial lumen) as a function of its pressure change, according to the following formula: PWV = √[(A / ρ)(∂A / ∂P)], where A is the arterial lumen area, ρ is the blood density, and ∂A / ∂P is the change in the arterial lumen area with the change in pressure. Thus, if the arterial pressure increases, the diameter of the arterial lumen also increases, depending on the stiffness-distensibility of the vessels (based on the elastin / collagen ratio). This also results in an increase in PWV.

[0011] It can therefore be seen why a single PWVcf measurement at a given time point alone cannot characterize a patient's overall arterial stiffness, especially when the arterial pressure is not known. Therefore, to accurately investigate a patient's arterial stiffness, it would be ideal to obtain PWVcf values ​​over a wide range of blood pressure levels, which is not easily achievable with currently available methods.

[0012] Considering the above, and in addition to the already complex nature of measuring PWVcf, making large changes in blood pressure in clinical routine to assess changes would make the task even more difficult and ethically inadvisable, since this would mean administering drugs that induce hypotension or hypertension to the patient. Some authors have tried to approach this goal by measuring PWVcf in the standing and lying positions, but with very limited success, since the obtained changes in blood pressure were not very large.

[0013] In summary, for at least these two reasons, PWV is very rarely measured in routine clinical practice.

[0014] Therefore, creating a procedure that allows continuous measurement of PWVcf (multiple measurements at multiple time points) and, more preferably, also relates it to blood pressure changes, could be a major advance for cardiovascular risk stratification, since it would allow a dynamic, individualized, and therefore more accurate analysis of arterial stiffness.

[0015] PWV can be estimated by measuring the arrival of the pulse wave at two arterial sites. TIFF2025505646000001.tif10128

[0016] This transit time is commonly called the pulse transit time (PTT).

[0017] Various authors have proposed to calculate PWV using the pulse wave arrival time (PAT) as an approximation of the PTT, in particular based on signals obtained by photoplethysmography (PPG). State-of-the-art estimation of the PAT consists of detecting characteristic points in the PPG waveform.

[0018] However, PAT=PEP+PTT, where PEP is the pulse ejection period, which is the time that elapses between the electrical depolarization of the left ventricle (QRS on the electrocardiogram (ECG)) and the onset of ventricular ejection, and represents the period of left ventricular contraction with the heart valves closed.

[0019] Considering the changes in pre-ejection time (PEP), approximating the PTT by using the PAT may yield unreliable results for PWV, and therefore formulas using only the PAT and distance (commonly the carotid-femoral distance, Dcf) may not be accurate.

[0020] Huttunen et al. (PLoS Comput Biol. 2019 Aug; 15(8): e1007259) proposed using machine learning and simulated training data to calculate PWV.

[0021] Considering that the use of characteristic points of PAT in signals obtained by (PPG) in particular leads to the risk of lack of reproducibility, Sola et al. (Physiol. Meas. 30 (2009) 603-615) (Non-Patent Document 2) proposed to define a new family of PAT estimators based on the entire pressure pulse waveform using a specific parametric model.

[0022] Campo et al. (Am J Hypertens. 2017;30(9):876-883 (Non-Patent Document 3) disclosed a method for measuring arterial stiffness using a weight scale, combining the principles of ballistocardiography (BCG) and impedance plethysmography on one leg.

[0023] Geshe et al. (Eur J Appl Physiol. 2012 Jan;112(1):309-15) disclose a function relating systolic blood pressure (SBP) to PWV and its reliability for determining absolute SBP. PWV is calculated from PTT (Pulse Transit Time), defined as the time delay between the R wave of the ECG and the arrival of the pulse wave at the periphery (finger), but the authors approximate PTT by PAT measurements. They also use the patient's height and a body correlation coefficient to approximate the carotid-femoral distance.

[0024] Van Velzen et al. (J Clin Monit Comput. 2019; 33(2): 241-247) compared pulse wave velocity measured using the Complior or Biopac systems (the Complior system measures PWV between the carotid and radial arteries by a piezoelectric clip, whereas the Biopac system measures PWV between the heart and the fingertip using an ECG and an optical sensor). PWV measured by the Biopac system was calculated by dividing the distance (D) between the PPG sensor on the left index finger and the sternoclavicular joint by the time difference between the R-peak of the ECG and the onset point of the pulse wave (i.e., by using the PAT). The authors found that either system could be used to measure PWV change over time.

[0025] Alivon et al. (Arch Cardiovasc Dis. 2015; 108(4): 227-34) propose to measure PWV using a finger-to-toe path, using two photodiode sensors placed on the fingers and toes, continuously recording the pulse wave for 20 seconds, and calculating the difference in pulse wave transit time between the toes and fingers. The distance is estimated using the subject's height.

[0026] The authors of "The Reference Values ​​for Arterial Stiffness' Collaboration" (European Heart Journal, Volume 31, Issue 19, October 2010, Pages 2338-2350) (Non-Patent Document 7) have defined reference and normal values ​​for PWV by combining a sizeable European population after standardizing the results of various PWV measurement methods.

[0027] Beutel et al. (IEEE Transactions on Biomedical Engineering, vol. 68, no. 9, pp. 2810-2820, Sept. 2021) (Non-Patent Document 8) disclose a proof-of-concept for a novel method for estimating central PWV and blood pressure.

[0028] Huttunen et al. (2019, PLOS Computational Biology 15(8): e1007259) investigated whether it is possible to estimate cardiovascular health indicators using machine learning approaches, in particular by performing a theoretical evaluation of estimating aortic pulse wave velocity, diastolic and systolic blood pressure, and stroke volume using pulse wave propagation / arrival timing derived from photoplethysmography signals. They concluded that aortic pulse wave velocity and diastolic blood pressure can be predicted with high accuracy, but prediction of systolic blood pressure is less accurate. [Prior art documents] [Non-patent literature]

[0029] [Non-Patent Document 1] Huttunen et al. (PLoS Comput Biol. 2019 Aug; 15(8): e1007259) [Non-Patent Document 2] Sola et al. (Physiol. Meas. 30 (2009) 603-615) [Non-Patent Document 3] Campo et al. (Am J Hypertens. 2017;30(9):876-883 [Non-Patent Document 4] Geshe et al. (Eur J Appl Physiol. 2012 Jan;112(1):309-15) [Non-Patent Document 5] Van Velzen et al. (J Clin Monit Comput. 2019; 33(2): 241-247) [Non-Patent Document 6] Alivon et al. (Arch Cardiovasc Dis. 2015; 108(4): 227-34) [Non-Patent Document 7] "The Reference Values ​​for Arterial Stiffness' Collaboration" (European Heart Journal, Volume 31, Issue 19, October 2010, Pages 2338-2350) [Non-Patent Document 8] Beutel et al. (IEEE Transactions on Biomedical Engineering, vol. 68, no. 9, pp. 2810-2820, Sept. 2021) Summary of the Invention

[0030] Disclosure of the Invention The present invention provides a simple method for estimating pulse wave velocity using values ​​from electrocardiogram (ECG) and photoplethysmograph, which can be combined in a formula to obtain a value of PWV. The inventors have shown that this formula should also take into account the age of the patient. This method can be repeated over multiple time points, thus allowing continuous monitoring of PWV. In particular, this method can be performed in the operating room during a surgical intervention, for the entire period of anesthesia of the patient, using only the usual monitoring tools that exist to monitor anesthesia. Rather than using PAT as an approximation of PTT, the inventors have created a special function relating PWV to PAT, which also takes into account the age of the patient.

[0031] The present invention therefore relates to an ex vivo method for assessing a patient's Pulse Wave Velocity (PWV) and obtaining an estimated PWV (PWVest), the method comprising the steps of combining the patient's age (expressed in years), the patient's carotid-femoral distance (Dcf) expressed in meters (m) and the pulse arrival time (PAT) expressed in seconds (s) in a function to obtain a final result, where the function is: TIFF2025505646000002.tif10128, In addition, 0.05≦k1≦0.15 3.5≦k2≦5.0 and The final result provides an estimated PWV expressed in m / s.

[0032] In a preferred embodiment, the method is performed by a computer.

[0033] In some embodiments, the method also includes at least one of receiving a signal from an ECG of the patient and a signal from a PPG of the patient.

[0034] The method may also include calculating the PAT (the time between the R-peak of the ECG signal and the rising edge of the pulse wave of the PPG signal).

[0035] Thus, a computer-implemented ex vivo method for assessing Pulse Wave Velocity in a patient is described herein, which is also the subject of the present invention, comprising the following steps: receiving a signal from an ECG of a patient; receiving a signal from a PPG of a patient; - calculating the pulse arrival time (PAT), which is the time between the R peak of the ECG signal and the rising point of the pulse wave of the PPG signal; - combining in a function the patient's age (years), the patient's carotid-femoral distance (Dcf) expressed in meters and the pulse arrival time (PAT) expressed in seconds to obtain a final result, where the function (Dcf(m) / PAT(s))×(k1×age(years)+k2) and In addition, 0.05≦k1≦0.15 3.5≦k2≦5.0 and The final result provides an estimated PWV expressed in m / s.

[0036] In one embodiment, the ECG from which the values ​​were obtained was taken using leads D1 and D2, however, an ECG made with any other lead would also provide the required signal (peak of the R wave).

[0037] In a preferred embodiment, the PPG was obtained from a plethysmograph attached to the patient's finger. In another embodiment, the plethysmograph is attached to the patient's toe. In this case, the distance taken into account may be changed and the patient's height may be used instead of the carotid-femoral distance. The carotid-femoral distance can be measured according to the teachings of the prior art.

[0038] This method is carried out ex vivo, and therefore does not include the step of collecting ECG data or PPG data, but uses such data after receiving them.It should also be noted that the method disclosed herein provides an estimate of PWV, but this alone is not sufficient to determine the health status of patient, which requires further doctor's expertise.This is an intermediate result that doctor may take into account to make a diagnosis of cardiovascular risk, taking into account age and other comorbidities (weight, body mass index, diabetes, hypertension, etc.).

[0039] However, in some embodiments, the method may also include obtaining / measuring ECG and PPG waves from the patient and then sending that information for analysis and calculation of an estimated PWV.

[0040] Although this method can be used to calculate a "flash" PWV (i.e., to calculate the PWV by using only one pulse arrival time calculated from an ECG signal and an associated PPG signal), in a preferred embodiment, it is preferable to obtain an estimated PWV from multiple "flash" measurements and then average them. Thus, in this embodiment, the estimated PWV is calculated as the average of multiple estimated PWVs calculated over a predetermined period of time. Each of the estimated PWVs from the plurality is calculated according to the method disclosed above using the PAT calculated from an ECG signal and an associated PPG signal.

[0041] There are several ways to calculate the pulse arrival time. Note that the pulse arrival time is the time delay from the R-peak of the electrocardiogram (ECG) waveform to the onset of the pulse wave of a photoplethysmogram (PPG), preferably worn on the patient's finger.

[0042] In a first embodiment, the rising point of the pulse wave is determined relative to the maximum of the second derivative with respect to time of the photoplethysmography signal at the rising edge of the pulse wave. This method is used in the art and is specifically disclosed in Chiu et al. (Am Heart J. 1991. 121, 1460) or US20200390347.

[0043] Specifically, the rising point of the pulse wave is determined by calculating the second derivative of the plethysmography signal, and corresponds to the maximum of this second derivative at the rising edge of the pulse wave. The first derivative can be weighted to focus only on the rising part of the signal (i.e., if the first derivative is not positive, the second derivative is given a zero value). Alternatively, to obtain a strong signal at each rising edge of the pulse wave, the obtained value can be squared and then integrated over a moving time window for a given time point, specifically 240 milliseconds centered on the time point (averaged over values ​​120 milliseconds before and after the desired time point). This signal can be compared to a threshold value. Preferably, this threshold value can be adapted in real time. The threshold value can be calculated by the following formula: the integral (as calculated above) averaged over a moving time window of 3 seconds (with or without a central time point) and multiplied by 1.5. The peak (maximum) of the second derivative (defining the rising point of the wave) is identified in the region where the integral exceeds this threshold value.

[0044] In another embodiment, the rising edge of the pulse wave is determined by a tangent crossing method, which is the intersection of (1) a tangent (which is a horizontal line) to a point at the minimum of the pulse wave and (2) a tangent to a point corresponding to the maximum of the first derivative (with respect to time) of the photoplethysmography signal on the rising edge of the pulse wave. This method is used in the art and is specifically disclosed in Chiu et al. (op. cit.).

[0045] As described by Chiu et al., op. cit., these two methods have been the most consistent and widely applicable methods for determining PWV. Other methods for identifying the onset point of the PPG pulse wave can also be contemplated, such as using the point of minimum diastolic pressure or the point where the first derivative of pressure is maximum (corresponding to the onset of the pulse wave).

[0046] Using a time point corresponding to the R-peak and a time point corresponding to the rising edge of the pulse wave, the pulse wave arrival time is defined as the time between these two points (for the same heartbeat). The times (instants) of the R-peak and the rising edge of the pulse wave can be determined by a timing unit such as an internal clock.

[0047] As previously indicated, estimated PWV (PWVest) is calculated according to the following formula: TIFF2025505646000003.tif10128 can be obtained by In addition, 0.05≦k1≦0.15, preferably 0.05≦k1≦0.10, preferably 0.06≦k1≦0.08, more preferably 0.07≦k1≦0.086, more preferably 0.075≦k1≦0.080, 3.5≦k2≦5.0, preferably 3.6≦k2≦4.6, preferably 3.85≦k2≦4.40, more preferably 4.00≦k2≦4.25.

[0048] In certain embodiments, k1 is about or exactly 0.079 and k2 is about or exactly 4.12 ("about" meaning the value ±2%).

[0049] As indicated above, the average PWV can be estimated by estimating multiple flash PWVs over a particular period of time and averaging these values.

[0050] It is also possible to repeat the methods disclosed herein at different times t to estimate multiple PWVs for a patient. This allows for plotting a curve of the estimated PWV as a function of time. If blood pressure (particularly mean arterial pressure) is also known as a function of time, it is possible to compare the change in the estimated PWV as a function of blood pressure.

[0051] The various estimates of PWV can be "flash" PWV estimates or estimates of multiple average PWVs at multiple time points. As an example, if the period is 12 heart beats, 12 estimated "flash" PWV values ​​can be obtained, or if one average PWV is calculated over 3 heart beats, four average PWV values ​​are obtained.

[0052] Advantageously, the method may be performed to estimate the PWV of an anaesthetised patient while the patient is under anaesthesia, particularly general anaesthesia. This is particularly advantageous because: (1) the method utilizes ECG and PPG signals obtained by devices already used in operating rooms to monitor anesthesia; (2) when anesthetized, the patient is essentially in a constant state (subject to possible fluctuations in mean arterial pressure), thereby increasing the reliability of the results; (3) because arterial pressure is monitored periodically (by a cuff, i.e., an oscillometric upper arm tension meter) or continuously (specifically according to the method of US20200390347, in particular by using the dicrotic wave height), it is possible to relate the estimated PWV at a given time point to the mean arterial pressure at that time point, thereby expressing the PWVad as a function of the mean arterial pressure; and (4) given the duration of anesthesia, the method can be repeated to obtain multiple PWV values, thereby providing information of interest to the physician (e.g., highest estimated PWV, lowest estimated PWV, average PWV over the entire period of data collection, median PWV over the entire period of data collection, standard deviation).

[0053] The methods disclosed herein may be performed by a device for estimating Pulse Wave Velocity of a patient, comprising: a. means for receiving electrocardiogram (ECG) signals and photoplethysmography signals from a patient; b. a means for identifying the R peak of the ECG signal; c. A means for identifying the leading edge of the pulse wave signal; d. A means for calculating Pulse Arrival Time (PAT); e. a means for calculating an estimated Pulse Wave Velocity (PWV) by combining the patient's age, the patient's carotid-femoral distance (Dcf), and the calculated Pulse Wave Arrival Time (PAT) in a function to obtain a final result, The function is (Dcf(m) / PAT(s)) × (k1 × age (years) + k2), In addition, i. 0.05≦k1≦0.15 ii. 3.5≦k2≦5.0 and The final result provides an estimated PWV expressed in m / s; f. Means for recording / storing the estimated PWV in a database, and preferably also the time (instant) at which it was calculated, so that these values ​​can be retrieved at a later time for further analysis.

[0054] The device may also include a memory unit / database that includes the patient's age and the (previously measured) carotid-femoral distance. The carotid-femoral distance can be measured as is known with ultrasound and tonometry techniques. Alternatively, it can be determined to be half the patient's height, as there is a highly significant correlation between fingertip distance and height.

[0055] The means for receiving electrocardiogram (ECG) and photoplethysmography (PPG) signals from the patient may include an analog-to-digital conversion unit for converting analog electrocardiogram (or PPG) signals into corresponding digital electrocardiogram (or PPG) signals. Such a type of unit is specifically disclosed in US8285369.

[0056] The means for identifying an R-peak of the ECG signal in a. is electronically coupled to the means for receiving an electrocardiogram (ECG) signal and includes a storage unit and a digital signal processor. The digital ECG signal is stored in the storage unit along with an associated time of the waveform, and an R-peak point of the ECG is identified by the signal processing unit as the highest value of the ECG signal. The time corresponding to this R-peak is stored in the storage unit.

[0057] The means for identifying the rising edge of the pulse wave signal is electronically coupled to the means for receiving the PPG signal and includes a storage unit and a digital signal processor. The digital PPG signal is stored in the storage unit along with the associated time of the waveform, and a point corresponding to the rising edge of the pulse wave is identified according to the method described above. The time corresponding to the rising edge of the pulse wave is stored in the storage unit.

[0058] The means for calculating the pulse arrival time (PAT) includes a processing unit that obtains the time of the R-peak and the time of the rising point of the pulse wave and determines the difference between these times, such that PAT=t(rising point of the pulse wave)-t(R-peak). The PAT value is stored in a database.

[0059] The means for calculating the estimated PWV includes a processing unit that obtains the PAT, the patient's age, and the carotid-femoral distance (Dcf) and combines these values ​​by the function disclosed above. In some embodiments, the means for calculating the estimated PWV obtains a plurality of PATs stored continuously in the database and averages these plurality of PATs to obtain an average PAT value (preferably with an associated time) that is stored in the database. In other embodiments, the means for calculating the estimated PWV further includes a processing unit that calculates an average (particularly a moving average) of the plurality of PWVs and stores the result in the database.

[0060] The final result may then be stored in a database (or storage unit), preferably together with its associated time (e.g. the time (instant) at which it was calculated, or the time of the R-peak, or the time of the rising point of the pulse wave). This allows retrieving these values ​​later for further analysis of the various estimated PWVs (to calculate the mean, median, maximum, minimum, standard deviation, etc.).

[0061] The device may also include means for displaying the estimated PWV on a monitor. Data stored in a storage unit or database of the device is preferred, especially if it can be exported for further analysis by the physician.

[0062] In some embodiments, the processing unit calculates the mean, median, maximum, minimum, and standard deviation of the multiple PWVests stored in the database. Such calculation results can be stored in an appropriate database (also including the patient's ID), displayed on a monitor, exported, or transmitted to a remote terminal.

[0063] The device may also include means for estimating mean arterial pressure (MAP) and obtain an estimated mean arterial pressure (MAPest). Such devices are disclosed in US20200390347. They include a processing unit that calculates the onset point of the pulse wave (disclosed above), the peak (maximum value) of the pulse wave, and the value (height) and time of the dicrotic wave.

[0064] As explained in US 20200390347, the peak of the pulse wave can be identified after the rising point of the pulse wave by (i) dividing the signal into several time frames (specifically 20 ms to 100 ms, in particular 50 ms frames) and (ii) noting the maximum value in each time frame (progressing frame by frame as long as a larger value is found in the last time frame examined). The local maximum (corresponding to a maximum value V found in a time frame, the maximum value in the next time frame being smaller than this value V) corresponds to the maximum value of the pulse wave. This makes it possible to obtain the value of the maximum value (value of absorbance given by the pulse oximeter, corresponding to the peak of the systolic wave) and the time at which this maximum value is reached.

[0065] As described in US20200390347, the value and time of the dicrotic wave can be determined by (i) taking the second derivative of the signal after the pulse wave maximum, (ii) dividing the signal over a predefined time frame (50ms to 300ms, in particular 150ms) after this pulse wave peak, (iii) searching for a local maximum of the second derivative of the signal in each time frame to identify a region of interest (a time frame in which this local maximum of the second derivative of the signal is present), and (iv) searching for an absolute minimum of the first derivative of the signal in this region of interest. This search can also be performed by dividing the region of interest into time frames (5ms to 15ms, in particular 8ms). The point corresponding to the dicrotic wave corresponds to the point where the absolute minimum of the first derivative is reached. The value (the value of absorbance given by the pulse oximeter) as well as the time between the rising point of the pulse wave and this point can then be measured and determined.

[0066] The processing unit can estimate the MAP for this pulse wave by the formula MAPest=Calib×Vpt, where Calib=(mean arterial pressure measured at a given time, e.g., when the arterial pressure was measured using a cuff) / (height of the dicrotic wave at this given time).

[0067] The estimated MAPest may be stored in a database in a storage unit along with the time at which it was estimated.

[0068] The device may also include means for storing, displaying, exporting, or transmitting multiple estimated PWVs and estimated MAPs at various points in time.

[0069] The device also measures arterial distensibility using the ratio (estimated PWV) / (estimated MAP) (e.g., m s -1 The present invention may also include a means for calculating the blood pressure (expressed in / mmHg).

[0070] As a result, a device specifically intended to carry out the methods disclosed herein allows for an estimate of PWV (and MAP, if applicable) to be obtained for each heartbeat (for each ECG and pulse wave). This device allows for these methods to be carried out continuously and for multiple values ​​to be obtained that provide better information to the physician who ultimately determines the prognosis regarding the patient's cardiovascular risk. If MAP is also evaluated continuously, such information would allow the physician to consider information regarding PWV alone together with MAP, allowing for a more accurate diagnosis.

[0071] The database provided during the implementation of the aforementioned method can be created to include, for the heartbeats, a table containing as data: -Digital image of ECG wave of heartbeat -Digital image of the heartbeat pulse wave -Time of the R peak of the ECG wave (hour, minute, second) -Time of the rising edge of the pulse wave (hour, minute, second) - Pulse arrival time calculated relative to the heartbeat - Pulse Wave Velocity calculated in relation to the heart rate.

[0072] This table shall be linked to another table containing patient identification information (e.g., first name, last name, identification number, date of birth), the patient's carotid-femoral distance, and the patient's age. Such linking is necessary to obtain the information required for the calculation of PWV.

[0073] The present invention also relates to a computer product / program comprising program code instructions recorded on a computer readable medium for performing the steps of the methods disclosed herein when the program is run on a computer, as well as a computer readable recording medium having recorded thereon a computer program comprising program code instructions for carrying out the steps of the methods disclosed herein.

[0074] The present invention also relates to computer program products containing instructions for performing the methods disclosed herein when such instructions are executed by a logic circuit or a processor.

[0075] The present invention also relates to a non-transitory computer-readable storage medium comprising program instructions for causing a computer device to execute successive steps of a method for estimating a patient's Pulse Wave Velocity (PWV) and optionally the patient's MAP by carrying out the method disclosed herein. In particular, the method comprises the following steps: receiving an electrocardiogram (ECG) signal; receiving a photoplethysmography (PPG) signal; - converting the ECG and PPG signals into digital signals - Identifying the R-peak and its time in the digitized ECG signal and the onset point and its time in the pulse wave in the PPG signal. - Calculating the Pulse Arrival Time (PAT) - Obtaining patient age and carotid-femoral distance (DCF) - estimating the patient's PWV according to the formulas disclosed herein.

[0076] The present invention also relates to a method for treating a subject, comprising carrying out the methods disclosed herein to assess PWV, particularly during anesthesia in a subject, and treating the subject with a cardiovascular drug, particularly an antihypertensive drug, if the assessed PWV is high. Such treatment may include initiating administration of a cardiovascular drug, or modifying / adapting the treatment if the subject is already undergoing cardiovascular treatment.

[0077] It should be noted that PWV increases with the age of the subject and with the presence of existing clinical conditions. Koivistoinen et al. (Clin Physiol Funct Imaging (2007) 27, pp191-196) showed that if the subject does not have symptoms of cardiovascular disease, normal values ​​depend on the age and sex of the subject.

[0078] [Table 1] Source: Koivistoinen et al. (op. cit.)

[0079] Diaz et al. (Int J Hypertens. 2014; 2014: 653239) provided reference values ​​for pulse wave velocity in healthy individuals from urban and rural Argentine populations and found the following values:

[0080] [Table 2] Source: Diaz et al. (op. cit.)

[0081] Thus, for subjects without signs of cardiovascular disease, an estimated PWV higher than 10 m / s may indicate the need for further advice to determine the presence of cardiovascular disease and / or treatment with cardiovascular drugs (especially in patients at or under the age of 59). The threshold may be 12 m / s for subjects at or over the age of 60.

[0082] Regarding dialysis patients, Ferreira et al. (Am J Nephrol. 2017;45(1):72-81) showed that PWV>12 m / s provides important prognostic information for cardiovascular mortality in patients under 60 years of age with end-stage renal disease. Using the methods disclosed herein leads to treatment of such patients with appropriate cardiovascular medications, particularly medications for managing hypertension.

[0083] Several drug classes are effective in the initial and subsequent management of hypertension and may be administered to subjects with elevated PWV as revealed by the methods disclosed herein. Examples include adrenergic modulators (e.g., central alpha 2-agonists (e.g., methyldopa, clonidine, guanabenz, guanfacine, among others) or postsynaptic alpha 1 blockers (e.g., prazosin, terazosin, doxazosin)), angiotensin converting enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, perindopril erbumine, quinapril, ramipril, trandolapril), angiotensin II receptor blockers (ARBs) (e.g., azilsartan, candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan), beta blockers ... Examples include acebutolol, atenolol, betaxolol, bisoprolol, carvedilol (including controlled release), labetalol, metoprolol (including sustained release), nadolol, nebivolol, penbutolol, pindolol, propranolol, timolol), calcium channel blockers (e.g. dihydropyridines (amlodipine, felodipine, isradipine, nicardipine (including sustained release), nifedipine (especially sustained release), nisoldipine)), direct renin inhibitors (especially aliskiren), direct vasodilators (including minoxidil and hydralazine) or diuretics (loop diuretics, potassium-sparing diuretics, thiazide-type diuretics).

[0084] The method disclosed herein can also be useful for administering appropriate drugs to a subject during anesthesia, especially when the subject has low blood pressure during anesthesia.In fact, when high PWV is revealed using the method disclosed herein, the doctor in charge of anesthesia does not only administer pure vasopressors such as phenylephrine or norepinephrine.The doctor can use a combination of vasopressors and inotropes or chronotropes (e.g., positive inotropes (especially digoxin, berberine, calcium, calcium sensitizers, levosimendan, catecholamines, dopamine, dobutamine, dopexamine, adrenaline (epinephrine), isoproterenol (isoprenaline), eicosanoids, prostaglandins, phosphodiesterase inhibitors, enoximone, milrinone, amrinone, theophylline, glucagon, insulin)).

[0085] On the other hand, if a subject has low blood pressure but not a very high PWV, a physician can safely use only a vasopressor (e.g., norepinephrine or phenylephrine) because the increased vascular tone induced by the vasopressor will not increase the PWV in a way that could be dangerous to the subject.

[0086] Therefore, estimating PWV values ​​during hypotensive episodes may help physicians restore hemodynamics by selecting appropriate drugs at the right time. [Brief description of the drawings]

[0087] [Figure 1] The relationship between PAT / TTm ratio and age. Y=0.07868X+4.124. r=0.8089. R2=0.6544. P<0.0001. [Diagram 2] The relationship between LAAsc and PAT / TTm ratio. Y=0.8743X+1.842. r=0.8089. R2=0.6544. P<0.0001. [Diagram 3] Increase in PAT / TTm ratio by age. Left: Under 50 years old. Center: 50-75 years old. Right: Over 75 years old. [Figure 4] The relationship between carotid-femoral TT and TTlrb. r=0.7942. R2=0.6307. p<0.0001. [Diagram 5] Mean values ​​of measured PWVcf and estimated PWV-lrb. [Figure 6] The relationship between PWV and PWV-lrb. r=0.7427. R2=0.5516. p<0.0001. [Figure 7] Bland-Altman diagram of PWVcf and PWVlrb. [Figure 8] Changes in PWVcf / MAP or PWVlrb / MAP for three patients (young, middle-aged, and elderly). Circles: Young patients with little change in PWV due to changes in PAM (black: PWVcf, gray: PWVlrb). Diamonds: Middle-aged patients with large changes in PWV due to changes in PAM (black: PWVcf, gray: PWVlrb). Triangles: Older patients with little change in PWV due to changes in PAM, but with higher PWV values ​​compared to the general population (black: PWVcf, gray: PWVlrb). EXAMPLES

[0088] The following examples illustrate various aspects and embodiments of the present invention. The aspects described in the examples are an integral part of the present invention.

[0089] Example 1 Principle During each anesthesia, a non-invasive and continuous measurement of PWV (carotid-femoral) was required to detect cardiovascular risk factors. The aim was to devise a method to estimate PWV continuously in the operating room throughout the entire intervention period using only the usual monitoring tools, i.e. electrocardiogram (ECG), digital photoplethysmography (PPG) and also an oscillometric brachial blood pressure monitor to measure blood pressure non-invasively (NIBP). Furthermore, the hemodynamic changes inherent to anesthesia not only make it possible to investigate PWVcf over a wide range of arterial pressure changes, but also to obtain a true arterial distensibility index expressed in m / s per mmHg.

[0090] Therefore, being easy to use, automated and widespread, continuous measurement of PWV in the operating room during each general anesthesia, taking into account changes in mean arterial pressure (MAP), would overcome the limitations described in the introduction and could therefore have a considerable impact regarding the screening and follow-up of patients at cardiovascular risk.

[0091] The study focused on measuring the time, i.e., the pulse arrival time (PAT) (the time between the R wave of the ECG and the rising point of the digital PPG wave, which corresponds to the "a" wave of the second derivative of the digital PPG signal), a parameter that can be continuously monitored in the operating room.

[0092] From a physiological perspective, the PAT is the sum of two times: - Pre-ejection period (PEP): corresponds to the period of isovolumic contraction before ventricular ejection Pulse Transit Time (PTT): corresponds to the transit time of the pulse wave between the opening of the aortic valve and the rising edge of the digital PPG wave signal measured using a finger.

[0093] Therefore, PAT=PEP+PTT.

[0094] Thus, when using digital PPG, the PAT is the sum of the time associated with the PEP and the propagation time from the ascending aorta, then the subclavian artery, then the brachial artery to the digital arteries, which can be approximated by the length between the aorta and the carotid artery.

[0095] The aim was to provide a formula relating measurements of PAT to PWV. This was achieved using a cohort of patients (who were anesthetized because they had to undergo surgery for various reasons) and it was found possible to express PWV as a function of the patient's PAT, age and carotid-femoral distance (Dcf). TIFF2025505646000006.tif12128Note, 0.05≦k1≦0.15, preferably 0.05≦k1≦0.10, preferably 0.06≦k1≦0.08, more preferably 0.07≦k1≦0.086, more preferably 0.075≦k1≦0.080, 3.5≦k2≦5.0, preferably 3.6≦k2≦4.6, preferably 3.85≦k2≦4.40, more preferably 4.00≦k2≦4.25.

[0096] In certain embodiments, k1 is about or exactly 0.079 and k2 is about or exactly 4.12 (about meaning the value ±2%).

[0097] Determination of the values ​​of k1 and k2 was accomplished by: Step 1 : Near-simultaneous measurement of PAT and PWVcf (using the gold standard method) in several patients at various blood pressure levels, which allowed obtaining the propagation time TT, since PWVcf=Dcf / TT, where Dcf is the carotid-femoral artery distance. For each patient, the PAT was observed to move in the same direction as the TT. Step 2 : Calculation of the PAT ratio for each patient at various levels of blood pressure. The PAT / TT ratio was found to be largely independent of blood pressure values. Step 3 : The mean ratio PAT / TTm, which corresponds to the mean value of the PAT / TT ratio at different levels of blood pressure, was calculated for each patient. As previously indicated, PAT=PEP+PTT, where PTT corresponds to the propagation time in the descending aorta, subclavian artery, brachial artery, and digital arteries. Step 4 : Estimation of ascending aortic length (LAAsc) for each cohort patient using the Sugarawa formula. Sugawara et al. (JACC Cardiovasc Imaging 1, 739-748, 2008) showed that the ascending aorta lengthened significantly with age, but this association was not observed in other aortic segments (descending thoracic aorta and abdominal aorta). They estimated ascending aortic length (LAAsc) using the following formula: LAAsc (cm) = 0.09 × age + 2.61. Step 5 : Analysis of the relationship between the PAT / TTm ratio and LAAsc for each patient. A strong linear relationship was found between PAT / TTm and LAAsc, with the following formula: PAT / TTm=0.8743×LAAsc+1.842. Therefore, the carotid-femoral pulse transit time (designated TTlrb) can be estimated from the length of the ascending aorta and the PAT as follows: TTlrb=PAT / (0.8743×LAAsc+1.842). Step 6 : Estimation of carotid-femoral PWV (PWVcf or PWVlrb) from the above results. PWVlrb(m / sec)=Dcf / (TTlrb) PWVlrb(m / sec)=Dcf / [PAT / {0.8743×(0.09×age+2.61)+1.842}] PWVlrb(m / sec)=Dcf / {PAT / (0.078687×age+2.281923+1.842)} PWVlrb(en m / s)=(Dcf / PAT)×(0.078687×age+4.123923) PWVlrb(en m / s)=Dcf / PAT×(k1×age+k2) where Dcf is expressed in m, TTlrb is expressed in seconds (s), and age is expressed in years. In this cohort, k1=0.078687 and k2=4.123923. This can be rounded to k1=0.079 and k2=4.12. The coefficients disclosed herein may vary slightly depending on the size of the cohort.

[0098] conclusion The completion of the two phases of the study allows us to conclude that this formula allows a simple method of estimating carotid-femoral pulse wave velocity from age, aortic length (estimated from carotid-femoral distance or shoulder-to-palm distance), and PAT measurements. Thus, PWVlrb (PWVest) measurements in the operating room in patients under general anesthesia appear to have the potential to overcome the limitations of PWVcf measurements in cardiovascular risk screening by: -By the simplicity of measuring PWVlrb. It does not require any special equipment other than ECG, digital photoplethysmography (PPG), and oscillometric upper arm tension meter, and is therefore less expensive compared to other methods and does not require special training. -By being able to continuously measure and estimate PWVlrb and combine it with timed measurements of arterial pressure, this allows the calculation of PWVlrb / PAM changes, i.e. a dynamic and individualized analysis of the patient's arterial stiffness.

[0099] Example 2 Application of the principle method: The study was performed in the operating room on adult patients undergoing anesthesia (general or spinal). A standard monitoring system consisting of an ECG, digital PPG, and blood pressure cuff was installed. In addition to this monitoring, a carotid tonometer and a thigh cuff (SphygmoCor XCEL®, AtCor Medical) were used to measure the ipsilateral PWVcf on the digital PPG signal. PWVcf measurements were performed at intervals: once in basal conditions (before anesthesia) and several times under anesthesia (1-3 measurements per patient). When the PWVcf measurement was started, a blood pressure cuff measurement was performed at the same time. Continuous recording of intraoperative parameters (ECG, digital PPG, BP) was performed with the iXtrend® software. Analysis of the raw signals of the ECG and digital PPG, allowing the measurement of the PAT, was performed with the Graphysio software. The PAT corresponded to the time between the peak of the R wave in the ECG and the peak of the "a" wave of the second derivative of the digital PPG signal (Figure 5). The PAT associated with the PWVcf measurements was averaged over four beats.

[0100] result: Forty-four patients were screened for at least one PWVcf measurement associated with a PAT measurement, yielding a total of 118 PWVcf-PAT measurement pairs. The average PAT / TTm was 8.734 (range, 8.073-9.395). PAT / TTm was strongly correlated with age and ascending aortic length (r=0.8089) (Figures 1 and 2). Patients younger than 50 years had a PAT / TTm ratio of 6.64 ± 0.93, patients aged 50–75 years had a PAT / TTm ratio of 8.83 ± 1.16, and patients aged 75 or older had a PAT / TTm ratio of 10.73 ± 1.84 (Figure 3). TTlrb was highly correlated with TTcf measured using Sphygmocor (r = 0.7942) (Figure 4). The mean value of all measured PWVcf was 10.66 ± 3.065, and the mean value of PWVlrb estimated by the method was 10.74 ± 2.536 (Figure 5). A high correlation was found between PWV-lrb and PWVcf (r = 0.7427) (Figure 6). Figure 7 shows that the measurements were in agreement in the Bland-Altman plot: the bias was 0.04 ± 2.07 m / s, but the 95% limits of agreement were [-4.012; 4.098].

[0101] Additionally, cross-correlation was performed on this cohort by splitting it in two and calculating the constants k1 and k2 for half the cohort and validating against the other half. Results are similar between PWVcf and PWVlrb. Finally, results were modeled by plotting the slope of the line between the change in blood pressure and the change in PWV (visualization of the PWV / PAM ratio or ΔPWV / ΔPAM). This modelling reveals three types of populations, characterised by three examples (Figure 8): (1) Younger patients with little PWV change due to PAM change; (2) Middle-aged patients showed a large change in PWV with changes in PAM; and finally (3) Very elderly patients, whose PWV changes with PAM are minimal, but whose PWV values ​​are higher than those in group (1). Using PWVlrb, this type of modeling can be performed continuously in the operating room by tracking anesthesia-induced changes in MAP.

[0102] conclusion This study shows that estimates of PWVcf can be obtained from conventional monitoring during anesthesia (ECG, digital PPG, blood pressure cuff) and with a simple additional anthropometric measurement (carotid-femoral artery distance) as calculated PWVlrb.

Claims

1. 1. A computer-implemented ex vivo method for assessing pulse wave velocity (PWV) in a patient, the method comprising the steps of: combining in a function the patient's age, the patient's carotid-femoral distance (Dcf) in meters and the pulse arrival time (PAT) in seconds to obtain a final result, The function is and In addition, ・0.05≦k1≦0.15 ・3.5≦k2≦5.0 and The final result provides an estimated PWV expressed in m / s.

2. 2. The ex vivo method of claim 1, wherein the estimated PWV is calculated as an average of multiple estimated PWVs calculated over a predetermined period of time.

3. 3. The ex vivo method of claim 1 or 2, wherein 0.07≦k1≦0.

086.

4. The ex vivo method of any one of claims 1 to 3, wherein 4.00≦k2≦4.

25.

5. The ex vivo method of any one of claims 1 to 4, wherein k1 = 0.079 and k2 = 4.

12.

6. The ex vivo method of any one of claims 1 to 5, wherein the method is repeated at different times t to estimate multiple PWVs for the patient.

7. The ex vivo method according to any one of claims 1 to 6, wherein the mean arterial pressure of the patient is also measured or estimated.

8. The ex vivo method according to any one of claims 1 to 7, which is performed while the patient is under anesthesia.

9. A device for continuously assessing a patient's Pulse Wave Velocity, including: a. means for receiving electrocardiogram (ECG) and photoplethysmography signals from said patient; b. means for identifying an R peak of said ECG signal; c. means for identifying the leading edge of said pulse wave signal; d. means for calculating a pulse arrival time (PAT), which is the time between the R peak of the ECG signal and the rising edge of the pulse wave of the PPG signal; e. a means for calculating an estimated Pulse Wave Velocity (PWV) by combining in a function the patient's age, the patient's carotid-femoral distance (Dcf), and the calculated Pulse Wave Arrival Time (PAT) to obtain a final result, The function is (Dcf(m) / [PAT(s))×(k1×age(years)+k2), In addition, i. 0.05≦k1≦0.15 ii. 3.5≦k2≦5.0 and said final result providing an estimated PWV expressed in m / s; f. A means for storing said estimated PWV in a database.

10. A means for estimating or measuring mean arterial pressure, and means for storing said estimated MAPest and the time at which it was measured or estimated; 10. The device of claim 9, further comprising:

11. means for calculating a dicrotic wave height (Vpt) at time t; The mean arterial pressure (MAPest) at time t is estimated by the formula MAPest=Calib×Vpt; Where Calib = (Mean arterial pressure measured at a given time) / (Height of the dicrotic wave at said given time) 11. The device of claim 10,

12. Means for displaying or exporting said estimated PWV The device of any one of claims 9 to 11, further comprising:

13. Means for calculating the mean PWV by calculating the average of the PWV estimated at different moments The device of any one of claims 9 to 12, further comprising:

14. Means for displaying or exporting said average PWV and / or the lowest estimated PWV and / or the highest estimated PWV.

14. The device of claim 13, further comprising:

15. A computer program product comprising instructions for carrying out the method of any one of claims 1 to 8, A computer program product in which the program is executed in a computer and such instructions are executed by logic circuits or a processor.

Images