Patent Application
20230390562
The present invention is concerned with a catheter that may be utilised in a system and a method for detecting dyssynergy resulting from dyssynchrony, a system and method for determining optimal electrode number and positions for cardiac resynchronisation therapy and/or a method and system for measuring time to fusion as a means of determining degree of parallel activation of the heart. Thus, the invention may be used in relation to patient's suffering dyssynchronous heart failure, and more specifically can apply to the identification of patients who are likely to respond to resynchronization therapy, as well as optionally determining optimal locations for placement of electrodes to stimulate the heart. The invention may also be used for patients who have suffered dyssynchronous heart failure.
Cardiac resynchronization therapy (CRT) is consistently provided according to recognized medical standards and guidelines provided by international medical societies in order to treat patients suffering from various conditions such as a widened QRS complex, (left or right) bundle branch block and heart failure. There are some minor differences between the medical guidelines regarding the specific conditions that should occur before CRT is utilized, such as how wide the QRS complex is, what type of bundle branch block is being suffered and the degree of heart failure.
CRT is associated with a reduction in mortality and morbidity; however, not all patients benefit from such therapy. In fact, some patients may experience deterioration after treatment, some experience devastating complications, and some experience both.
In this regard, it would be beneficial to provide a unifying strategy that reduces the number of non-responders to CRT and optimize the treatment of potential responders, and therefore increases the effectiveness of therapy.
Viewed from a first aspect, the present invention provides a catheter for assessing cardiac function, the catheter comprising
As discussed below, such a catheter may fund particular use when determining function of the heart, and particularly when providing measures indicating whether dyssynergy resulting from dyssynchrony is present within a patient. When the catheter is suitably positioned in the left heart chamber with electrodes opposing each other at the septum and contralateral wall and the sensor within the chamber, with each heartbeat a voltage gradient is registered between each electrode and a reference electrode. Such a voltage gradient represents electric activation of the heart at the site of the electrode. The time course of activation of the different electrodes determines the degree of dyssynchrony. Further, and following on from the above, the sensor(s) register events related to the onset of synergy, i.e. events that relate to the rapid increase in rate of pressure rise within the left ventricle, which reflects the point where all segments of the heart begin to actively or passively stiffen. The time to this event is compared with electrical activation and the degree of dyssynchrony, and the presence of dyssynergy resulting from dyssynchrony is registered. Whilst herein the rapid increase in pressure of the left ventricle is referred to, the skilled person would understand that such an event could manifest in a more general in pressure within the heart of a patient. In this way, the catheter may not necessarily be placed within the left ventricle of the patient.
The heart can then be stimulated from one or more electrode. With each heartbeat a voltage gradient is registered between each electrode and a reference electrode, which as described above can represent the electric activation of the heart. The one or more sensor again registers events related to the onset of synergy. The new set of time events may then be compared to the first set of events and the presence or absence of resynchronization is registered.
Advantageously, with such a system, it may be possible to quickly and efficiently determine such measures for various positions of electrodes. In this way, not only may it be determined if a patient is indeed a potential responder for cardiac resynchronisation therapy, but also the ideal number and positions of electrodes may be quickly determined.
The at least one sensor comprises a pressure sensor, a piezoelectric sensor, a fiberoptic sensor, and/or an accelerometer. Such sensors can find particular use in detecting events relating to the rapid increase in the rate of pressure increase in the left ventricle, as further discussed below.
The stiffness of the elongate shaft may vary along its length between the proximal end and the distal end. In this way the elongate shaft may have a structure that is ideal for quick and easy positioning within the patient's heart. Optionally, the elongate shaft is provided with a stiff proximal end, a middle part which is of an intermediate stiffness, and a flexible tip at the distal end. Again, such a structure provides for a catheter that may be easily manoeuvred within the heart.
The at least one electrode may comprise a plurality of electrodes disposed along the shaft such that, in use, at least two electrodes may be positioned opposing each other in the heart of the patient. Optionally, the at least one electrode is configured to be placed within the septum of the patient, and at least one electrode is configured to be placed in the contralateral wall of the patient.
In a second aspect, there is provided a system comprising
Such a system may be utilised to quickly and easily determine how moving the catheter about the heart, and therefore moving the attached electrodes effects the functioning of the heart, and particularly whether pacing makes any marked difference in reducing dyssynchrony and/or dyssynergy.
The data processing module is configured to determine a characteristic response relating to the onset of myocardial synergy from the event relating to the rapid increase in the rate of pressure increase within the left ventricle of a patient.
The sensor(s) may be any kind of appropriate sensor, or a combination of appropriate sensors, such as an acceleration, rotation, vibration and/or a pressure sensor. The sensor(s) may be configured to provide data regarding the pressure within the heart to the data processing module, and wherein the data processing module is configured to filter the pressure data to identify the characteristic response relating to the onset of myocardial synergy. The characteristic response may comprise the beginning of a pressure rise above the pressure floor in a pressure signal filtered above the first harmonic of the pressure signal. The characteristic response may comprise the presence of high frequency components (above 40 Hz) of the pressure signal. The characteristic response may comprises a band-pass filtered pressure trace crossing zero. By filtering the pressure trace it is possible to remove associated noise and more accurately and reliably determine a point that relates to the onset of myocardial synergy.
Additionally or alternatively, the sensor(s) may be configured to provide acceleration data from within the heart to the data processing module, and the data processing module may be configured to filter the acceleration data to identify a characteristic response relating to the onset of myocardial synergy. For example, the data processing module may be configured to calculate a continuous wavelet transform of the acceleration data to identify a characteristic response relating to the onset of myocardial synergy. The data processing module may be configured to calculate the center frequency of the continuous wavelet transform, wherein the characteristic response is the peak of the center frequency. The data processing module is configured to average the center frequency over a number of heart cycles. By filtering the acceleration trace it is possible to remove associated noise and more accurately and reliably determine a point that relates to the onset of myocardial synergy.
As would be appreciated, in addition or as an alternative to the above, there are provided several further methods herein that enable a characteristic response relating to the onset of myocardial synergy to be determined. The data processing module may be configured to perform one or more of such methods.
For example, the increase of pressure within the heart (for example, pressure within the left ventricle) over time for two different stimuli may be compared. For example, a pressure curve that results from the pacing of the right ventricle and a pressure curve that results from biventricular pacing may be compared. The pressure rises resulting from the two stimuli may be fitted together relative to their stimulation timing, and the pressure level adjusted to fit the diastolic portion of the curves prior to ventricular pacing. The point at which the pressure curve resulting from the stimuli begin to deviate from one another may then be detected, which indicates the time of the onset of synergy of the stimuli that results in the earliest pressure rise.
The portion of the pressure rise curve that follows the time of the onset of synergy on the pressure curve resulting of the stimulus that results in an earlier pressure rise may then be shifted so as to fit on the portion of the pressure rise curve of the stimulus that results in a comparatively delayed pressure rise. The point on the pressure rise curve of the stimulus that results in a comparatively delayed pressure rise at which the curve following the onset of synergy of the stimulus that results in the earlier pressure rise is the point of onset of synergy in the delayed pressure rise curve. The delay may then be calculated between the two determined points of onset of synergy. From such a calculation, a recommendation may be made to which pacing regime should be following in an implanted pacemaker.
The above process may be automated and for the data resulting from any number of pacing regimes/stimuli, whether by a simple matching of the curves (for example, by the fitting of a template to the pressure trajectory with a least squares method) or by a comparison of the mathematical formulae that represent the curves. In this way, an explicit plotting of the pressure curve and a visual matching of the curve may not be necessary, but rather the raw data may be analysed so as to allow for similar conclusions to be reached.
In this way, there can be an automatic detection in the data of the exponential pressure rise, up to the peak dP/dt which results from the onset of synergy. There may be an automatic calculation of the exponential formula that fits the pressure curve, and the time when the exponential formula fits one of a number of curves can be determined.
There may be a template match, and there may be calculated a time offset between the exponential formula and the template matches, or equally a cross-correlation between other measures.
The above method may equally be performed using filtered pressure measurements.
Additionally or alternatively, an advancement of the onset of synergy may be detected by an advancement of the zero-crossing of the band-pass filtered (e.g. 4-40 Hz) pressure curve (Tp) with stimulation from a certain pacing regime compared to another kind of pacing. Such data may be used to indicate the presence of synergy with a certain pacing regime, and therefore that it may be desirable to undergo CRT with that pacing regime.
The method may include calculating a baseline interval (B) by determining a time period between intrinsic atrial activation (Ta) and the associated zero crossing of the resulting pressure curve (Tp). A corresponding time period (Tp1) may be calculated following pacing from a first electrode at a set pacing interval (PI1) after Ta, and the pacing interval reduced until the Ta to Tp interval is less than B. A corresponding time period (Tp2) may be calculated following pacing from a second electrode at a set pacing interval (PI2) after Ta, and the pacing interval reduced until the Ta to Tp interval is less than B. A corresponding time period (Tp3) may be calculated following pacing from the first and second electrodes at a set pacing interval (P13) after Ta, where P13 is the same time interval of the lower of PI1 and PI2. By determining which pacing has the shortest corresponding time period Tp, the pacing regime that leads to the highest degree of synergy may be identified.
The data processing module may be configured to identify reversible cardiac dyssynchrony by identifying a shortening of a delay to onset of myocardial synergy as a result of pacing. Specifically, the data processing module may be configured to identify reversible cardiac dyssynchrony of a patient using the at least one sensor to measure the time of the event relating to the rapid increase in the rate of pressure increase within the left ventricle of a patient by identifying the characteristic response in the data received from the one or more sensors, the event relating to the rapid increase in the rate of pressure increase within the left ventricle being identifiable in each contraction of the heart.
The data processing module may be configured to measure the time of the event relating to the rapid increase in the rate of pressure increase within the left ventricle by;
Further, the data processing module may be configured to determine the degree of parallel activation of a heart undergoing pacing. Specifically the data processing module may be configured to determine the degree of parallel activation of a heart undergoing pacing via a method comprising:
Further, the data processing module is configured to determine the optimal electrode number and position for cardiac resynchronization therapy on the heart of the patient based on node(s) of a 3D mesh 3D mesh of at least part of the heart with a calculated degree of parallel activation of the myocardium above a predetermined threshold. Specifically, the system may be configured to perform a method determining optimal electrode number and positions for cardiac resynchronization therapy on a heart of a patient, via a method comprising;
The catheter may be configured to be provided into a patient's heart through arterial access, venous access, subclavian access, radial access and/or femoral access such that the electrode(s) and sensor(s), in use, may be provided within the heart of the patient.
Certain preferred embodiments will now be described by way of example only and with reference to the accompanying drawings, in which:
Assessment of Cardiac Dyssynchrony
A representation of a normal heart may be seen in
The locations of said electrodes 102 may be represented on a 3D surface geometry model of the heart, thereby showing a heart model display with colour maps representing measurement zones relative to the electrodes as seen in
Firstly, the system may comprise a bioimpedance measurement system is provided to connect to pacing wires that are situated within any chambers and/or vessels of the heart and surface electrodes for current injection. Measurements of complex impedance, phase and amplitude will allow characterization of the time of onset of myocardial synergy.
An example system for measuring bioimpedance may be seen in
The electrodes may be placed on the surface of the body, for example perpendicular to the axis of the heart (from center of mitral valve orifice to the LV apex) for current injection. Current injection may also be performed from electrodes located within the heart.
The system may further include one or more sensors to provide measures of onset of synergy as described above. For example, an accelerometer or a piezo-resistive sensor or a fibreoptic sensor may also be provided either on the body surface, or embodied within a catheter in the heart (such as an ablation catheter for detection of the His potential) to detect the heart sounds, aortic valve opening or closure. An ultrasound sensor may be used to provide similar measurements. A pressure transducer may be positioned on a catheter within the right or left ventricle, so as to detect peak pressure rise in the time domain, and/or to detect trajectory advancement. The transducer may also measure any delay compared to any trajectory in either the time derivative of the pressure curve trajectory or in the pressure curve trajectory itself. Additionally, and/or alternatively, surface electrodes for producing an ECG may also be provided.
The data provided by the sensors may then be processed and used to calculate a degree of offset between the onset of pacing and the onset of myocardial synergy as a measure of cardiac dyssynchrony.
For example, a circuit implemented in hardware and/or software is used to receive signals from one or more of the above described sensors and/or measurements, corresponding to the time when the cardiac activation and contraction leads to ejection.
The circuit may then additionally receive the ECG signal of the heart, which corresponds to time point when the heart starts depolarizing, as well as when it is fully depolarized. The ECG can be used as a time reference, and the resulting signals can be related to the onset/offset of intrinsic activation of the heart, and/or onset of pacing as seen in the surface ECG. Such information may be utilized as a reference to provide a time interval relative to onset of pacing and/or onset/offset of the ECG.
Such a utilization of measurements as a way of measuring the delay to onset of myocardial synergy may be seen in
The measured impedance is represented with complex impedance (phase), corresponding to the contraction of the heart muscle, and the amplitude, corresponding to the blood volume within the heart. In this way, the amplitude of the impedance signal may be used as a surrogate for volume changes within the left heart chamber, as changes in the amplitude signal is paralleled by changes in ventricular blood volume. The phase of the impedance is used as a surrogate of muscle contraction, as changes are paralleled by changes in muscle volume and intracardiac blood volume.
The time from a reference point until the impedance curves meet and deviate (1) may be measured as a representation of onset of synergy. Such a point occurs at the point where the muscle shortens and blood is ejected from the heart. Acceleration from any acceleration sensor within (or connected to the surface of) the body of the patient can be used to determine onset of acceleration after a given reference point (4). Any part of the stable acceleration signal that reproduces itself from beat to beat and stimulation site may be used as a representation of onset of synergy. For example, the part of the acceleration signal used to determine the onset of synergy may correspond to any heart sound, aortic valve opening or closure.
Further, the ECG signal can be used as the reference point, from any of onset, offset or full duration of the QRS signal (3), and equally the acceleration signal can be used as a reference (2) from onset, offset or full duration (2). As described above, any such measurements can further be visualized on a surface of a heart geometry using color coded zones and a scale, relative to electrodes.
As would be appreciated, other measurements may be utilized to relate to the onset of synergy, such as measurements of the myocardial acceleration or when using a phonocardiogram or from seismocardiography. For example, echocardiography, sonography and cardiac ultrasound within or from outside the body to may be utilized to measure myocardial wall velocity, strain or any other measure that repeats in each cycle to measure onset of synergy. Specifically, at least one of onset of S-wave velocity, onset of S-wave strain rate, onset of global ejection, aortic valve opening, onset of aortic flow may be measured.
As seen in
A pressure curve can be compared with any pressure curve with the same time reference (5) to measure the time offset (2) between the curves or the different timing of two comparable curves with same reference, i.e. by calculating time delay 4 minus time delay 3. An example of such a comparison may be seen in
Such a delay may, for example, be due to dyssynchrony with isolated areas of the myocardium contracting, causing passive stretch of the myocardium, which is reflected in the comparatively low pressure increase. In this way, typical measures of mechanical activation, such as electromechanical delay (EMD) are measures of time of regional activation to onset shortening, only indicating the performance of the immediate area of myocardium. Further, in dyssynchronous hearts, EMD may vary within the heart, and this may also vary throughout the heart due to other issues, such as dyskinesia.
In contrast, onset of synergy is a global marker and reflects the phenomenon when active forces increase with global active or passive stiffening of segments (and any event that directly follows); a time when exponential pressure rise onsets (onset of myocardial synergy); a time at when any segmental contraction increases force and subsequently the pressure, without shortening segmental length (isometric contraction); once most segments are electric actively or passively stiffened. Mitral valve closure is typically an event resulting around the time of onset of myocardial synergy, and closure is a needed to allow a rapid pressure rise and isometric segmental contraction. Onset of myocardial synergy exist also in a situation when the mitral valve does not close, however, with incomplete closure of the mitral valve, segmental shortening will occur also after onset of synergy, and onset of synergy reflects in a rapid volume change of the left heart chamber rather than a rapid pressure increase.
Typically in the cardiac cycle one would name the electromechanical delay and the isovolumic contraction as the pre-ejection phase, and keep the EMD and IVC separate. IVC is characterized that there is contraction without shortening (i.e. that the volume is constant). In dyssynchrony there is a great overlap between EMD and isovolumic contraction, and during the isovolumic contraction period there is shortening and hence typically physiological characteristics of this period is lost. The pre-ejection period is therefore very different in a normal compared to a dyssynchronous heart, as is EMD and IVC.
An illustration of physiological conditions experienced during heart contraction may be seen in
As described above, activation of the heart muscle requires electromechanical coupling. Electrical currents pass through the heart muscle within the specialized conduction system at high speed and within conductive muscle tissue at lower speed. With conduction block, in specialized tissue, propagation delays and becomes dyssynchronous with a pattern of conduction no longer determined by the specialized conductive tissue, but by the conductive properties in the heart tissue itself (muscle, connective tissue, fat and fibrous tissue).
Electrical activation is defined from the onset of an electrical stimulus that leads to depolarization of cardiac tissue (for example, as measured from the ECG curve or a pacing artefact) to the off-set of the QRS complex. An electromechanical delay is seen between the on-set of pacing and the beginning of local contraction (and also between local electrical and mechanical activation). However, as can be readily seen in
The onset of synergy relates to this point where the shortening of the muscle stops the myocardium contracts simultaneously, beginning to increase the force at a constant volume/load in the heart (a characteristic response seen with isometric myocardial contraction). This occurs at some point between the earliest, and latest regional EMD or later, and could be early or late in this phase, but rather reflects the degree of dyssynchrony. In itself, this point is difficult to measure, but this point is reflected in a number of measures, for example (but not limited to), early cardiac vibrations, pressure increase, peak derivative of pressure, aortic valve opening, aortic root vibrations, coronary sinus vibrations, filtered pressure waves, peak negative derivative of pressure. Such measures may have a constant relationship in time to the onset of synergy, such that the measurement of the time of such events will directly reflect the onset of synergy, and therefore may be used as a measure of onset of synergy. Therefore, by using such measurements to measure a representation of onset of synergy in time, it is possible to compare different pacing methods and their efficacy in reducing the time to onset of synergy. If shortening occurs when comparing to a different way of pacing, less dyssynchrony is present, and when the time delay gets longer more dyssynchrony is present.
Based on the results of the sensor measurements, it may also be possible to determine the most effective pacing regime to be applied. For example, a second circuit implemented in hardware and/or software may comprise an algorithm to determine how many electrodes should be included and in what position they should be placed in the pacing strategy, and further determines which pacing strategy to follow. For example, it may be determined that the most effective pacing may be achieved by CRT, His bundle, biventricular, multipoint or multisite, or endocardial pacing, or any combination of the mentioned in the form of a suggested algorithm of pacing. For example, if the onset of myocardial synergy with intrinsic activation is short, or if onset of myocardial synergy with optimal electrode positions gets longer, then physiologic/His pacing may be desirable.
A screen may be additionally provided for visualization of the heart model with any fiducials and representations of any sensor connected. Such a system may allow for an accurate measurement of cardiac dyssynchrony by the indirect measurement of the onset of myocardial synergy described above, such as by way of an accurate measurement of Time to peak dP/dt, time to zero crossing of a filtered pressure signal, time to peak Fc(t) based on CWT from acceleration or pressure signal, time to early vibrations in a time window of interest, and/or time to bioimpedance signal deviation. In this way, any shortening in the time to onset of myocardial synergy may be visualized with a corresponding shortening of any directly measured parameter as previously described, thereby indicating the presence of dyssynchrony. Equally, any pacing measures applied may be reversed when it is determined that dyssynchrony is not present. For example, when measuring the impedance phase and amplitude as an indirect measure of the onset of myocardial synergy in a case where dyssynchrony is not present, the impedance curves will not change with pacing at different locations because no change in contraction occurs with resynchronization.
As would be appreciated, certain limitations must be applied to the measurements to allow for meaningful data to be extracted from the measurements, and the measurements must be compared to a known time point. For example, it may be that measurements can only be performed during pacing if at least one of the following conditions apply:
In order to provide effective pacing, any atrioventricular (AV) delay should preferably be calculated so that AP−VP is shorter than the shortest of AP−RVs and AP−QRS.
Preferably AP−VP should be calculated so as to equal 0.7*(AP*RVs), or if AP−QRS onset is known, the AV−delay interval should preferably be 0.8*(AP−QRS).
Measurements may be performed during ventricular pacing with intrinsic conduction, but only when the onset of the QRS complex is not ahead of pacing, unless the QRS onset−VP interval is corrected for in the measurement.
Measurements may be performed during atrial fibrillation with ventricular pacing when no fusion with intrinsic conduction is present. However, during atrial fibrillation pacing should preferably occur at a rate shorter than the shortest RR interval seen during a reasonable period in time so that when pacing occurs QRS complexes are not fused with intrinsic conduction, but are fully paced.
Measurements performed utilizing one sensor should only be compared with a similar sensor, unless a known correction factor is used to calibrate for differences between sensors. The detection of the reference in time should be similar, and carefully chosen to be the best representation possible of the similar time reference as compared with. A pacing stimulus may be initially negative, then positive in some configurations and equally may be initially positive, then negative in others. While the onset of the signal represents an unbiased reference in time that disregards polarity of the signal, then the maximum peak might be different in time between the two references, and the maximum should be compared to the minimum when this is the best possible detection for the signals with different polarity when compared. When intrinsic activation is detected, as in an intrinsic QRS complex, the onset of the QRS complex may be difficult to exactly define. In such a case, the earliest off-set from the isoelectric line should be chosen.
When the myocardium is paced (artificially stimulated), there is a delay from the pacing stimulus to the onset of activation such that there is a time delay from the onset of the pacing spike to the QRS onset. When comparing a measurement with a time reference from the QRS onset or the QRS complex with a measurement with a time reference from a pacing spike, such a time delay should be taken in account, for example by adding the same time delay to the non-paced measurement. The delay will typically be calculated based on the type of applied pacing. For example, the delay may be in the range of 10 to 20 ms. In typical disease, like a myocardial scar, pacing from within such a region may delay this interval beyond this range. Such a delay, typically beyond 20 ms up to 80 ms should be carefully analysed and compensated (either by pacing or by calculation) before utilized carefully for comparison.
In summary, when time reference or sensor is different between measurements, the off-set between the different time references or the sensors should be accounted for in the measurements for comparison.
In this way, it may be necessary to make sure, before measuring, that no activation occurs through the conduction system that would need to be compensated for in the measurement. The measurement of onset of synergy only takes meaning when one is not pacing the ventricle only for comparison with the surface ECG offset for determination of resynchronization potential as described.
By using the above described methods to measure the onset of synergy, it is possible to identify patients for potential CRT therapy. Traditional measures such as electromechanical activation and delay, onset of force generation, or local electromechanical delay cannot be utilized as suggested herein. As discussed, it is difficult to know exactly when to measure an electromechanical delay, as mechanical activation occurs over a wide range in time across the heart. Such issues can occur with all known methods of measuring electromechanical delay.
For example, should an isolated measure of electromechanical delay be measured using aortic valve opening, there would be many associated issues with such. In such a case, if one were to pace LV early, and allow intrinsic activation from RV, and measure from LV pace; then if pacing LV late, aortic valve opening would be determined by RV activation and not by LV, but the time from LV to aortic valve opening would be short. This gives a false measure of the efficacy of pacing in improving the physiological function of the heart.
Rather, by knowing the timing of activation through the normal conduction system, it is possible to compensate for measurements performed before pacing occurs. For example, if intrinsic activation occurs before pacing, then one should measure from onset of intrinsic and add the interval from pacing to activation, to allow comparison with other measurements when pacing.
It has been further found by the inventors that the signature of the cardiac phases lies in the frequency spectrum after the 2nd harmonic of the left ventricular pressure trace, where the harmonic is represented by 1/paced cyclerate (s). Early contractions at low pressures (i.e. the contractions that are associated with dyssynergy) do not produce high-frequency pressure components. However, the rapid increase of pressure that occurs with onset of synergy results in high-frequency components of the LVP trace. In this way, the crossing of the x-axis at zero for the 2nd and above harmonics captures only the synergy components, and can therefore be used as a reference measure to compare with QRS onset or onset of pacing. Similarly, dyssynergy (being characterised in early contractions) does not produce high-frequency components.
With the onset of contraction load against initial load (LO), contraction velocity rapidly increases (Vmax). With contraction, the load increases to Lmax, at the point where V goes to 0. Tension follows a sinus wave, and with synergy tension increases above the sinus envelope.
As can be seen in
High-frequency components can be assessed as vibrations and translate from the left ventricle to the aorta and surrounding tissue through the solid fluids and tissue. Filtering high pressure components from aortic pressure (AoP) waveforms or atrial pressure waveforms or coronary sinus waveforms, or detecting vibrations using accelerometers or any other sensor will therefore reflect synergy, and as long as the measurement occurs at a similar position on the measured trace/curve, for example, when the trace crosses zero, from the onset of vibrations or a certain characteristic of a waveform, or a template waveform. Such high frequency components (for example, those above 40 Hz) may additionally find use in improving the identifying of onset of synergy in the mid range filtered signal (such as a 4-40 Hz) signal, as the high frequency components identifies the onset of pressure rise prior to zero-crossing.
Further information regarding the onset of synergy may be deduced from filtering various measured signals, as seen in
Starting from
Then, there is dyssynergy when the mechanical force begins to slowly increase, due to the passive stretch of the myocardium. Low-frequency components in left ventricular pressure (less than 2nd to 4th harmonics of the heart rate) are typical for dyssynergy. With dyssynergy there is onset of active force with sarcomeric cross-bridge formation at high rate in specific regions of the heart that result in shortening of the sarcomers (and myofibrills) that leads to stretch of not yet contracting segments and regions of the heart, with only a small increase in pressure resulting (with low-frequency components), as discussed extensively above.
The onset of synergy is reflected in a rapid increase of force at a relatively constant volume, which is reflected in the increased rate of increase of pressure. With activation of all segments and synergy, pressure increases rapidly (with high-frequency components) when approaching isometric (and isovolumic) conditions as load increases. This can, for example, be seen in the identifiable change in the rate of increase of the left ventricular pressure between the initial (relatively) slower increase in pressure due to dyssynergistic contraction and the exponential increase of the synergistic contraction. This may be seen in a step change in the rate of increase of the left ventricular pressure, and/or may be identified by further post-processing of the data. For example, this change can be measured in the frequency range, as the frequencies contained in the pressure trace increase when there is a step change in the pressure change. This occurs beyond the low order harmonics of the frequency spectrum, and the OoS may become evident when low order harmonics are filtered with a low pass filter or band pass filter. Filtering at, for example, a band-pass 2-40 Hz or 4-40 Hz removes the low, slow frequencies that are associated with dyssynergy and the onset of synergy may be seen as the onset of the pressure increase that leads to, or is directly prior to aortic valve opening or maximum pressure. Alternatively or additionally, this may be seen in the peak second order derivative of pressure rise in the left ventricle. Filtering can be adaptive applying harmonics relative to the paced heart rate or any other adaptive filtering technique.
This change in rate of pressure increase is because of increasing and exponential cross-bridge formation while passive stretched segments tension increase, either because depolarization or because elasticity model reaches its near maximum. Rapid cross bridge formation with isometric or eccentric contraction leads to high-frequency components in the pressure curve frequency spectrum, reflecting onset of synergy. This phase of the cardiac cycle may be seen when filtering LVP with high pass filter above the 1st or 2nd harmonics. The filtered and characteristic waveform has a near linear increase, from onset of synergy to crossing 0, and continues with a linear increase up to aortic valve opening. The line of linear increase reflects the period with synergy, crossing zero at halfway in the phase, which corresponds to peak dP/dt as described above, and onset of synergy is reflected in where this line starts to rise above the floor of the filtered pressure curve or at its nadir.
Ejection then occurs with the opening of the aortic valve, thereby reducing the LV volume at a relatively constant pressure. Another example trace is seen in
Other data may alternatively or additionally be analysed in order to determine a measure of the onset of synergy. In this way, other measures may be used either as a supplement to measuring pressure traces, and determining therefrom the time of onset of synergy (or an event related thereto) as considered above, or as an alternative to pressure traces. For example, acceleration data may be analysed, such as that provided by an accelerometer sensor, as is illustrated in
As would be appreciated, acceleration data may be used as a standalone measure. or alternatively, it may be used in combination with other measures such as the pressure traces, and/or filtered pressure traces so as to determine the time until the onset of synergy.
As would be appreciated from the above (and following) description, the point of the onset of synergy may be determined in a number of ways, essentially by detecting the point (or a point directly related to) the time during cardiac activation where the myofibrills work in synergy and begins to contract isometrically as most of the myocardium stiffen from either active contraction or passive stress (increased resting tension), which results in an exponential pressure increase (rapid pressure rise) within the heart. The following example methods are not intended as an exhaustive list of ways in which the point of onset of synergy can be measured, and utilized, but are rather presented as examples to illustrate the present invention.
When it is possible to determine the point of the onset of synergy, and how it changes with various types of treatment (for example, with intrinsic rhythm, RV pacing, LV pacing and/or BIVP amongst others), it is possible to identify whether the concept of synergy exists within a patient. Where it is identified that the time to onset of synergy can be shortened, then it may be said that “synergy” exists for a determined pacing regime, and therefore that a patient may benefit from treatment.
It is important to note that, as would be understood by the skilled person, the methods presented herein do not require the presence of a patient, nor do they explicitly require the collection of data from the patient. Whilst patient data is required, the measurements may be (and typically are) performed after the collection of data, and away from the patient. It is therefore envisaged that the inventions described herein may be performed on pre-existing data sets, without the presence of a patient. In this way, an examination of a patient involving the collection of data is not integral to the present invention. Any reference herein to steps that involve the collection of data would be understood such that they refer to steps and measurements that have already been performed. In this way, the methods herein may be considered as methods of processing such data so as to give technical information regarding the patient, which may then be used for in planning how best to give/improve the prognosis of the patient from whom the data was previously collected.
Cardiac Resynchronization Therapy (CRT) is understood, and can be achieved in multiple ways either by direct stimulation of the conduction system of the heart chambers (left bundle branch or His bundle) or with stimulation at more than one site (resynchronization therapy). CRT can be permanently applied with a pacemaker or temporarily with electrophysiology catheters or pacing leads to perform artificial stimulation of the myocardium. CRT also implies that there is an intention to perform resynchronization with any kind of artificial stimulation of the heart chamber or chambers. One may also consider intrinsic conduction in a patient as resynchronization, and compare the intrinsic activation to an artificially paced beat or an ectopic intrinsic beat in the heart of the patient.
The calculation of the time of the onset of synergy may be utilized as a prognostic biomarker, in that if a patient (after having Cardiac Resynchronization Therapy) has a late onset of synergy during stimulation (with CRT or pacing electrodes), then the prognosis of the patient will be poor. In this way, it could be said that there is described a method to determine the prognostic results from resynchronization therapy, from data that has been obtained from a subject when controlling their heart rate and sensing the ventricle, either by stimulation of the atrium or by sensing the atrial electrical activity while sensing the ventricle. Then CRT is applied and the signals from sensing electrodes and sensors are collected. Measurements of the intervals and comparison of the data is performed in a processor outside of the body after collection of the data to determine if the pacing pulses have provided synergy or not. The finding of an improvement in synergy is present when a first interval is shorter than another interval. If with CRT, synergy is present, then the prognosis is determined to be good.
As described above, it may be desirable that, for an accurate measure of the onset of synergy, it is ensured that the electrical activation and resulting pressure increase in a data set results only from the stimulated sites and not from the intrinsic activation of the heart. Therefore, in combination of the methods that are considered herein or alone, pacing electrodes may have been placed in the atrium and ventricle(s), and pacing may be applied from the atrium and/or, for example if atrial fibrillation is present, then from the ventricle, both pacing being at rates 10% above the intrinsic heart rate. Therefore, from data received during pacing at a higher rate that the intrinsic activation, an automatic detection of a set of intervals may occur, for example:
In order to provide a fixed interval until the chambers are activated, and ensure that intrinsic activation does not interfere with the measured response, there may be pacing with a paced atrial to paced ventricular interval at 40% shorter than any of the detected intervals. This ensures that the chambers are not activated by intrinsic activation, and therefore that the paced activation and the intrinsic activation are not competing, which can lead to an inaccurate measure of the time of the onset of synergy.
The measurements above relating to the identification of the onset of synergy may be utilized in various different ways to give an indication of whether pacing results in (an increase of) synergy. Other ways of illustrating and/or measuring the point of the onset of synergy are envisaged, such as that of
For example,
From comparing these curves, whether synergy is present (i.e. whether the time to the onset of synergy has been shortened by providing BIVP), and the timing of the onset of synergy may be measured by finding the point of deviation between the fitted pressure curves that are compared.
As can be seen in
The inventors have recognized that, despite the difference in timing of the onset of synergy, the pressure rise preceding the onset of synergy will follow a common diastolic pressure increase, and then the pressure rise resulting from the onset of synergy will always have the same shape (i.e. follow the same mathematical equation on a plot between pressure and time beginning from the onset of synergy), despite the delay, and change between the relative resting tension. Therefore, from the determination of this point, it is possible to fit this portion of the pressure curve resulting from BIVP onto the corresponding portion of the pressure curve resulting from RVP. From this, it is possible to use the amount that it has shifted in order to determine pertinent information about how BIVP has changed the onset of synergy, and thereby determine whether synergy is present with such a method of pacing.
For example, as shown in
By comparing the difference in the onset of synergy during BIVP (at point 3802), and the onset of synergy during RVP (at point 3805), it is possible to obtain valuable information regarding how the change in pacing effects the function of the heart. The time delay (t 38 in the example of
As would be appreciated by the skilled person, this process can be automated and for the data resulting from any number of pacing regimes, whether by a simple matching of the curves (for example, by the fitting of a template to the pressure trajectory with a least squares method) or by a comparison of the mathematical formulae that represent the curves. There can be an automatic detection in the data of the exponential pressure rise, up to the peak dP/dt which results from the onset of synergy. From this, there may be an automatic calculation of the exponential formula that fits the pressure curve, and from this, the time when the exponential formula fits one of a number of curves can be determined. For example, there could be a template match, and there be calculated a time offset between the exponential formula and the template matches, or equally a cross-correlation between other measures. Additionally, whilst this is shown in the example of
From the above, an output of the time to onset of synergy and the offset between exponential pressure rise curves, or offset between band pass filtered curves, or between derivatives of pressure curves can be provided. If the onset of synergy is shorter than just in RV pacing then it might be decided that it would be beneficial to program an implanted pacemaker to pace from both RV and LV channels. Equally, it might be recommended to modify pacing so as to occur with multiple channels, and the delay to onset of synergy is shorter with any multipoint/multisite pacing, then it might be suggested to program the pacemaker to pace in a multipoint/multisite way.
As discussed above, synergy is the phenomenon by which stimulation by a given pacing regime leads to a sooner onset of synergy. This may be identified by the advancement of rapid pressure rise, which can be identified by a leftward shift in the zero-crossing of the band pass filtered pressure curve. The onset of synergy (OoS) is the corresponding onset of pressure rise along the tangent of zero, as can be seen in
The OoS can be compared to the rapid pressure rise with pacing or with intrinsic rhythm from onset of electrical activation, and if OoS is advanced when compared to the other then it may be said that more synergy is present.
In order to populate the traces of
As above, the pressure signal can be band pass filtered at 4-40 Hz to remove the high and low frequency waves, and simplify the subsequent analysis. The corresponding ECG signal, to which the pressure signal is aligned and compared.
The ECG signal is passed on to a processor unit, and a time of atrial intrinsic activation/stimulation (Ta) can be determined. The signal from the pressure sensor is also provided to a processor unit, where the value of 0 can be determined from the BP-filtered pressure waveform, and the time may be extracted (thereby giving a measure of Tp). From this, a baseline interval B can be calculated, as equal to Ta-Tp (i.e. the time between activation and zero crossing of the pressure curve for intrinsic activation). Intervals PI, Ta-Tp, Td and QRS-onset are demonstrated in
Then, following pacing of the heart chamber from a first electrode (for example, one of the electrodes positioned in the RV or LV) at a set pacing interval (PI1) after Ta (but before QRS-onset), a corresponding Tp1 may be calculated. The value of 0 is determined from the BP-filtered pressure waveform and the time is extracted (Tp1).
The pacing interval (PI1) is reduced, typically to more than 20 ms before QRS-onset, until the corresponding interval Ta-Tp (Ta-Tp1) is less than B (the baseline interval between activation and zero crossing of the pressure curve for intrinsic activation). For example, the pacing interval that results in a Ta-Tp<B is PI1, and the corresponding Ta-Tp interval (Ta-Tp1) at PI1 equals T1.
Then, pacing of the heart chamber is performed from a second electrode (i.e. another one of the electrodes) at a set pacing interval (PI2) after Ta, and the corresponding Tp2 is registered. In this way, the zero-crossing is collected from the corresponding BP-filtered pressure waveform and the time is extracted (Tp2). Again, the pacing interval (PI2) is reduced until the corresponding interval Ta-Tp (Ta-Tp2) is less than B, which is again typically more than 20 ms. For example, the pacing interval that results in a Ta-Tp<B is PI2, and the Ta-Tp (Ta-Tp2) interval at PI2 equals T2.
Then, pacing of the heart chamber is performed from multiple electrodes (for example, both the RV and LV electrodes) relative to Ta at a set P13, which corresponds to the lower of PI1 and PI2. Then T1 and T2 is repeated with P13 with stimulation at each electrode, the value of 0 is collected from the BP-filtered pressure waveform and the time is extracted for T1 and T2. Then stimulation of combined electrodes with P13 and the corresponding interval Ta-Tp (Ta-Tp3) is registered. The resulting Ta-Tp (Ta-Tp3) interval at PI3 equals T3, and it may be said that synergy is present if T3 is lower than T1 and T2 at P13. If this is the case, then it is desirable to perform synergistic pacing from multiple electrodes in CRT. Conversely, if T3 is higher than T1 or T2 then synergy is not present and synergistic stimulation cannot be performed. Following a positive determination for BIVP, a pacemaker can be programmed with corresponding intervals for P13 relative to Ta for synergistic stimulation of the heart. The steps can be repeated with different electrode positions to find the shortest interval T3 compared to T3 from different electrode positions.
Finally, a Tbaseline can be calculated by measuring the interval from QRS-onset to Tp and adding 15 ms+P13. Td BIV equals removing the interval P13 from T3, and Td baseline equals removing the interval P13 from Tbaseline. It may be said that synergy is present if T3 is lower than T baseline (i.e. that the time to Td has been shortened when comparing between pacing, and intrinsic conduction). In sum, when calculating Td it may be said that synergy is present when Td BIV is lower than Td baseline. When pacing the specialized conduction system with only one electrode (T2 and P13), it can be said that synergy is present if T2 is lower than Tbaseline.
Similar data may be employed for synergistic pacing from different PIs from a pacemaker. In such a method, a pacemaker is programmed with corresponding intervals for PI1 for the first electrode, and PI2 for the second electrode to provide synergistic pacing to the heart. Each PI must result in a corresponding Ta-Tp shorter than B. The value of 0 is collected from the BP filtered pressure waveform and the time is extracted (Tp1). The onset of the QRS complex is identified and time is extracted (Tqrs) at baseline and with each pacing. Td baseline is the Tqrs to Tp interval with intrinsic activation without pacing the heart chamber. Td for the pacing electrodes and PIs equals the time interval from Tqrs to Tp1. Then a new P13 is added for any of the electrodes or a new electrode and pacing is provided from two or more electrodes, a new Tp2 and corresponding Td (Tqrs to Tp2) is calculated. Again, a lower Td indicates that more synergy is present with the corresponding PIs. If Td with pacing (BIVP) multiple electrodes and PIs is lower than Td baseline then Synergy is said to be present with pacing and the pacemaker can be programmed to stimulate the heart at the corresponding electrodes with the corresponding PIs. If synergy is present, then the pacemaker can be programmed to stimulate at the two electrodes. As would be readily appreciated by the skilled person, further, additional electrodes and PIs can be added and stimulated simultaneously, or with a delay between the electrodes (configurations). Typical delays (PIs) are between 10-60 ms.
In such a case, various configurations may be noted. A configuration that shortens Td below all other time intervals is noted as improved synergy, and therefore the pacemaker can be programmed to stimulate electrodes with the applied configuration that results in the soonest/earliest Onset of Synergy.
Such a method may similarly be performed with the detection of synergy from the pressure curves, as described more fully above with regards to
Summary of Onset of Synergy
Essentially, the inventor in this case has discovered a new measure that can be used to effectively identify patients that are suitable candidates for cardiac resynchronisation therapy, by measuring the point, termed onset of synergy (OoS), at which the myofibrils in the left heart chamber starts contracting isometrically and hence develop force rapidly which leads to an exponential pressure increase before ejection. OoS occurs within the pre-ejection interval, after the earliest mechanical activation and before aortic valve opening. OoS is therefore otherwise independent of the electromechanical coupling interval and the pre-ejection interval/isovolumic contraction period. By identifying how this point in time changes with therapy, it is possible to determine not only if a given therapy method would be effective in improving the prognosis of a patient, but also what would be the most effective therapy. A simple visual representation of an advancement of a measure that directly relates to the point of OoS, and how it varies with various kinds of pacing that may then be used to determine that BIVP would be the most effective treatment in this example may be seen in
Whilst several methods are identified herein that allow for the point of OoS (or a similar point that directly relates to OoS) to be identified, such an identification requires unconventional data analysis steps that have been outlined herein to allow for detection, from which reliable conclusions can be reached. For example, the methods and systems described herein will only produce meaningful results under conditions were knowledge of the heart rate is known, knowledge of conduction through the AV node, knowledge of the time from stimulating the atrium either intrinsic or artificial to activation of the heart (whether intrinsic or artificial), or knowledge of the exact surface ECG configuration, so that if stimulation (intrinsic or artificial) is performed it can be recognized in the surface ECG or by VCG or electrical activation patterns of the heart.
Stimulation needs to be performed to avoid other activation than that from stimulation, calculated based on the knowledge above. For example, when stimulation from one electrode is performed, it should be tested that the stimulated heartbeat is that from stimulation and not that from intrinsic, as a combination of stimulations may lead to an inaccurate measurement of the time OoS,
When a new electrode is stimulated, again it should be checked that the stimulated heartbeat is that from the stimulus only, and not from intrinsic, premature, preexcitation or other stimulation. Similar considerations are to be taken into account before stimulating two electrodes or more in combination. Measurements of OoS can only be made on beats where the measured responses result from the stimulated electrodes, and where the measured responses change when stimulation is removed.
When configurations (i.e. non-synergistic pacing from is performed and pacing of one or more electrodes) occur later than the earliest recognizable intrinsic activation of the heart, then this earliest activation should be used for reference rather than that resulting from the artificial stimulus.
By taking the above factors into account, not only when pacing the heart but also when analysing the sensed and measured data, it is possible to obtain knowledge of a potential electrode position and configuration that can be used to program an implantable pacemaker to provide synergistic stimulation of the heart.
Electrode Positioning Using Cardiac Parallelity
By measuring the degree of cardiac parallelity (i.e. the degree of parallel activation of the myocardium), it is possible to characterize cardiac synchronicity as well as identify anatomical pacing zones that result in more parallel activation of the myocardium to reduce cardiac dyssynchrony (resynchronization). Such a measure may be utilized to guide and optimize CRT.
Firstly, in order to measure the degree of cardiac parallelity, a recruitment curve is generated, showing the area of the heart that is recruited following pacing from an electrode against time. From such a graph, the degree of parallelity may be determined.
With reference to the method 10 of
As can be seen in
The resulting geometry then contains multiple nodes with electrical time intervals measured between them and assigned to them. As the geodesic distance between all nodes may be calculated and calibrated, the geodesic propagation velocity of the electrical activation may then be calculated. The propagation velocity is then input to all existing nodes in the heart geometry (step 14).
In step 15, the propagation from multiple nodes or electrodes 1006 may then be calculated, resulting in a visualization of time propagation of electrical activation throughout the heart as coloured isochrones 1007, taking velocity at each vertex of the heart model mesh into account as can be seen in
The geodesic distance between each node of the patient may be calculated. With reference to
As may be seen in
A similar process may be performed using separation time, as seen in
Using a combination of one or more of the measurements described above, it is possible to build additional compound measures and present them on a geometric model of the heart of the patient.
For example, as seen in
By further adding geodesic distance, as in
As seen in
When the velocity at each vertex has been interpolated as outlined above, the propagation of electrical activation from the nodes may be represented on a heart model, as seen in
Further, echocardiographic data using segmentation may be transferred onto the heart model, and be used to modify and enhance the tissue characteristics of the heart model. For example, as shown in
Similarly, scar tissue 2201 of the heart muscle, such as that which may be identified by a 3D MRI scan may be used to assign tissue characteristics of the heart geometry. This is further visualized in
In step 16, the additional recruited area (of activated sarcomeres) at each point in time from the calculated velocity models can be calculated from multiple electrodes and the recruitment curve for said electrode(s) can be drawn based on the time propagation in the heart model when considering the added area at each time step until the full area, or a limited area, of the model is covered in isochrones, and their propagation from time=0 to time=x+1, as can be seen in
Given the recruitment curve for a given node, a parabola may be fitted to the recruitment curve as can be seen in
As can be seen in
If the sensed activation pattern indicates too slow propagation through the tissue, the geodesic velocity is below a threshold, or the inability to provide sufficient parallel activation in the presence of scar tissue, the implantation of a CRT device should not take place, as such symptoms are not representative of dyssynchrony that may benefit from resynchronization therapy.
With pacing from each of the electrodes, a vectorcardiogram (VCG) recording the magnitude and the direction of the electrical forces that are generated during pacing of the heart is created. For each position that is tested, pacing is performed at each electrode, as well as for the two electrodes in combination, and a VCG is created for each situation. As seen in the example of
The synthetic VCG LVP+RVp and the real VCG BIVp are then compared, as seen in
The time interval between the pacing stimulus and the point of deviation of the curve trajectories represents the time to fusion (i.e. the time until the electrical propagation in cardiac tissue from multiple sites meet). The longer period of time until the point of deviation indicates more parallel activation of the myocardium. Therefore, the time to the point of deviation between the synthetic and the real VCG should be as long as possible. The time to fusion may be calculated in isolation, or relative to QRS width to determine the degree of synchronicity (parallel activation).
A similar method may be performed with electrograms (EGMs) and electrocardiograms (ECGs) in one or multiple dimensions. If adding an electrode stimulus site does not shorten the time interval to deviation of the curve trajectories, or if the time to deviation increases; an additional benefit of adding the electrode is seen, such that the electrode can be added to the stimulation site and number of electrodes.
The method allows analyzing the additional effect of adding one electrode and compare this new state of pacing an additional electrode to the state of not pacing this electrode. If the new electrode does not decrease time to fusion, this indicates that the addition of this electrode allows capture and activation of tissue without promoting fusion at an earlier stage than without. Thus, more parallel activation occurs when time to fusion does not decrease with adding an electrode.
Whilst the recruitment curves described above suggest positions for the electrodes, the generated VCGs may be further used to validate them. In this regard, VCGs and recruitment curves are measures of electrical activation that should reflect each other. When these measures are concordant, it gives validity to the suggested electrode positions and validity to the model. To this point, once good positions are found for the location of the electrode based on the generated recruitment curves, this position is then validated based on VCG. As would be appreciated by the skilled person, these measures are not necessarily only used in combination, rather each of the recruitment curves or determining the point of deviation may both be used individually to determine suitable electrode positions. Both of these measures reflect parallelity, the degree of parallel activation of the myocardium, and therefore may be utilized alone to identify anatomical pacing zones that result in more parallel activation of the myocardium to reduce cardiac dyssynchrony (resynchronization). Such a measure may be utilized to guide and optimize CRT.
An inverse solution ECG may also be utilized in addition, or as an alternative to using implanted electrodes to measure the degree of electrical activation. By utilizing data obtained from surface electrodes applied to patients, it is possible to extrapolate a map of electrical activation onto the heart model using an inverse solution approach, given that the heart model has been positioned in an anatomically correct position as described above and the relative electrode position to the heart model is correct and known.
In such a case, activation of each node in the heart geometry is seen relative to the distance from the first activated area, and therefore calculation of velocity can be performed for the model. This velocity can then be used to calculate recruitment curves. When pacing from a single electrode, the activation can be calculated, similar to the calculation of activation from a different electrode. These measurements can form the basis of propagation velocity calculations and recruitment curves.
In such a case, body surface electrodes are used to determine parallelity (i.e. the degree of parallel activation of the myocardium) by collecting surface potentials. Such surface potentials may then be extrapolated onto the heart model that has been aligned so as to be collocated with the actual location of the patient's heart, as previously described. Thereby, an inverse solution ECG activation map of the heart may be produced, and the activation map may be manipulated as described above in order to determine propagation velocity, and thereby the presence of dyssynchrony.
In order to obtain such an inverse solution ECG, a system may be provided with surface electrodes to acquire multiple surface biopotentials (ECG). The system may be configured such as to provide an inverse solution, in order to calculate electrical propagation on a segmented model of the heart, which can include scar tissue including scar. By utilizing the geodesic distance (from the heart model which is aligned with the patient's heart) in combination with the electrical propagation together, the system may be configured to calculate propagation velocity in the heart model based on the inverse solution electrical wavefront activation of the heart in combination with the geodesic distance. Once geodesic velocity is assigned to each vertex in the heart model, time propagation and parallelity can be measured from any and multiple sites in the model.
Further, the surface potentials may be incorporated in the cardiac model as a characteristic utilized to calculate propagation velocity from single or multiple points on the heart model. This, as described above with respect to measurements directly from electrodes implanted into the heart, allows for the generation of multiple propagation velocity curves in order to calculate the differences multiple different points. Using such a comparison between the multiple propagation velocity curves, it is possible to choose the ones having better acceleration, peak velocity or propagation time as an indication of the preferred location for placement of electrodes.
Example Method
The systems and methods described herein may be used both before and during treatment of patients with presumably dyssynchronous heart failure, with a resynchronization pacemaker (CRT) in order 1) identify the presence of an underlying substrate that identifies patients that are likely to respond positively (manifest resynchronization potential present) to, 2) identify optimal locations for placement of pacing leads/electrodes, and 3) validate placement of optimal electrodes and resynchronisation of the heart.
Patients are currently referred for implantation of a CRT pacemaker based on international guidelines that describe indication criteria. These criteria are based on inclusion criteria in larger clinical trials and, amongst other things, consists of symptoms of heart failure, reduced ejection fraction (heart function) and a widened QRS complex (preferably left bundle branch block) beyond 120-150 ms. However, currently only 50-70% of patients with one or more indications for treatment with a CRT actually respond to treatment. Reasons for these non-responders are multiple, but lead position, the underlying substrate (dyssynchrony), scar and fibrosis and electrode positions are the most prominent reasons. By improving the detection of the underlying substrate that indicates dyssynchronous heart failure, it is possible improve the selection of responders (in a diagnostic capacity) for optimization of treatment (allowing therapy to be personalized to the patient).
Firstly, it is desirable to detect and define the underlying substrate (resynchronization potential) that defines whether a patient will respond to CRT, and whether the substrate is present or not in patients with standard inclusion criteria. When the substrate is present, one should proceed implantation of a CRT pacemaker, but when the substrate is not present one should follow other guidelines that apply.
When underlying substrate is present, or even if the underlying substrate has not yet been identified, an optimal position for the leads may be found, based on measures of parallelity, which takes scar and fibrosis into account. The measurement of parallelity is performed with guidewires or leads with electrodes inside the heart (for example, in veins or chambers of the heart). Optimal positions are for the placement of the electrodes is then suggested.
When the leads are in optimal position, according to the determined optimal position taking into account the measured parallelity from each node, it is then possible to confirm the response (by either direct or indirect measurements of onset of myocardial synergy), or alternatively reject the position.
If the desired response is confirmed, then a CRT pacemaker should be implanted. If the response is not confirmed, the mapping and measurements of parallelity should be refined before final confirmation. If response is not able to be confirmed, the implantation should be abandoned and known guidelines should be followed for alternative implantations.
It is envisaged that all of the methods and systems described herein may be used together, or equally may be used separately. In this regard, it is possible to detect the presence dyssynchrony and resynchronization potential, and confirm resynchronization without selecting the optimal lead position, and equally, it is possible to select optimal lead position without confirming underlying substrate and resynchronization.
Therefore, a system may be provided that includes connection to electrodes that allow visualization of signals from the patient and measurements time intervals. Alternatively or additionally, a system may also be provided that includes sensors and electrodes and allows visualization of a heart model and calculations based on the heart model's geometry. Both of the above systems can be combined in the operating room.
An implementation of the above systems and methods will be further described herein by way of an example implementation during surgery.
A patient is firstly taken in to the operating room and sensors and electrodes are fixed on the patient's body surface.
In order to determine the delay to onset of myocardial synergy (OoS), one or more additional sensors may be utilized. For example, one or more of a pressure sensor, piezo-resistive sensor, fibreoptic sensors, an accelerometer, an ultrasound and a microphone may be utilized. Measurements from the additional sensors may be taken in real-time and be processed on location. If the delay to onset of myocardial synergy is short relative to the QRS complex or short in absolute values (for example either shorter than 120 ms or less than 80% of the QRS duration), then the implantation of a CRT device should not occur. When the delay to onset of myocardial synergy is measured to be long compared to the QRS complex or long in absolute values (for example either longer than 120 ms or longer than 80% of the QRS duration), then implantation of the CRT device should occur.
Body surface electrodes are used to determine parallelity (the degree of parallel activation of the myocardium) by collecting surface potentials for an inverse solution ECG activation map of the heart as described above to determine propagation velocity, and thereby the presence of dyssynchrony. Additionally or alternatively, electrodes implanted within the patient's heart may also be used to produce electrical activation maps, and thereby determine the presence of dyssynchrony. If the sensed activation pattern indicates too slow propagation through the tissue, or the inability to provide sufficient parallel activation in the presence of scar tissue, the implantation of a CRT device should not take place.
The patient is then prepared for surgery and sterile draped. Surgery is started as usual and leads are placed in the patient's heart through a skin incision below the left clavicle and puncture of the subclavian vein. The leads are then moved into position in the right atrium and right ventricle.
Dyssynchrony may then be introduced by pacing the right ventricle, and can be confirmed when measuring the delay of myocardial synergy as discussed above. A sensor may be placed in the left heart chamber, or in the right heart chamber, in order to determine the delay of onset of myocardial synergy. In this way, the same calculation may be performed as previously utilized in order to calculate the delay to onset of myocardial synergy.
Once the leads are in position, the coronary sinus is cannulated and an angiography in two planes are performed to visualize the coronary veins.
Once the coronary vein is visualized, cannulation can be performed with either a thin guide wire with an electrode at the tip, or any catheter with one or multiple electrodes for mapping purposes. Measurements of time intervals are then used to characterize one or more of the intrinsic activation, tissue properties and vein properties. The coronary anatomy is then reconstructed in software, and measurements are assigned to positions in the heart model relative to the reconstructed coronary sinus vein.
This data may then be used, in a method performed outside of the body, to calculate parallelity in order to highlight the electrode positions with the highest value of parallelity. Based on these measurements, the surgeon is advised to position the left ventricular (LV) lead with electrodes in a desired position/vein. Similar advice can be given also to reposition the right ventricular (RV) lead. Based on the acquired measurements and the processing thereof, advice can also be provided to include other and/or further electrodes to achieve a higher degree of parallelity. Other electrodes refer to other electrode positions than those available (endocardial, surgical access), and further electrodes refers to the use of multiple electrodes (more than two).
As a result of the above, the coronary vein branches are now seen in two planes and a suitable vein is selected for placement of a left ventricular lead.
When the LV electrodes are in position, the sensors may be used to determine the delay to onset of myocardial synergy, when pacing both the RV and the LV. Different electrodes may be analyzed by repositioning the LV lead at different positions. Measurements of the delay to myocardial synergy may occur using one or more of a pressure sensor, piezo-resistive sensor, fibreoptic sensor, an accelerometer, an ultrasound or by measured bioimpedance (when connected to the RV and LV leads). If the delay to myocardial synergy is not shortened, at least to less than for example 100% of the intrinsic measured value or when the bioimpedance measurements indicate by paradoxical movements that resynchronization is not taking place, the proposed lead positions should be abandoned. The intrinsic value measured from the QRS onset does not include the time from the onset of pacing to ventricular capture, and hence is by definition shorter than that measured from the stimulus. 110% would therefore approximate the time interval measured with intrinsic activation. In this way, the intrinsic delay to onset of synergy measured from the QRS complex can be calibrated by adding, for example, 15 ms to the value reflecting the time from pacing spike onset to electrical tissue capture that occur when artificially pacing.
When pacing the RV, the LV or both, a VCG can be reconstructed and the time to fusion can be calculated. The time to fusion may further be used in order to confirm the already measured parallelity. Surface electrodes can be used for inverse modelling to measure time to fusion. If the measured time to fusion, and the measured parallelity does not concur, the causes of such a discrepancy should be further reviewed.
It is possible that LV leads with multiple electrodes can be used on the discretion of the physician. The use of multiple electrodes can be used in measuring parallelity, and when found to increase parallelity, such an increase in parallelity can be confirmed using time to fusion, and by measuring the delay to onset of myocardial synergy.
Once the lead is in desired position, wherein the delay to onset of myocardial synergy is less than (for example) 110% of initial intrinsic value and less than (for example) 100% of the biventricularly paced QRS complex and, the CRT may be implanted and the device generator connected and implanted in a subcutaneous pocket. If the lead is found not to capture the myocardium or if the location is determined suboptimal based on scientific empiric data or measured intervals (QLV), the lead is repositioned and retested before the device generator is connected. The skin incision is then sutured and closed.
The systems described above may be embodied in an overall system that contains a signal amplifier or analogue digital converter (ECG, electrograms and sensor signals), a digital converter (sensor signals), processor (computer), software, connector to x-ray (either by direct communication with a dicom server or PACS server, or indirect with a framegrabber and an anglesensor). It is possible to use the system with different sensors at user discretion. Further, the system may also be used to solve other problems as well. For example, the systems may be utilized for identification of His region and placement of a pacing lead in the His bundle, with additional measurement of the delay to onset of myocardial synergy.
Example System
Also provided is a catheter than can be used in the methods described above. In this way, a catheter is provided with a system that can be used to detect dyssynergy caused by dyssynchrony, as well as to help select the right patient for therapy. The catheter may comprise a cardiac catheter with a lumen for guidewire and saline flush. The catheter comprises one or more sensors. For example, the catheter may comprise vibrations, pressure, acceleration, and electrodes for sensing electrical local and global cardiac signals. The catheter can be placed in the left or right heart chamber through venous or arterial access, and/or in the coronary vein. Electrodes can be used for sensing electrical signals in a bipolar or unipolar fashion (to a reference electrode on the catheter, or any other electrode connected to the patient body), and the electrodes can be used for pacing the heart at various positions. The catheter connects to a system for processing of the data, either through cables or wirelessly. A guidewire can be passed through the lumen of the catheter to increase the diameter of the distal curve, and a guidewire can be passed through the end of the lumen to get in contact with the cardiac tissue and be used as a sensing and pacing electrode.
When the catheter is passed into the heart chamber, it is possible to use the electrograms provided from the sensors of the catheter to measure the electrical delay from one electrode to the other (or to an electrode that is external to the catheter), and as such determine the electrical activation time. Additionally, using the catheter, it is possible to measure other factors such as vibrations, pressure and acceleration, and then filter the signals to receive measures that can be used to determine the onset of synergy in the heart. Therefore, the catheter can be used to obtain measurements that can be further used to measure the degree of resynchronization and the resynchronization potential. Equally, the catheter maybe provided as part of a system that, for a given set of electrode positions, can measure all data required to calculate the time to onset of synergy. Therefore, system comprising the catheter may be used to quickly and easily determine the resynchronisation potential of a patient.
Such a catheter may provide several uses. As considered above, the catheter may be used to obtain all measurements to be used to detect the onset of synergy following pacing, and determining the resynchronisation potential of a patient. For example, such a method for determining the onset of synergy is defined above, or in GB1906064.9. The catheter may find use in taking measurements to determine the degree of parallel activation. For example, such a method for determining the degree of parallel activation is described above, or in GB1906055.7. Equally, the catheter may be utilised to take measurements to determine the time to fusion in a heart. For example, such a method for determining the time to fusion in a heart is described above, or in GB1906054.0. The catheter may be provided additionally with a data processing module that can additionally process the data received from the catheter to provide a measure of any of the above values, without need for further post-processing of the data.
Such a catheter 2600 may be seen in
The sensors may be any desired sensor. For example, where the catheter is for use in determining the delay to onset of myocardial synergy, it may be desired that the sensor is a pressure sensor such that it is possible to invasively measure the pressure within the heart, and thereby measure the change of pressure within the left ventricle. Additionally or alternatively, the sensor may comprise a piezoelectric, fiberoptic and/or an, accelerometer sensor. The sensor may detect and transmit events such as cardiac contraction, onset of synergy, valve events, and pressure to a receiver connected to a processor.
The distal end 2608 of the catheter 2600 is a floppy pigtail, such that the electrodes 2601 positioned at the curved distal end may be moved by advancing the relatively stiff guidewire 2607 along the shaft of the catheter. By advancing the guidewire through the catheter 2600, the diameter of the curve provided at the distal end 2608 of the catheter 2600 is increased. This allows for the distal end 2608 of the catheter 2600 to be moved, and thereby allows for movement of the electrodes 2601. Such variable positions are shown in broken lines 2611 in
Communication means 2604 may transmit data received from the electrodes 2601, and communication means 2605 may transmit data from the sensor(s) 2602. As shown, these may be provided as physical wires to plug into an external data processing module. Alternatively, they could provide wireless transmission, to transmit the data without a physical connection. The shaft of the catheter 2600 may be of any suitable diameter. For example, the shaft may be a 5 Fr shaft. A saline flush may additionally be provided through hemostatic vent 2606.
A more detailed view of the guidewire 2607 may be seen in
Various different locations within the heart in which the catheter 2600 may be placed are illustrated in
A more detailed view of the structure of the catheter 2600 is seen in
The processing module 3206 may be configured to take the data gathered by the catheter 2600 and further process the data so as to provide meaningful assessments as to the cardiac function of the patient. For example, the data processing module may be configured to calculate the delay to onset of synergy, the time to fusion or a measure of parallelity of the heart of the patient.
For example, the catheter may be provided with at least one piezo-electric sensor 2602 (and/or optical sensor 2602, and/or accelerometer 2602) that is configured to directly measure pressure within the heart. Utilising such information, the catheter 2600 and the processing module 3206 may be configured to automatically and reliably detect a point relating to the onset of synergy, which is distinct from and occurs at some point between the pre-ejection interval (PEI) and electromechanical delay (EMD).
For example, whilst this may be relating to a rapid pressure rise originating from the onset of synergy, the point of the onset of synergy may be better and more reliably represented by filtered pressure traces. Therefore, the system 3200, and more specifically the piezo-electric sensors 2602 of the catheter 2600 and processing module 3206 may be configured to detect the pressure change within the heart, and filter the pressure traces so as to give an accurate representation of the onset of synergy. This may be achieved by removing the first harmonics of the pressure wave by band-pass filtering at, for example, 2-40 Hz. This curve, as described above, has a linear upstroke that originates from the onset of synergy and that crosses zero at peak dP/dt. Filtering at, for example, a band-pass 2-40 Hz or 4-40 Hz removes the low, slow frequencies that are associated with dyssynergy and the onset of synergy may be seen as the onset of the pressure increase that leads to, or is directly prior to aortic valve opening or maximum pressure.
This change in rate of pressure increase is because of increasing and exponential cross-bridge formation while passive stretched segments tension increase, either because depolarization or because elasticity model reaches its near maximum. Rapid cross bridge formation with isometric or eccentric contraction leads to high-frequency components in the pressure curve frequency spectrum, which reflects onset of synergy. This phase of the cardiac cycle may be seen when filtering LVP with high pass filter above the 1st or 2nd harmonics. The filtered and characteristic waveform has a near linear increase, from onset of synergy to crossing 0, and continues with a linear increase up to aortic valve opening. The line of linear increase reflects the period with synergy, crossing zero at halfway in the phase, which corresponds to peak dP/dt as described above, and onset of synergy is reflected in where this line starts to rise above the floor of the filtered pressure curve or at its nadir. Additionally, the catheter 2600 and processing module 3206 may be configured to utilise high frequency components (above 40 Hz) of the pressure trace to identify the onset of synergy in the mid range filtered (4-40 Hz) signal as the high frequency components identifies the onset of pressure rise prior to zero-crossing.
One or more of these points in the pressure trace (the beginning of the linear increase in a band-pass filtered pressure trace, the crossing of zero in a band-pass filtered pressure trace, the onset of high frequency pressure components of the pressure trace), taking data that is filtered from the piezo-electric (or other optical) sensors 2602 of the catheter 2600 may be utilised by the data processing module 3206 to accurately and reliably represent the onset of synergy. Additionally or alternatively, the sensors 2602 may comprise accelerometers that gather accelerometer data within the heart, and from such data determine the onset of synergy, for example as described above and illustrated in
As would be appreciated, any of the measures considered herein of detecting onset of synergy (or points relating directly thereto) may be combined to provide a more accurate measurement of the onset of synergy and/or how it varies with treatment. For example, a measure of the time of onset of synergy or a point related thereto before/after treatment calculated by filtering pressure data may be compared and contrasted with the point of onset of synergy calculated using raw acceleration data within the heart before/after treatment. In this way, a reduction in the time to onset of synergy (thereby indicating that reversible cardiac dyssynchrony is present) may be validated using more than one measure.
By utilising any of the above measures, the system may therefore, for each position of the catheter and therefore the electrode(s), automatically determine how time until the onset of synergy varies. In this way, the system can give immediate (or near immediate) feedback on the efficacy of various electrode placements in reversing dyssynchrony and dyssynergy.
In one example, as a representation of the time of onset of synergy, the zero crossing from a filtered signal or a template match from a filtered signal may be detected within a timeframe from a reference time. For example, the zero crossing within a timeframe of ±40 ms of QRSend (so as to ensure that the first zero crossing, being the zero crossing associated with the same heartbeat) is measured. Alternatively, the onset of synergy may be indicated by the timing of the nadir (i.e. the point of pressure increase from the pressure floor) together with high frequency components. As would be appreciated, both of these measures (and others) can represent the onset of synergy, being the point where all segments of the heart begin to actively or passively stiffen. This is practically manifested in the beginning of the rapid pressure rise within the heart.
Whilst the point of onset of synergy is manifested in the increase of pressure within the left ventricle due to the point where all segments of the heart begin to actively or passively stiffen, it will be appreciated by the skilled person that this point can also indirectly be measured in other positions. In this way, and in addition to positioning within the left heart chamber, the catheter may for example be positioned within the coronary veins or in the right heart chamber to provide similar measurements indicative of the onset of synergy, with appropriate filtering of the signal.
In sum, it may be said that the catheter measures pressures and/or vibrations, and can subsequently apply different filters for the assessment of the pressure/vibrations, together with the electrical signals detected by the catheter to determine if dyssynchrony is present or not. Whilst a reduction in the delay to onset of synergy (for example, calculated as described above) indicates that dyssynchrony is present, a prolongation of the interval with stimulation when compared to the baseline (i.e. a case with no stimulation) identifies an iatrogenic potential. Such a situation may be detrimental to the patient's health and should be avoided.
Sensor Calibration Effect on dP/Dt:
Advantageously, the sensors of the catheter may not require calibration for time events when using the derivative of pressure that relates to the measurement of onset of synergy.
In theory the offset and gain of the pressure signal should not affect the results of when dP/dt=0 or when dP/dt peaks. The offset will not affect when dP/dt=0 or when dP/dt peaks because the derivative of the offset will go to zero. While the gain will affect the value and slope of the pressure sensor signal, the gain will not affect the time the maximum/minimum of the pressure signal occurs (which is when dP/dt=0) or the time the maximum/minimum slope of the pressure signal occurs (which is when dP/dt peaks).
This effect is illustrated by the below simplified example demonstrating how neither the offset nor gain will affect a cyclical pressure signal.
For example, if the true pressure signal was characterized by the equation:
P
true=sin(60t)
And the catheter had an offset of 100 mmHg, with a gain of 5 times more than the actual signal. Then the pressure signal reading would be characterized by the equation:
P
reading=5 sin(60t)+100
Even given the differences in the true pressure signal and the reading pressure signal, the derivative of both equations with respect to time (t) would be:
Whilst the amplitudes of the two dP/dt equations differ, the time when dP/dt=0 and when dP/dt peaks will be equivalent for both equations
respectively, where n is the value of any integer). This is shown in
It should be noted that signal changes due to temperature, drift, and atmospheric pressure all have a time dependency, which means, in theory these changes may have some effect on when dP/dt=0 or when dP/dt peaks. However, the largest discrepancies caused by temperature and drift will occur when the catheter is first being introduced in the body, as this is when the sensor is transitioning from a dry state at room temperature to a “wet” state at body temperature. By the time the catheter is deployed/positioned and data starts to be analyzed, the amplitudes and frequencies of the changes due to temperature, drift, and atmospheric pressure are all be minimal compared to the amplitude and frequencies of the pressures in the heart. Therefore, even without correcting for changes due to temperature, drift, and atmospheric pressure, the effects to dP/dt=0 or when dP/dt peaks should be negligible.
An exemplary catheter is shown in
In sum, in the above system, the distal segment of the catheter is adapted to be positioned with electrodes opposing each other in the heart. The distal segment has an area intended to contact the heart tissue. The distal segment carries one or more electrodes and one or more sensors (for example a pressure sensor, piezoelectric sensor, fiberoptic sensor, accelerometer) located proximal on the distal end of the catheter. The sensor(s) provide data on cardiac contraction, onset of synergy, valve events, pressure to a receiver connected to the processor. The electrodes connect to an amplifier that connect to a processor. The electrodes connect to a stimulator. The processor may analyse the data received to determine a point relating to the onset of synergy, and utilise this to determine if dyssynchrony and dyssynergy is present, and then further if stimulating the electrodes results in reversal of dyssynchrony and dyssynergy.
When the catheter is suitably positioned in the left heart chamber with electrodes opposing each other at the septum and contralateral wall and the sensor within the chamber, with each heartbeat a voltage gradient is registered between each electrode and a reference electrode. Such a voltage gradient represents electric activation of the heart. Further, and following on from the above, the sensor(s) register events related to the onset of synergy, i.e. events that relate to the rapid increase in rate of pressure rise within the left ventricle, which reflects the point where all segments of the heart begin to actively or passively stiffen to a maximal extent. The time to this event is compared with electrical activation, and the presence or absence of dyssynchrony and dyssynergy is registered.
The heart can then be stimulated from one or more electrode. With each heartbeat a voltage gradient is registered between each electrode and a reference electrode, which as described above can represent the electric activation of the heart. The one or more sensor again registers events related to the onset of synergy. The new set of time events may then be compared to the first set of events and the presence or absence of resynchronization is registered.
Advantageously, with such a system, it may be possible to quickly and efficiently determine such measures for various positions of electrodes. In this way, not only may it be determined if a patient is indeed a potential responder for cardiac resynchronisation therapy, but also the ideal number and positions of electrodes may be quickly determined.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2016234.3 | Oct 2020 | GB | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/EP2021/078365 | 10/13/2021 | WO |
