WO2011075429A1 - Marqueurs alternatifs utilisés pour l'évaluation quantitative d'événements électriques cardiaques - Google Patents

Marqueurs alternatifs utilisés pour l'évaluation quantitative d'événements électriques cardiaques Download PDF

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WO2011075429A1
WO2011075429A1 PCT/US2010/060041 US2010060041W WO2011075429A1 WO 2011075429 A1 WO2011075429 A1 WO 2011075429A1 US 2010060041 W US2010060041 W US 2010060041W WO 2011075429 A1 WO2011075429 A1 WO 2011075429A1
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markers
loop
signal
qrs
interval
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PCT/US2010/060041
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Ljupco Hadzievski
Branislav Vajdic
Ihor Gussak
Bosko Bojovic
Uros Mitrovic
Dorin Panescu
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Newcardio, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/318—Heart-related electrical modalities, e.g. electrocardiography [ECG]
    • A61B5/339—Displays specially adapted therefor
    • A61B5/341—Vectorcardiography [VCG]

Definitions

  • the disclosed inventions relate to the field of medical electronics.
  • it concerns electronic systems, devices, and methods for acquisition, processing, and presentation of diagnostic data for use with humans and animals, such as electrocardiogram data.
  • ECG electrocardiogram
  • vector ECG (or "VCG") includes the improvement of a spatial aspect to the ECG (see Frank, E., An Accurate, Clinically Practical System For Spatial Vectorcardiography, Circulation 13: 737, May 1956).
  • VCG uses a dipole approximation of electrical heart activity. The dipole size and orientation are presented by a vector that continuously changes during the heartbeat cycle.
  • VCG VCG
  • the measurement points are positioned in such a way that three derived signals correspond to three orthogonal axes (X, Y, Z), and these signals are presented as projections of the vector hodograph onto three planes (frontal, sagittal, and horizontal).
  • VCG represents a step towards spatial presentation of the signal, but the cardiologist's spatial imagination skills were still necessary to interpret the ECO signals, particularly the connection to the heart anatomy.
  • a time-dependence aspect i.e., the signal waveform
  • this aspect is very important for ECG interpretation.
  • VCG introduces useful elements which cannot be found within the standard 12-lead ECG, however, the incomplete spatial presentation and loss of the time dependence are major reasons why VCG, unlike ECG, has never been widely adopted, despite the fact that (in comparison to ECG) VCG can more often correctly diagnose cardiac problems, such as myocardial infarction.
  • 3D VCG projects the hodograph onto one plane (see Morikawa, J., et al., Angiology, 1987; 38(6):449-56.
  • Flu-dimensional ECG is similar to “3D VCG,” but differs in that every heartbeat cycle is presented as a separate loop, where the time variable is superimposed on one of the spatial variables (see Morikawa, J., et al., Angiology, 1996; 47: 1 101 -6.).
  • “Chronotopocardiogram” displays a series of heart-activity time maps projected onto a sphere (see Titomir, L.I., et al., Int J Biomed Comput 1987;20(4):275-82). None of these modifications of VCG have been widely accepted in diagnostics, although they have some improvements over VCG.
  • Electrocardiographic mapping is based on measuring signals from a number of measurement points on the patient's body. Signals are presented as maps of equipotential lines on the patient's torso (see McMechan, S.R., et al.,.J Electrocardiol. 1995;28 Suppl:184-90). This method provides significant information on the spatial dependence of electrocardiographic signals. The drawback of this method, however, is a prolonged measurement procedure in comparison to ECG, and a loose connection between the body potential map and heart anatomy. Inverse epicardiac mapping includes different methods, all of which use the same signals for input data as those used in ECG mapping; and they are all based on numerically solving the so-called inverse problem of electrocardiography (see A. van Oosterom, Biotechnikischtechnik., vol. 42-EI, pp. 33-36, 1997). As a result, distributions of the electric potentials on the heart are obtained. These methods have not resulted in useful clinical devices.
  • Cardiac electrical activity can be detected at the body surface using an electrocardiograph, the most common manifestation of which is the standard 12-lead ECG.
  • a typical ECG signal is shown in present Fig. 1.
  • the P-wave 2 represents atrial depolarization and marks the beginning of what is referred to as the "P-R interval" 18.
  • the QRS complex 4 represents depolarization of the ventricles, beginning with QRS onset after the PR segment 5 and ending at a point known as the "J point" 6. Ventricular re-polarization begins during the QRS and extends through the end of the Twave 14, at a point which may be termed "Tend" 8.
  • the S-T segment 10 extends from the J point 6 to onset or start of the Twave 12.
  • the Twave 14 extends from the Twave onset 12 through Tend 8.
  • U waves (not shown) are present on some ECGs. When present, they merge with the end of the Twave or immediately follow it.
  • the Twave is the ECG manifestation of repolarization gradients, that is, disparities in degree of re-polarization at a particular time point between different regions of the heart. It is likely that the Twave originates primarily from transmural re-polarization gradient (see Yan and Antzelevitch; Circulation 1998;98:1928-1936; Antzelevitch, J. Cardiovasc Electrophysiol 2003; 14:1259-1272). Apico-basal and anteriorposterior re-polarization gradients may also contribute (see Cohen IS, Giles WR, and Noble D; Nature. 1976; 262: 657-661 ).
  • Transmural re-polarization gradients arise because the heart's outer layer (epicardium) re-polarizes relatively quickly, the mid-myocardium re-polarizes relatively slowly, and the inner layer (endocardium) re-polarizes in an intermediate fashion.
  • a Twave 14 begins at a position which may be termed "Ton" 12, when the epicardial layer moves toward resting potential ahead of the other two layers.
  • Tpeak the peak of the Twave
  • epicardial re-polarization is complete and the transmural re-polarization gradient is at its maximum.
  • endocardial cells begin their movement towards resting potential, thereby narrowing the transmural gradient and initiating the down-slope of the Twave.
  • the M cells re-polarize, accounting for the latter part of the Twave down-slope.
  • the Twave is complete at Tend 8 when all layers are at resting potential and the transmural gradient is abolished.
  • the QT interval 9 may be estimated from an ECG by measuring time from the end of the PR segment 5 to Tend 8.
  • Abnormalities in the QT interval often mark susceptibility to life-threatening arrhythmias. Such abnormalities may be associated with genetic abnormalities, various acquired cardiac abnormalities, electrolyte abnormalities, and certain prescription and nonprescription drugs. An increasing number of drugs have been shown to prolong the QT interval and have been implicated as causes of arrhythmia.
  • the QT interval may be viewed as viewed as a "marker" ECG parameter, indicative of effects a drug may or may not have on the heart rhythm of the patient.
  • extension of a patient's QT interval caused by a particular drug may be predictive of negative pro-arrhythmic events.
  • Sotalol is known to prolong the QT interval significantly and to have the potential of triggering critical arrhythmias, including Torsades de pointes. Towards this end, U.S.
  • the QT interval is not an adequate marker for predicting potentially pro-arrhythmic effects of certain drugs.
  • Moxifloxacin an antibiotic
  • the QT interval is considered a benign positive test with respect to Moxifloxacin.
  • suitable cardiac electrical activity markers could be used for more accurately predicting (whether positive or negative) the potential for adverse pro-arrhythmic effect of the drug(s) being tested.
  • alternative cardiac electrical event markers for use in drug safety studies and clinical applications may be very broadly classified as (i) vector magnitude (VM) signal markers, (ii) 3D markers, and (iii) markers based on a degree of variability of certain ECG parameters.
  • VM vector magnitude
  • 3D markers markers based on a degree of variability of certain ECG parameters.
  • VM signal markers include without limitation (i) time duration markers, e.g., based on a duration of a specified portion of the RR interval or a ratio of the durations of two different specified portions of the RR interval, (ii) voltage markers such as a measured voltage at a particular time point on the RR interval or a ratio of the measured voltages at two defined time points of the RR interval, or (iii) combined time-voltage markers, such as a two-dimensional area covering some portion of the VM signal, a Twave slope marker, or a QRS wave slope marker.
  • time duration markers e.g., based on a duration of a specified portion of the RR interval or a ratio of the durations of two different specified portions of the RR interval
  • voltage markers such as a measured voltage at a particular time point on the RR interval or a ratio of the measured voltages at two defined time points of the RR interval
  • combined time-voltage markers such as a two-dimensional area covering some portion of the VM signal,
  • 3D markers include without limitation (i) T-loop markers, such as Tvelocity markers, Tangle markers, and markers based on the morphology of the T- loop (planarity, roundness, symmetry, etc.), (ii) QRS loop markers, such as QRSvelocity markers, QRSangle markers, and markers based on the morphology of the QRS-loop (planarity, roundness, symmetry, etc.), or (iii) combined QRS - T-loop markers, such as angles between directions of QRS and T loop, and angles between QRS and T loop planes.
  • T-loop markers such as Tvelocity markers, Tangle markers, and markers based on the morphology of the T- loop (planarity, roundness, symmetry, etc.)
  • QRS loop markers such as QRSvelocity markers, QRSangle markers, and markers based on the morphology of the QRS-loop (planarity, roundness, symmetry, etc.)
  • markers based on the degree of variability of some ECG parameters include without limitation (i) markers based on a variability of the parameters defined on the VM signal, and (ii) markers based on a variability of the parameters defined on the respective T-loops and QRS loops.
  • one or more of the alternative cardiac electrical event markers are analyzed from ECG signal data obtained from a statistically valid size patient population before the respective patients are given a particular drug whose safety is being studied to determine the patients' baseline marker data.
  • the drug under study is then administered, and the patients' ECG signal data is continued to be acquired for an additional several, e.g., 8 to 16 (or more) hours.
  • the collected patient ECG signal data is analyzed in order to determine and evaluate differences between the base-line ("off-drug") and "on-drug" values of the respective one or cardiac electrical event markers (including whether the differences are in themselves statistically valid - i.e., non-noise) in order to predict whether the drug may be pro-arrhythmic.
  • any significant change detected in the patient heart rhythm as measured by the change in respective marker value over a several- hour long time period may be indicative of increased likelihood of a negative cardiac event.
  • multiple marker values are analyzed in order to detect whether a change in one marker value is in fact a "benign positive" test.
  • the particular cardiac electrical event markers used for a drug study may be more specifically selected based on the type and nature of the drug, since some markers may be more accurate than others in predicting the pro-arrhythmic tendency of certain classes of drugs.
  • Fig. 1A illustrates a conventional ECG signal.
  • Fig. 1 B illustrates a vector magnitude (VM) ECG signal.
  • Figs. 2A and 2B are graphical representations of the calculated differences between the mean measured QT interval values of patient ECG recordings made "on drug” and the baseline (i.e., "off drug") recordings for Sotalol (Fig. 2A) and
  • Fig. 3 is a diagrammatic presentation of the classification of various cardiac safety markers, in accordance with a general aspect of the disclosed inventions.
  • Fig. 4 is a VM signal showing the Tmax_Tend qVm and Tend qVm markers.
  • Figs. 5A and 5B illustrate exemplary combined time-voltage markers on a VM signal.
  • Fig. 6 is an illustration of Twave slope markers on a VM signal.
  • Fig. 7 is an illustration of 3D Tloop angular width markers.
  • Figs. 8A and 8B illustrate the calculation of a Tloop area marker.
  • Fig. 9 depicts a T or QRS loop marker, including a projection of the respective loop on a preferential plane.
  • Fig. 10 is an illustration of the QRS-T angle marker, alongside a graphic rendering of the heart depicting the respective vector components from which the angle marker is determined.
  • Fig. 11 is an illustration of the respective QRS-T angle and QRS-T angle mass markers.
  • Figs. 12A and 12B are graphical representations of the calculated differences in the mean Tv_L/R ratio in patient ECG recordings made "on drug” and the baseline (i.e., "off drug") recordings for Sotalol (Fig. 12A) and Moxifloxacin (Fig. 12B).
  • Figs. 13A and 13B are graphical representations of the calculated differences between the mean Ts_L response values of patient ECG recordings made "on drug” and the baseline (i.e., "off drug") recordings for Sotalol (Fig. 13A) and Moxifloxacin (Fig. 13B).
  • Figs. 14A and 14B are graphical representations of the calculated differences between the mean T dir response values of patient ECG recordings made "on drug” and the baseline (i.e., "off drug”) recordings for Sotalol (Fig. 14A) and Moxifloxacin (Fig. 14B).
  • Fig. 15 depicts an ECG system which may be integrated with embodiments of the disclosed inventions.
  • Fig. 16 depicts an ambulatory Holter monitor system which may be integrated with embodiments of the disclosed inventions.
  • Fig. 17 depicts an electrophysiology mapping system which may be
  • Fig. 18 depicts an echocardiography system which may be integrated with embodiments of the disclosed inventions.
  • Figs. 19A and 19B depict fluoroscopy-based systems which may be integrated with embodiments of the disclosed inventions.
  • alternative cardiac electrical event markers can be used in drug safety studies in addition to, or as a substitute for, the standard QT interval marker for better predicting potentially pro-arrhythmic effects of certain drugs.
  • Such alternative cardiac electrical event markers may also be advantageously used in clinical applications, such as individual cardiac health diagnosis and detecting different heart diseases like acute myocardial infarction (AMI), left ventricular hypertrophy (LVH), right bundle branch block (RBBB) and others whose symptoms are not always apparent.
  • AMI acute myocardial infarction
  • LHL left ventricular hypertrophy
  • RBBB right bundle branch block
  • the QT interval is known to not be accurate in predicting potential fatal arrhythmias, such as Torsades de pointes, for at least some well-known drugs. Given its reduced specificity, some drugs may be falsely deemed pro-arrhythmic if judged only based on a resulting prolonged QT (or QTc) interval.
  • Fig. 2A shows the calculated differences (i.e., the delta) in mean QT interval values in milliseconds (QTcF(ms) mean) from patient ECG recordings made "on drug” over the patient ECG baseline (i.e., "off drug") QT interval values taken from the results of a new chemical entity (NCE) study for Sotalol.
  • NCE new chemical entity
  • the mean difference QT interval values were significantly prolonged (as much as 40 ms) for several hours following the Sotalol dosing.
  • the + and - 90% confidence interval values (QTcF(ms) CI90%) and (QTcF(ms) -CI90%) are also depicted in order to demonstrate that the mean values are statistically valid differences.
  • the QT interval marker predicts the pro-arrhythmic effects of Sotalol. It turns out based on data collected from patients taking Sotalol that this prediction was statistically valid.
  • Fig. 2B shows the calculated differences (i.e., the delta) in mean QT interval values in milliseconds (QTcF(ms) mean) from patient ECG recordings made "on drug” over the patient ECG baseline (i.e., "off drug") QT interval values taken from the results of a study, including a placebo undertaken by the Cardiac Safety Research Consortium (CSRC - a group of companies, universities and the U.S. FDA interested in cardiac safety with respect to drugs) for Moxifloxacin.
  • CSRC Cardiac Safety Research Consortium
  • Moxifloxacin may be pro- arrhythmic, like Sotalol. However, it turns out based on data collected from patients taking Moxiflxacin that this prediction was statistically invalid. Thus, the QT interval is an inadequate marker for at least Moxifloxacin, providing a "false positive" result. If an ideal marker for discriminating pro- arrhythmic from non-arrhythmic drugs was used instead of the QT interval, the (placebo-adjusted) results for Moxifloxacin would be within the band marked by the +/- 90% confidence interval in Fig. 2B, as the marker response, if any, would have not have reached statistical significance.
  • alternative cardiac electrical event markers for use in drug safety studies and clinical applications may be very broadly classified as vector magnitude (VM) signal markers 30, 3D markers 40, and markers based on a degree of variability of certain ECG parameters 50.
  • VM vector magnitude
  • Examples of VM signal markers 30 include without limitation (i) time duration markers 32, e.g., based on a duration of a specified portion of the RR interval or a ratio of the durations of two different specified portions of the RR interval, (ii) voltage markers 34 such as a measured voltage at a particular time point on the RR interval or a ratio of the measured voltages at two defined time points of the RR interval, or (iii) combined time-voltage markers 36, such as a two-dimensional area covering some portion of the VM signal, a Twave slope marker, or a QRS wave slope marker.
  • Time markers 32 can often be predictors of pro-arrhythmic drug effects, since they assess potential propagation timing disturbances that are precursors to arrhythmias.
  • Voltage markers may be suitable for assessing effects that abnormal cardiac tissue de- polarization or re-polarization have on the overall cardiac performance.
  • 3D markers 40 include without limitation (i) T-loop markers 42, such as Tvelocity markers, Tangle markers, and markers based on the morphology of the T-loop (planarity, roundness, symmetry, etc.), (ii) QRS loop markers 44, such as QRSvelocity markers, QRSangle markers, and markers based on the morphology of the QRS-loop (planarity, roundness, symmetry, etc.), or (iii) combined QRS - T- loop markers 46, such as angles between directions of QRS and T loop, and angles between QRS and T loop planes.
  • Velocity markers can be indicative of abnormalities in both cardiac signal conduction patterns and in de- polarization or repolarization patterns.
  • a slow re-polarization velocity could be indicative of ventricular function abnormalities.
  • acute ischemic events are known to affect QRS-plane to T-plane angles, or to distort the planarity of the QRS or T loops. See U.S. application serial number 12/614,354, the contents of which are fully incorporated herein by reference. Consequently, 3D markers 40, given their ability to detect changes in the parameters of the cardiac vector 3D dynamics, may be more sensitive and more specific in discriminating pro- arrhythmic from non-arrhythmic drugs.
  • markers based on the degree of variability of some ECG parameters 50 include without limitation (i) markers based on a variability of the parameters defined on the VM signal, and (ii) markers based on a variability of the parameters defined on the respective T-loops and QRS loops.
  • Previous modalities of VCG interpretation have lacked adequate temporal information.
  • novel modalities such as those described herein, can be used to compute and interpret temporal VCG changes (e.g. beat-to-beat changes), resulting in cardiac electrical activity markers that are useful as indicators and/or predictors.
  • markers that assess the ECG or VCG variability compute temporal fluctuations that a cardiologist may not see by naked eye. For example, a certain amount of cardiac parameter fluctuation is normal. However, if the variability is computed to exceed tolerable limits, these variability markers may also predict potential pro-arrhythmic effects of drugs.
  • alternative cardiac electrical event markers can be based on some defined portion of the RR interval, such as:
  • RR interval i.e., the time interval between respective R points of consecutive heart beats on the VM signal
  • QT interval i.e., the time interval between the respective Q and Tend (72) points on the VM signal
  • QTc interval i.e., the Q to Tend interval, corrected using Fridericia's method (divided by cubic root of RR);
  • PR interval i.e., the time interval between the P and Q points on the VM signal
  • PRc interval i.e., the P to Q interval, corrected using Fridericia's method (divided by cubic root of RR);
  • QRS interval i.e., the duration of the QRS complex on the VM signal
  • TmaxTend interval i.e., the time interval between the Tmax (70) and Tend
  • TmaxTendc interval i.e., the Tmax to Tend interval
  • Fridericia's method (divided by cubic root of RR);
  • QTmax interval i.e., the time interval between the Q and Tmax (70) points on the VMS signal
  • QTmaxc interval i.e., the Q to Tmax interval, corrected using Fridericia's method (divided by cubic root of RR).
  • Alternative cardiac electrical event markers may also include a ratio of two portions of the RR interval, such as:
  • PR/QTmax a ratio of the PR and QTmax intervals
  • PR/TmaxTend a ratio of the PR and TmaxTend intervals
  • TmaxTend/QT a ratio of the TmaxTend and QT intervals
  • TmaxTend/QTmax a ratio of the TmaxTend and QTmax intervals
  • markers consisting of the foregoing ratios using the corrected values of the respective time intervals, QTc, PRc, TmaxTendc, and QTmaxc, may also be measured and used.
  • alternative cardiac electrical event markers may also include measured voltages at particular points on the VM signal, such as:
  • Tmax qVm the voltage of Tmax point on the
  • Tmax_Tend qVm (66), the Tmax voltage divided by Tend voltage on the
  • the choice of the reference point for the above voltage markers can be any time point in the RR interval.
  • TPelev the difference of the average voltage of the PQ segment 62 and TP segment 64 on the VM signal
  • Vd(V ⁇ d, V2d, V3d, V4d, V5d, V6d) MT ⁇ Vb(I, II, V2) , and wherein the elements of the matrix MT are calculated using the least square method described in U.S. Patent No. 7,647,093, filed February 21 , 2006.
  • time-voltage markers that may be used include one or more two-dimensional areas over some portion of the VM (or ⁇ , ⁇ , ⁇ signals), such as: Twave area 74, the Tmax to Tend signal voltage integral (sum) on the VM signal, using Q - 20ms as a reference point;
  • Twave area corrected the Tmax to Tend signal voltage integral (sum) on the VM signal, using Q - 20ms as a reference point, corrected using Fridericia's method (divided by cubic root of RR), and averaged over all independent beats;
  • J-Tend area 76 the J to Tend signal voltage integral (sum) on the VM signal using Q - 20ms as a reference point;
  • JTend area corrected the J to Tend signal voltage integral (sum) on the VM signal using Q - 20ms as a reference point, corrected using Fridericia's method (divided by cubic root of RR);
  • Neg. J-Tend area the J to Tend signal voltage (negative only) integral (sum) on ⁇ , ⁇ , ⁇ signals, using Q - 20ms as a reference point;
  • Neg JTend area corrected the J to Tend signal voltage (negative only) integral (sum) on ⁇ , ⁇ , ⁇ signals using Q - 20ms as a reference point, corrected using Fridericia's method (divided by cubic root of RR);
  • a further group of alternative cardiac electrical event markers include markers based on the slopes of the initial and terminal part of the T wave on the VM signal, as follows: Ts_L 1 10, the slope of the first (initial) part of T wave calculated from the linear interpolation of the VM curve in the interval Tmax-DT to Tmax , where DT is the time interval from Tmax to the time point when the amplitude of the T-wave decreases to 0.5 * VM(Tmax) (50% of its maximal value);
  • Ts_R 1 12 the slope of the second (terminal) part of T wave calculated from the linear interpolation of the VM curve in the interval Tmax to Tmax+DT , where DT is the time interval from Tmax to the time point when the amplitude of the T-wave decreases to 0.5 * VM(Tmax) (50% of its maximal value);
  • DT can be defined as the time interval from Tmax to the time point when the amplitude of the T-wave decreases to some percentage of the VM(Tmax), e.g., 0.3 * VM(Tmax) (30% of its maximal value), or 0.25 * VM(Tmax) (25% of its maximal value).
  • QRS wave slope markers can be defined in analogy with the T wave slope markers.
  • QRS wave slope markers include: Qs_L, the slope of the first (initial) part of QRS complex calculated from the linear interpolation of the VM curve in the interval R-DT to R, where DT is the time interval from R to the time point when the amplitude of VM decreases to 0.5 * VM(R) (50% of its maximal value);
  • Qs_R the slope of the second (terminal) part of QRS complex calculated from the linear interpolation of the VM curve in the interval R to R + DT, where DT is the time interval from Tmax to the time point when the amplitude of the VM decreases to 0.5 * VM(R) (50% of its maximal value);
  • the time interval for calculation the slopes can be modified with new definition of DT.
  • the DT can be defined as the time interval from R to the time point when the amplitude of the VM decreases to some percentage of the VM(R), e.g., 0.3 * VM(R) (30% of its maximal value), or 0.25 * VM(R) (25% of its maximal value).
  • Identified 3D markers include T-loop markers, markers based on the morphology of the T-loop, such as velocity and Tangle markers. In understanding such markers, it is useful to first set forth some definitions, starting with definitions of heart vector and vector magnitude:
  • the Heart Vector velocity is the first derivative of the Heart Vector: dH(t) dX dY - dZ
  • HVA Magnitude HVAM
  • T2 Tl + N x At inside the T or QRS loop is calculated with the formula:
  • Tr ⁇ H(T1 + (i + l)At) - H(T1 + iAt) ⁇ which is equivalent to
  • Tr ⁇ t (ri + 0 ' + l At - x ( Tl + iAt f + ⁇ - Y ( Tl + 0 ' + l At - Y ( Tl + iAt f + - z ( Tl + + l At - z ( Tl + iAt f
  • the velocity, acceleration and trajectory markers can be constructed as the velocity, acceleration and trajectory at the specific time point or a maximal, minimal or average velocity, acceleration and trajectory over some portion of the T or QTS loops.
  • Such T-loop velocity, acceleration and trajectory markers include:
  • Tv_Tmax the maximal magnitude of the 3D velocity in the time point Tmax
  • Tv_Tmax_av the average magnitude of the 3D velocity in the interval Tmax- DT1 to Tmax+DT1 , where DT1 can take values 2 ms, 4 ms, 6 ms;
  • Tv_La / Tv_Ra Tv_La / Tv_Ra
  • Tv_Trl_-Trajectory of the vector H during the first part of the T loop from Tmax-DT to Tmax , where DT Tend-Tmax;
  • the time interval for calculation the maximal, average velocity, maximal acceleration and trajectories can be modified with new definition of DT.
  • DT can be defined as the time interval from Tmax to the time point when the amplitude of the T-wave decreases to some percentage of the VM(Tmax), e.g., 0.3 * VM(Tmax) (30% of its maximal value), or 0.5 * VM(Tmax) (50% of its maximal value).
  • T loop 120 angle markers include:
  • the time interval for calculation the T loop angular widths can be modified with new definition of DT.
  • DT can be defined as the time interval from Tmax to the time point when the amplitude of the T-wave decreases to some percentage of the VM(Tmax), e.g., 0.3 * VM(Tmax) (30% of its maximal value), or 0.5 * VM(Tmax) (50% of its maximal value).
  • Roundness value is expressed as ratio of area of the T or QRS loop 120, 130 (entire loop or part of the loop) and circle area defined using VM(Tmax) for T loop 120 or VM(R) for QRS loop 130 as diameter.
  • a calculation of loop area can be done by splitting the loop area into elementary triangles and summing all areas of these triangles (Fig. 8A). Calculation of the loop are can be done also with splitting of the loop are into triangles or stripes normal to vector H(Tmax) fort T loop or H(R) 142 for QRS loop 130 and summing the area of all triangles or stripes 128. (Fig. 8B).
  • the preferential plane 132 of the T or QRS loop 120, 130 is defined by the first two principal components and ⁇ 2 (Fig. 9) obtained applying standard
  • PCA Principle Component Analysis
  • Projection 134 of the T or QRS loop 120, 130 on the preferential plane 132 is the orthogonal projection of the points of the T or QRS loop 120, 130 on the plane defined by first two principal components and ⁇ 2 (Fig. 9).
  • the best fitted ellipse 136 of the projection of the T or QRS loop 120, 130 is the ellipse constructed on the first two principal components and i 2 (Fig. 9).
  • Alternative cardiac electrical event markers based on the morphology of the T loop include:
  • T loop roundness L/R a ratio of the left and right roundness which is equal to the ratio of the marker values T loop roundness, left and T loop roundness, right;
  • T loop ellipse, left the difference in surface of the left part in the time interval
  • T loop ellipse, L/R a ratio of the marker values T loop ellipse, left and T loop ellipse, right.
  • the time interval for calculation the T loop roundness, planarity and ellipticity can be modified with new definition of DT.
  • the DT can be defined as the time interval from Tmax to the time point when the amplitude of the T-wave decreases to some percentage of the VM(Tmax), e.g., 0.3 * VM(Tmax) (30% of its maximal value), or 0.5 * VM(Tmax) (50% of its maximal value).
  • QRS loop 3D velocity markers can be defined in analogy with the above- described T loop 3D velocity markers, and include:
  • Qv_R the maximal magnitude of the 3D velocity in the time point R
  • Qv_R_av the average magnitude of the 3D velocity in the interval R-DT to R+DT, where DT can take values 2 ms, 4 ms, 6 ms;
  • the time interval for calculation the maximal, average velocity, maximal acceleration and trajectories can be modified with new definition of DT.
  • the DT can be defined as the time interval from R to the time point when the amplitude VM decreases to some percentage of the VM(R), e.g., 0.3 * VM(R) (30% of its maximal value), or 0.5 * VM(R) (50% of its maximal value).
  • the time interval for calculation the QRS angular widths can be modified with new definition of DT.
  • the DT can be defined as the time interval from R to the time point when the amplitude of the QRS wave decreases to some percentage of the VM(R), e.g., 0.3 * VM(R) (30% of its maximal value), or 0.5 * VM(R) (50% of its maximal value).
  • QRS angle markers include:
  • QRS elevation the elevation angle ⁇ ⁇ of the vector H(R) ; and Q Roll, the angle Q between normal n Q of the QRS loop plane defined by first principal components and ⁇ 2 and some reference direction n R , where
  • Markers based on the morphology of the QRS loop 130 are also defined with analogy of the corresponding T loop markers, and include:
  • QRS loop roundness L/R a ratio of the left and right roundness which is equal to the ratio of the marker values QRS loop roundness, left and QRS loop roundness, right; QRS loop planarity, the integral of distance of the points of the QRS loop
  • QRS loop ellipse, L/R a ratio of the marker values QRS loop ellipse, left and QRS loop ellipse, right.
  • the time interval for calculation the QRS loop roundness, planarity and ellipticity can be modified with new definition of DT.
  • the DT can be defined as the time interval from R to the time point when the amplitude of the QRS wave decreases to some percentage of the VM(R), e.g., 0.3*VM(R) (30% of its maximal value), or 0.5 *VM(R) (50% of its maximal value).
  • combined QRS - T-loop markers include: QRS-T angle 138, the angle between heart vectors H in time points R and
  • the time interval DT1 for calculation the mass center of QRS loop 130 can be modified with new definition of DT1 .
  • the DT1 can be defined as the time interval from R to the time point when the amplitude of the QRS wave decreases to some percentage of the VM(R), e.g., 0.3*VM(R) (30% of its maximal value), or 0.5 *VM(R) (50% of its maximal value).
  • the time interval DT2 for calculation the mass center of T loop can be modified with new definition of DT2.
  • the DT2 can be defined as the time interval from Tmax to the time point when the amplitude of the T wave decreases to some percentage of the VM(Tmax), e.g., 0.3*VM(Tmax) (30% of its maximal value), or 0.5 *VM(Tmax) (50% of its maximal value).
  • QRS-T Pitch the pitch angle of the relative positions of the T-loop 120 defined with the preferential plane and the directional vector H(Tmax) with respect to QRS loop 130 defined with its preferential plane and the directional vector H(R) ;
  • QRS-T Yaw the yaw angle of the relative positions of the T-loop 120 defined with the preferential plane and the directional vector H(Tmax)with respect to QRS loop 130 defined with its preferential plane and the directional vector H(R) ;
  • QRS-T Roll the roll angle of the relative positions of the T-loop 120 defined with its preferential plane and the directional vector H(Tmax)with respect to QRS loop 130 defined with its preferential plane and the directional vector H(R) , wherein the definitions of the angles' pitch, yaw and roll angles are same as are well-known for aeronautics.
  • embodiments of the disclosed inventions employ a standard deviation of the parameter values over all independent heart beats.
  • additional new markers may be defined as standard deviations of the marker values of the all previously defined markers of all independent heart beats, for example, SDQTc, the standard deviation of all independent beats' QTc values.
  • the standard deviation can be calculated for three consecutive beats for all previously defined markers, for example, SDQTc 3C, the standard deviation of the QTc values for three consecutive beats.
  • the mean difference in the Tv_L/R ratio was well above and outside of the +- 90% confidence interval values (also depicted in Fig. 12A) for the vast majority of the time period following patient Sotalol dosing, demonstrating that the mean difference in the Tv_L/R ratio is a statistically meaningful difference, and that the Tv_L/R ratio marker (like the QT response interval) accurately predicts the pro- arrhythmic effects of Sotalol.
  • Fig. 12B shows the differences in the Tv_L/R ratio determined from patient
  • the alternative markers Tv_L/R, Ts_L and T_dir for analyzing the Sotalol and Moxi data with reference to Figs. 12-14 were selected by way of example.
  • the particular cardiac electrical event marker(s) to be used in a particular drug cardiac safety study and/or for clinical diagnosis purposes will be determined based, by way of example, on the type of drug being tested, or based on the particular cardiac disease being diagnosed, with some markers being better predictors than others depending in the circumstances. Additionally, some markers may perform well in generally discriminating pro- arrhythmic from non- arrhythmic drugs. In practice, the cardiac electrical event marker data described with reference to Figs.
  • 1 B and 3-11 may be acquired and then analyzed using on one or more computing systems, such as a personal computer, utilizing customized software, semi-customized software based, for example, on spreadsheets or customized configurations in applications such as the software package available under the tradename LabView (RTM) by National Instruments, Inc., and/or hardware configured to run embedded software.
  • computing systems such as a personal computer, utilizing customized software, semi-customized software based, for example, on spreadsheets or customized configurations in applications such as the software package available under the tradename LabView (RTM) by National Instruments, Inc., and/or hardware configured to run embedded software.
  • RTM LabView
  • an ECG acquisition system 78 and associated electrodes 80 preferably are integrated with a computer 100 using a wired or wireless coupling 84 whereby the computer 100 may receive and/or request data from the ECG system 78, and control activities and/or receive information from an embedded device 88, such as a card comprising integrated circuits and/or memory (and in one embodiment housed in a card housing and comprising an electromechanical card interface to connect with a bus comprising the ECG system), an application specific integrated circuit (“ASIC”), or a field programmable gate array (“FPGA”), each of which preferably would be configured to conduct primary and/or secondary analysis on raw data received by the ECG system 78 form the electrodes 80, in accordance with any instructions or control sequences that may be received from the computer 100, should the computer be connected at the time of sampling or before sampling.
  • an embedded device 88 such as a card comprising integrated circuits and/or memory (and in one embodiment housed in a card housing and comprising an electromechanical card interface to connect with a bus comprising the
  • an ambulatory, portable, Holter style ECG system 88 may also be similarly coupled to an embedded device 82 configured to conduct primary and/or secondary analysis based upon raw data received by such system 88 from an operatively coupled electrode set 86.
  • a bus or connector 90 may be provided for computing system (not shown) connectivity.
  • an electrophysiology mapping system 92 such as those available from Biosense Webster under the trade name CartoXP (RTM) may also be operatively coupled to an embedded device 82 configured to conduct primary and/or secondary analysis based upon raw data received by such system 92 from an operatively coupled electrode set (not shown) coupled to an electrode connectivity bus panel 94.
  • RTM CartoXP
  • the results of any drug safety analysis or patient cardiac health diagnosis may be directed to the one or more displays 96.
  • an echocardiography system 98 such as those available from Siemens Medical Systems, Inc. under the trade name Sequoia (RTM), may be operatively coupled to a computing system 100 and an ECG system 78.
  • An embedded device 82 configured to conduct analysis based upon raw data received from the ECG system 78, may be coupled to any one of the respective ECG system 78, the computing system 100, or the chocardiography system 98. Data pertinent to such analysis preferably may be directed to either of the echocardiography display 96 or the computing system display 97.
  • a relatively simple fluoroscopy system 102 such as that depicted in Fig. 19A
  • a more complex angiography system 104 such as that depicted in Fig.
  • 19B may be operatively coupled and/or embedded with a device configured to conduct primary and/or secondary analysis based upon raw data received by electrodes operatively coupled to a computing system 100, associated ECG system 78, the embedded device, or other system.
  • Connectivity of the various components of such system configurations, such as the processor, memory device, and operating room electronic device, may be conducted using Ethernet, wireless technologies, and/or communication protocols such as TCPIP, FTP, or HTTP.

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Abstract

Cette invention concerne un système permettant d'évaluer l'effet d'un médicament en cours d'étude sur des événements de l'activité électrique cardiaque, ledit système comprenant un dispositif de mémoire configuré pour stocker des données de niveau de base respectif et des données de signaux d'ECG produits sous l'effet du médicament acquis chez une population de patients étudiée, et un processeur couplé de manière fonctionnelle au dispositif de mémoire et configuré pour accéder et évaluer les données de niveau de base respectif et les données de signaux d'ECG produits sous l'effet du médicament pour déterminer des différences statistiquement pertinentes, le cas échéant, des valeurs du niveau de base et des valeurs d'ECG produites sous l'effet du médicament d'un ou de plusieurs marqueurs associés aux événements électriques cardiaques. Le ou les marqueurs sont sélectionnés dans un groupe comprenant des marqueurs dérivés des événements de signaux de magnitude vectorielle (MV) d'un cycle cardiaque ayant un intervalle RR, des marqueurs 3D choisis dans le groupe constitué de marqueurs de l'onde T, de marqueurs de l'onde QRS, et de marqueurs de l'onde QRS-onde T combinés, et de marqueurs basés sur un degré de variabilité d'un paramètre d'ECG.
PCT/US2010/060041 2009-12-14 2010-12-13 Marqueurs alternatifs utilisés pour l'évaluation quantitative d'événements électriques cardiaques WO2011075429A1 (fr)

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TWI483706B (zh) * 2012-07-24 2015-05-11 Livestrong Biomedical Technology Co Ltd 一種具有心臟狀態之量化功能的裝置
US10271823B2 (en) 2017-10-02 2019-04-30 General Electric Company Extracting a cardiac-cycle signal from echocardiogram data
CN110367936A (zh) * 2019-08-05 2019-10-25 广州视源电子科技股份有限公司 心电信号检测方法及装置
WO2023037006A1 (fr) * 2021-09-13 2023-03-16 Mycor Gmbh Procédé et dispositif de détermination de potentiels d'excitation du coeur humain
WO2023036447A1 (fr) * 2021-09-13 2023-03-16 Mycor Gmbh Procédé et dispositif de détermination de potentiels d'excitation du cœur humain

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