WO2011075429A1 - Alternative markers for quantitative assessment of cardiac electrical events - Google Patents

Abstract

A system for assessing an impact on cardiac electrical activity events by a drug being tested, the system comprising a memory device configured to store respective baseline and on-drug ECG signal data acquired from a test population of patients, and a processor operatively coupled to the memory device and configured to access and evaluate the respective baseline and on-drug ECG signal data to determine statistically relevant differences, if any, in the baseline and on-drug ECG values of one or more markers related to cardiac electrical events. The one or more markers are selected from a group comprising markers derived from vector magnitude (VM) signal events of a heart cycle having an RR interval, 3D markers selected from the group consisting of T-loop markers, QRS loop markers, and combined QRS- T-loop markers, and markers based on a degree of variability of an ECG parameter.

Description

ALTERNATIVE MARKERS FOR QUANTITATIVE ASSESSMENT OF

CARDIAC ELECTRICAL EVENTS

RELATED APPLICATION DATA

The present application claims the benefit under 35 U.S.C. § 1 19 to U.S.

provisional patent application serial nos. 61/286,374, filed December 14, 2009 and 61/286,763, filed December 15, 2009. The foregoing applications are hereby incorporated by reference into the present application in their entirety.

FIELD OF THE INVENTION

The disclosed inventions relate to the field of medical electronics. In particular, 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.

BACKGROUND

Although the electrocardiogram (frequently referred to as "ECG" or "EKG") is a universally accepted diagnostic method in cardiology, frequent mistakes are made in interpreting ECGs, because the most common approach for interpretation of ECGs is based on human memorization of waveforms, rather than using vector concepts and basic principles of electrocardiography (see Hurst, J. W., Clin. Cardiol. 2000 Jan; 23(1 ):4-13). Another problem with traditional ECG recordings is that the ECG may not provide adequate indications of electrical activity of certain regions of the heart, especially the posterior region. The timing of cardiac electrical events, and the time intervals between two or more such events, has diagnostic and clinical importance. However, medical diagnosis and drug development has been significantly limited by the lack of adequate ECG measurement tools. Furthermore, prior analysis of ECG recordings required a substantial amount of training and familiarity with reading of the recorded waveforms. There have been many attempts to extract additional information from the standard 12-lead ECG measurement when measuring the electric potential distribution on the surface of the patient's body for diagnostic purposes. These attempts have included new methods of measured signal interpretation, either with or without introducing new measurement points, in addition to the standard 12-1 ead ECG points.

One of the oldest approaches, 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). Like conventional ECG interpretation, 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. Instead of presenting signal waveforms from the measurement points (waveforms), as it is the case with standard 12-lead ECGs, in 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). In this way, 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. Furthermore, a time-dependence aspect (i.e., the signal waveform) is lost with this procedure, and 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.

There have been numerous attempts to overcome the drawbacks of the VCG method described above. These methods exploit the same signals as VCG (X, Y, Z), but their signal presentation is different than the VCG projection of the vector hodograph onto three planes. "Polarcardiogram" uses Aitoff cartographic projections for the presentation of the three-dimensional vector hodographs (see Sada, T., et al., J Electrocardiol. 1982; 15(3):259-64). "Spherocardiogram" adds information on the vector amplitude to the Aitoff projections, by drawing circles of variable radius (see Niederberger, M., et al., J Electrocardiol. 1977; 10(4):341 -6). "3D VCG" projects the hodograph onto one plane (see Morikawa, J., et al., Angiology, 1987; 38(6):449-56. "Four-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, Biomedizinisch Technik., 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. Physiologically, 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. Referring again to Fig. 1 , during the S-T segment 10, all layers have partially re-polarized to a more or less equal extent, and the ST segment 10 is approximately isoelectric. 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. At the peak of the Twave (Tpeak) 16, epicardial re-polarization is complete and the transmural re-polarization gradient is at its maximum. Subsequently, endocardial cells begin their movement towards resting potential, thereby narrowing the transmural gradient and initiating the down-slope of the Twave.

Finally, 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. As a result, drug regulatory agencies are conducting increasingly detailed review of drug-induced abnormalities in cardiac electrical activity based on measured changes in the QT interval timing of test subjects after administering a drug under evaluation. 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. In particular, extension of a patient's QT interval caused by a particular drug may be predictive of negative pro-arrhythmic events. For example, 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. patent applications 12/484,153 and 12/484,156, filed June 12, 2009, disclose and describe systems and methods providing accurate and reproducible cardiac interval measurements, and the QT interval measurement. The complete contents of these two applications are hereby incorporated by reference herein for all that they teach and disclose.

On the other hand, the QT interval is not an adequate marker for predicting potentially pro-arrhythmic effects of certain drugs. For example, Moxifloxacin, an antibiotic, is known to moderately prolong the QT interval without, on average, producing fatal arrhythmias, such as torsades. As such, the QT interval is considered a benign positive test with respect to Moxifloxacin. However, it would be preferable for testing new drugs for cardiac safety that 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.

SUMMARY OF THE INVENTION

In accordance with the inventions disclosed and described herein, 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.

Examples of 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. Examples of 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.

Examples 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.

In one embodiment, 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. Thereafter, 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. In this regard, 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. Preferably, multiple marker values are analyzed in order to detect whether a change in one marker value is in fact a "benign positive" test.

In accordance with one embodiment of the disclosed inventions, 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.

Other and further aspects and embodiments are disclosed and described in the accompanying figures and the following detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

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

Moxifloxacin (Fig. 2B).

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

integrated with embodiments of the disclosed inventions.

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.

DETAILED DESCRIPTION

It is proposed that 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.

In particular, 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. By way of example, 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. As can be observed, 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. Thus, based on the mean QT interval delays staying well outside of the +- confidence values for a time period lasting over several hours (10 hours in the illustrated data), 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. As can be observed the mean QT interval delays are well outside of the +- confidence values for the entire 15 hour time period. Thus, although prolonged by a lesser amount the QT interval data presented in Fig. 2B predicts that 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.

With reference to Fig. 3, 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.

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.

Examples of 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. As such, they may be accurate predictors of potential pro- arrhythmic drug effects. For example, a slow re-polarization velocity could be indicative of ventricular function abnormalities. Similarly, by way of a different example, 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.

Examples 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. However, given the computational power that exists in today's micro-computers, 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. In particular, 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.

Referring to the VM signal illustrated in Fig. 1 B, 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

(72) points on the VM signal;

TmaxTendc interval, i.e., the Tmax to Tend interval, corrected using

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; and

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/QT, a ratio of the PR and QT intervals;

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; and TmaxTend/QTmax, a ratio of the TmaxTend and QTmax intervals.

It will be appreciated that 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.

With reference to Fig. 4, alternative cardiac electrical event markers may also include measured voltages at particular points on the VM signal, such as:

Tend qVm (68), the voltage of Tend (72) point on the |V| signal, with Q-20ms as a reference point;

Tmax qVm, the voltage of Tmax point on the |V| signal, with Q-20ms as a reference point; and

Tmax_Tend qVm (66), the Tmax voltage divided by Tend voltage on the |V| signal, with Q-20ms as a reference point.

It will be appreciated that the use of Q-20 ms as a reference point is

convenient but arbitrary, and the choice of the reference point for the above voltage markers can be any time point in the RR interval.

Referring again to Fig. 1 B, other voltage markers include:

TPelev, the difference of the average voltage of the PQ segment 62 and TP segment 64 on the VM signal; non_dipol_T_T, a sum of the differences of the actual voltages in the ECG leads V1 -V6 during the time interval Tmax-DT to Tmax + DT, where DT = Tend- Tmax, and the derived voltages V1 d-V6d are obtained by multiplication of the transformation matrix MT (3x6) with the voltages of the leads I, II i V2 chosen as a basis vector, Vb(l,ll, V2) , where

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. non_dipol_T_T_max, the maximal difference of the actual voltages in the ECG leads V1 -V6 during the time interval Tmax-DT to Tmax + DT, where DT = Tend-Tmax, and the derived voltages V1 d-V6d are obtained by multiplication of the transformation matrix MT (3x6) with the voltages of the leads I, II i V2 (as described above for the marker non_dipol_T_T); non_dipol_Q_Q, the sum of the differences of the actual voltages in the ECG leads V1 -V6 during the time interval R - DT to R + DT, where DT = J-R, and the derived voltages V1 d-V6d are obtained by multiplication of the transformation matrix MQ (3x6) with the voltages of the leads I, II i V2 chosen as a basis vector,

Vb(I, II, V2) , where Vd(V\d, V2d, V3d, V4d, V5d, V6d) = MQ^■ Vb(I, II, V2) , and wherein the elements of the matrix MQ are calculated using the least square method disclosed and described in the above-incorporated U.S. Patent No. 7,647,093; and non_dipol_Q_Q_max, the maximal difference of the actual voltages in the ECG leads V1 -V6 during the time interval R - DT to R + DT, where DT = J-R, and the derived voltages V1 d-V6d obtained by multiplication of the transformation matrix MQ (3x6) with the voltages of the leads I, II i V2.

With reference to Figs. 5A and 5B, combined time-voltage markers that may be used include one or more two-dimensional areas over some portion of the VM (or Χ,Υ,Ζ 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 Χ,Υ,Ζ signals, using Q - 20ms as a reference point; Neg JTend area corrected, the J to Tend signal voltage (negative only) integral (sum) on Χ,Υ,Ζ signals using Q - 20ms as a reference point, corrected using Fridericia's method (divided by cubic root of RR);

Pos. J-Tend area, the J to Tend signal voltage (positive only) integral (sum) on Χ,Υ,Ζ signals using Q - 20ms as a reference point; and

Pos. J-Tend area corrected, the J to Tend signal voltage (positive only) integral (sum) on Χ,Υ,Ζ signals using Q - 20ms as a reference point, corrected using Fridericia's method (divided by cubic root of RR).

Again, it will be appreciated that the use of Q-20 ms as a reference point is convenient but arbitrary, and the choice of the reference point for the above voltage markers can be any time point in the RR interval.

With reference to Fig. 6, 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);

Ts_L/R, the ratio of the markers values Ts_L 1 10 and Ts_R 1 12 (Ts_L/R=

Ts U Ts_R);

Ts_L+R, the sum of the markers values Ts_L 1 10 and Ts_R 1 12 (Ts_L/R=

Ts L+ Ts_R); and Ts_L-R, the difference of the markers values Ts_L 1 10 and Ts_R 1 12

(Ts_L/R= Ts_L- Ts_R).

Notably, the time interval for calculation the slopes can be modified with new definition of "DT". For example, 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. Examples of such 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);

Qs_L/R - The ratio of the markers values Qs_L and Qs_R (Qs_L/R= Qs_L/ Qs_R); Qs_L+R - The sum of the markers values Qs_L and Qs_R (Qs_L/R= Qs_L+

Qs_R); and

Qs_L-R - The difference of the markers values Qs_L and Qs_R (Qs_L/R= Qs_L- Qs_R).

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:

Let x{t) , Y(t) , and z(t) be components of a heart vector at time t: Heart Vector - H = (Χ, Υ,Ζ) = Χί + Yj + Zk , and its magnitude at time t is

VM = \H(t)\ = s]x(t)² + Y(t)² + Z{tf

The Heart Vector velocity is the first derivative of the Heart Vector: dH(t) dX dY - dZ

Heart Vector Velocity (3D velocity) HVV = ^^ =— i +—j +—k which

dt dt dt dt

approximately reflects the speed of movement of the point across the 3D loop in the 3D vector space. The magnitude of the heart vector velocity is the square root of the sum of squares, that is, HVV Magnitude = HVVM =

The numerical calculation of the velocity can be performed with the following two point formulas: a) Forward difference scheme

H(t + At) - H(t)

HVV

At b) Backward difference scheme

H(t) - H(t - At)

HVV

At b) Central difference scheme

H(t + At) - H(t - At)

HVV

2At The calculation of the velocity can be also done with the some of the multipoint formulas for numerical differentiation. dHW{t) d²X r d²Y→ d²Z→ . . .

Heart Vector Acceleration HVA -i +— j +—-k which

dt dt dt dt

approximately reflects the acceleration of the point across the 3D loop in the 3D vector space. The magnitude of the heart vector acceleration is the square root of the sum of squares, that is, HVA Magnitude = HVAM

The numerical calculation of the acceleration can be performed with the following central difference three point formulas:

Hjt + At) + Hjt - At) - 2H(t)

HVA(t)

2At² Or, in the alternative, with the some of the multipoint formulas for numerical differentiation. The trajectory of the vector H between two time points T1 and

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

i=0

^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_L, the maximal magnitude of the 3D velocity in the first (initial) part of T loop defined in the interval Tmax - DT to Tmax, where DT= Tend-Tmax;

Tv_R, the maximal magnitude of the 3D velocity in the second (terminal) part of T loop defined in the interval Tmax to Tmax+ DT, where DT= Tend - Tmax; Tv_L/R, a ratio of the values of the markers Tv_L and Tv_R (Tv_L/R = Tv_L /

Tv_L); Tv_La, an average magnitude of the 3D velocity in the first (initial) part of T loop defined in the interval Tmax-DT to Tmax, where DT= Tend-Tmax;

Tv_Ra, an average magnitude of the 3D velocity in the second (terminal) part of T loop defined in the interval Tmax to Tmaxv+ DT, where DT= Tend-Tmax; Tv_La/Ra, a ratio of the values of the markers Tv_La and Tv_Ra (Tv_La/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;

Tv_TrR, a trajectory of the vector H during the second terminal part of the T loop from Tmax to Tmax+DT: where DT= Tend-Tmax; Tv_TrR, a ratio of the trajectory (Tr1 ) of the vector H during the first part of the T loop from Tmax-DT to Tmax with the trajectory (Tr2) of the vector H during the second terminal part of the T loop from Tmax to Tmax+DT: (Tv_TrR = Tv_Trl_ / Tv_TrR), where DT= Tend-Tmax,

Ta_L , the maximal magnitude of the 3D acceleration in the first (initial) part of T loop defined in the interval Tmax-DT to Tmax, where DT= Tend-Tmax;

Ta_R, the maximal magnitude of the 3D acceleration in the second (terminal) part of T loop defined in the interval Tmax to Tmax+DT, where DT= Tend-Tmax; and

Ta_L/R, a ratio of the values of the markers Ta_L and Ta_R (Ta_L/R = Ta_L / Ta_L). The time interval for calculation the maximal, average velocity, maximal acceleration and trajectories can be modified with new definition of DT. For example, 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).

With reference to Fig. 7, T loop 120 angle markers include:

T_dir, the angle between heart vectors = H(Tmax) in the point Tmax and some reference direction (for example, reference direction can be H_r (1,1,-1) and in that case this marker is the angle γ_τ between H_maxand H_r which can be calculated

H H

with the equation: cos(/_T) =——— - ; however, any other direction can be used as max

reference direction);

T loop angular width, left 122, the angular difference a_L between leftmost vector H_L in the interval Tmax-DT of the T loop 120 and vector H_max = H(Tmax) , where DT= Tend-Tmax, where the angle a_L is calculated with the formula: cos(a_z) L max

T loop angular width, right 124, the angular difference a_R between rightmost vector H_R in the interval Tmax+DT of the T loop 120 and the vector m_ax = H(Tmax) , where DT= Tend-Tmax, where the angle a_R is calculated with the

H„ - H

formula: cos(<¾) R ^± max

H_R - H_n

T loop angular width L+R 126, the angular difference a_LR between leftmost vector H_L in the interval Tmax-DT and rightmost vector H_R in the interval Tmax+DT of the T loop, where DT= Tend-Tmax, where the angle a_LR is calculated with the formula: cos(a,„) = ^{H∑ Hr} ; and

L^{R J} HL^■ H_R

T loop angular width L/R, a ratio of the angles a_L and a_R (T loop angular width L/R= a_L l a_R ).

The time interval for calculation the T loop angular widths can be modified with new definition of DT. For example, 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).

Other T angle markers include: T azimuth, the azimuth angle φ_τ of the vector H(Tmax) ; T elevation, it is elevation angle θ_τ of the vector H(T max) ; T Roll, the angle β_τ between normal n_T of the T loop plane defined by first principal components and λ₂ and some reference direction ^ , cos( 7_g) = ^{Άτ r} , where the orientation of the normal n_T is according to the right-hand rule and the reference direction is arbitrary, for example ¾ (1,0,0) .

With reference to Figs. 8A-8B and Fig. 9, markers based on the morphology of the T loop will now be described. Again, it is useful to start with some definitions:

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 λ₂ (Fig. 9) obtained applying standard

Principle Component Analysis (PCA) (see for example MathLab subroutine).

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 λ₂ (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 i₂ (Fig. 9).

Alternative cardiac electrical event markers based on the morphology of the T loop include:

T loop roundness, left, a ratio of the area of the left half of T loop 120 in the time interval between Tmax-DT and Tmax, with the half of the area of the circle with the diameter equal to VM(Tmax), where DT= Tend-Tmax;

T loop roundness, right, a ratio of the area of the right half of T loop 120 in the time interval between Tmax+DT and Tmax, with the half of the area of the circle with the diameter equal to VM(Tmax), where DT= Tend-Tmax;

T loop roundness L+R, a ratio of the area of the T loop 120 defined in the time interval between Tmax-DT and Tmax+DT, with the area of the circle with the diameter equal to VM(Tmax), where DT= Tend-Tmax; 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;

Tloop planarity, an integral of distance of the points of the T-loop 120 from the T-loop plane defined by first two principal components and X₂ , in the time interval Tmax-DT to Tmax+DT, where DT= Tend-Tmax; T loop planes angle, the angle between the planes defined by first two principal components and λ₂ of the left part of T loop 120 in the time interval Tmax-DT and right part of the T loop in the time interval Tmax+DT, to, where DT= Tend-Tmax; T loop ellipse, left, the difference in surface of the left part in the time interval

Tmax-DT to Tmax of the T loop projection on its preferential plane defined by first two principal components from the best fitted half ellipse of the T loop projection, where DT= Tend-Tmax;

T loop ellipse, right, the difference in surface of the right part in the time interval Tmax to Tmax+DT of the T loop projection on its preferential plane defined by first two principal components from the best fitted half ellipse of the T loop projection, where DT= Tend-Tmax;

T loop ellipse L+R, the difference in surface of T loop projection in the time interval Tmax-DT to Tmax+DT on its preferential plane defined by first two principal components from the best fitted ellipse of the T loop projection, where DT= Tend- Tmax; and

T loop ellipse, L/R, a ratio of the marker values T loop ellipse, left and T loop ellipse, right.

Again, 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;

Qv_L, the maximal magnitude of the 3D velocity in the first (initial) part of QRS loop defined in the interval R-DT to R, where DT= J-R; Qv_R, the maximal magnitude of the 3D velocity in the second (terminal) part of QRS loop defined in the interval R to R+DT, where DT= J-R;

Qv_L/R, a ratio of the values of the markers Tv_L and Tv_R (Tv_L/R = Qv_L / Qv_R);

Qv_La, the average magnitude of the 3D velocity in the first (initial) part of QRS loop defined in the interval R-DT to R, where DT= J-R;

Qv_Ra, the average magnitude of the 3D velocity in the second (terminal) part of QRS loop defined in the interval R to R+DT, where DT= J-R;

Qv_La/Ra, a ratio of the values of the markers Qv_La and Qv_Ra (Qv_La/Ra = Qv_La / Qv_Ra); Qv_Trl_, a trajectory of the vector H during the first part of the QRS loop from R-DT to R , where DT= J-R;

Qv_TrR, a trajectory of the vector H during the second terminal part of the QRS loop from R to R+DT, where DT= J-R;

Qv_TrR a ratio of the trajectory (Tr1 ) of the vector H during the first part of the QRS loop from R-DT to R with the trajectory (Tr2) of the vector H during the second terminal part of the QRS loop from R to R+DT: (Qv TrR = Qv TrL /

Qv TrR), where DT= J-R;

Qa_L, the maximal magnitude of the 3D acceleration in the first (initial) part of QRS loop defined in the interval R-DT to R, where DT= J-R;

Qa_R, the maximal magnitude of the 3D acceleration in the second (term part of QRS loop defined in the interval R to R+DT, where DT= J-R; and Qa_L/R, the ratio of the values of the markers Qa_L and Qa_R (Qa_L/R = Qa_L / Qa_L).

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).

QRS angle markers are also defined with analogy of the corresponding T angle markers, and include: Qdir, the angle between heart vectors H_gmax = H(R) in the point R and some reference direction (e.g., the reference direction can be H_r (1,1,-1) and in that case this marker is the angle χ_β between H_emax and H_r which can be calculated from the

H H

equation cos(^_e) =——— - , although any other direction can be used as reference direction); QRS loop angular width, left, the angular difference a_QL between leftmost vector H_QL in the interval R-DT of the QRS loop 130 and vector H_gmax = H(R) , where DT= J-R, and where the angle a_QL is calculated from the formula

∞ a_QL) =— ,

QL gmax

QRS loop angular width, right, the angular difference a_QR between rightmost vector H_QR in the interval R+DT of the QRS loop 130 and the vector H_gmax = H(R) , where DT= J-R, and where the angle a_QR is calculated from the formula cos(a_QR) - ^{Hqr '} ^^{2max ■}

HQR ^■ Hgmax QRS loop angular width L+R, the angular difference a_QLR between leftmost vector H_QL in the interval R-DT and rightmost vector H_QR in the interval R+DT of the QRS loop 130, where DT= J-R, and where the angle a_QLR is calculated from the

H H

formula cos(a_m„) =———— ; and

QL ^' QR QRS loop angular width L/R, the ratio of the angles a_QL and a_QR (QRS loop angular width L/R= a_QL l a_QR ).

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).

Other QRS angle markers include:

QRS azimuth, the azimuth angle <p_Q of the vectorH(R) ;

QRS elevation; the elevation angle θ_β 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 λ₂ and some reference direction n_R , where

n_n ^■ n„

cos( ?_e) =— , and where the orientation of the normal n_Q is according to the n_Q - n_R

right-hand rule and the reference direction is arbitrary, for example n_R (1,0,0) .

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, left, a ratio of the area of the left half of QRS loop 130 in the time interval between R-DT and R, with the half of the area of the circle with the diameter equal to VM(R), where DT= J-R; QRS loop roundness, right, a ratio of the area of the right half of QRS loop 130 in the time interval between R and R+DT, with the half of the area of the circle with the diameter equal to VM(R), where DT= J-R;

QRS loop roundness L+R, a ratio of the area of the QRS loop 130 defined in the time interval between R-DT and R+DT, with the area of the circle with the diameter equal to VM(R), where DT= J-R;

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

130 from the QRS loop plane defined by first two principal components, in the time interval R-DT to R+DT, where DT= J-R;

QRS loop planes angle, the angle formed between the planes defined by first two principal components of the left part of QRS loop 130 in the time interval R- DT and right part of the QRS loop 130 in the time interval R+DT, to where DT= J-R;

QRS loop ellipse, left, the difference in surface of the left part in the time interval R-DT to Tmax of the QRS loop projection on its preferential plane defined by first two principal components from the best fitted half ellipse of the QRS loop projection, where DT= J-R; QRS loop ellipse, right, the difference in surface of the right part in the time interval R to R+DT of the QRS loop projection on its preferential plane defined by first two principal components from the best fitted half ellipse of the QRS loop projection, where DT= J-R;

QRS loop ellipse L+R, the difference in surface of QRS loop projection in the time interval R-DT to R+DT on its preferential plane defined by first two principal components from the best fitted ellipse of the QRS loop projection, where DT= J-R; and

QRS loop ellipse, L/R, a ratio of the marker values QRS loop ellipse, left and QRS loop ellipse, right. Again, 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).

With reference to Figs. 10 and 11 , combined QRS - T-loop markers include: QRS-T angle 138, the angle between heart vectors H in time points R and

Tmax /angle between H(R) and H(Tmax) , defined by cos(^) = ^(τ"¹^)

(Fig. 10); and QRS-T angle mass 140, the angle y_m between vector H_Qm pointing to the mass center of QRS- loop 130 and vector H_Tm pointing to the mass center of T-loop

120 (Fig. 11 ). The mass center of the QRS loop 130 is a point which coordinates are mean value the QRS loop coordinates in the time interval R-DT1 to R+DT1 , where DT1 =J-R. The mass center of the T loop is a point which coordinates are mean value the T loop coordinates in the time interval Tmax-DT2 to Tmax+DT2, where DT2=Tend-Tmax: cos(r_m) - ^{Qm ' Tm}

Qm Tm

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). Similarly, 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).

Further combined QRS - T-loop markers include: 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) ; and

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.

As a measure of the ECG parameters variability, embodiments of the disclosed inventions employ a standard deviation of the parameter values over all independent heart beats. In this way, 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. Alternatively, 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.

By way of a few examples using alternative cardiac electrical event markers, Fig. 12A shows the differences in the Tv_L/R ratio (i.e., the ratio of the values of the markers Tv_L and Tv_R (Tv_L/R = Tv_L / Tv_L); Tv_La, an average magnitude of the 3D velocity in the first (initial) part of T loop defined in the interval Tmax-DT to Tmax, where DT= Tend-Tmaxs can be observed) determined from patient ECG recordings made "on drug" over the ECG baseline (i.e., "off drug") Tv_L/R ratios taken from the data obtained in the above-mentioned NCE study for Sotalol. Notably, 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

ECG recordings made "on drug" over the ECG baseline (i.e., "off drug") Tv_L/R ratios ascertained from the data obtained in the above-mentioned CSRC study for Moxifloxacin. Notably, the mean difference in the Tv_L/R ratio feel within the +- 90% confidence interval values (also depicted in Fig. 12B) for the majority of the time period following patient Sotalol dosing, demonstrating that the mean difference in the Tv_L/R ratio is not a statistically meaningful difference. Thus, while both the QT response interval and the Tv_L/R ratio are accurate markers for determining the pro-arrhythmic effects of Sotalol, unlike the QT response interval, the Tv_L/R ratio marker does not provide a "false positive" result for Moxifloxacin. Similar results are shown in Figs. 13A-B for the marker Ts_L (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)), and in Figs. 14A-B for the marker T_dir (the angle between heart vectors H_max = H(Tmax) in the point Tmax and some reference direction).

It should be appreciated that 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. Furthermore, 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. In some embodiments, it is preferred to have pertinent systems electronically integrated to facilitate real time or near-real time analysis in accordance with the techniques described above.

For example, referring to Fig. 15, in one embodiment, 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. By way of example, referring to Fig. 16, 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.

Other medical information processing systems commonly associated with ECG signal processing may also be desirably integrated with or embedded with primary and secondary processing infrastructure. For example, referring to Fig. 17, 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. The results of any drug safety analysis or patient cardiac health diagnosis may be directed to the one or more displays 96.

Referring to Fig. 18, 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. Similarly, a relatively simple fluoroscopy system 102, such as that depicted in Fig. 19A, or 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.

While multiple embodiments and variations of the many aspects of the invention have been disclosed and described herein, such disclosure is provided for purposes of illustration only. For example, wherein methods and steps described above indicate certain events occurring in certain order, those of ordinary skill in the art having the benefit of this disclosure would recognize that the ordering of certain steps may be modified and that such modifications are in accordance with the variations of this invention. Additionally, certain of the steps may be performed concurrently in a parallel process when possible, as well as performed sequentially.

Claims

What is claimed is:

1 . A system for assessing an impact, if any, on cardiac electrical activity events by a drug being tested, comprising:

a memory device configured to store respective baseline and on-drug ECG signal data acquired from a test population of patients; and

a processor operatively coupled to the memory device and configured to access and evaluate the respective baseline and on-drug ECG signal data to determine statistically relevant differences, if any, in the baseline and on-drug ECG values of one or more markers related to cardiac electrical events, wherein the one or more markers are selected from a group comprising:

markers derived from vector magnitude (VM) signal events of a heart cycle having an RR interval,

3D markers selected from the group consisting of T-loop markers, QRS loop markers, and combined QRS- T-loop markers, and

markers based on a degree of variability of an ECG parameter.

2. The system of claim 1 , wherein the markers derived from VM signal events include one or more of:

a duration of the QRS complex on the VM signal;

a time interval between Tmax and Tend pints on the VM signal; and a time interval between Q and Tmax points on the VMS signal.

3. The system of claim 1 , wherein the markers derived from VM signal events include one or more of:

a ratio of respective durations of two different portions of the RR interval; an absolute voltage at a specified time point on the RR interval;

a ratio of respective measured voltages on the |V| signal;

a difference of an average voltage of respective portions of the VM signal; a two-dimensional area covering some portion of the VM signal; and a slope of a Twave or a QRS wave in the VM signal.

4. The system of claim 1 , wherein at least one of the one or more markers assesses propagation timing disturbances in the VM signal comprising precursors to arrhythmias.

5. The system of claim 1 , wherein at least one of the one or more markers is a voltage marker indicative of changes in cardiac tissue de-polarization or repolarization in the on-drug ECG signals.

6. The system of claim 1 , wherein the T-loop markers include one or more of Tvelocity markers, Tangle markers, and markers based on the morphology of the T- loop.

7. The system of claim 1 , wherein the QRS-loop markers include one or more of QRSvelocity markers, QRSangle markers, and markers based on the morphology of the QRS-loop.

8. The system of claim 1 , wherein the combined QRS- T-loop markers include angles between directions of QRS and T loop, and angles between QRS and T loop planes.

9. The system of claim 1 , wherein at least one of the markers is a velocity marker indicative of abnormalities in one or both of cardiac signal conduction patterns and de-polarization or re-polarization patterns.

10. The system of claim 1 , further comprising a display operatively coupled to the processor, wherein the processor is further configured to cause a graphical image of the differences, if any, in the baseline and on-drug ECG values of the one or more markers for a time period during which the on-drug ECG signal data was acquired to be depicted on the display, including a graphical indication of whether the displayed differences are statistically relevant.

1 1 . The system of claim 1 , wherein the processor and memory device are operatively coupled to an analog signal acquisition system selected from the group consisting of an electrocardiogram system, an electroencephalogram system, and an electromyogram system.

12. A method of assessing an impact, if any, on cardiac electrical activity events by a drug being tested, comprising:

acquiring baseline ECG signal data from a test population of patients;

acquiring on-drug ECG signal data from the test population of patients after dosing the respective patients with a drug being tested; and

evaluating the respective baseline and on-drug ECG signal data to determine statistically relevant differences, if any, in the baseline and on-drug values of one or more markers related to cardiac electrical events, wherein the one or more markers are based on vector magnitude (VM) signal events of a heart cycle having an RR interval.

13. The method of claim 12, wherein at least one of the one or more markers is a duration of a specified portion of the RR interval.

14. The method of claim 12, wherein the specified portion of the RR interval is selected from the group consisting of:

a duration of the QRS complex on the VM signal;

a time interval between Tmax and Tend pints on the VM signal; and

a time interval between Q and Tmax points on the VMS signal.

15. The method of claim 12, wherein at least one of the one or more markers is a ratio of respective durations of two different specified portions of the RR interval.

16. The method of claim 15, the specified portions of the RR interval including a PR interval, a QT interval, a QTmax interval, and a TmaxTend interval, wherein the at least one marker is selected from the group consisting of:

PR/QT, a ratio of the PR and QT intervals;

PR/QTmax, a ratio of the PR and QTmax intervals;

PR/TmaxTend, a ratio of the PR and TmaxTend intervals; and

TmaxTend/QT, a ratio of the TmaxTend and QT intervals.

17. The method of claim 12, wherein the VM signal comprises an absolute voltage |V| signal, and wherein at least one of the one or more markers is an absolute voltage at a specified time point on the RR interval.

18. The method of claim 17, wherein the measured voltage is a voltage of a Tend point on the |V| signal or a voltage of a Tmax point on the |V| signal.

19. The method of claim 12, wherein the VM signal comprises an absolute voltage |V| signal, and wherein at least one of the one or more markers comprises a ratio of respective measured voltages on the |V| signal.

20. The method of claim 12, wherein the VM signal comprises an absolute voltage |V| signal, and wherein at least one of the one or more markers is a difference of an average voltage of a PQ segment and an average voltage of a TP segment on the VM signal.

21 . The method of claim 12, wherein at least one of the one or more markers comprises a two-dimensional area covering some portion of the VM signal.

22. The method of claim 12, wherein at least one of the one or more markers is based on a slope of a Twave in the VM signal or a slope of a QRS wave in the VM signal.

23. The method of claim 12, wherein at least one of the one or more markers assesses propagation timing disturbances in the VM signal comprising precursors to arrhythmias.

24. The method of claim 12, wherein at least one of the one or more markers is a voltage marker indicative of changes in cardiac tissue de-polarization or repolarization in the on-drug ECG signals.

25. A method of assessing an impact, if any, on cardiac electrical activity events by a drug being tested, comprising:

acquiring baseline ECG signal data from a test population of patients;

acquiring on-drug ECG signal data from the test population of patients after dosing the respective patients with a drug being tested; and

evaluating the respective baseline and on-drug ECG signal data to determine statistically relevant differences, if any, in the baseline and on-drug values of one or more markers related to cardiac electrical events, wherein the one or more markers include at least one 3D marker selected from the group consisting of T-loop markers, QRS loop markers, and combined QRS- T-loop markers.

26. The method of claim 25, wherein the T-loop markers include one or more of Tvelocity markers, Tangle markers, and markers based on the morphology of the T-loop.

27. The method of claim 26, wherein markers based on T-loop morphology are based on one or more of T-loop planarity, roundness and symmetry.

28. The method of claim 25, wherein the QRS-loop markers include one or more of QRSvelocity markers, QRSangle markers, and markers based on the morphology of the QRS-loop.

29. The method of claim 28, wherein markers based on QRS-loop morphology are based on one or more of QRS-loop planarity, roundness and symmetry.

30. The method of claim 25, wherein the combined QRS- T-loop markers include angles between respective directions of the QRS and T loops.

31 . The method of claim 25, wherein the combined QRS- T-loop markers include angles between QRS and T loop planes.

32. The method of claim 25, wherein at least one of the markers is a velocity marker indicative of abnormalities in cardiac signal conduction patterns.

33. The method of claim 25, wherein at least one of the markers is a velocity marker indicative of abnormalities in cardiac de-polarization or re-polarization patterns.

34. A method of assessing an impact, if any, on cardiac electrical activity events by a drug being tested, comprising:

acquiring baseline ECG signal data from a test population of patients;

acquiring on-drug ECG signal data from the test population of patients after dosing the respective patients with a drug being tested; and

evaluating the respective baseline and on-drug ECG signal data to determine statistically relevant differences, if any, in the baseline and on-drug values of one or more markers related to cardiac electrical events, wherein the one or more markers include at least one marker based on a degree of variability of an ECG parameter.

35. The method of claim 34, wherein the at least one marker based on a degree of variability of an ECG parameter is based on a variability of parameters defined on a vector magnitude (VM) signal of a heart cycle.

36. The method of claim 34, wherein the at least one marker based on a degree of variability of an ECG parameter is based on a variability of parameters defined on a T-loop or QRS loop of a heart cycle.

37. A method for assessing cardiac health of a patient, comprising:

acquiring ECG signal data from the patient; and

evaluating values of one or more markers in the ECG signal data related to cardiac electrical events, wherein the one or more markers are selected from a group comprising:

markers derived from vector magnitude (VM) signal events of a heart cycle having an RR interval, 3D markers selected from the group consisting of T-loop markers, QRS loop markers, and combined QRS- T-loop markers, and

markers based on a degree of variability of an ECG parameter.

38. The method of claim 37, wherein the markers derived from VM signal events include one or more of:

a duration of the QRS complex on the VM signal;

a time interval between Tmax and Tend pints on the VM signal; and

a time interval between Q and Tmax points on the VMS signal.

39. The method claim 37, wherein the markers derived from VM signal events include one or more of:

a ratio of respective durations of two different portions of the RR interval;

an absolute voltage at a specified time point on the RR interval;

a ratio of respective measured voltages on the |V| signal;

a difference of an average voltage of respective portions of the VM signal; a two-dimensional area covering some portion of the VM signal; and

a slope of a Twave or a QRS wave in the VM signal.

40. The method of claim 37, wherein at least one of the one or more markers assesses propagation timing disturbances in the VM signal comprising precursors to arrhythmias.

41 . The method of claim 37, wherein at least one of the one or more markers is a voltage marker indicative of changes in cardiac tissue de-polarization or repolarization in the on-drug ECG signals.

42. The method of claim 37, wherein the T-loop markers include one or more of Tvelocity markers, Tangle markers, and markers based on the morphology of the T-loop.

43. The method of claim 37, wherein the QRS-loop markers include one or more of QRSvelocity markers, QRSangle markers, and markers based on the morphology of the QRS-loop.

44. The method of claim 37, wherein the combined QRS- T-loop markers include angles between directions of QRS and T loop, and angles between QRS and T loop planes.

45. The method of claim 37, wherein at least one of the markers is a velocity marker indicative of abnormalities in one or both of cardiac signal conduction patterns and de-polarization or re-polarization patterns.