- an RMS of the high frequency signal of the QRS complex, which typically decreases during ischemia;
- detection and quantification of a reduced amplitude zone (RAZ) in the high frequency signal of the QRS complex.

The high frequency electrogram is optionally measured in various configurations allowing for the analysis of electrical activity in multiple vectors according to the location of the electrodes relative to the device's can and/or between pairs of electrodes and/or combinations of electrodes.

Locations for the implantable device

The implantable device for the electronics for performing at least the pickup of the HF signals, as well as optionally the pickup of regular-frequency ECG signals, in different embodiments, may be found as:

an implanted device, by way of a non-limiting example such as depicted inFIG. 2A, 2B and 2D;

an external device, by way of a non-limiting example such as depicted inFIG. 2E.

In some embodiments an implanted device is optionally included in a pacemaker can, optionally a smart pacemaker.

In some embodiments an implanted can is optionally a can implanted separately from an existing pacemaker, if any.

In some embodiments the can optionally serves for HF electrogram signal pickup, and transfers the signals to an external analysis unit. In some embodiments the transfer of the signals is optionally performed wirelessly. In some embodiments the transfer of the signals is optionally performed by wire.

Internal/External Electrodes

In some embodiments the pickup electrodes are implanted electrodes common with pacemaker electrodes.

In some embodiments the pickup electrodes are implanted electrodes separate from pacemaker electrodes.

In some embodiments the pickup electrodes are inserted into a subject's body via a catheter, and optionally used while the catheter is inside the subject's body, without being implanted.

Electrode Locations

In various embodiments the pickups are located in various locations, such as, by way of some non-limiting examples:

a right atrium (RA);

a right ventricle (RV);

a left ventricle (LV);

a coronary sinus (CS);

an epicardial location; and

an electrode located in the chest.

Internal/External Analysis

In some embodiments analysis of the HF electrogram signals is performed within an implanted can.

In some embodiments analysis of the HF electrogram signals is performed externally of a subject's body.

During Angiogram/Angio-Stent

In some embodiments monitoring and/or analysis of the HF electrogram signals is performed during a procedure in which electrodes are inserted into a subject's body, such as, by way of a non-limiting example, during an angiogram, with electrodes inserted via catheter.

Detecting the QRS Complex

In some embodiments, a temporal location of the QRS complex is optionally detected by analyzing a signal from an electrode in the right atrium.

A natural heart pacing starts at the right atrium.

In some embodiments detecting onset of a pulse optionally provides an indication when to start recording at a HF sampling rate.

In some embodiments HF sampling is optionally synchronized with a pacemaker pacing pulse.

In some embodiments an estimation is made as to when a next QRS complex signal is expected based on timing and rate of previous heart beats.

HF Sampling in a Sub-Portion of the Cardiac Cycle

The terms cardiac cycle portion, cardiac cycle sub-portion and cardiac cycle segment are used interchangeably in the specification and claims.

In some embodiments, especially implantable embodiments, power and current consumption may impose constraints on the device and/or method of detection and monitoring of myocardial ischemia. In such embodiments it is preferable to save in power consumption of the device.

In some embodiments, to facilitate the saving, a specific mode of the device is optionally configured to sample the electrogram at a high sampling rate., e.g. 1000 samples per second, only during specific portions of the signal or of the cardiac cycle, e.g. during and around the QRS complex. At other times, which typically constitute more than 50% and up to 90% of the cardiac cycle, the signal may be sampled at a lower frequency, for example, fewer than 150 samples per second. In some embodiments, the sampling rate is lowered even further, and/or suspended altogether.

In some embodiments the device is optionally configured to perform HF sampling only during, by way of some non-limiting example: the QRS complex interval;

the P wave interval;

the T wave interval;

the Q wave interval:

the R wave interval: and

the S wave interval.

In some embodiments, a beginning and/or and end of the segment of the cardiac cycle is defined to start and/or end based, by way of some non-limiting examples, on one or more of:

detection of a specific point in a cardiac cycle, optionally using analysis of the HF electrogram and/or a low frequency ECG;

a timing offset from a trigger such as the above specific point, for example a P wave maximum plus 10 milliseconds; and

a timing offset from a trigger such as a pacing signal, for example a P wave maximum plus 10 milliseconds.

Generally, high frequency signals are analyzed in a range of frequencies between 100 and 1000 Hz, and low frequency ECG signals are analyzed in a range of frequencies between 0.05 and 100 Hz. In some embodiments analysis of the high frequency signal samples is optionally performed for a frequency between 100 and 300 Hz, optionally with signals sampled at a rate of 1000 Hz or more. In some embodiments analysis of the high frequency signal samples is optionally performed for a frequency above 500 Hz.

In some embodiments an intracardiac electrogram is measured during a QRS complex with a high sampling rate, and during a rest of the cardiac cycle using low sampling rate. Some non-limiting example include a high sampling rate greater than 500 samples per second, and even greater than 1,000 samples per second. Some non-limiting example include a low sampling rate greater than 150 samples per second, lower than 100 samples per second, and even lower than 60 samples per second.

In some embodiments detecting the QRS complex is performed by detecting the QRS complex in a low frequency electrogram, that is, detecting the QRS complex in a regular ECG.

In some embodiments detecting the QRS complex is performed by detecting the QRS complex by analyzing a high frequency electrogram.

Cleaning Up the HF Signal

The high frequency signal used for detecting myocardial ischemia may be relatively low in amplitude, even for intracardiac signals. In some embodiments the HF signal is optionally aligned and averaged over several QRS complexes which are close in time. Such an averaging procedure potentially increase the SNR (Signal to Noise Ratio), potentially enabling a more accurate analysis. A non-limiting example method of cleaning up the HF signal is described in above-mentioned U.S. Pat. No. 8,626,275.

In some embodiments the high frequency electrogram signals are optionally aligned based on one or more of the following:

- a time of depolarization onset of the heart as detected in an electrogram, optionally an electrogram picked up by an electrode in the heart, preferably in the right atrium; and
- a time of pacing by a pacemaker in the Right Atrium (RA), Right Ventricle (RV) or Left Ventricle (LV).

Reference is now additionally made toFIGS. 2H and 21, which aregraphs710720 showing good correlation and bad correlation of HF signals714715716724725726 according to an example embodiment of the invention.

FIG. 2H depicts thegraph710 of the HF signals714715716 showing the HF signals714715716 having a relatively good correlation with each other.

FIG. 21 depicts thegraph720 of the HF signals724725726 having a relatively worse correlation with each other.

It is additionally noted that thegraphs710720 have a Y-axis711 of arbitrary correlation units, and anX-axis712 of time in milliseconds.

FIGS. 2H and 21 illustrate that HF signals may be aligned with each other, optionally by shifting the HF signal in time forward and backward to achieve an optional correlation, and/or a correlation coefficient value which is above a specific correlation coefficient threshold. A non-limiting example of such a specific correlation coefficient threshold is optionally 0.7, or 70%, and a range of 0.5 (50%) to 0.95 (95%) is a range contemplated for such values

In some embodiments, measuring correlation between HF electrogram signals is optionally used to detect noisy HF signals, and optionally to disregard the noisy signals.

In some embodiments, the alignment may optionally be performed based on aligning low-frequency electrogram signals.

Reference is now additionally made toFIG. 2J, which depicts graphs771-986 of HF signals of 16 different QRS complexes according to an example embodiment of the invention.

The graphs771-986 depict HF signals of consecutive QRS complexes, depicting some signals which appear clean and lend themselves well to be correlated to each other, and some which appear noisier and are not so well correlated to each other.

In some embodiments, performing correlation between two electrogram signals which have been sampled for different heartbeats is optionally performed by performing a mathematical correlation function between two vectors which contain sample values of amplitudes of the two electrogram signals. A result of the correlation is a correlation coefficient.

In some embodiments correlation is performed at different time-shifts between the two vectors, and a maximum value of the correlation coefficient is optionally determined.

In some embodiments, a time-shift corresponding to the maximum value is determined to be a time-shift desired for aligning the two electrogram signals.

Reference is now additionally made toFIG. 2K, which depicts agraph820 of alignment of anunfiltered electrogram signal826 to atemplate824 according to an example embodiment of the invention.

Thegraph820 depicts anelectrogram signal826 and an inherent electrogram signal which acts as atemplate824 for a QRS complex of a heartbeat, both without filtering for HF frequencies. Theelectrogram signal826 and thetemplate824 have a shape like a familiar low-frequency QRS complex signal because low frequency components of an electrogram signal typically have a much larger amplitude than high frequency components of the electrogram signal.

Thegraph820 has a Y-axis822 of voltage in microvolt units, and anX-axis821 of time in milliseconds.

FIG. 2K depicts an inherent shape of the electrogram signal as portrayed by thetemplate824.

In some embodiments, an unfiltered electrogram signal such as theunfiltered electrogram signal826 is optionally used to align electrogram signals, including HF signals, that is, to determine a time shift between electrogram signals from different heartbeats, so as to compare the electrogram signals to each other and/or to a baseline.

In some embodiments, a filtered low-frequency electrogram signal (not shown) is optionally used to align the electrogram signals.

In some embodiments, the alignment is based on one of the alignment methods described above, and it is high-frequency components of the electrogram signals which are then compared to each other and/or to a baseline.

In some embodiments theQRS complex template824 is optionally produced by curve fitting a mathematical function to an inherent electrogram signal or to a QRS complex section of an inherent electrogram signal. The inherent QRS complex signal is optionally an exemplary QRS complex signal, optionally produced from one or more unfiltered, or low-frequency electrogram signals or QRS complex sections of such electrogram signals.

In some embodiments, an inherent HF signal is calculated. Such an inherent HF signal is depicted inFIG. 2L, and described below.

In some embodiments the curve fitting optionally involves calculating a number of coefficients for the mathematical function to fit the inherent HF signal.

In some embodiments the mathematical function is a polynomial function.

In some embodiments the mathematical function is for example cubic spline.

In some embodiments the number of coefficients for producing thetemplate824 is typically 20 or more, or between 5 and 30, and even a range of 3, 5, 10, 20, 50 or 100 coefficients are contemplated.

In some embodiments theQRS complex template824 is optionally produced by averaging a number of electrogram signals, by way of a non-limiting example such as theelectrogram signal826, over several heartbeats.

Reference is now additionally made toFIG. 2L, which is agraph800 depicting an HF portion of aninherent electrogram signal806 and anactual HF signal804, according to an example embodiment of the invention.

The HF portion of an electrogram signal, including both theinherent electrogram signal806 and theactual HF signal804 is potentially less dependent on noise originating from a patient's movement, and potentially supports better detection and/or monitoring of a patient's heart condition.

FIG. 2L depicts the HF portion of theinherent electrogram signal806, and theactual HF signal804, either of which can be compared to a baseline (not shown) and potentially detect changes in a patient's physiological condition.

Thegraph800 has a Y-axis802 of millivolt units, and an X-axis732 of time in milliseconds.

In some embodiments analysis of the high frequency signal is optionally filtered for a frequency above 500 Hz.

Noise

In some embodiments, a heartbeat period which produces a noisy electrogram signal is discarded from use in the analysis.

In some embodiments determining that an electrogram signal is noisy is optionally performed based on a high-frequency-filtered electrogram signal. In some embodiments determining that an electrogram signal is noisy is optionally performed based on a low-frequency-filtered electrogram signal. In some embodiments determining that an electrogram signal is noisy is optionally performed based on an electrogram signal which includes both high and low frequencies.

In some embodiments, detecting a noisy HF electrogram signal is optionally performed by measuring noise in a quiet segment of an HF electrogram signal, such as in an ST segment, and/or between a T segment and a following P segment, and/or in a T segment, and/or simply outside of a QRS complex segment.

In some embodiments, detecting a noisy HF electrogram signal is optionally performed by calculating a correlation coefficient of the electrogram signal to an inherent electrogram signal, and comparing the correlation coefficient to a threshold value.

In some embodiments, a threshold level for determining that a HF electrogram signal is noisy is measuring noise, by way of a non-limiting example RMS noise of less than 1 microvolt. In some embodiments, the RMS noise threshold for the HF signal is optionally between 0.2 microvolts and 2 microvolts.

In some embodiments, upon detecting an electrogram signal having a noise value greater than the noise threshold, the signal is discarded from use for any purpose. In some embodiments, the noisy signal is discarded from use in determining a patient's condition. In some embodiments, a noisy signal is tagged as noisy, and saved associated with the tag.

The Breathing cycle

The terms breathing cycle portion and breathing cycle segment are used interchangeably in the specification and claims.

A linkage between a breathing cycle and heart rate is known in the literature and referred to as Respiratory Arrhythmia. The heart rate, in turn, is among the factors which govern the behavior of the high frequency ECG signal, which results in a potential coupling between analysis of high frequency ECG signals parameters and the breathing cycle.

In some embodiments the breathing cycle is optionally analyzed and comparison of high frequency ECG analysis results is optionally done between measurements taken at similar times in the breathing cycle. For example, a comparison of high frequency ECG parameters is performed between high frequency ECG parameters measured at maximum exhalation.

Reference is now made toFIG. 3, which is a simplified prior art illustration of effects of breathing on electrocardiogram signals.

FIG. 3 depicts agraph300 of respiration-induced modulation of QRS complex amplitude in a regular ECG signal. Anupper trace302 depicts an ECG trace, and alower trace304 depicts respiration as measured by a pneumatic respiration transducer (PRT) placed around a chest of a subject. Theupper trace302 and thelower trace304 depict measurements over a duration of 10 seconds. Thegraph300 is taken from the above-mentioned article titled “Derivation of Respiratory Signals from Multi-lead ECGs” by Moody et al.

FIG. 3 depicts and the article teaches a method for analyzing QRS complex amplitude in a regular ECG signal and respiratory actions. By way of a non-limiting example, the amplitude of the QRS complex is seen to increase and decrease in relation to the respiration.

In some embodiments, high frequency ECG parameters are measured only during a specific portion of a breathing cycle, by way of some non-limiting examples, when QRS complex amplitude is maximal or when QRS complex amplitude is minimal.

In some embodiments detecting the segment of the breathing cycle includes measuring amplitude of a QRS complex of a low frequency electrogram.

In some embodiments, high frequency ECG parameters are measured only during a specific portion of a breathing cycle, by way of some non-limiting examples, when the cardiac cycle is shorter than average or when the cardiac cycle is longer than average.

In some embodiments detecting the segment of the breathing cycle comprises measuring a duration of a cardiac cycle.

In some embodiments, high frequency ECG parameters are measured only once during a breathing cycle instead of every heartbeat. Such embodiments provide a method of potentially saving power.

In some embodiments the stages of the breathing are optionally measured by one or more motion sensors in or connected to the implanted device.

In some embodiments the stages of the breathing are optionally measured by a strap around the chest. In such embodiments the strap is optionally communicating with an analysis unit, optionally an external analysis unit using electrodes with a body, such as inserted via a catheter.

In some embodiments the stages of the breathing are optionally measured by an audio sensor. Such detection by audio sensors can potentially operate both in implantable devices and in external devices.

In some embodiments the stages of the breathing are optionally measured by a spirometric device. A spirometric device may be in a unit external to a subject's body, sending a signal to an implanted unit to enable detecting the stages of the breathing.

In some embodiments, use of the stages of breathing during HF signal analysis is enabled when a signal from the spirometric device is received by the implanted device. In some embodiments, the stages of breathing are not used during HF signal measurements when a signal from the spirometric device is not received by the implanted device.

In some embodiments, detecting a portion of the breathing cycle is optionally performed by using motion sensors and analysis to detect cyclic movement of a subject's chest.

In some embodiments, the specific stages of the breathing cycle are optionally selected based on characterization of electrogram based on low frequency features such as amplitude of the QRS complex and/or a time within a cardiac cycle.

Additional Physiological Sensors

Using state-of-the-art physiological sensors such as, by way of a non-limiting example, a bioimpedance sensor such as Optivol by Medtronic, it is possible to measure physiological parameters, such as, by way of a non-limiting example, blood pressure in various loci, for example, in the pulmonary arteries. Additional non-limiting examples of physiological sensors include implantable hemodynamic monitoring using the Chronicle IHM system by Medtronic and the pressure monitor named heartPOD by St Jude Medical. Such measurements provide a potentially more accurate description of a subject's status, and potentially correlate to the High frequency ECG results as well as to other parameters relating to a given physiological conditions.

The High frequency ECG parameters may potentially have natural variations, even under normal circumstances. Gating or triggering an analysis of the HF signal based on values of physiological parameters such as blood pressure, pulse and breathing cycle, potentially render the High frequency ECG analysis more sensitive and accurate, increasing its usefulness for the indication of ischemic states and ischemic disease.

Simultaneous acquisition, and/or registration and/or analysis of High frequency ECG and additional variables (such as blood pressure, Heart rhythm and rate, ST changes, T-wave abnormalities, late potentials, T-wave alternans, etc.) potentially provide at least the following two consequences. First, the High frequency ECG is optionally analyzed and evaluated with respect to a multi-parameter state when recording a person's baseline. Second, High frequency ECG measurements are optionally made or analyzed only at certain, possibly predetermined, multi-parameter states.

In some embodiments the system also includes means for measuring and analyzing a low frequency electrogram signal. Low frequency electrogram analysis optionally includes analysis of: heart rate, ST segment changes, heart rate variability, T wave abnormalities including T-wave inversion and T-wave alternans; and QT interval.

In some embodiments, specific categories are defined, each category including a range of values for variables. The variables include results of analysis, such as values of HF electrogram analysis indexes and values of low frequency electrogram analysis; and values of physiological measurements, such as blood pressure, heart rhythm and rate, ST changes, T-wave abnormalities, T-wave alternans, etc.

In some embodiments a medical pathological condition is optionally detected when there is a consistent change in both High frequency electrogram indexes and other parameters such ST changes in a regular ECG trace, and/or a change in heart rate. When a correlation between the HF electrogram indexes and the other parameters appears more than a specific number of times in a row this is optionally an indication for ischemia. In some embodiments, when more than one, two, 5 or 10 such correlations appear per day an alert is produced.

In some embodiments, determining a baseline for use in a later comparison, in order to detect ischemia, is optionally done by continuous measurements and constant updating.

In some embodiments ischemia is detected by reaching specific high frequency ECG values. By way of example when changes in RMS values of the high frequency ECG are greater than 5%, 10%, 20%, 30%, 40%, or 50% of a reference RMS value.

In some embodiments, for a morphological index as described in above-mentioned U.S. Pat. No. 8,626,275, a change in the morphological index greater than 2%, 4%, 5%, 7%, 10%, or 15% of a reference morphological index value optionally indicates possible ischemia.

In various embodiments, reference values, also termed baseline values, are determined by various methods. Some non-limiting example methods include:

using a historical average value which was measured over a previous day, week, month or year. In some embodiments the historical average is optionally selected so as to be sensitive to heart rate and optionally to additional physiological conditions; and

using a baseline value which was measured at one time during a setup period or a set up test.

In some embodiments the baseline value is optionally measured under similar conditions, such as similar heart rate (pulse) and/or similar breathing rate and/or a similar portion of a cardiac cycle and/or a similar portion of a breathing cycle.

In some embodiments acute ischemia is detected by detecting changes compared to the baseline.

In some embodiments the baseline value changes over time—e.g. a baseline measured and calculated for a window of N consecutive heartbeats once every M heartbeats, and/or every period of time such as several times an hour, a day, a week, a month.

In some embodiments acute ischemia is detected by detecting changes in HF electrogram parameters measured at a low heart rate period and at a higher heart rate period. In some embodiments that change in heart rate between the two periods is greater than 10%, 20%, 40%, 50%, 100%.

In some embodiments the change in heart rate is optionally in term of a standard deviation relative to an average and standard deviation of a population of N heartbeats.

In some embodiments, by tracking the physiological and High frequency ECG parameters of the baseline itself a slow deterioration in a subject's condition is optionally detected.

In some embodiments, the High frequency ECG parameters are used for a differential diagnosis between ventricular tachycardia (VT) and supraventricular tachycardia (SVT). During VT a morphological index and/or amplitude of the HF signal changes from beat to beat, while in SVT a change from beat to beat is typically not significant.

In some embodiments, trends of calculated values are calculated and/or stored and/or transmitted. The calculated values include, by way of some non-limiting example, regular ECG values, HF electrogram values, values as described in patent U.S. Pat. No. 8,626,275, and so on.

In some embodiments, correlations between calculated values are calculated and/or stored and/or transmitted.

Intracoronary Electrodes

In some embodiments, one or more intracoronary electrodes are used for acquisition of the electrogram.

In some embodiments, the intracoronary electrodes are optionally located near to a known and/or to a suspected partial or complete occlusion in an artery. The electrogram signal is optionally measured proximally and distally from the occlusion, and High frequency ECG values of the signal are optionally compared to examine differences in the electrical characteristics of the tissues proximal and distal to the occlusion. The differences potentially indicate changes in vitality and potentially indicate an ischemic condition. By way of a non-limiting example, a change in HF indexes between a point before blockage and a point after the blockage change significantly. A change in RMS HF values of greater than 5%, 10%, 20%, 30%, 40%, or 50% of a reference HF RMS value and/or a change in a morphological index by more than 1%, 2%, 3%, 4%, 5% or 6% of a reference morphological index.

Reference is now made toFIG. 4A, which is a simplified illustration of electrodes for picking up an electrogram within a blood vessel according to an example embodiment of the invention.

FIG. 4A depicts an example blood vessel, anartery402. Theartery402 has, for example, ablockage404. Afirst electrode406 having abipolar pickup407 is inserted up until beyond theblockage404. Asecond electrode408 having abipolar pickup409 is inserted until before theblockage404.

In some embodiments one or both of theelectrodes406408 may be monopolar electrodes (not shown) or multipolar electrodes (not shown).

In some embodiments there is a use of single electrode configuration which measures the electrogram at both locations: before and beyond theblockage404.

Reference is now made toFIG. 4B, which is a simplified illustration of electrodes for picking up an electrogram within a blood vessel according to an example embodiment of the invention.

FIG. 4B depicts an example blood vessel, anartery402. Theartery402 has, for example, ablockage404. Afirst electrode416 having abipolar pickup417 is inserted up until beyond theblockage404. Thefirst electrode416 also includes anelectronics unit422, which optionally communicates wirelessly with anexternal analyzer424, transmitting a signal corresponding to an HF signal picked up by thebipolar pickup417.

Asecond electrode418 having abipolar pickup419 is inserted until before theblockage404. Thesecond electrode418 also includes anelectronics unit420, which optionally communicates wirelessly with theexternal analyzer424, transmitting a signal corresponding to an HF signal picked up by thebipolar pickup419.

In some embodiments one or both of theelectrodes416418 may be monopolar electrodes (not shown) or multipolar electrodes (not shown). In some embodiments there is a use of single electrode configuration which measures the electrogram at both locations: before and beyond theblockage404, at different times.

In some embodiments High frequency ECG measurement by intracoronary electrodes potentially assists in determining whether stent placement is recommended.

A change in RMS HF values of greater than 5%, 10%, 20%, 30%, 40%, or 50% of a reference HF RMS value, and/or a change in a morphological index by more than 1%, 2%, 3%, 4%, 5% or 6% of a reference morphological index optionally assist in determining whether stent placement is recommended.

In some embodiments High frequency ECG measurement by intracoronary electrodes is optionally combined with FFR (fractional flow reserve) analysis and also potentially assists in determining whether stent placement is recommended.

FFR analysis typically measures local pressure in a blood vessel. If the pressure drops below a set pressure the drop is an indication that there might be a benefit for inserting a stent. The FFR method typically evaluates whether there is a collateral blood supply or whether tissue is necrotic due to lack of blood circulation.

The above-mentioned determinations of coronary vessel condition and/or treatment may be performed both by implantable electrodes and by electrodes temporarily inserted by catheter.

The above-mentioned determinations of coronary vessel condition are potentially useful for post-revascularization evaluation of the revascularization efficacy.

In some embodiments, the coronary blood vessel in which the electrogram is measured with relation to the occlusion is a coronary artery. In some embodiments, the coronary blood vessel the coronary blood vessel is a coronary vein. In some embodiments the coronary blood vessel is the coronary sinus.

In some embodiments detection of ischemia onset is performed based on a change in one or more of the following parameters of the HF signal of an electrogram over at least one intracardiac electrode:

an RMS level of the HF signal of the electrogram;

a function of the RMS levels of the HF signal of the electrogram in different portions of the cardiac cycle, such as, for example, a P or a T portion of the cardiac cycle;

an envelope maximum of the high frequency signal of the electrogram;

a function of the envelope levels in different portions of the cardiac cycle, of the high frequency signal of an electrogram;

an envelope width of the high frequency signal of an electrogram, as described in above-mentioned U.S. Pat. No. 8,626,275;

an area of a reduced amplitude zone (RAZ) of the electrogram HF signal, as described in above-mentioned U.S. Pat. No. 8,626,275; and

an area of a RAZ in the envelope of the electrogram HF Signal, as described in above-mentioned U.S. Pat. No. 8,626,275.

In some embodiments warning is provided of potential onset of an ischemic event, optionally based on a significant reduction in the HF intensity during an increase in heart rate. Optionally, reduction levels are adjusted for individual patients, and are typically 50% reduction during a heart rate increase of 30%, and/or when a patient traverses 70% of the patient's maximal heart rate. A potential scenario includes the patient experiencing a significant reduction in the HF content every time the patient has a significant heart rate increase.

In some embodiments when a system detects a repeating pattern the system increases a confidence value to produce an alert.

In some embodiments the alert optionally produces a sound alert for the patient and/or sends a message to medical personnel tracking the patient.

In some embodiments sound is produced by using a simple sound generator built into the device. In some embodiments the alert is produced by vibration of the device.

In some embodiments, for communication purposes, an implantable device includes a communication module. In some embodiments the communication module optionally transmits information through a receiving station, which in some cases optionally includes a smart phone, to a medical professional center.

In some embodiments a HF portion of an electrogram is measured using at least one intracardiac electrode.

In some embodiments the following configurations are optionally used for measuring an intracardiac electrogram HF signal:

a single monopolar electrode that measures a signal between an intracardiac electrode and a can (container) of an implantable device;

a bipolar electrode;

two intracardiac electrodes placed at different places within the heart;

one intracardiac and one epicardiac electrode; and

two epicardiac electrodes.

In some embodiments a bipolar electrode, also termed a lead, is optionally used, having two electrical pickup points, which may also be termed two electrodes.

In some embodiments the distance between the two electrical pickup points is 1-3 millimeters, or 1-5 millimeters, or 1-7 millimeters or 1-10 millimeters, which potentially measure a local change in an electrogram, potentially measuring a difference in the electrogram between the two adjacent electrical pickup points.

In some embodiments detection of ischemia and/or of onset of ischemia is optionally based, at least in part, on a function of RMS values of an electrogram HF signal, optionally measured using one of the above-mentioned electrode configurations.

In some embodiments detection of ischemia and/or of onset of ischemia is optionally based, at least in part, on a comparison of RMS values of an electrogram

HF signal, optionally at different instances of similar heart rate values, such as, for example:

a difference between the RMS values exceeding a threshold difference value; and

a ratio between the RMS values exceeding a threshold ratio value.

In some embodiments detection and differentiation between ventricular tachycardia and supraventricular tachycardia is optionally based, at least in part, on a function of RMS values of electrogram HF signal, using one of the above-mentioned electrode configurations.

In some embodiments differentiating between ventricular tachycardia and supraventricular tachycardia is optionally based, at least in part, on a comparison of RMS values of electrogram HF signal at different instances of similar heart rate values. The difference and/or the ratio of the RMS values measured, using one of the above-mentioned electrode configurations, are optionally considered for the differentiation.

By way of a non-limiting example, if at different time periods which have an approximately similar high heart rate there is a significant difference in a HF RMS value, the difference potentially indicates existence of tachycardia originating from the ventricle (VT), as described above.

In some embodiments acquisition of the high frequency electrogram signal is performed using intracoronary monopolar and/or bipolar electrodes in one or more locations relative to a complete and/or partial occlusion and/or suspected occlusion of a coronary artery. In some embodiments, the HF electrogram signal proximally and distally from an occlusion is optionally acquired and optionally compared. In some embodiments, one or more of the following parameters is optionally compared between a proximal and a distal HF electrogram signal:

a difference between RMS values at the proximal and distal locations;

a ratio between the RMS values at the proximal and distal locations; and

a function of numerical characteristics of the HF signal envelopes at the proximal and distal locations.

In some embodiments detection of a difference in ischemic condition and/or vitality between two locations near a complete or partial occlusion of a coronary artery is optionally based, at least in part, on the methods and apparatus described above.

In some embodiments detection of difference in ischemic condition and/or vitality between two electrode locations near a complete or partial occlusion of a coronary artery is optionally based, at least in part, on the methods and apparatus described above, optionally also combined with results from FFR (fractional flow reserve) analysis.

In some embodiments detection of difference in ischemic condition and/or vitality between two locations near a complete or partial occlusion of a coronary artery is optionally based on the methods and apparatus described above, optionally for assisting in determining whether stent therapy is needed.

In some embodiments detection of difference in ischemic condition and/or vitality between two electrode locations near a complete or partial occlusion of a coronary artery is optionally based, at least in part, on the methods and apparatus described above, optionally for post-revascularization assessment of revascularization results and current ischemic condition.

Reference is now made toFIG. 5, which is a flow chart of a method for analyzing a high frequency (HF) electrogram signal according to an example embodiment of the invention.

The example embodiment depicted inFIG. 5 includes: providing at least one electrogram signal from an electrode located within a subject's body (505);

sampling the electrogram signal at a high frequency, generating a high frequency (HF) electrogram signal (510);

having a computer measure at least one time-varying parameter of the HF electrogram signal (515);

having a computer detect a change in the time-varying parameter in comparison to a baseline value of the time-varying parameter (520); having the computer generate an alert based, at least in part, on the detection (525).

Reference is now made toFIG. 6, which is a flow chart of a method for analyzing a high frequency (HF) electrogram signal according to an example embodiment of the invention.

The example embodiment depicted inFIG. 6 includes:

providing a first electrogram signal from a first location of an intracoronary electrode adjacent to an occlusion of a coronary blood vessel (605);

sampling the first electrogram signal at a high frequency, generating a first high frequency (HF) electrogram signal (610);

providing a second electrogram signal from a second location of an intracoronary electrode adjacent to the occlusion of the coronary blood vessel (615);

sampling the second electrogram signal at a high frequency, generating a second high frequency (HF) electrogram signal (620);

having a computer measure at least one parameter of the first HF electrogram signal and the second HF electrogram signal (625); and

having the computer compare the at least one parameter of the first HF electrogram signal and the second HF electrogram signal and produce a result of the comparison (630).

In some embodiments, the coronary blood vessel is a coronary artery.

In some embodiments, the coronary blood vessel is a coronary vein, by way of a non-limiting example the coronary sinus.

Reference is now made toFIG. 7A, which is a flow chart of a method for analyzing a high frequency (HF) electrogram signal according to an example embodiment of the invention.

The example embodiment depicted inFIG. 7A includes:

(a) providing at least one electrogram signal from an electrode located within a subject's body (905);

(b) measuring the electrogram signal at a high frequency only during a specific segment of a cardiac cycle, generating a HF electrogram signal for the specific segment of the cardiac cycle (910); and

(c) calculating at least one time-varying parameter of the generated HF electrogram signal (915),

in which the specific segment of the cardiac cycle is a one of a group consisting of: a P segment; a Q segment; a R segment; a S segment; a T segment; and a QRS complex.

Reference is now made toFIG. 7B, which is a flow chart of a method for analyzing a high frequency (HF) electrogram signal according to an example embodiment of the invention.

The example embodiment depicted inFIG. 7B includes:

(a) providing at least one electrogram signal from an electrode located within a subject's body (955);

(b) measuring the electrogram signal at a high frequency only during a specific segment of a breathing cycle, generating a HF electrogram signal for the specific segment of the breathing cycle (960); and

(c) having a computer measure at least one time-varying parameter of the HF electrogram signal (970).

Reference is now made toFIG. 8, which is a flow chart of a method for analyzing a high frequency (HF) electrogram signal according to an example embodiment of the invention.

The example embodiment depicted inFIG. 8 includes:

receiving an electrogram signal from at least two subcutaneous, above-rib pickup locations at a can for subcutaneous, above-rib implantation, the can including a signal pickup configured to pick up an electrogram signal including a high frequency (HF) component; a signal filter connected to the signal pickup and configured to measure a high frequency (HF) component from the electrogram signal;

and an analyzer for analyzing the HF component of the electrogram signal, wherein the analyzer is configured to analyze at least one time-varying parameter of the HF component of the electrogram signal; and the signal filter is configured to measure the electrogram signal by using a signal picked up from at least two pickup locations (1002).

picking up an electrogram signal (1004); and

analyzing the HF component of the electrogram signal (1006).

In some embodiments the at least two subcutaneous, above-rib locations may be located, by way of some non-limiting examples, at:

two electrodes at mid-chest subcutaneous pickup locations;

two electrodes at right-of-sternum subcutaneous pickup locations; and

two electrodes at left-of-sternum subcutaneous pickup locations.

In some embodiments the two subcutaneous pickup locations include a subcutaneous, above-rib electrode pickup location and a subcutaneous can pickup location.

In some embodiments the signal pickup is also configured to pick up a low frequency component; the signal filter is also configured to measure the low frequency component from the electrogram signal; and the analyzer is also configured to analyze the low frequency component of the electrogram signal.

In some embodiments the analyzer is configured to analyze three voltage potential difference signals simultaneously, including voltage potential difference signals between the can and a first subcutaneous pickup location; the can and a second subcutaneous pickup location; and the first subcutaneous pickup location and the second subcutaneous pickup location.

In some embodiments the analyzer analyzes the HF component of the electrogram signal and the low frequency component of the electrogram signal simultaneously.

Reference is now made toFIG. 9, which is a flow chart of a method for analyzing a high frequency (HF) electrogram signal according to an example embodiment of the invention.

The example embodiment depicted inFIG. 9 includes: providing at least one electrogram signal from a first electrogram signal pickup located adjacent to and upstream of a narrowing of a subject's blood vessel (1010);

providing at least one electrogram signal from a second electrogram signal pickup located adjacent to and downstream of the narrowing of the blood vessel (1012);

measuring a HF component of the electrogram signals from the upstream and the downstream locations (1014); and analyzing at least one time-varying parameter of the HF electrogram signals (1016).

In some embodiments, the electrogram signals are from an inside of the blood vessel, from a first electrogram signal pickup located within the subject's blood vessel upstream of the narrowing of the blood vessel and from a second electrogram signal pickup located within the subject's blood vessel downstream of the narrowing of the blood vessel.

In some embodiments, the electrogram signals are not necessarily from inside a blood vessel, but rather from a first electrogram signal pickup located outside and adjacent to a subject's blood vessel upstream of a narrowing of the blood vessel and from a second electrogram signal pickup located outside and adjacent to the subject's blood vessel downstream of the narrowing of the blood vessel.

In some embodiments, the electrogram signals from the upstream and the downstream locations are compared to each other.

In some embodiments, a parameter of the electrogram signals from the upstream and the downstream locations which is compared is an amplitude of the HF component of the upstream and the downstream electrogram signals.

In some embodiments, a parameter of the electrogram signals from the upstream and the downstream locations which is compared is an amplitude and/or an RMS amplitude of the HF component of the upstream and the downstream electrogram signals, averaged over a heartbeat, or over several seconds, or over several minutes.

In some embodiments, a parameter of the electrogram signals from the upstream and the downstream locations which is compared is existence of a Reduced Amplitude Zone (RAZ), or a time span of a RAZ.

In some embodiments, following comparison of the electrogram signals from the upstream and the downstream locations, a difference between the signals is optionally considered significant when one signal is reduced, relative to the other, by 5%, 10%, 15%, 25% or even 50%.

In some embodiments, following comparison of the electrogram signals from the upstream and the downstream locations, a difference between the signals is optionally considered significant when one signal is different from the other, by a number of standard deviation units, for example by more than 0.5, 1, 2, 3 standard deviations.

In some embodiments, following comparison of the electrogram signals from the upstream and the downstream locations, a difference between the signals is optionally considered significant when a correlation function between the signals at the 2 location results in a correlation index smaller than 0.98, 0.95, 0.9, 0.8, 0.7, or 0.6.

In some embodiments, when a difference between the signals is considered significant, the significant difference is optionally taken as an indication for ischemia.

In some embodiments, when a difference between the signals is considered significant, the significant difference is optionally taken as an indication for cardiac hibernation.

In some embodiments, the first electrogram signal pickup and the second electrogram signal pickup are in one electrode.

In some embodiments, the first electrogram signal pickup and the second electrogram signal pickup are in separate electrodes.

In some embodiments, at least one of the electrogram signal pickups is a bipolar pickup.

In some embodiments, the first electrogram signal pickup and the second electrogram signal pickup are electrically connected to an electronics unit which communicates wirelessly with an external analyzer, transmitting a signal based on an HF signal picked up by the electrogram signal pickups.

In some embodiments, the electrogram signal from the first electrogram signal pickup and the electrogram signal from the second electrogram signal pickup are measured by the same electrogram signal pickup located upstream of the narrowing of the blood vessel at one time, and downstream of the narrowing of the blood vessel at a different time.

In some embodiments, the above-mentioned analysis includes also FFR (fractional flow reserve) analysis.

In some embodiments, a determination whether stent placement is recommended is based, at least in part, on the analyzing at least one time-varying parameter of the HF electrogram signals and on the FFR (fractional flow reserve) analysis.

In some embodiments, post-revascularization efficacy of revascularization is optionally based, at least in part, on the analyzing at least one time-varying parameter of the HF electrogram signals and on the FFR (fractional flow reserve) analysis.

It is expected that during the life of a patent maturing from this application many relevant electrogram acquisition techniques will be developed and the scope of the term electrogram is intended to include electrograms acquired by all such new technologies a priori.

It is expected that during the life of a patent maturing from this application many relevant wireless transmission techniques will be developed and the scope of the term wireless transmission is intended to include wireless transmission performed by all such new technologies a priori.

It is expected that during the life of a patent maturing from this application many relevant implantable electrodes will be developed and the scope of the term implantable electrodes is intended to include all such new technologies a priori.

As used herein the term “about” refers to ±10%.

The terms “comprising”, “including”, “having” and their conjugates mean “including but not limited to”.

The term “consisting of” is intended to mean “including and limited to”.

The term “consisting essentially of” means that the composition, method or structure may include additional ingredients, steps and/or parts, but only if the additional ingredients, steps and/or parts do not materially alter the basic and novel characteristics of the claimed composition, method or structure. As used herein, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a unit” or “at least one unit” may include a plurality of units, including combinations thereof.

The words “example” and “exemplary” are used herein to mean “serving as an example, instance or illustration”. Any embodiment described as an “example or “exemplary” is not necessarily to be construed as preferred or advantageous over other embodiments and/or to exclude the incorporation of features from other embodiments.

The word “optionally” is used herein to mean “is provided in some embodiments and not provided in other embodiments”. Any particular embodiment of the invention may include a plurality of “optional” features unless such features conflict.

Throughout this application, various embodiments of this invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub-ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub-ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases “ranging/ranges between” a first indicate number and a second indicate number and “ranging/ranges from” a first indicate number “to” a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals therebetween.

As used herein the term “method” refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.

It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

Although the invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents and patent applications mentioned in this specification are herein incorporated in their entirety by reference into the specification, to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application shall not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as necessarily limiting. In addition, any priority document(s) of this application is/are hereby incorporated herein by reference in its/their entirety.