Accurate localization of cardiac arrhythmias using internal electrocardiogram (ECG) signals sensed and stored by implantable device

Abstract

The present disclosure relates to precise localization of cardiac arrhythmias using internal electrocardiogram (ECG) signals sensed and stored by an implantable device. Certain aspects of the present disclosure provide methods and apparatus for determining a precise location of an arrhythmia origin site or departure site in a heart of a subject using internal electrocardiogram (ECG) signals sensed and stored by an implantable device implanted in the subject. One example method of analyzing arrhythmia in a subject generally includes reading, from an implantable device implanted in the subject, a plurality of internal ECG signals sensed and stored by the implantable device while the subject is experiencing an arrhythmia event (e.g., at any time, including while the subject is walking); performing an analysis of the read internal ECG signal; and determining a location of an arrhythmia associated with the arrhythmia event based on the analysis.

Description

[0001] This application is a divisional application of the invention patent application PCT / US2019 / 014793 with Chinese application number 201980015840.6 and application date January 23, 2019, and entitled “Precise positioning of cardiac arrhythmias using internal electrocardiogram (ECG) signals sensed and stored by an implantable device”. Technical Field

[0002] The present disclosure relates generally to implantable medical devices, and more particularly to the localization of cardiac arrhythmias using internal electrocardiogram (ECG) signals sensed by such implantable devices. Background Art

[0003] Heart disease is the leading cause of death in the United States (approximately 610,000 people per year) and other developed countries, and accounts for a higher mortality rate than all types of cancer combined. Contrary to popular belief, heart attacks are not the direct cause of cardiac death. Instead, most cardiac deaths occur without warning (hence the term sudden cardiac death or SCD), primarily due to lethal ventricular arrhythmias (VA) originating in the ventricles. Fortunately, with the advent of implantable cardioverter / defibrillators (ICDs), most of these SCDs due to VA can now be prevented. As demonstrated by a large number of randomized multicenter clinical trials, ICD implantation is the most reliable therapy for reducing SCD mortality. Currently, recognized clinical indications for ICD implantation include: (1) primary prevention for those patients who are at high risk for SCD but have not had a previous SCD event, such as those with a history of a major heart attack, and (2) secondary prevention for those patients who have already had a SCD event but survived. It is worth noting that the probability of surviving a SCD event without an ICD is very low (<4% if the SCD occurs outside of a hospital). Many of these survivors may suffer brain damage and remain in a vegetative state even when he or she is resuscitated.

[0004] However, implanting an ICD does not prevent fatal VA from occurring. Instead, the ICD delivers an electric shock to the heart to "reset" the electrical activity of the ventricles, thereby attempting to restore normal heart rhythm. Although the application of electric shocks saves lives, these shocks often cause severe discomfort and increase patient morbidity. Both physical and psychological trauma may ensue. Pharmacological agents (antiarrhythmic drugs) can be used to suppress these fatal VAs. However, the effectiveness of these agents is limited, and side effects are common. Catheter-based ablation - a technique that uses thermal energy, usually heat generated from radiofrequency (RF) energy, to destroy the substrate of the arrhythmia - is an effective treatment for arrhythmias including VA. During ablation, a catheter is inserted percutaneously through an artery or vein and advanced to the heart. The success of the ablation procedure depends on the precise positioning of the VA source to guide the delivery of RF energy, which is the most time-consuming part of the ablation procedure and can take 5 to 8 hours. The longer the process time, the higher the likelihood of complications.

[0005] Surface lead electrocardiogram (ECG) signals are non-invasively generated from a set of electrodes (e.g., typically 10 electrodes) placed on the skin of the patient's chest and limbs and connected to a recording machine that measures the electrical activity of the heart. Surface lead (or external) ECG signals recorded during VA can be analyzed to identify the origin of VA and thereby guide ablation. Unfortunately, in most cases, such ECG recordings cannot be obtained during VA. ICDs are designed to deliver electric shocks within seconds after a fatal VA is identified. During a fatal VA, there is no time to perform a surface ECG recording unless the patient is always connected to an ECG recorder, which is impractical. In addition, VA often causes hemodynamic collapse and should be terminated immediately. Therefore, there will not be ample time to perform an ECG recording. Summary of the invention

[0006] Certain aspects of the present disclosure generally relate to determining the location of a cardiac arrhythmia (eg, a ventricular arrhythmia or an atrial arrhythmia) using internal electrocardiogram (ECG) signals sensed and stored by an implantable device.

[0007] Certain aspects of the present disclosure provide a method for analyzing arrhythmias in a subject. The method generally includes reading from an implantable device implanted in the subject a plurality of internal ECG signals sensed and stored by the implantable device while the subject is experiencing an arrhythmic event; performing an analysis of the read internal ECG signals; and determining the location of the arrhythmia based on the analysis.

[0008] Certain aspects of the present disclosure provide a non-transitory computer-readable medium having instructions stored thereon, which, when executed by at least one processor, cause the processor to perform operations for analyzing a subject's body for arrhythmia. The operations generally include reading from an implantable device implanted in the subject's body a plurality of internal ECG signals sensed and stored by the implantable device while the subject's body is experiencing an arrhythmia event; performing an analysis of the read internal ECG signals; and determining the location of the arrhythmia based on the analysis.

[0009] Certain aspects of the present disclosure provide a system for analyzing arrhythmias in a subject's body. The system includes a wireless communication device and at least one processor communicatively coupled to the wireless communication device. The wireless communication device is typically configured to read from an implantable device implanted in the subject's body a plurality of internal ECG signals sensed and stored by the implantable device when the subject's body is experiencing an arrhythmic event. The processor is typically configured to perform an analysis of the read internal ECG signals and determine the location of the arrhythmia based on the analysis.

[0010] Certain aspects of the present disclosure provide an implantable device for implantation in a subject's body. The implantable device typically includes a memory and a plurality of leads having a plurality of electrodes for sensing a plurality of internal ECG signals. The memory is typically configured to store the sensed internal ECG signals at least when the subject's body is experiencing an arrhythmia, and subsequently read out the stored internal ECG signals for analysis to determine the location of the arrhythmia. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] In order that the manner in which the above-mentioned features of the present disclosure are understood in detail, a more specific description briefly outlined above may be made by reference to some of the aspects illustrated in the accompanying drawings. It should be noted, however, that the accompanying drawings illustrate only certain typical aspects of the present disclosure and are therefore not to be considered as limiting the scope thereof, as the description may admit of other equally effective aspects.

[0012] Figure 1A An exemplary implantable cardioverter / defibrillator (ICD) system is shown as an exemplary implantable device with leads fed through blood vessels to the heart.

[0013] Figure 1B yes Figure 1A An exemplary block diagram of an ICD system.

[0014] Figure 2 is a flow chart of example operations for analyzing cardiac arrhythmias in accordance with certain aspects of the present disclosure.

[0015] Figure 3is a graph of an exemplary unipolar internal electrocardiogram (ECG) signal over time according to certain aspects of the present disclosure.

[0016] Figure 4A A graph of an exemplary unipolar internal ECG signal over time showing different amplitudes sensed for the same phase is provided in accordance with certain aspects of the present disclosure.

[0017] Figure 4B Graphs of exemplary bipolar internal ECG signals over time according to certain aspects of the present disclosure are provided.

[0018] Figure 5 is a diagram illustrating determination of a plane perpendicular to a line connecting two exemplary unipolar recording sites according to certain aspects of the present disclosure.

[0019] Figure 6 is an example diagram showing three vectors between three unipolar recording sites, three planes perpendicular to the three vectors, and exemplary candidates for arrhythmia origin sites or departure sites in accordance with certain aspects of the present disclosure.

[0020] Figure 7 is a diagram showing the distance between a determined point and a plane.

[0021] Figure 8 is a flow chart of example operations for locating an arrhythmia origin site or exit site using vector analysis in accordance with certain aspects of the present disclosure.

[0022] Fig. 9 Shown is a 3D ellipsoid representing a ventricle of a heart divided into voxels and exemplary voxels in accordance with certain aspects of the present disclosure.

[0023] Fig.10 FIG. 2 shows a flow chart of ... determined by a conduction time index (CTI) for each voxel in accordance with certain aspects of the present disclosure. Fig. 9 The fastest conduction pathway (PATH) between two exemplary near-field bipolar electrode pairs of a voxel.

[0024] Fig.11 According to certain aspects of the present disclosure, Fig. 9 Example isochronal contours of a single near-field bipolar recording electrode pair drawn on a 3D ellipsoid.

[0025] Fig.12 An intersection of multiple exemplary isochronal contours for multiple near-field bipolar electrode pairs to locate the site of origin or the site of departure of a ventricular arrhythmia (VA) in accordance with certain aspects of the present disclosure is shown.

[0026] Fig.13An overlay of multiple exemplary isochronal contours for multiple near-field bipolar electrode pairs locating VA origin or departure sites in accordance with aspects of the present disclosure is shown.

[0027] Fig.14 is a flow chart of example operations for locating an arrhythmia origin site or exit site using conduction time analysis in accordance with certain aspects of the present disclosure. DETAILED DESCRIPTION

[0028] Certain aspects of the present disclosure provide methods and apparatus for determining precise localization of an arrhythmia (e.g., a ventricular arrhythmia (VA) origin site or departure site) in the heart of a subject using internal electrocardiogram (ECG) signals sensed and stored by an implantable device implanted in the subject's body. By using internal ECG signals, rather than surface leads or external ECG signals, the localization of the arrhythmia site can be determined more accurately so that the arrhythmia can be treated more effectively. The internal ECG signals result in more precise localization because the internal ECG signals are recorded from internal electrodes placed closer to the signal source and their anatomical positions are registered with reference to the heart, compared to external or surface lead ECG signals recorded from surface electrodes placed farther away from the heart and at standard anatomical positions referenced to the torso rather than the heart (which represent a significant source of error due to individual variations in heart orientation within the chest). Certain aspects of the present disclosure may be active or operable in any environment (e.g., outpatient or inpatient) in which an implantable device is present in the body of a subject, regardless of whether the subject is ambulatory, stationary, or restrained during a medical procedure (e.g., an ablation procedure).

[0029] The present disclosure utilizes the non-limiting example of ventricular arrhythmias (VA) to illustrate various aspects of the present disclosure in the text and figures. It should be noted that the same methods can be applied to atrial arrhythmias (AA), except that the atrial electrogram complex, 3D atrial geometry, and / or tissue properties of the atrial myocardium will be used instead of those of the ventricles.

[0030] The various aspects of the present disclosure will be described more fully below with reference to the accompanying drawings. However, the present disclosure can be implemented in many different forms and should not be interpreted as being limited to any specific structure or function presented throughout the present disclosure. On the contrary, these aspects are provided to make the present disclosure thorough and complete, and to fully convey the scope of the present disclosure to those skilled in the art. Based on the teachings of this article, it should be understood by those skilled in the art that the scope of the present disclosure is intended to cover any aspect of the present disclosure disclosed herein, whether it is implemented independently of any other aspect of the present disclosure or implemented in combination with any other aspect of the present disclosure. For example, any number of aspects set forth herein can be used to implement a device or practice method. In addition, the scope of the present disclosure is intended to cover such devices or methods that are practiced using other structures, functions, or structures and functions other than the various aspects of the present disclosure set forth herein or different from the various aspects of the present disclosure set forth herein. It should be understood that any aspect of the disclosure disclosed herein can be embodied by one or more elements of the claims.

[0031] As used herein, the term "determining" includes a variety of actions. For example, "determining" may include calculating, computing, processing, deriving, investigating, searching (e.g., searching in a table, database, or other data structure), ascertaining, etc. Also, "determining" may include receiving (e.g., receiving information), accessing (e.g., accessing data in a memory), etc. Also, "determining" may include resolving, selecting, choosing, establishing, etc.

[0032] As used herein, the term "subject" may refer to a human or other animal, such as a pig or a dog.

[0033] Exemplary Implantable Devices

[0034] An implantable device may include any device that can be implanted into the body of a subject. Examples of implantable devices include implantable cardioverter / defibrillators (ICDs), pacemakers, internal electrocardiogram (ECG) recording devices, and the like.

[0035] Figure 1A An ICD system 100 is shown as an example of an implantable device for use with certain aspects of the present disclosure. Although the term "ICD" is used in the present disclosure for ease of description, the reader should understand that the term "ICD" may be replaced by "implantable device" throughout the specification, and certain aspects of the present disclosure may be implemented by any suitable implantable device capable of performing similar functions associated with the arrhythmia localization techniques as described herein.

[0036] like Figure 1A As shown, ICD system 100 includes a generator 104 connected to leads 102 that are fed through blood vessels to various locations in a heart 120. Figure 1AA four-chamber heart 120 is shown having a right atrium (RA) 122, a left atrium (LA) 124, a right ventricle (RV) 126, and a left ventricle (LV) 128. Although Figure 1A A four-chamber heart is shown as a non-limiting example in , but aspects of the present disclosure may also be applied to hearts having more or less than four chambers (eg, a three-chamber heart) for different species.

[0037] The generator 104 may include a hermetically sealed housing (e.g., a can made of a metal such as titanium). The housing may contain an integrated circuit (IC), a battery 158, a capacitor 160 for storing charge and delivering the shock, and other electrical and mechanical hardware, some of which may be Figure 1B 154 . The IC may include, for example, a processor 152, a memory 154 coupled to the processor, an analog circuit, a digital circuit, a mixed signal circuit (having digital and analog components), a programmable logic device (e.g., a field programmable gate array (FPGA)), and / or an application specific integrated circuit (ASIC). The processor 152 may read data and instructions from the memory 154, and write data to it. The generator 104 may include a power supply circuit 156 coupled to a battery 158 and various circuits such as the processor 152 and a charging circuit 162. The power supply circuit 156 may be implemented as a DC-DC converter for converting the battery voltage to one or more voltage levels for various circuits. The charging circuit 162 may include a transformer and may be controlled by the processor 152 to charge the capacitor 160 for delivering the therapeutic shock. The generator 104 may also include a therapy delivery circuit 164 and an input signal processing circuit 166. Therapy delivery circuit 164 may receive energy from capacitor 160 and deliver shock pulses to heart 120 via one or more shock coils (e.g., distal coil 140 or proximal coil 144), typically over RV lead 102 and the housing (e.g., a metal can) of generator 104. Therapy delivery circuit 164 may be activated or otherwise controlled by processor 152. Input signal processing circuit 166 may receive energy from capacitor 160 and deliver shock pulses to heart 120 via one or more shock coils (e.g., distal coil 140 or proximal coil 144), typically over RV lead 102 and the housing (e.g., a metal can) of generator 104. 1 ,lead 2 ,lead N) receives internal ECG signals from electrodes (e.g., 130, 132, 134, 136, 138) in the ICD system 100 and processes these signals (e.g., by amplifying, filtering, converting analog signals to digital signals, and / or extracting certain features, digitally or in the analog domain) for analysis by the processor 152 and / or recording in the memory 154. For example, the processor 152 can recognize that the internal ECG signals indicate an arrhythmic event (e.g., a ventricular arrhythmia (VA) event or an atrial arrhythmia event), and can write the internal ECG signals (or a representation thereof) to the memory 154 to capture the arrhythmic event for subsequent analysis. The generator 104 may also include a transceiver (Tx / Rx) 168 and at least one antenna 170 for wireless communication between the ICD system 100 and an external device such as an ICD programmer. The transceiver 168 may be coupled to the processor 152 for receiving signals from the processor for transmission via the antenna 170, and for sending signals received by the antenna and processed by the transceiver to the processor. For example, transceiver 168 and antenna 170 may be responsible for transmitting recorded internal ECG signals indicative of an arrhythmic event to an external device.

[0038] Leads 102 may be wires with one or more electrodes embedded in at least some of the leads. Figure 1A As a non-limiting example, three leads 102 (eg, right atrial lead 102 RA , right ventricular lead 102 RV and left ventricular lead 102 LV ), but aspects of the invention may use more or less than three leads (e.g., two leads). The ICD generator 104 is typically implanted subcutaneously in the left or right pectoral region. For certain aspects, the ICD generator 104 may alternatively be implanted subcutaneously in the upper abdomen. The ICD leads 102 are connected to the generator 104 at one end and inserted at the other end into each of the heart chambers (e.g., the right atrium 122 and the right ventricle 126) or into the epicardial aspect of the left ventricle 128 through the coronary sinus and its branches around the heart. For example, at least some of the electrodes on the ICD leads 102 are used to deliver electrical current, for example, to excite or pace the myocardium (similar to a pacemaker) or to shock or electroshock the heart to reset a lethal VA with high electrical energy (e.g., defibrillation or ICD shock). At least some of the electrodes on the ICD leads 102 are used to sense the electrical activity of the heart 120, and the electrodes may be the same or different than the electrodes used to deliver current.

[0039] Certain aspects of the present disclosure utilize electrodes on the ICD leads to monitor electrical activity of the atria and / or ventricles during normal rhythm and during arrhythmias (e.g., ventricular tachycardia (VT)) (e.g., continuously throughout the ICD battery life). The electrodes can be located on an existing set of leads 102 associated with the ICD function and / or can be located on one or more additional leads. The electrodes can be intracorporeal (inside various parts of the body, but outside the heart) and / or intracardiac (inside the heart itself). The intracorporeal and / or intracardiac signals sensed by these electrodes in a bipolar or unipolar configuration may be referred to as internal electrocardiogram (ECG) signals and may be stored in a memory 154 internal to the generator 104. A unipolar configuration refers to an electrode signal referenced to a common electrode signal, while a bipolar configuration refers to the signal difference between the two electrodes.

[0040] For example, RV lead 102 RV A pair of electrodes 130 may be included at or near the distal end of the RV lead, such as Figure 1A Similarly, the RA lead 102 RA A pair of electrodes 132 may be included at or near the distal end of the RA lead, such as Figure 1A LV lead 102 LV The LV lead 102 may be fed through the coronary sinus and may include a set of electrodes 134 (eg, two to four electrodes) located at or near the distal end of the LV lead. LV A pair of electrodes 136 may be included that are located near the middle of the coronary sinus and closer to the distal end of the LV lead, and / or a pair of electrodes 138 that are located at or near the coronary sinus and even closer along the LV lead than the pair of electrodes 136. Electrodes 130, 132, 134, 136, and 138 may be used by the ICD system 100 as sensing and / or pacing electrodes. In addition to sensing electrodes, lead 102 may include one or more shocking electrodes. For example, RV lead 102 RV A distal defibrillation coil 140 may be included, which may be positioned in the right ventricle 126, such as Figure 1A For some aspects, RV lead 102 RV A proximal defibrillation coil 144 may be included, which may be positioned in the superior vena cava (SVC).For certain aspects, either or both of coils 140 and 144 may be used as a sensing electrode and a pacing electrode.

[0041] Internal ECG signals offer several advantages over external surface ECG signals captured by electrodes outside the body. For example, internal ECG signals are sensed by electrodes that: (1) are placed closer to the source of cardiac electrical activity; (2) have less signal loss, and thus a better signal-to-noise ratio (SNR), because the electrical signals do not need to pass through intervening tissue (e.g., lung and adipose tissue) between the heart and the surface electrodes of a conventional external ECG, which acts as a low-pass filter and attenuates the signals of the external surface ECG; and (3) have more consistent placement, because individual subjects, even within a species, have different body shapes, resulting in variations in the placement of surface ECG electrodes relative to individual hearts. By using quantitative analysis techniques, one or more mathematical models can be used to "calculate" or predict the precise location of the site of arrhythmia origin (e.g., in the case of focal VA) or arrhythmia departure (in the case of re-entrant VA) based on the recorded internal ECG signals from these electrodes embedded on implanted leads.

[0042] For example, a patient with an implanted ICD may be seen in a hospital or clinic with a history of shocks (one or more) from the ICD. The patient may be experiencing a normal heart rhythm, so measuring the surface ECG signal at that time is of little value in determining any arrhythmias the patient has previously experienced. In contrast, an external device - such as one that can use a telemetry stick, WiFi, or Bluetooth Communication technology such as an ICD programmer that wirelessly communicates with the ICD to perform data transfer can be used to extract previously recorded internal ECG signals (i.e., signals that occurred in the past (such as during VA)) from the ICD. The internal ECG signals can be quantitatively analyzed to determine the precise location of the arrhythmia origin site or departure site (e.g., with a resolution of 2.0 cm or better, such as about 0.5 cm).

[0043] Certain portions of the quantitative analysis may be performed, for example, by one or more processors in the ICD system 100, by one or more external processors after reading signals from the ICD system, by one or more processors in other implantable devices (e.g., a second device other than the ICD system), or by a combination of ICD, external and / or other implantable device processors. The processing system may be implemented as a specific stand-alone system or as part of a more complex system such as a hardware system used during an ablation procedure (e.g., a multi-channel electrophysiology recording system or a three-dimensional mapping system). For certain aspects, the quantitative analysis may utilize one or more images (e.g., three-dimensional (3D) images) of the subject's heart and the anatomical locations of the recording electrodes (with reference to the subject's heart). The image (one or more) may be generated by any of a variety of suitable imaging modes (such as computed tomography (CT), magnetic resonance imaging (MRI), cardiac nuclear scanning using radioisotopes such as thallium or sestamibi, echocardiography, or positron emission tomography (PET)) performed on the patient prior to implantation of the ICD in the patient. For certain aspects, data about the geometry of the heart and tissue properties of the myocardial tissue, as well as anatomical information about the location of the electrodes, can be extracted from the image(s) and can be used in the quantitative analysis. For certain aspects, the quantitative analysis may involve any of various suitable techniques (such as vector analysis, conduction time analysis, morphological matching in the time or frequency domain, spectral characteristics, amplitude and timing information of local near-field electrograms, analysis of far-field electrograms) for deriving the location of the origin or departure site of an arrhythmia using the recorded internal ECG signals (and electrode locations), or a combination of two or more of these and other techniques for identification and interpretation. Exemplary quantitative analysis techniques for deriving the location of the origin or departure site of an arrhythmia are described in more detail below.

[0044] Once the arrhythmia origin site or exit site is precisely located, treatment (e.g., ablation treatment) can be administered. For example, an ablation catheter can be guided to the determined arrhythmia origin site or exit site, and ablation of cardiac tissue can be performed at that site. For other aspects, one or more of the same or different quantitative analysis techniques can be performed with the inserted ablation catheter prior to ablating the tissue in an attempt to refine the location of the arrhythmia origin site or exit site.

[0045] Exemplary Operations for Analyzing Internal ECG Signals Sensed and Stored During Arrhythmia

[0046] Figure 22 is a flow chart of exemplary operations 200 for analyzing arrhythmias (e.g., atrial arrhythmias or ventricular arrhythmias (VA)) in a subject (e.g., a human patient or other animal) in accordance with certain aspects of the present disclosure. At least some of the operations 200 may be performed by a user having a wireless communication device (e.g., via telemetry of radio frequency (RF) signals, such as WiFi or other radio access technology) and one or more processors coupled to the wireless communication device and configured to read signals received from the implantable device via the wireless communication device. For example, the system may include a processor such as The programmer communicates with the ICD using wireless communication methods such as wireless technology, RF signals, or other telecommunication technologies.

[0047] Operation 200 may begin at block 202 by reading a plurality of internal electrocardiogram (ECG) signals from an implantable device implanted in a subject's body. The plurality of internal ECG signals are sensed and stored by the implantable device at any time while the subject's body is experiencing an arrhythmic event (e.g., while the subject's body is ambulatory and experiencing an arrhythmic event). As used herein, the term "ambulatory" generally refers to being able to walk independently or with assistance, as opposed to being restrained to an operating table, for example.

[0048] At block 204, analysis of the read internal ECG signal may be performed (eg, by the same system that reads the internal ECG signal). At block 206, the location of the arrhythmia may be determined based on the analysis (eg, by the same system that reads the internal ECG signal).

[0049] According to certain aspects, operation 200 may further require guiding (or assisting in guiding) a catheter inserted into the subject's body to the location of the determined arrhythmia, and using the catheter to perform ablation of the subject's cardiac tissue at the location. For certain aspects, operation 200 may also involve delivering electrical (pacing) stimulation at multiple sites in one or more chambers of the subject's heart via a mobile catheter; sensing multiple other internal ECG signals during the delivery of electrical stimulation; and analyzing the differences between multiple other internal ECG signals (from pacing) and multiple internal ECG signals sensed and stored by the implantable device. For certain aspects, operation 200 may further require refining the location of the arrhythmia based on the analysis. In this case, ablation can be performed on the refined location of the arrhythmia.

[0050] According to certain aspects, operation 200 may also involve employing a catheter inserted into the subject's heart to create an internal ECG footprint or template by pacing stimulation at various sites in the subject's heart, which will be used as a reference point for analysis of the internal ECG during an arrhythmia in order to increase the spatial accuracy of determining the location of the arrhythmia.

[0051] According to certain aspects, the implantable device is capable of delivering an electric shock to the heart of the subject. In this case, the implantable device may include an implantable cardioverter / defibrillator (ICD). For other aspects, the implantable device includes a pacemaker, an internal ECG device, or other implantable medical device.

[0052] According to certain aspects, the implantable device can have a plurality of leads with a plurality of electrodes for sensing internal ECG signals. For certain aspects, the implantable device includes at least two leads with at least four electrodes. For other aspects, the implantable device includes an appropriate number of leads (with embedded electrodes) for determining the location of the arrhythmia at block 206 with the desired accuracy.

[0053] According to certain aspects, there is a delay between the time the internal ECG signal is stored or generated during an arrhythmia event and the time of reading (e.g., data retrieval) at block 202. For example, the delay may be several minutes or more than several hours, a day, or longer.

[0054] According to certain aspects, the determined location has a spatial resolution of 2.0 cm or better (eg, 0.5 cm), compared to typical ablation lesion sizes of 0.4 to 0.6 cm in diameter.

[0055] According to certain aspects, performing the analysis at box 204 includes performing a vector analysis of the internal ECG signal. For certain aspects, performing the analysis at box 204 also includes determining the locations of a plurality of electrodes associated with the implantable device and used to sense the internal ECG signal implanted in the subject's body. In this case, performing the vector analysis may require performing the vector analysis based on the determined locations of the plurality of electrodes. For certain aspects, determining the locations of the electrodes involves performing a computed tomography (CT) scan, a magnetic resonance imaging (MRI) scan, or one or more other imaging modes of the subject's body.

[0056] According to certain aspects, performing the analysis at block 204 entails performing a conduction time analysis of the internal ECG signal. For certain aspects, the conduction time analysis can utilize data of tissue properties of the myocardium obtained from a computed tomography (CT) scan of the subject's body, a magnetic resonance imaging (MRI) scan, a positron emission tomography (PET) scan, a nuclear scan utilizing an isotope such as thallium, and / or one or more other imaging modalities. For certain aspects, these 3D cardiac imaging modalities can be used alone or in combination and can be performed before or after ICD implantation.

[0057] According to certain aspects, the subject is a human patient. For other aspects, the subject can be, for example, a pig or a dog.

[0058] In accordance with certain aspects, an implantable device may store internal ECG signals and their derivatives (which may be processed in digital or analog form) during single or multiple arrhythmic events that may originate from single or multiple cardiac sites for comparison, analysis, and localization of arrhythmias by medical personnel during device interrogation.

[0059] According to certain aspects, performing the analysis at block 204 includes performing the analysis based on a derivative (eg, dV / dt) of the sensed internal ECG signal.

[0060] According to certain aspects, operation 200 also requires receiving one or more tissue characteristics (e.g., myocardial tissue characteristics) of the heart of the subject body. In this case, performing the analysis at block 204 may include performing an analysis of the read internal ECG signal and the received tissue characteristics. The one or more tissue characteristics may include any of a variety of suitable characteristics inherent to the myocardium that may affect the conduction of the activation wavefront in the heart. For certain aspects, the one or more tissue characteristics include at least one of scar content, ischemic score, or myocardial edema level.

[0061] According to certain aspects, operation 200 may also include reading from the implantable device implanted in the subject a plurality of other internal ECG signals sensed and stored by the implantable device when the subject experiences other arrhythmia events; performing an analysis of the other plurality of internal ECG signals; determining a location of the other arrhythmia based on the analysis of the other plurality of internal ECG signals; and comparing the location of the arrhythmia with the location of the other arrhythmia to determine that the locations include the same location in the heart of the subject.

[0062] Example Quantitative Analysis Techniques for Arrhythmia Localization

[0063] As described above, an external device (e.g., an ICD programmer or other processing system) can perform a quantitative analysis of the internal ECG signals and imaging data received from the implantable device and then determine the location of the arrhythmia origin or exit site based on the analysis. The following paragraphs describe the general approach in more detail and provide two different example analysis techniques: (1) vector analysis and (2) conduction time analysis.

[0064] The general method involves first determining the location and configuration of electrodes (e.g., electrodes 130, 132, 134, 136, and / or 138) for sensing internal ECG signals of a particular subject. RV It may have two electrodes (eg, electrode pair 130) at or near its distal tip: RVd1 (the most distal electrode, also referred to as the RV tip electrode) and RVd2 (very close but slightly closer to RVd1). RV lead 102 RVThere may also be one or two shock coils (e.g., coils 140 and / or 144): RVdCoil (distal ICD shock coil, typically located in the right ventricle) and RVpcoil (proximal ICD shock coil, typically located in the superior vena cava (SVC), which may not be present in some ICD systems). For certain aspects, the shock coils may also serve as recording electrodes for sensing internal ECG signals.

[0065] Right Atrial (RA) Lead 102 RA At or near its tip, there may be two electrodes (e.g., electrode pair 132): RA1 and RA2, where by convention, RA1 is the more distal electrode. A coronary sinus (CS) lead (e.g., LV lead 102LV) has a set of electrodes (e.g., two to four electrodes 134) at its distal end: CSd1, CSd2, CSd3, and CSd4, where by convention, CSd1 is the most distal one. Certain aspects of the present disclosure may also include two additional electrodes (e.g., electrode 138) located at or near the CS ostium: CSp1 and CSp2, where by convention, CSp2 is the more proximal one. Certain aspects of the present disclosure may also include at the LV lead 102LV, a plurality of electrodes (e.g., electrodes 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 200, 201, 2 LV Two additional electrodes (eg, electrode 136) are located in the middle portion of the coronary sinus, typically in the middle of the trunk of the coronary sinus: CSm1 and CSm2, where by convention CSm2 is the more proximal one.

[0066] The ICD system may also include a reference electrode, which may also be referred to as a common electrode or indifferent electrode (IE), for unipolar recording. For example, the reference electrode may be located on the RV lead, a very proximal portion of the CS lead (in the left subclavian vein or even the left axillary vein), or more likely on the RA lead or on a separate lead (e.g., an IVC lead) that may be inserted and positioned in the inferior vena cava (IVC). Alternatively, the housing of the generator 104 (e.g., an ICD can) may serve as the reference electrode. For other aspects, a virtual reference electrode, conceptually similar to the Wilson center terminal, may be derived from the average of the three or more electrodes described above and effectively used as a reference "electrode."

[0067] Any two of the above-mentioned electrodes can form a pair to record bipolar internal ECG signals. For electrode pairs that are not adjacent to each other, as a rule, the electrode that is more on, more in front and more on the left will carry positive polarity, and the other electrode will carry negative polarity. These bipolar configurations can be used to record far-field bipolar internal ECG signals. For electrode pairs that are directly adjacent to each other, usually on the same lead (e.g., CSp1 and CSp2), the more distal electrode will carry positive polarity, and the more proximal electrode will carry negative polarity. These directly adjacent bipolar configurations can be used to record near-field bipolar internal ECG signals.

[0068] The unipolar and far-field bipolar internal ECG signals can be used to detect the onset of arrhythmias and their vectors, while the near-field bipolar internal ECG signals can be used to detect the timing of local activation of the myocardium immediately beneath the bipolar electrode pair in close proximity to each other (i.e., local activation time (LAT)). As a non-limiting example, one of the methods of defining LAT is to use the maximum dV / dt of the unipolar or far-field bipolar internal ECG as a time marker for the timing of local activation, where V(t) represents the amplitude of the internal ECG in millivolts over time t in seconds, and dV / dt is the first derivative of V(t).

[0069] The general method also involves establishing an individualized 3D coordinate system, particularly for an individual subject body. An example coordinate system can be established by first defining the position of the most distal electrode on the RV (e.g., RVd1) as the origin (0, 0, 0) of the coordinate system. The X-axis can then be defined as a straight line through the origin (RVd1) and the most distal coronary sinus or LV electrode (e.g., CSd1, whose coordinates are XCSd, 0, 0, where XCSd is the linear distance between RVd1 and CSd1). The XZ plane can then be considered to be a plane defined by the following three points: the origin (RVd1), CSd1, and the position of the most proximal coronary sinus electrode (e.g., CSp2) at or near the CS mouth. The Z axis can then be defined as a straight line through the origin (RVd1) in the XZ plane and perpendicular to the X axis. The Y axis can then be defined as a straight line perpendicular to the XZ plane through the origin (RVd1). All other locations, including the locations of other electrodes, atrial anatomical sites, ventricular anatomical sites, and / or arrhythmia sites, will be defined by their projections onto the above-described X, Y, and Z coordinate systems.

[0070] To establish a coordinate system, the actual location of the electrodes for a particular subject body may be determined based on 3D cardiac imaging modalities and / or other localization modalities, including but not limited to electroanatomical mapping and its integration with live fluoroscopy or computed tomography (CT) scanning, which may enable registration of electrode locations during ICD implantation intraoperatively or after implantation when electrodes are available. These imaging modalities may include but are not limited to cardiac CT, computed tomography angiography (CTA), cardiac magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), positron emission tomography (PET), 3D ultrasound, etc., which provide anatomical boundaries for quantitative analysis of internal ECG data.

[0071] For certain aspects, in addition to the geometric structural data of the heart and the anatomical location of the electrodes, the quantitative analysis can involve defining tissue properties of the myocardium using information derived from cardiac imaging, including but not limited to CT, MRI, PET, nuclear isotope scanning, and echocardiography. For certain aspects, the quantitative analysis can quantify and calculate the conduction properties of volume elements (voxels) of the myocardium based on these derived tissue properties.

[0072] Example vector analysis

[0073] Based on the personalized 3D coordinate system established above, an example vector analysis technique for locating an arrhythmia origin site or exit site based on an internal ECG signal previously recorded during an arrhythmia event is given below. Although this particular exemplary vector analysis will be explained below with respect to locating a ventricular arrhythmia (VA) origin site or exit site, a person of ordinary skill in the art will understand that the technique can also be applied to locating atrial arrhythmia sites.

[0074] This vector analysis can be performed by determining the initial or first phase of VA activation (called the "phase 0 (Phase 0 The earliest time point (VA start time or T) when any deflection (positive or negative) in all unipolar and far-field bipolar internal ECG signals is detected during a VA event 0 ) is defined as the startup time or Phase of VA 0 The earliest time point (T) when the first derivative (dV / dt) of any unipolar or far-field bipolar internal ECG signal during VA reaches zero (i.e., the amplitude of the signal V(t) is a local maximum) 1 ) is defined as the initial phase of activation during VA. 0 ) is the end of 1 Represents the moment when the activation wavefront begins to bend or change direction.

[0075] T 0 and T 1 The time interval between the two represents the initial phase of VA activation. 0 ), during which the direction of the VA vector remains essentially unchanged. Figure 3 is a graph 300 of an example unipolar internal ECG signal (eg, UNIRVdcoil, which is the RVd1 electrode sensed relative to a reference electrode) over time, showing T 0 、T 1 and Phase 0 . Figure 4AA graph 400 of three example unipolar internal ECG signals (ie, UNIRVpcoil, UNIRVdCoil, and UNIRVd2) over time is provided in accordance with certain aspects of the present disclosure, and Figure 4B A graph 450 of three example bipolar internal ECG signals (i.e., RVdCoil-RVd2, RVdcoil-CSp2, and RVd1-RVd2) is provided. Figure 3 , 4A and 4B, the pacing pulse is followed by an internal ECG signal with an initial positive deflection followed by a negative deflection. Figure 3 and 4A Also shown are the measurements of A and D of the internal ECG signal, where A is Phase 0 The amplitude of the deflection during the period, D, is the starting time at T 0 and ends at T 1 Phase 0 duration.

[0076] In determining the Phase of the internal ECG signal 0 The next step in vector analysis then involves determining the internal ECG vector matrix during the initial phase of VA. 0 ). Vector Matrix Vector 0 is derived from multiple unipolar internal ECG signals over the same time period, some of which are Figure 4A The Phase of each signal is shown in the graph 400. 0 The vector magnitude is labeled A 1 , A 2 and A 3 In graph 400, note that A1≠A2≠A3. For comparison, Figure 4B Two example far-field bipolar internal ECG signals from RVdcoil-RVd2 and RVdcoil-CSp2 and one example near-field bipolar recording from RVd1-RVd2 are shown in graph 450 of FIG. Figure 4A Graph 400 was obtained during the same study. The directions of the individual vectors are determined by the anatomical locations of their respective electrodes.

[0077] Figure 5 is a diagram illustrating the determination of a plane P perpendicular to a line connecting two monopolar recording sites according to certain aspects of the present invention. 12 (x, y, z) is plotted 500. To simplify the description, instead of using a specific unipolar recording site (e.g., UNIRVpcoil or UNIRVdCoil), Figure 5 Using the more general term U 1 and U 2To represent any two unipolar recording sites. Based on the 3D coordinate system listed above, the curve 500 describes the 1 (x 1 ,y 1 , z 1 ) and U 2 (x 2 ,y 2 , z 2 ) at two monopolar recording sites. 0 During this period, the amplitudes of their internal ECG signals are A 1 and A 2 Therefore, connect U 1 and U 2 Line U 1 U 2 The distance L of a vector is defined by the following equation:

[0078]

[0079] Based on electrophysiology, U 1 and U 2 The source of the internal ECG signal may be a line U perpendicular to the line with intercept I(xi,yi,zi) 1 U 2 The plane P 12 Anywhere in (x, y, z). Because L1 and L2 are defined by the intercept ratio

[0080]

[0081] Therefore, the coordinates of the intersection point I(xi, yi, zi) are determined by the following formula

[0082]

[0083] or

[0084]

[0085] Therefore, the vertical plane P 12 The equation for (x, y, z) is defined by

[0086] (x 2 -x 1 )(xx i )+(y 2 -y 1 )(yy i )+(z 2 -z 1 )(zz i )=0……Equation 5 where x i ,y i and zi It can be found in Equation 3 and Equation 4.

[0087] The next step in vector analysis is to determine the VA origin or departure site based on the initial phase vector matrix. As shown above, any pair of monopolar recording sites can be used to define a vector between them and a plane perpendicular to that vector. When multiple pairs of monopolar recordings are available, multiple perpendicular planes can be determined, such as Figure 6 600. The intersection of these planes can be used to determine candidate points for VA origin or departure sites.

[0088] Figure 6 The graph 600 includes three monopolar recordings U 1 , U 2 and U 3 ; Three vectors U 1 U 2 , U 2 U 3 and U 1 U 3 ; and their respective associated vertical planes P 12 , P 23 and P 13 According to analytic geometry, point p 0 :(x 0 ,y 0 , z 0 ) to the plane P: Ax+By+Cz+D=0 can be calculated as

[0089]

[0090] This concept is Figure 7 The graph 700 is shown in FIG.

[0091] According to equation 5, Figure 6 The equations for the three perpendicular planes in can be obtained and simplified to

[0092] P 12 :A 12 x+B 12 y+C 12 z+D 12 =0

[0093] P 23 :A 23 x+B 23 y+C 23 z+D 23 =0……Equation 7

[0094] P 13 :A 13 x+B 13 y+C 13 z+D13 =0

[0095] In by Figure 6 In the region enclosed by the three perpendicular planes, any given point p 0 :(x 0 ,y 0 , z 0 ) to each of the three perpendicular planes defined by Equation 7 can be calculated according to

[0096] 6, as shown in Equation 8 below.

[0097]

[0098]

[0099] As long as these perpendicular planes are not parallel to each other, there is a single point called the geometric median whose total distance to each perpendicular plane is minimal. The geometric median can be defined using existing algorithms such as the Weiszfeld algorithm. When more than 3 (e.g., N) monopole records are available, the total distance of a point to all perpendicular planes can be calculated by Equation 9.

[0100]

[0101] Thus, the geometric median can be determined by determining the point with the smallest total distance to each perpendicular plane, for example using the Weiszfeld algorithm described above. The coordinates of the geometric median can be considered as candidate coordinates for a VA origin or departure site.

[0102] Note that vector and statistical analysis performed in this manner may produce an estimated or calculated VA site that is located in space (e.g., in the ventricular cavity) rather than in cardiac tissue. In this case, the putative origin or departure site of the VA (VAsite 0 ) can be defined as the point on the cardiac tissue that is closest to the estimated or calculated VA site determined by vector and statistical analysis.

[0103] From a geometric perspective, the heart 120 is a 3D feature. Although vector analysis can be performed in 3D using 3D coordinates as described above, the 3D heart (or a portion thereof, such as a ventricle) and recording electrode sites can be projected into a 2D plane (similar to a 3D sphere of the earth projected onto a 2D world map). Vector analysis can then be performed in the 2D plane, and the candidate coordinates can then be back-projected into 3D space to locate the VA origin or exit site, although such forward and back projections can result in less accurate localization of the VA origin or exit site.

[0104] Figure 88 is a flow diagram of example operations 800 for locating VA origin or exit sites using vector analysis in accordance with certain aspects of the present invention. Operations 800 may be performed, for example, by an implantable device storing internal ECG signals, by another implantable device, by an external device receiving recorded internal ECG signals, or by a combination thereof.

[0105] Operations 800 may begin at block 802 by acquiring geometric data of a ventricle. Block 802 may be accomplished using any of a variety of suitable imaging modalities, such as MRI, CTA, PET, echocardiography, and the like.

[0106] At block 804 , the coordinates of the electrodes (eg, RVdCoil, RVpcoil, CSd1 , etc.) of the recorded internal ECG signal are determined.

[0107] This coordinate determination may be performed as described above and may involve an imaging system.For certain aspects, a lookup table (LUT) may be created using these coordinates.

[0108] At block 806, internal ECG (iECG) signal data may be read. For example, memory 154 may be read by processor 152 to extract internal ECG signal data. For certain aspects, the data may be processed and wirelessly transmitted to another implantable device and / or an external device (e.g., an ICD programmer) via transceiver 168. At optional block 808, the internal ECG signal data may be filtered (e.g., to remove noise and / or other unwanted signal content, such as high frequency transients).

[0109] At block 810, a number of processes may be performed on each channel of internal ECG signal data (e.g., for each unipolar recording). For example, beat detection may be performed on the channel to identify a ventricular electrogram complex. From the ventricular electrogram complex, the T of each channel may be determined. 0 、T 1 and Phase 0 , and the Phase of each channel 0 The duration D and amplitude A of the internal ECG signal during this period are as described above.

[0110] At block 812, for each electrode pair combination of the monopolar recording site, the intercept ratio (e.g., L1:L2) can be calculated to determine the intersection point along the vector (e.g., I(xi, yi, zi)), and the vertical plane that intersects the vector at the intersection point can be determined. Once the vertical plane has been determined for all electrode pair combinations of the vector matrix, as determined at block 814, the operation 800 proceeds to block 816.

[0111] At block 817, a system of equations for the sum of the perpendicular distances of the points to the perpendicular plane is established (eg, Equation 9).

[0112] At block 820, the coordinates of the point with the minimum sum distance are determined (eg, using the Weiszfeld algorithm). The resulting point (or the closest point of actual cardiac tissue to the point with the minimum sum distance) is considered the local VA origin or departure site.

[0113] For certain aspects performed in 2D, the coordinates of the located VA origin or exit site may be back-projected from the 2D plane to the 3D geometry of the ventricle.

[0114] Example Conduction Time Analysis

[0115] Conduction time analysis is another type of quantitative analysis that can be performed based on internal ECG signals previously recorded during an arrhythmic event to locate an arrhythmia origin or exit site. Although this particular exemplary conduction time analysis is described below with respect to locating a ventricular arrhythmia (VA) origin or exit site, one of ordinary skill in the art will appreciate that the technique can also be applied to locate atrial arrhythmia sites.

[0116] The conduction time analysis may begin by determining a conduction time index (CTI) matrix based on the intrinsic myocardial tissue properties of the ventricles of the individual subject and their 3D distribution. These tissue properties may include, but are not limited to, scar content, degree of ischemia, and / or degree of myocardial edema.

[0117] The ventricle can be viewed as consisting of basic anatomical and functional units of myocardial tissue (volume elements, called "voxels") that are sufficiently small in volume that the tissue properties within a given voxel can reasonably be considered uniform. Although voxels of any size can be defined, as a non-limiting example, it may be reasonable to set the voxel size to 1.0×1.0×1.0 cm. The actual size of the voxel may depend on the spatial resolution of the imaging modality employed. Smaller voxel sizes may be used with better spatial resolution, which may be more desirable for certain applications. Furthermore, the size of the voxel need not be equal on all sides (e.g., as in the case of a cuboid). Fig. 9 A 3D ellipsoid 900 is shown showing a ventricle of the heart 120 divided into voxels 902 and example voxels, in accordance with certain aspects of the present disclosure.

[0118] As used herein, scar content (SC) generally refers to the volumetric percentage of scar in a given voxel 902 obtained from a cardiac imaging modality. Suitable cardiac imaging modalities may include, but are not limited to, MRI T1-weighted images enhanced and / or unenhanced with contrast agents such as gadolinium, PET scans utilizing isotopes such as fluorodeoxyglucose (FDG), and nuclear scanning techniques utilizing isotopes such as thallium with feasibility protocols to define scar regions (one or more) in the heart. Each voxel 902 for an individual subject volume may be characterized by the SC provided by the imaging modality performed on the subject volume. As used herein, ischemia score (IS) generally refers to a quantification of ischemia as determined by the severity of ischemia and the volumetric percentage of ischemia in a given voxel 902, wherein the severity of ischemia is typically normalized to the myocardium with an intact blood supply as obtained from the cardiac imaging modality (generally identified as the region with the highest isotope count). Suitable cardiac imaging modalities for determining IS include, but are not limited to, utilizing imaging modalities such as 82 PET scans using isotopic agents such as Rb or nuclear scans using isotopic agents such as thallium. Each voxel 902 for an individual subject body can be characterized additionally or alternatively by an IS provided by an imaging mode performed on the subject body. Similarly, the degree of edema in the ventricular myocardium can be determined by a cardiac imaging mode including but not limited to MRI T2 weighted mapping. Each voxel 902 for an individual subject body can be characterized additionally or alternatively by the degree of edema provided by an imaging mode performed on the subject body. These indices (SC, IS, and degree of edema) are non-limiting examples of tissue characteristic parameters that can be used in quantitative analysis of internal ECG signals based on their effects on the conduction characteristics of individual voxels.

[0119] To calculate the conduction time index (CTI) matrix, the CTI for a given voxel 902 may be defined by the tissue properties of the ventricle and derived from the values ​​of SC and IS obtained from the cardiac scan as described above. The CTI may be calculated according to an empirical equation, the following equation 10 being a non-limiting example:

[0120]

[0121] Wherein EE (Effect of Edema) is a coefficient reflecting the negative effect of edema on myocardial conduction, which can be obtained from the analysis of a regression model relating the degree of myocardial edema of each voxel to intraventricular conduction during pacing procedures, wherein the degree of myocardial edema of each voxel is quantified by cardiac imaging techniques such as MRI T2-weighted mapping. EE will be a non-zero positive real number because there is always a certain degree of water content in any living myocardial tissue. In equation 10, if the myocardium represented by voxel 902 is composed entirely of fibrotic or scar tissue, which indicates conduction block at that part of the voxel, then CTI will be the highest. If the myocardium represented by voxel 902 is completely healthy, without any fibrotic or scar content, with normal blood supply and no edema (i.e., SC and IS are essentially zero, and EE is minimal), then CTI will be minimal.

[0122] The reader will appreciate that Equation 10 is merely an example equation for calculating CTI; other equations based on the same or different tissue properties may be used instead. For example, a polynomial equation may be used to determine the CTI for each voxel based on statistically determined polynomial coefficients.

[0123] Once the CTI matrix has been determined for voxel 902, the fastest conduction path (PATH) between the two pairs of near-field bipolar electrodes is determined, where the fastest conduction path is defined as the path through the voxels connecting the two pairs of near-field bipolar electrodes with the minimum sum of CTIs (∑CTI). The positions of the bipolar electrodes and voxel 902 can be registered based on the above-mentioned coordinate system. For example, Fig.10 A first pair of near-field bipolar electrodes CSd1-CSd2 and a second pair of near-field bipolar electrodes RVd1-RVd2 are shown. A PATH is defined between the two pairs of electrodes based on the CTI. In this example, the fastest conduction pathway (path) is also the shortest path (here an arc) in terms of the distance through the voxels 902 between the two pairs of electrodes, but this may not be the case. For example, the shortest distance between the two pairs of electrodes may include voxels 902 with very high CTIs, indicating slow conduction or even conduction block. Therefore, the fastest conduction pathway may travel around the voxel or bypass several voxels in the region. The PATH will have a specific distance (DIS) through the underlying myocardium between the two pairs of near-field bipolar electrodes. The PATH and the DIS associated therewith for each different combination of the two pairs of near-field bipolar electrodes can be determined based on the minimum ∑CTI between the two pairs of near-field bipolar electrodes.

[0124] Conduction time analysis also involves determining the pacing conduction time (PCT) between each different combination of two pairs of near-field bipolar electrodes. The PCT for each combination of two pairs of electrodes is defined as the time for the pacing activation wavefront to travel from one near-field bipolar electrode pair to the other near-field bipolar electrode pair (assuming a PATH between them). The PCT can be determined using an ICD or other implantable device to deliver a pacing signal to the patient via one of the near-field bipolar electrode pairs (e.g., Figure 1A An electrical pacing stimulus is introduced into the heart 120 of the subject using one of the electrode pairs in the DIS, such as electrode pair 130, and a local activation time (LAT) recorded on another near-field bipolar electrode pair (e.g., a distal electrode pair on the coronary sinus or LV lead, such as electrode pair 134) is measured, which represents the PCT from the pacing site (e.g., electrode pair 130) to the recording site (e.g., electrode pair 134). The LAT is anatomically defined at the midpoint between the recording pairs of near-field bipolar electrodes. Once the PCT is determined, the average conduction velocity (ACV) along the PATH defined by the DIS can be calculated, as shown in Equation 11 below:

[0125]

[0126] The ACV can be calculated for each combination of two pairs of electrodes.

[0127] Conduction analysis can then be performed by determining the voxel conduction time (VCT) matrix. For a given voxel indexed by i along the PATH, the VCT is estimated by dividing the voxel's CTI by the sum of all CTIs along the PATH and then multiplying by the PCT of the PATH, as shown in Equation 12 below:

[0128]

[0129] The sum of the VCTs of all voxels 902 along the PATH is equal to the PCT for the PATH. The VCT at a given voxel represents the estimated conduction time for the activation wavefront to traverse the voxel. For certain aspects, a lookup table (LUT) for the VCT may be established to correlate the value of the CTI with the value of the VCT along the PATH. Alternatively, one or more regression curves or models may be established to correlate the CTI with the VCT along the PATH. The VCT values ​​at voxels not along the PATH may be determined by reference to the corresponding CTI values ​​of the LUT or by a regression curve. The complete set of VCTs (e.g., for all voxels 902) would be a VCT matrix.

[0130] The VCT matrix forms the basis for drawing 3D isochronal contours in the myocardium centered at the midpoint between each pair of near-field bipolar recording electrodes. The isochronal contours for a given near-field bipolar electrode pair connect surrounding voxels where the activation wavefront initiated by the electrical pacing stimulus delivered via that near-field bipolar electrode pair arrives at the voxel simultaneously (or at least within the same time range), hence the term "isochronal". For certain aspects, the isochronal contours may be constructed in uniform increments in time (e.g., 5 ms or 10 ms increments) or at specific selected time values ​​for the activation wavefront.

[0131] Fig.11 Example isochronal contours iC1 and iC2 for a single pair of near-field bipolar recording electrodes (CSd3-CSd4) are shown plotted on 3D ellipsoid 900. Fig.11 Two isochronal contours are shown in FIG, but each pair of near-field bipolar recording electrodes may be associated with more than two isochronal contours. Note that more precisely, the isochronal contours are centered at the midpoint between the near-field bipolar electrode pair (here CSd3 and CSd4) (e.g., Fig.11 centered at voxel 902 (marked by the star in ). Isochrone contour line iC1 represents a contour line along voxel 902 where the propagation time of the activation wavefront from the electrode pair to the voxel is uniformly equal to 10 ms (or within a range of, for example, 10 ms ± 5 ms). Isochrone contour line iC2 similarly represents a contour line where the wavefront propagation time is equal to 20 ms (or within a range of, for example, 20 ms ± 5 ms). The non-limiting example increment of 10 ms between the isochrone contour lines used in this illustration may be fixed or variable. Furthermore, the increments between the isochrone contour lines may be constant, vary linearly, or vary nonlinearly.

[0132] If the propagation conditions are uniform, the isochron contours may be symmetrical. In the case of scar tissue, ischemic tissue, etc., the contours are usually asymmetrical. For a given region of ventricular myocardium, the closer the isochrones are, the slower the propagation of the activation wavefront, or the lower the conduction velocity.

[0133] As mentioned above, the VA startup time (T 0 ) is defined as the earliest time that the unipolar and far-field bipolar internal ECG signals from any electrode show a deflection, which can be positive or negative. As used herein, the local activation time (VA-LAT) of the near-field bipolar electrode pair during VA is defined as the time from T 0 The time interval to when the myocardium underlying the individual near-field bipolar electrode pair is activated. Methods for determining the time of local activation are well known to those skilled in the art.

[0134] Then, the putative origin or departure site of VA (VAsite 0) can be determined as the location where all isochronal contours meet or intersect based on the value of VA-LAT for a given near-field bipolar electrode pair. Fig.12 In order to simplify the description and facilitate the understanding of the concept, the symmetrical oval isochronal contour lines 1202, 1204, 1206 are projected onto Fig.12 The right and left ventricles (RV and LV) are separated on a 2D plane 1201 in FIG. 1 , although isochronal contours in the 3D ellipsoid 900 may be used instead (i.e., the determination of the intersection points may be performed in 3D space rather than in a 2D plane). Fig.12 , the isochron profile 1202 of CSp1-CSp2 and the isochron profile 1204 of RVpcoil-RVdCoil intersect at points A and X. Similarly, the isochron profile 1204 of RVpcoil-RVdCoil and the isochron profile 1206 of RVd1-RVd2 intersect at points B and X, while the isochron profile 1202 of CSp1-CSp2 and the isochron profile 1206 of RVd1-RVd2 intersect at points C and X. The shared intersection point X between the isochron profiles 1202, 1204, 1206 is a candidate for a VA origin site or a departure site.

[0135] However, typically, all three isochron contours do not share a single, common intersection point. In this case, the point with the smallest sum of distances to the isochron contours can be identified as the VA origin or departure site, as described below.

[0136] Once the coordinates of the final VA origin or exit candidate site (e.g., point X) in the 2D plane 1201 are determined, the VA site (VA origin or exit) can be found by back-projecting the 2D coordinates of point X onto the 3D ellipsoid representing the ventricle 900. In other cases, the coordinates of the final VA site can be determined in 3D space to begin.

[0137] Fig.13 The overlap of three example isochronal contours of a near-field bipolar electrode pair represented by E1, E2 and E3 is illustrated in accordance with aspects of the present invention. Fig.13 In the example of FIG. 1 , electrode pair E1 has an isochronal profile of 240 ms VA-LAT, electrode pair E2 has an isochronal profile of 175 ms VA-LAT, and electrode pair E3 has an isochronal profile of 120 ms VA-LAT. In this case, all three isochronal profiles do not intersect at a single point, such as Fig.12 In contrast, the location of VA origin or departure sites can be viewed as points within the region overlapped by all three isochron contours, as shown in Fig.13 For example, this candidate point can be obtained from the center of the overlapping area or from the point with the minimum sum of distances to the isochron contour line.

[0138] Fig.14 14 is a flow diagram of example operations 1400 for locating a VA origin or exit site using conduction time analysis according to certain aspects of the present disclosure. Operations 1400 may be performed, for example, by an implantable device storing internal ECG signals, by another implantable device, by an external device receiving recorded internal ECG signals, or by a combination thereof.

[0139] Operations 1400 may begin at block 1402 by acquiring 3D geometry data of a ventricle (eg, ellipsoid 900). If the conduction time analysis is performed in 2D, the acquired 3D geometry data may be mapped to a 2D plane for further analysis in 2D.

[0140] At block 1404, coordinates of near-field bipolar electrode pairs (e.g., RVpcoil-RVdCoil, CSp1-CSp2, RVd1-RVd2, etc.) recording internal ECG signals are determined. Such coordinate determination may be performed as described above and may involve an imaging system. For certain aspects, a table may be created using these coordinates.

[0141] At block 1406, intrinsic tissue properties (e.g., SC, IS, and / or EE) of the ventricle of the individual subject body may be determined using any of a variety of suitable techniques (e.g., PET, MRI T1, and / or MRI T2) as described above. These tissue properties may be assigned to corresponding voxels (e.g., voxel 902) in the 3D geometry, and the CTI for each voxel may be calculated. At block 1408, a PATH may be determined based on the CTI. The ACV for each PATH may then be calculated, and the VCT for the voxel may be determined, as described above.

[0142] At block 1410, internal ECG (iECG) signal data may be read. For example, memory 154 may be read by processor 152 to extract internal ECG signal data. For certain aspects, the data may be processed and wirelessly transmitted to another implantable device and / or an external device (e.g., an ICD programmer) via transceiver 168. At optional block 1412, the internal ECG signal data may be filtered (e.g., to remove noise and / or other unwanted signal content, such as high frequency transients).

[0143] At block 1414, a number of processes may be performed on each channel of (filtered) internal ECG signal data (e.g., on each near-field bipolar recording). For example, beat detection may be performed on the channel to determine a ventricular electrogram complex (one or more). As described above, from the ventricular electrogram complex, the T of each channel may be determined. 0 、T 1 and Phase 0, and the VA-LAT of each channel.

[0144] At box 1416, as described above, the isochronal contours for each near-field bipolar electrode pair may be determined. At box 1418, the combination of the three isochronal contours is analyzed to determine whether the three contours intersect at a single point. If not determined at box 1420, another combination of the three isochronal contours is analyzed at box 1418. If determined at box 1420, the coordinates of the intersection are recorded as a candidate for a VA origin or departure site at box 1422. If it is determined at box 1424 that all possible combinations of isochronal contours have not been analyzed, operation 1400 returns to box 1418 to analyze another combination of the three isochronal contours. If it is determined at box 1424 that all combinations of isochronal contours have been analyzed, operation 1400 proceeds to box 1426.

[0145] At block 1426, a statistical analysis may be performed on the coordinates of the candidate VA origin or departure site. For example, the coordinates may be averaged, a weighted average of the coordinates may be calculated, or a least squares error analysis based on the coordinates and / or isochronal contours may be performed. The coordinates resulting from the statistical analysis are considered to be the proposed VA origin or departure site (VAsite 0 )’s location.

[0146] As an alternative to the operations described in blocks 1418 to 1426, at optional block 1428, a putative VA origin or exit site may be derived by identifying a point in the ventricular myocardium where the sum of the conduction times calculated based on the VCT matrix from that point to all isochronal contours (determined at block 1416) is minimized. The coordinates of this point are considered to be the putative VA origin or exit site (VAsite 0 )’s location.

[0147] If operation 1400 is performed in 2D, the coordinates of the local VA origin or exit site may be back-projected from the 2D plane to the 3D geometry of the ventricle. However, such forward and back projections between 3D and 2D space may result in less accurate localization of the VA origin or exit site.

[0148] Example of intraoperative refinement of arrhythmia localization

[0149] Quantitative analysis of the internal ECG data (iECG0) recorded during VA events led to the identification of putative VA origins or departures (VAsite 0 ). However, due to the simplified nature of the above quantitative analysis and the complexity and individual differences in the anatomy and underlying pathophysiology of the mammalian heart, VAsite 0Further refinement may be performed during or prior to the ablation procedure to increase the anatomical accuracy of determining the VA origin or exit as the ultimate target for ablation energy application. Although the intraoperative refinement technique is described below with respect to locating the VA origin or exit site, one of ordinary skill in the art will appreciate that the technique may also be applied to locating atrial arrhythmia sites.

[0150] For some aspects, vector analysis can be used for this intraoperative refinement. In this case, in VAsite 0 Pacing with ambulatory pacing or ablation catheter will generate a new set of internal ECG data (iECG 1 ). From iECG 1 Subtract iECG 0 (Initial iECG data recorded during VA) generates ΔiECG 1 From ΔiECG 1 , can be exported in Phase 0 The new vector matrix (Vector 1 ), where Phase 0 As defined above. Vector 1 The starting point will be VAsite 0 , whose magnitude and direction are determined by Vector 1 OK. Vector 1 The endpoint will be the updated assumed VA origin (VAsite 1 ), which can also be fixed to the nearest ventricular myocardial surface.

[0151] Next, the same wandering catheter or a separate pacing catheter can be moved to the VAsite 1 , and the above process can be repeated n times, where n is a positive integer, until (1) from ΔiECG n The magnitude of the derived vector is below a predetermined threshold (e.g., within an error tolerance, such as 2.5 or 0.5 mm); (2) all unipolar and far-field bipolar internal ECG signals iECG during pacing n The morphologies of the images match their counterparts recorded during VA with a correlation coefficient above a certain percentage (e.g., 90%, 95%, or higher); or (3) a Vector n The minimum value of the minimum Vector n The final value of can be an indicator of the endocardial, intramural, or epicardial location of the VA. Upon completion of the process, the final updated site of the VA (VAsite final ) can be considered as the site of origin (for focal VAs) or the site of departure (for reentrant VAs).

[0152] For other aspects, conduction time analysis can be used for intraoperative refinement. In this case, the collection of local activation times at all near-field bipolar electrode pairs during VA forms the VA-LAT matrix. 0 Pacing with ambulatory pacing or ablation catheters will be performed on all near-field bipolar electrode pairs (iECG 1 ) generates a new set of local activation times or P-LAT 1 , and there is also a pacing stimulus. 1 Subtract VA-LAT to generate ΔLAT 1 , which can be mathematically represented as a "time" vector (T-vector 1 ) and converted into a displacement vector (D-vector 1 ), which starts at VAsite 0 , ending at the updated assumed VA origin VAsite 1 .D-vector 1 The direction of the T-vector 1 has the same direction, and its magnitude will be determined by the T-vector 1 The magnitude in time and the VCT of each voxel along the same direction are determined so that the sum of these CVTs is equal to the T-vector 1 The amplitude of .

[0153] Next, the same wandering catheter or a separate pacing catheter will be moved to the VAsite 1 , and the above process can be repeated n times, where n is a positive integer, until (1) from T-vector n Exported D-vector n The amplitude of all unipolar and far-field bipolar iECG signals during pacing is below a predetermined threshold (e.g., within an error tolerance, such as 2.5 or 0.5 mm); (2) the amplitude of all unipolar and far-field bipolar iECG signals during pacing is below a predetermined threshold (e.g., within an error tolerance, such as 2.5 or 0.5 mm); n The morphologies of the images match their counterparts recorded during VA with a correlation coefficient above a certain percentage (e.g., 90%, 95%, or higher); or (3) a D-vector is achieved. n The minimum value of the minimum D-vector n The final value of VA can be an indicator of the endocardial, intramural, or epicardial location of the VA. final ) will be considered the site of origin (for focal VAs) or exit (for reentrant VAs).

[0154] The quantitative analysis techniques described herein are intended to illustrate how a device can utilize information contained in stored internal ECG data and are not intended to be exclusive. Other methods, such as internal ECG morphology matching alone, or in combination with surface lead ECG morphology, may be used if available. Furthermore, the quantitative analysis described herein and other quantitative analysis techniques may be performed alone or in combination (e.g., their results may be combined to locate a VA origin or departure site). For example, conduction time analysis may be used to identify an initial putative VA site (VAsite 0 ), vector analysis can then be used intraoperatively to fine-tune the localization of the VA origin or exit site, as described above. Likewise, this order of techniques can be altered or reversed.

[0155] Exemplary computer-readable media and systems for analyzing VA

[0156] Certain aspects of the present disclosure provide a non-transitory computer-readable medium having instructions stored thereon, which, when executed by at least one processor, causes the processor to perform operations for analyzing arrhythmias in a subject's body. The operations (e.g., operation 200) generally include reading from an implantable device implanted in the subject's body a plurality of internal electrocardiogram (ECG) signals sensed and stored by the implantable device when the subject's body is experiencing an arrhythmic event; performing an analysis of the read internal ECG signals; and determining the location of the arrhythmia based on the analysis.

[0157] According to certain aspects, an implantable device has a plurality of leads with a plurality of electrodes for sensing internal ECG signals.

[0158] According to certain aspects, there is a delay between the time the internal ECG signal is stored and the time it is read. For example, the delay can range from a few minutes to a few days to a few weeks.

[0159] According to certain aspects, the determined position has a resolution of at most 2.0 cm, 1.0 cm, or 0.5 cm.

[0160] According to certain aspects, performing the analysis includes performing a vector analysis of the internal ECG signal. For certain aspects, performing the analysis also requires determining the physical locations of a plurality of electrodes associated with the implantable device and used to sense the internal ECG signal implanted in the subject's body. In this case, the processor may perform the vector analysis based on the determined physical locations of the plurality of electrodes. For certain aspects, the determined physical locations of the electrodes are based on computed tomography (CT), magnetic resonance imaging (MRI), echocardiography, or positron emission tomography (PET) performed on the subject's body.

[0161] According to certain aspects, performing the analysis includes performing a conduction time analysis of the internal ECG signal. For certain aspects, performing the analysis also requires determining the physical locations of a plurality of electrodes associated with the implantable device and used to sense the internal ECG signal implanted in the subject's body. In this case, the processor may perform the conduction time analysis based on the determined physical locations of the plurality of electrodes. For certain aspects, the determined physical locations of the electrodes are based on computed tomography (CT), magnetic resonance imaging (MRI), echocardiography, or positron emission tomography (PET) performed on the subject's body.

[0162] According to certain aspects, the operations further involve receiving one or more (myocardial) tissue properties of the heart of the subject. In this case, performing the analysis may entail performing an analysis of the read internal ECG signal and the received tissue properties.

[0163] According to certain aspects, the subject is a human patient. For other aspects, the subject can be, for example, a pig or a dog.

[0164] According to some aspects, the operation also includes reading a derivative of a sensed internal ECG signal stored by the implantable device from the implantable device. For some aspects, at least one sensed internal ECG signal or its derivative is stored in a digital format. For other aspects, at least one sensed internal ECG signal or its derivative is stored in an analog format.

[0165] According to certain aspects, an implantable device is capable of delivering an electrical shock to a subject's heart.

[0166] According to certain aspects, the implantable device comprises an implantable cardioverter / defibrillator (ICD).For other aspects, the implantable device comprises a pacemaker.

[0167] Certain aspects provide a system for analyzing arrhythmias in a subject's body. The system generally includes a wireless communication device and at least one processor communicatively coupled to the wireless communication device. The wireless communication device is configured to read from an implantable device implanted in the subject's body a plurality of internal ECG signals sensed and stored by the implantable device when the subject's body is experiencing an arrhythmic event. The at least one processor is configured to perform an analysis of the read internal ECG signals and determine the location of the arrhythmia based on the analysis.

[0168] According to certain aspects, the subject is a human patient. For other aspects, the subject can be, for example, a pig or a dog.

[0169] According to certain aspects, an implantable device has a plurality of leads with a plurality of electrodes for sensing internal ECG signals.

[0170] According to certain aspects, there is a delay between the time the internal ECG signal is stored and the time it is read. For example, the delay ranges from a few minutes to a few days (or to a few weeks).

[0171] According to certain aspects, the determined position has a resolution of at most 2.0 cm, at most 1.0 cm, or at most 0.5 cm.

[0172] According to certain aspects, the processor is configured to perform the analysis by performing a vector analysis of the internal ECG signal. For certain aspects, the processor is also configured to perform the analysis by determining the physical location of a plurality of electrodes associated with the implantable device and used to sense the internal ECG signal implanted in the subject's body. In this case, the processor is configured to perform the vector analysis based on the determined physical location of the plurality of electrodes. For certain aspects, determining the physical location of the electrodes requires performing CT, MRI, echocardiography, or PET on the subject's body.

[0173] According to certain aspects, the processor is configured to perform the analysis by performing a conduction time analysis of the internal ECG signal. For certain aspects, the processor is also configured to perform the analysis by determining the physical location of a plurality of electrodes associated with the implantable device and used to sense the internal ECG signal implanted in the subject's body. In this case, the processor is configured to perform the conduction time analysis based on the determined physical locations of the plurality of electrodes. For certain aspects, determining the physical location of the electrodes requires performing CT, MRI, echocardiography, or PET on the subject's body.

[0174] According to certain aspects, the processor is further configured to receive one or more (myocardial) tissue properties of the heart of the subject. In this case, the processor can be configured to perform the analysis by performing an analysis of the read internal ECG signal and the received tissue properties.

[0175] According to certain aspects, an implantable device is capable of delivering an electrical shock to a subject's heart.

[0176] According to certain aspects, the implantable device comprises an ICD.For other aspects, the implantable device comprises a pacemaker.

[0177] According to certain aspects, the wireless communication device is further configured to read from the implantable device a derivative of the sensed internal ECG signal stored by the implantable device.The sensed internal ECG signal or its derivative may be stored in a digital format, an analog format, or some combination thereof.

[0178] Certain aspects of the present disclosure provide an implantable device for implantation in a subject. The implantable device generally includes a plurality of leads having a plurality of electrodes for sensing a plurality of internal ECG signals; and a memory configured to store the internal ECG signals sensed at least when the subject is experiencing an arrhythmia, and subsequently read out the stored internal ECG signals for analysis to determine the location of the arrhythmia.

[0179] According to certain aspects, the implantable device further includes a transmitter configured to transmit the stored internal ECG signal to an external device for analysis to determine the location of the arrhythmia.

[0180] According to certain aspects, the implantable device further includes a processor configured to analyze the stored internal ECG signal read from the memory to determine the location of the arrhythmia.

[0181] According to certain aspects, the implantable device further includes a capacitive element configured to apply an electrical shock to a heart of the subject via at least a portion of the lead.

[0182] According to certain aspects, the implantable device comprises an ICD.For other aspects, the implantable device comprises a pacemaker.

[0183] According to certain aspects, the implantable device includes at least two leads having at least four electrodes. For example, the implantable device may include at least two leads, each of the at least two leads having at least two electrodes.

[0184] According to certain aspects, the plurality of electrodes are configured to be positioned to determine the location of an arrhythmia within a chamber of the subject's heart with a spatial resolution (e.g., <2.0 cm, such as 0.5 cm) sufficient to guide an ablation catheter to the determined location for ablation therapy.

[0185] According to certain aspects, the memory is further configured to store a derivative of the sensed internal ECG signal and to read out the derivative.The sensed internal ECG signal or its derivative may be stored in digital and / or analog format.

[0186] Any of the operations described above, such as operations 200, 800, and 1400, may be included as instructions in a computer-readable medium for execution by a processing system. The (non-transitory) computer-readable medium may include any suitable memory or other storage device for storing instructions, such as a read-only memory (ROM), a random access memory (RAM), a flash memory (e.g., a USB flash drive), an electrically erasable programmable ROM (EEPROM), a compact disk ROM (CD-ROM), a floppy disk, or a digital versatile disk ROM (DVD-ROM).

[0187] The methods disclosed herein include one or more steps or actions for implementing the described methods. The method steps and / or actions may be interchangeable with each other without departing from the scope of the claims. In other words, unless a specific order of steps or actions is specified, the order and / or use of specific steps and / or actions may be modified without departing from the scope of the claims.

[0188] As used herein, including the appended claims, a phrase referring to "at least one of" a list of items refers to any combination of those items, including single members. As an example, "at least one of: x, y, and z" is intended to cover: x, y, z, xy, xz, yz, xyz, and any combination thereof (e.g., xyy and xxyz).

[0189] While the foregoing is directed to certain aspects of the present disclosure, other and further aspects may be devised without departing from the basic scope of the present disclosure, and the scope of the present disclosure is determined by the following claims.

[0190] Priority Claims Under 35 U.S.C. § 119

[0191] This application claims the benefit of priority to U.S. Provisional Patent Application Serial No. 62 / 620,589, filed on January 23, 2018, entitled “Precise Localization of Ventricular Arrhythmia Using Internal Electrocardiograph (ECG) Signals Sensed and Stored by Implantable Device,” the entire contents of which are incorporated herein by reference.

Claims

1. A system for analyzing arrhythmia in a subject, comprising: a communication device configured to read a first plurality of internal electrocardiogram (ECG) signals sensed and recorded while the subject is experiencing an arrhythmic event; and at least one processor, communicatively coupled to the communication device and configured to: performing a conduction time analysis of the first plurality of internal ECG signals, wherein the conduction time analysis comprises generating a 3D isochronal contour based on conduction times across a portion of the myocardial tissue; determining an initial location of the arrhythmia based on the conduction time analysis; analyzing differences between a second plurality of ECG signals sensed during at least one of electrical stimulation and pacing delivered via the wandering catheter at the initial location and the first plurality of internal ECG signals to produce a precise location; and The precise location of the arrhythmia is identified as endocardial, intramural, or epicardial based at least in part on the analyzed differences.

2. The system of claim 1 , wherein the at least one processor is configured to analyze differences between the second plurality of ECG signals and the first plurality of internal ECG signals by: determining a vector based at least in part on the analyzed differences; and The initial position is refined to produce a refined position until the magnitude of the vector is a minimum. 3 . The system of claim 2 , wherein the minimum value indicates whether the refined location is endocardial, intramural, or epicardial.

4. The system of claim 2, wherein the vector is a transmission time difference vector including a direction and a magnitude.

5. The system of claim 2, wherein the vector is a transmission time difference vector, and wherein the at least one processor is further configured to: The transit time difference is converted into a displacement vector starting at the initial position and ending at the refined position.

6. The system of claim 2, wherein the at least one processor is configured to refine the initial position until a magnitude of the vector is below a predetermined threshold.

7. The system of claim 2, wherein the at least one processor is configured to refine the initial position until a morphology of the second plurality of ECG signals matches a morphology of the first plurality of internal ECG signals.

8. A system according to claim 1, wherein the at least one processor is configured to determine the initial location of the arrhythmia by identifying the 3D isochronal contour that matches at least one local activation time recorded from at least one internal electrode during the arrhythmia.

9. The system of claim 1, wherein the at least one processor is further configured to: performing vector analysis on the analyzed differences; and The initial location of the arrhythmia is refined based on the vector analysis.

10. The system of claim 1, wherein the at least one processor is configured to perform a conduction time analysis based on determining a tissue property of a portion of the myocardial tissue.

11. A system for analyzing cardiac arrhythmias in a subject, comprising: a communication device configured to read a first plurality of internal electrocardiogram (ECG) signals sensed and recorded while the subject is experiencing an arrhythmic event; and at least one processor, communicatively coupled to the communication device and configured to: performing a conduction time analysis of the first plurality of internal ECG signals, wherein the conduction time analysis comprises generating a 3D isochronal contour based on conduction times across a portion of the myocardial tissue; Based on the conduction time analysis, at least one of the following is determined: a first single origin of the at least one arrhythmic event, wherein the at least one arrhythmic event is a single arrhythmic event; and a second plurality of origins of the at least one arrhythmic event, wherein the at least one arrhythmic event is a plurality of arrhythmic events; determining physical locations of a plurality of electrodes implanted in the subject's body to sense the first plurality of internal ECG signals, wherein the physical locations of the plurality of electrodes are determined with reference to a region of a heart of the subject's body; and Based on the determined physical locations of the plurality of electrodes, a conduction time analysis of the first plurality of internal ECG signals is performed.

12. The system of claim 11, wherein the at least one processor is configured to perform the conduction time analysis based on determining tissue properties of a portion of the myocardial tissue.

13. The system of claim 12, wherein the tissue characteristic comprises at least one of scar content, ischemia score, or degree of myocardial edema.

14. The system of claim 11, wherein the at least one processor is configured to determine the physical positions of the plurality of electrodes by performing at least one of fluoroscopy, computed tomography (CT), magnetic resonance imaging (MRI), echocardiography, or positron emission tomography (PET) on the subject.

15. The system of claim 11, wherein the communication device comprises a plurality of leads having a plurality of electrodes for sensing the first plurality of internal ECG signals.

16. A non-transitory computer readable medium having stored thereon instructions that, when executed by at least one processor, cause the at least one processor to perform operations for analyzing a cardiac arrhythmia in a subject, the operations comprising: reading a plurality of internal electrocardiogram (ECG) signals sensed and recorded while the subject is experiencing an arrhythmic event; performing an analysis of the plurality of internal ECG signals; as well as determining a location of the arrhythmia based on the analysis, The operations for performing the analysis include further operations, including: For each voxel in the plurality of voxels in the myocardial tissue: determining a conduction time index based on at least one tissue characteristic of the portion of myocardial tissue associated with the voxel; determining a conduction pathway based at least in part on the conduction time index; and deriving a voxel conduction time across the voxels for the conduction time index along the conduction path based on at least one paced conduction; generating at least one 3D isochronal contour line based at least in part on the voxel conduction time of each voxel in the plurality of voxels; and The location of an arrhythmia is determined based at least in part on the at least one 3D isochronal contour.

17. An implantable device for implantation into a subject, comprising: a plurality of leads having a plurality of electrodes for sensing a plurality of internal electrocardiogram (ECG) signals; as well as A memory configured to store internal ECG signals sensed at least when the subject is experiencing an arrhythmia, and subsequently read out the stored internal ECG signals for analysis to determine the location of an origin or exit site of the arrhythmia within a chamber of the heart of the subject.

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