Detecting sources of heart rhythm abnormalities

Abstract

Apparatus and method are described including an array (22) of multiple electrodes (24) at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject's heart. A computer processor (28) drives stimulating currents via respective electrodes according to a sequence and pacing parameters, and detects electrical signals at others of the electrodes (24) resulting from the stimulating currents. Based upon the detected electrical signals, the computer processor (28) derives indications of conduction and / or repolarization at the locations within the subject's heart at which respective electrodes (24) contact the tissue of the heart. In response thereto, the computer processor (28) identifies at least some of the locations within the subject's heart as being sources of a heart rhythm abnormality. Other applications are also described.

Description

[0001] DETECTING SOURCES OF HEART RHYTHM ABNORMALITIES

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority from US Provisional Application No. 63 / 716,438 to Anter, filed November 05, 2024, entitled “Detecting Sources and / or Drivers of Heart Rhythm Abnormalities,” which is incorporated herein by reference.

[0004] TECHNICAL FIELD

[0005] Some applications of the present disclosure generally relate to medical apparatus and methods. Specifically, some applications of the present disclosure relate to apparatus and methods for detecting sources and / or drivers of heart rhythm abnormalities.

[0006] BACKGROUND

[0007] Cardiac rhythm disorders, or arrhythmias, are a significant global health issue, contributing to increased morbidity, mortality, and reduced quality of life. Among these, atrial fibrillation (AF), ventricular tachycardia (VT), and ventricular fibrillation (VF) present the most complex therapeutic challenges due to their intricate underlying mechanisms. Fibrillation is a type of irregular heart rhythm caused by reentry, a phenomenon where electrical impulses continuously circle an abnormal circuit in the heart, rather than following a single path.

[0008] While simpler rhythm disorders, such as atrial tachycardia and atrial flutter, can be effectively managed with medications or catheter-based ablation, the treatment of complex arrhythmias remains limited. Pharmacological treatments, particularly for atrial fibrillation, ventricular tachycardia, and ventricular fibrillation, have demonstrated inconsistent effectiveness, often failing to provide long-term solutions. This has led to a growing reliance on non- pharmacological interventions, such as catheter ablation, which has become increasingly common in clinical practice.

[0009] Catheter ablation involves navigating a catheter to the heart and applying energy to the arrhythmogenic site. Although this approach is highly effective for simpler arrhythmias, its success significantly diminishes with complex conditions. For instance, in patients with atrial fibrillation, ablation success rates are around 60% after one year but drop to approximately 16% over ten years. Existing electro-anatomical mapping systems used in clinical practice are designed to create three-dimensional models of the heart and measure cardiac biopotentials, such as voltage amplitude and activation times, to localize arrhythmia sources. These systems are particularly useful for detecting focal arrhythmias or organized reentrant circuits. By integrating spatial and electrical data, they guide more precise treatment interventions. Some systems have further advanced by incorporating body surface electrocardiographic signals, projecting electrical potentials onto the heart, enabling non-invasive or minimally invasive mapping of arrhythmogenic regions.

[0010] SUMMARY

[0011] As described in the Background, electro-anatomical mapping systems used in clinical practice are designed to create three-dimensional models of the heart and measure cardiac biopotentials, such as voltage amplitude and activation times, to localize arrhythmia sources. These systems are particularly useful for detecting focal arrhythmias or organized reentrant circuits. By integrating spatial and electrical data, they guide more precise treatment interventions. Some systems have further advanced by incorporating body surface electrocardiographic signals, projecting electrical potentials onto the heart, enabling non-invasive or minimally invasive mapping of arrhythmogenic regions.

[0012] Despite these advances, existing electro-anatomical mapping systems often fall short in identifying the sources of more complex arrhythmias, such as persistent atrial fibrillation. Various mapping and ablation techniques, including the ablation of complex fractionated atrial electrograms (CFAEs), empiric ablation lines (e.g., mitral lines, roof lines, and posterior wall isolation), and targeting anatomical sites exhibiting low voltage amplitude or late activation times, have not demonstrated consistent, reproducible benefits in large, randomized studies. Additionally, attempts to target atrial fibrillation drivers, such as rotors, have produced inconsistent outcomes, often failing to achieve the expected therapeutic results. This lack of precision in identifying and localizing arrhythmia sources often leads to empiric ablation, resulting in unnecessary tissue destruction that could be minimized through more accurate targeting of affected areas.

[0013] This challenge is particularly pressing in the treatment of ventricular arrhythmias like ventricular tachycardia and ventricular fibrillation, which are major causes of sudden cardiac death. While implantable cardioverter-defibrillators (ICDs) are commonly used to manage ventricular tachycardia / ventricular fibrillation, there is growing interest in catheter ablation to prevent recurrent implantable cardioverter-defibrillators shocks. However, the precise sources of ventricular fibrillation remain poorly understood in humans, limiting the effectiveness of existing ablation strategies.

[0014] A well-documented electrophysiological abnormality leading to both atrial and ventricular fibrillation is the shortening of the effective refractory period. In patients with atrial fibrillation, the atrial effective refractory period (AERP) shortens due to electrical remodeling. Although this shortening is a normal physiological response to increased heart rate, known as the rate adaptation of refractoriness, it becomes maladaptive in atrial fibrillation patients. Even after the heart rate returns to normal, these patients exhibit a persistently shortened atrial effective refractory period, indicating a lasting impairment in the adaptive capacity of cardiomyocytes. This maladaptive electrical remodeling is heterogeneous, with varying degrees of refractoriness across different regions of the atria. Regions where atrial effective refractory period is abnormally shortened and conduction is slowed, so called areas with heterogeneity in excitation and recovery of excitability, create an environment conducive to the initiation and perpetuation of atrial fibrillation.

[0015] Despite the critical role that conduction heterogeneity and refractoriness play in arrhythmia dynamics, existing electro-anatomical mapping systems do not measure these properties or provide meaningful insights into their spatial distribution. Therefore, there remains an urgent need for systems capable of directly assessing these key parameters to better identify and treat the sources of complex arrhythmias such as atrial fibrillation, ventricular tachycardia, and ventricular fibrillation. This need is particularly critical for atrial fibrillation and other complex rhythm disorders, where an ideal system would enable the detection of sources for ablation using minimally invasive methods.

[0016] In accordance with some applications of the present disclosure, two or more electrodes are used to drive electrical stimulation currents into respective locations within the patient’s heart. For some applications, a multipolar catheter, which includes an array of multiple electrodes, is used to drive electrical stimulation currents into respective multiple locations within the patient’s heart. Metrics related to local heterogeneity in conduction and repolarization resulting from the stimulation currents are measured and locations within the heart are identified as being sources of a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation) are identified in response thereto. For example, in response to a stimulation current being driven via an electrode (e.g., a first electrode within the array), the computer processor may detect electrical signals resulting from the stimulation signal at one or more additional electrodes (e.g., all or a portion of the additional electrodes within the array). Based on the measured electrical signals at the electrodes, the computer processor determines an indication of the conduction and / or the repolarization properties at the locations corresponding to the respective electrodes. For some applications, the computer processor drives the electrodes within the array to automatically stimulate respective locations within the heart according to a predetermined sequence and at variable cycle lengths and / or coupling intervals. For some applications, the computer processor drives the electrodes within the array to stimulate respective locations within the heart according to a dynamically determined sequence, and at dynamically determined variable cycle lengths and / or coupling intervals.

[0017] It is noted that, unlike typical existing systems, which primarily focus on passively recorded voltage amplitude and activation times, in accordance with the apparatus and methods described herein cardiac tissue is actively stimulated, the response is recorded, and data indicative of local conduction and / or repolarization are analyzed to identify arrhythmogenic sites.

[0018] The system described herein typically functions automatically, eliminating the need for manual selection of stimulating electrodes, cycle length, and coupling intervals. This automation streamlines what is traditionally a complex, multi-step process that is time-consuming and requires a high level of expertise. By automating these steps, the system enables physicians to rapidly and efficiently obtain critical data. Key metrics, such as conduction and repolarization properties, are automatically measured, allowing the system to accurately identify specific locations within the heart responsible for arrhythmias, including atrial fibrillation, ventricular tachycardia, and ventricular fibrillation.

[0019] Typically, locations exhibiting heterogeneous electrical properties with localized gradients (in conduction and / or repolarization) are identified as being sources of a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation). For some applications, locations having electrical properties (e.g., conduction and / or repolarization) that exhibit local gradients relative to neighboring locations are identified as being sources of a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation).

[0020] In some applications, a location at which there is a local gradient in repolarization period and / or activation-repolarization interval that exceeds a threshold is identified as being a source of a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation). For some applications, the threshold repolarization gradient in repolarization and / or activation-repolarization interval is between 20 ms per 10 mm and 200 ms per 10 mm (e.g., between 40 ms per 10 mm and 100 ms per 10 mm). For some applications, the threshold repolarization gradient in repolarization period and / or activation-repolarization interval is approximately 50 ms per 10 ms. In some applications, the system computes and displays spatial maps of the repolarization gradient in real-time to assist in identifying sites with abrupt local transitions in repolarization, which correspond to areas with increased vulnerability for reentry and therefore likely sources of a heart rhythm abnormality.

[0021] In some applications, the identified locations are targeted for ablation to modify the underlying cause of the heart rhythm abnormality. In some applications, the electrodes belonging to the multipolar catheter are used to ablate the identified locations (typically by radiofrequency and / or pulsed-field ablation), typically while maintaining the position of the multipolar catheter with respect to patient’s heart between the procedure for identifying the sources of a heart rhythm abnormality and the ablation of those locations. There is therefore provided, in accordance with some embodiments of the present disclosure, apparatus including: a multipolar catheter including an array of multiple electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart; and at least one computer processor configured to: drive stimulating currents via respective electrodes according to a sequence and pacing parameters, and detect electrical signals at others of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, derive indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identify at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

[0022] In some embodiments, the computer processor is configured to calculate arrhythmogenicity metrics for respective locations within the subject’s heart based on the indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

[0023] In some embodiments, the apparatus is for use with an output device and the computer processor is configured to generate a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three-dimensional electro-anatomical map including: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

[0024] In some embodiments, the computer processor is configured to identify at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality by detecting locations that exhibit local gradients in repolarization period and / or activation-repolarization interval relative to neighboring locations.

[0025] In some embodiments, the computer processor is configured to identify locations at which there is a gradient in repolarization period and / or activation-repolarization interval of between 20 ms per 10 mm and 200 ms per 10 mm as being sources of a heart rhythm abnormality.

[0026] In some embodiments, the computer processor is configured to automatically drive the stimulating currents via respective electrodes according to a predetermined sequence and predetermined pacing parameters.

[0027] In some embodiments, the computer processor is configured to automatically drive stimulating currents via respective electrodes according to predetermined pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

[0028] In some embodiments, the computer processor is configured to drive the stimulating currents via respective electrodes according to a dynamically determined sequence and pacing parameters.

[0029] In some embodiments, the computer processor is configured to drive stimulating currents via respective electrodes according to dynamically determined pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

[0030] In some embodiments, the computer processor is configured to detect one or more signal characteristics and to thereby determine that only some of the electrode are in contact with tissue of the heart.

[0031] In some embodiments, the computer processor is configured to apply the stimulation currents only via electrodes that are in contact with the tissue of the heart.

[0032] In some embodiments, the computer processor is configured to receive electrograms and to thereby detect a presence of tissue capture in response to a stimulating current that was driven via one or more of the electrodes. In some embodiments, the computer processor is configured to detect the presence of tissue capture by evaluating signal frequency and depolarization timing between the electrodes.

[0033] In some embodiments, the computer processor is configured to drive stimulating currents via at least one of the electrodes at varying coupling intervals, and to derive indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals.

[0034] In some embodiments, the computer processor is configured to derive a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

[0035] In some embodiments, the computer processor is configured to derive an indication of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by signal analysis that includes calculating activation-recovery intervals at the given location.

[0036] In some embodiments, the computer processor is configured to derive an indication of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by directly determining a refractory period at the given location.

[0037] In some embodiments, the computer processor is configured to directly determine the refractory period at the given location by measuring the refractory period as a longest coupling interval that fails to capture tissue of the heart in response to a given stimulus strength.

[0038] In some embodiments, the computer processor is configured to drive stimulating currents via respective electrodes by driving a series of stimulation signals via at least one of the electrodes, each of the stimulation signals includes an extrastimulation following a train of beats and a coupling interval between the train of beats and the extrastimulation varies over the series.

[0039] In some embodiments, the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving a train of baseline beats followed by the extrastimulation, a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

[0040] In some embodiments, the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving the extrastimulation following a train of sinus beats, and a coupling interval between the train of sinus beats and the extrastimulation varies over the series. In some embodiments, the computer processor is configured to derive a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture tissue of the heart at the given location in response to a given stimulus strength.

[0041] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

[0042] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

[0043] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

[0044] There is further provided, in accordance with some embodiments of the present disclosure, apparatus including: two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart; and at least one computer processor configured to: drive stimulating currents via at least one of the electrodes at varying coupling intervals, and detect electrical signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, derive indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identify at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

[0045] In some embodiments, the computer processor is configured to calculate arrhythmogenicity metrics for respective locations within the subj ect’ s heart at least partially based on the indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

[0046] In some embodiments, the apparatus is for use with an output device and the computer processor is configured to generate a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three-dimensional electro-anatomical map including: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

[0047] In some embodiments, the computer processor is configured to derive a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

[0048] In some embodiments, the computer processor is configured to derive indications of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by signal analysis that includes calculating activation-recovery intervals at the given location.

[0049] In some embodiments, the computer processor is configured to identify at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality by detecting locations that exhibit local gradients in repolarization period and / or activation-repolarization interval relative to neighboring locations.

[0050] In some embodiments, the computer processor is configured to detect locations at which there is a gradient in repolarization period and / or activation-repolarization interval of between 20 ms per 10 mm and 200 ms per 10 mm as being sources of a heart rhythm abnormality.

[0051] In some embodiments, the computer processor is configured to derive indications of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by directly determining a refractory period at the given location.

[0052] In some embodiments, the computer processor is configured to directly determine the refractory period at the given location by measuring the refractory period as a longest coupling interval that fails to capture tissue of the heart in response to a given stimulus strength.

[0053] In some embodiments, the electrodes include an array of multiple electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart.

[0054] In some embodiments, the computer processor is configured to automatically drive stimulating currents via respective electrodes according to a predetermined sequence.

[0055] In some embodiments, the computer processor is configured to automatically drive stimulating currents via respective electrodes according to a dynamically determined sequence. In some embodiments, the computer processor is configured to automatically drive stimulating currents via respective electrodes according to pacing parameters that include one or more parameters selected from the group consisting of frequency, cycle length, coupling interval, and current.

[0056] In some embodiments, the computer processor is configured to drive stimulating currents via at least one of the electrodes at varying coupling intervals by driving a series of stimulation signals via the at least one of the electrodes, each of the stimulation signals includes an extrastimulation following a train of beats and a coupling interval between the train of beats and the extrastimulation varies over the series.

[0057] In some embodiments, the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving a train of baseline beats followed by the extrastimulation, and a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

[0058] In some embodiments, the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving the extrastimulation following a train of sinus beats, and a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

[0059] In some embodiments, the computer processor is configured to derive a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location at the given location in response to a given stimulus strength.

[0060] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

[0061] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

[0062] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum interval over the series.

[0063] There is further provided, in accordance with some embodiments of the present disclosure, apparatus including: an output device; two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart; and at least one computer processor configured to: drive stimulating currents via at least one of the electrodes, and detect electrical conduction signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical conduction signals, derive indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; in response thereto, identify at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality; and generate a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three-dimensional electro-anatomical map including: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

[0064] In some embodiments, the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell correspond to sites with high reentry vulnerability.

[0065] In some embodiments, the computer processor is configured to automatically determine a suitable strategy for ablating locations that are identified as being sources of the heart rhythm abnormality.

[0066] In some embodiments, the computer processor is configured to generate an indication of the determined ablation strategy on the output device.

[0067] In some embodiments, the computer processor is configured to drive stimulating currents via at least one of the electrodes by driving a series of stimulation signals via the at least one of the electrodes, each of the stimulation signals includes an extrastimulation following a train of beats and a coupling interval between the train of beats and the extrastimulation varies over the series.

[0068] In some embodiments, the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving a train of baseline beats followed by the extrastimulation, and a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

[0069] In some embodiments, the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving the extrastimulation following a train of sinus beats, and a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

[0070] In some embodiments, the computer processor is configured to derive a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

[0071] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

[0072] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

[0073] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

[0074] There is further provided, in accordance with some embodiments of the present disclosure, a computer software product for use with an array of multiple electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the computer software product including a non-transitory computer- readable medium in which program instructions are stored, which instructions, when read by a computer cause the computer to perform the steps of: driving stimulating currents via respective electrodes according to a sequence and pacing parameters, and detecting electrical signals at others of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality. In some embodiments, deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart includes calculating arrhythmogenicity metrics for respective locations within the subject’s heart based on the indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

[0075] In some embodiments, the instructions, when read by the computer further cause the computer to perform the step of: generating a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three-dimensional electro-anatomical map including: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

[0076] In some embodiments, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality includes detecting locations that exhibit local gradients in repolarization period and / or activation-repolarization interval relative to neighboring locations.

[0077] In some embodiments, the instructions, when read by the computer cause the computer to perform the step of identifying locations at which there is a gradient in repolarization period and / or activation-repolarization interval of between 20 ms per 10 mm and 200 ms per 10 mm as being sources of a heart rhythm abnormality.

[0078] In some embodiments, driving stimulating currents via respective electrodes according to the sequence and pacing parameters includes automatically driving the stimulating currents via respective electrodes according to a predetermined sequence and predetermined pacing parameters.

[0079] In some embodiments, automatically driving the stimulating currents via respective electrodes according to the predetermined sequence and predetermined pacing parameters includes automatically driving stimulating currents via respective electrodes according to predetermined pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

[0080] In some embodiments, driving stimulating currents via respective electrodes according to the sequence and pacing parameters includes driving the stimulating currents via respective electrodes according to a dynamically determined sequence and pacing parameters. In some embodiments, driving the stimulating currents via respective electrodes according to the dynamically determined sequence and pacing parameters includes driving stimulating currents via respective electrodes according to pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

[0081] In some embodiments, the instructions, when read by the computer further cause the computer to perform the step of detecting one or more signal characteristics and thereby determining that only some of the electrode are in contact with tissue of the heart.

[0082] In some embodiments, driving stimulating currents via respective electrodes according to the sequence and pacing parameters includes applying the stimulation currents only via electrodes that are in contact with the tissue of the heart.

[0083] In some embodiments, the instructions, when read by the computer further cause the computer to perform the step of receiving electrograms, thereby detecting a presence of tissue capture in response to a stimulating current that was driven via one or more of the electrodes.

[0084] In some embodiments, detecting the presence of tissue capture in response to a stimulating current that was driven via one or more of the electrodes includes evaluating signal frequency and depolarization timing between the electrodes.

[0085] In some embodiments, driving stimulating currents via respective electrodes according to the sequence and pacing parameters includes driving stimulating currents via at least one of the electrodes at varying coupling intervals, and the instructions, when read by the computer further cause the computer to perform the step of deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals.

[0086] In some embodiments, deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals includes deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

[0087] In some embodiments, deriving indications of repolarization at the locations within the subj ect’ s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals includes deriving an indication of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by signal analysis that includes calculating activation-recovery intervals at the given location.

[0088] In some embodiments, deriving indications of repolarization at the locations within the subj ect’ s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals includes deriving an indication of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by directly determining a refractory period at the given location.

[0089] In some embodiments, directly determining a refractory period at the given location includes measuring the refractory period as a longest coupling interval that fails to capture tissue of the heart in response to a given stimulus strength.

[0090] In some embodiments, driving stimulating currents via respective electrodes includes driving a series of stimulation signals via at least one of the electrodes, each of the stimulation signals includes an extrastimulation following a train of beats and a coupling interval between the train of beats and the extrastimulation varies over the series.

[0091] In some embodiments, driving each of the series of stimulation signals via the at least one of the electrodes includes driving a train of baseline beats followed by the extrastimulation, and a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

[0092] In some embodiments, driving each of the series of stimulation signals via the at least one of the electrodes includes driving the extrastimulation following a train of sinus beats, and a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

[0093] In some embodiments, the instructions, when read by the computer cause the computer to perform the step of deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

[0094] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

[0095] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

[0096] In some embodiments, the coupling interval between the train of beats the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series. There is further provided, in accordance with some embodiments of the present disclosure, a computer software product for use with two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the computer software product including a non-transitory computer-readable medium in which program instructions are stored, which instructions, when read by a computer cause the computer to perform the steps of: driving stimulating currents via at least one of the electrodes at varying coupling intervals; detecting electrical signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

[0097] In some embodiments, the computer software product is for use with an array of multiple electrodes and driving stimulating currents via at least one of the electrodes at varying coupling intervals includes automatically driving stimulating currents via respective electrodes according to a predetermined sequence.

[0098] In some embodiments, the computer software product is for use with an array of multiple electrodes and driving stimulating currents via at least one of the electrodes at varying coupling intervals includes automatically driving stimulating currents via respective electrodes according to a dynamically determined sequence.

[0099] In some embodiments, the computer software product is for use with an array of multiple electrodes and driving stimulating currents via at least one of the electrodes at varying coupling intervals includes automatically driving stimulating currents via respective electrodes according to predetermined pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

[0100] In some embodiments, the instructions, when read by the computer further cause the computer to perform the step of calculating arrhythmogenicity metrics for respective locations within the subject’s heart at least partially based on the indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

[0101] In some embodiments, the instructions, when read by the computer further cause the computer to perform the step of generating a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on an output device, the three-dimensional electro-anatomical map including: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

[0102] In some embodiments, deriving indications of repolarization at the given location within the subject’s heart at which the respective electrodes contacts the tissue of the heart includes deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

[0103] In some embodiments, deriving indications of repolarization at the given location within the subject’s heart at which the given electrode contacts the tissue of the heart includes using signal analysis that includes calculating activation-recovery intervals at the given location.

[0104] In some embodiments, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality includes detecting locations that exhibit local gradients in repolarization period and / or activation-repolarization interval relative to neighboring locations.

[0105] In some embodiments, the instructions, when read by the computer cause the computer to perform the step of identifying locations at which there is a gradient in repolarization period and / or activation-repolarization interval of between 20 ms per 10 mm and 200 ms per 10 mm as being sources of a heart rhythm abnormality.

[0106] In some embodiments, deriving indications of repolarization at the given location within the subject’s heart at which the given electrode contacts the tissue of the heart includes directly determining a refractory period at the given location.

[0107] In some embodiments, directly determining the refractory period at the given location includes measuring the refractory period as a longest coupling interval that fails to capture tissue of the heart in response to a given stimulus strength.

[0108] In some embodiments, driving stimulating currents via at least one of the electrodes at varying coupling intervals includes driving a series of stimulation signals via the at least one of the electrodes, each of the stimulation signals includes an extrastimulation following a train of beats and a coupling interval between the train of beats and the extrastimulation varies over the series. In some embodiments, driving each of the series of stimulation signals via the at least one of the electrodes includes driving a train of baseline beats followed by the extrastimulation, and a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

[0109] In some embodiments, driving each of the series of stimulation signals via the at least one of the electrodes includes driving the extrastimulation following a train of sinus beats, a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

[0110] In some embodiments, the instructions, when read by the computer cause the computer to perform the step of deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

[0111] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

[0112] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

[0113] In some embodiments, the coupling interval between the train of beats the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

[0114] There is further provided, in accordance with some embodiments of the present disclosure, a computer software product for use with two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the computer software product including a non-transitory computer-readable medium in which program instructions are stored, which instructions, when read by a computer cause the computer to perform the steps of: driving stimulating currents via at least one of the electrodes, and detecting electrical conduction signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical conduction signals, deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality; and generating a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three-dimensional electro-anatomical map including: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

[0115] In some embodiments, the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell correspond to sites with high reentry vulnerability.

[0116] In some embodiments, the instructions, when read by the computer further cause the computer to perform the step of automatically determining a suitable strategy for ablating locations that are identified as being sources of the heart rhythm abnormality.

[0117] In some embodiments, the instructions, when read by the computer further cause the computer to perform the step of generating an indication of the determined ablation strategy on the output device.

[0118] In some embodiments, driving stimulating currents via at least one of the electrodes includes driving a series of stimulation signals via the at least one of the electrodes, each of the stimulation signals includes an extrastimulation following a train of beats and a coupling interval between the train of beats and the extrastimulation varies over the series.

[0119] In some embodiments, driving each of the series of stimulation signals via the at least one of the electrodes includes driving a train of baseline beats followed by the extrastimulation, and a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

[0120] In some embodiments, driving each of the series of stimulation signals via the at least one of the electrodes includes driving the extrastimulation following a train of sinus beats, and a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

[0121] In some embodiments, the instructions, when read by the computer cause the computer to perform the step of deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

[0122] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

[0123] In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series. In some embodiments, the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

[0124] There is further provided, in accordance with some embodiments of the present disclosure, a method for use with an array of multiple electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the method including: using at least one computer processor: driving stimulating currents via respective electrodes according to a sequence and pacing parameters, and detecting electrical signals at others of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

[0125] There is further provided, in accordance with some embodiments of the present disclosure, a method for use with two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the method including: using at least one computer processor: driving stimulating currents via at least one of the electrodes at varying coupling intervals; detecting electrical signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

[0126] There is further provided, in accordance with some embodiments of the present disclosure, a method for use with an output device and two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the method including: using at least one computer processor: driving stimulating currents via at least one of the electrodes, and detecting electrical conduction signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical conduction signals, deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality; and generating a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three-dimensional electro-anatomical map including: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

[0127] The present disclosure will be more fully understood from the following detailed description of embodiments thereof, taken together with the drawings, in which:

[0128] BRIEF DESCRIPTION OF THE DRAWINGS

[0129] Fig. 1A is a schematic illustration of a system that includes a multipolar catheter an electrode array of which is shown positioned within a patient’s heart, in accordance with some applications of the disclosure;

[0130] Fig. IB is a schematic illustration of signals received from the multipolar catheter in response to automatic sequential stimulation of one or more electrodes within the electrode array, in accordance with some applications of the disclosure;

[0131] Fig. 2A is a schematic illustration of tissue with normal conduction properties under baseline conditions;

[0132] Fig. 2B is a schematic illustration of the same tissue as in Fig. 1A, with the tissue being stimulated to thereby induce conduction slowing, in accordance with some applications of the disclosure; Fig. 2C is a schematic illustration of the same tissue as in Fig. 1A, and with arrhythmia having been initiated as a result of conduction slowing and shortened atrial refractoriness, in accordance with some applications of the disclosure;

[0133] Figs. 3A and 3B shows reconstructed anatomical shells of a patient’s left atrium respectively in anterior and posterior projections, as generated using a commercially available electro-anatomical mapping system, with numbers representing the effective repolarization periods measured at each location, in accordance with some applications of the disclosure;

[0134] Figs. 4A and 4B display signals measured at specific cardiac locations following tissue interrogation through stimulation at decreasing coupling intervals of 210 and 200 msec, in accordance with some applications of the disclosure; and

[0135] Fig. 5 is a flow diagram illustrating the mechanism of atrial fibrillation initiation, triggered by atrial premature contractions at sites with abnormal conduction and / or repolarization properties, as identified by certain applications of the disclosure.

[0136] DETAILED DESCRIPTION OF EMBODIMENTS

[0137] Reference is first made to Fig. 1A, which is a schematic illustration of a system 10 that includes a multipolar catheter 20, the catheter including an array 22 of multiple electrodes 24 that are positioned within a patient’s heart 25, in accordance with some applications of the disclosure. The heart is represented by a three-dimensional electro-anatomical map in Fig. 1A. For some applications, catheter 20 is advanced into the subject’s heart (e.g., into the subject’s left atrium and / or into a different chamber of the heart, and / or a different location within the heart) percutaneously. Array 22 of electrodes is typically disposed at the distal end of the catheter, while a proximal end of the catheter is typically disposed outside the patient body. A computer processor 28, which is typically housed within a control module 30 is configured to drive electrical current into tissue of the subject’s heart via the electrodes and to sense electrical signals generated at the electrodes, as described in further detail hereinbelow. For some applications, system 10 includes a display 32, which is disposed within the control module and / or is operatively associated with the control module, as described in further details hereinbelow.

[0138] For some applications, the array includes two or more electrodes, e.g., between 2 and 100 electrodes, between 20 and 200 electrodes, or between 30 and 100 electrodes. Typically, the array of electrodes is disposed on a flexible substrate 26, with the flexibility of the substrate maximizing the number of electrodes that are brought into direct contact with cardiac tissue of the patient. In accordance with some applications of the present disclosure, computer processor 28 drives electrical stimulation currents into respective multiple locations within the patient’s heart via respective electrodes 24 within array 22. Metrics related to local heterogeneity in conduction and repolarization resulting from the electrical stimulation currents are measured. For example, in response to a stimulation current being driven via a first electrode within the array, the computer processor detects electrical signals resulting from the stimulation at all or a portion of the additional electrodes within the array. Typically, the computer processor drives the electrodes within the array to automatically stimulate respective locations within the heart according to a predetermined sequence and at variable cycle lengths and / or coupling intervals. Based on the measured signals at each of the electrodes, the computer processor determines an indication of the local conduction and / or the repolarization properties at the locations corresponding to the respective electrodes.

[0139] As noted in the Summary, unlike typical current systems, which primarily focus on passively record voltage amplitude and activation times, system 10 actively stimulates cardiac tissue, the response is recorded, and data indicative of local conduction and repolarization are analyzed to identify arrhythmogenic sites.

[0140] System 10 typically functions automatically, eliminating the need for manual selection of stimulating electrodes and manual measurement of coupling intervals. This automation streamlines what is traditionally a complex, multi-step process that is time-consuming and requires a high level of expertise. By automating these steps, the system enables physicians to rapidly and efficiently obtain critical data. Key metrics, such as conduction heterogeneity and repolarization properties, are measured, allowing the system to accurately identify specific locations within the heart responsible for arrhythmias, including atrial fibrillation, ventricular tachycardia, and ventricular fibrillation.

[0141] Typically, the indication of conduction is determined at least partially by measuring the activation time for a signal to be generated at a given electrode in response to a stimulation signal that was applied to the heart via another electrode within the array. Further typically, the indication of repolarization is determined at least partially by determining the time taken for a given location to repolarize between the conduction of consecutive signals via the location. As described above, the cycle lengths and / or coupling intervals at which the stimulation signals are applied are typically varied. In some embodiments, an indication of the repolarization period of a given location is determined by determining what is the longest coupling interval that fails to capture the cardiac tissue at that location in response to a given stimulus strength. For some applications, the stimulation signal is applied as a single extrastimulation (S2) following a train of baseline beats (SI). For some applications, the train of baseline beats (SI) includes a train of between 2 and 12 beats (e.g., between 4 and 10 beats) that are applied at a cycle length of between 350 ms and 1000 ms (e.g., between 400 ms and 800 ms, or between 400 ms and 600 ms). For some applications, the stimulation signal includes a series of stimulation signals which are repeatedly applied with the coupling interval (S1-S2) between the train of baseline beats (SI) and the extrastimulation (S2) incrementally decreasing with each repetition, as described in further detail below. For some applications, the stimulation signal is repeatedly applied with the coupling interval between the train of baseline beats (SI) and the extrastimulation (S2) incrementally increasing with each repetition, as described in further detail below. For some applications, the stimulation signal is repeatedly applied until the repolarization period at a location within the heart is determined as the longest S1-S2 coupling interval that fails to capture tissue of the heart at the location. For some applications, the stimulation signal is applied as pairs or triplets of extrastimuli (S2, S3, S4) following a train of baseline beats (SI). For some applications, the train of baseline beats and the extrastimulation are delivered via different electrodes from each other. For some applications, generally similar techniques to those described above are applied, but the extrastimulation signal is applied as an extrastimulation after a train of sinus beats, as an alternative to (or in addition to) being applied after the train of baseline beats. In such cases, the coupling interval between the train of sinus beats and the extrastimulation is varied over the series.

[0142] For some applications, the stimulation signal includes a series of stimulation signals in which trains of baseline beats (SI) are applied before applying the extrastimulation (S2) at decremental S1-S2 coupling intervals. For example, in a first stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of 300 ms following a train of baseline beats (SI); in a second stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of 290 ms following a train of baseline beats (SI); in a third stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of 280 ms following a train of baseline beats (SI); etc. More generally, in a first stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of x ms following a train of baseline beats (SI); in a second stimulation signal in a second stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of (x-y) ms following a train of baseline beats (SI); in a third stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of (x-2y) ms following a train of baseline beats (SI); etc. In some applications, the system automatically executes programmed electrical stimulation protocols, including S1-S2 decrements in steps of between 5 and 50 ms (e.g., 10-30 ms), to identify the coupling interval at which local tissue capsule fails, there is a conduction delay, block, or arrhythmia initiation occurs. For some applications, relatively small coupling interval adjustments, as described above, enable precise delineation of local tissue capture failure, conduction delay, decremental response, and repolarization behavior at each electrode site. As described above, for some applications, the stimulation signal is repeatedly applied until the repolarization period of a location within the heart is determined as the longest S1-S2 coupling interval that fails to capture tissue of the heart at the location. For some applications, the train of baseline beats and the extrastimulation are delivered via different electrodes from each other. For some applications, generally similar techniques to those described above are applied, but the extrastimulation signal is applied as an extrastimulation after a train of sinus beats, as an alternative to (or in addition to) being applied after the train of baseline beats. In such cases, the coupling interval between the train of sinus beats and the extrastimulation is varied over the series.

[0143] For some applications, the stimulation signal includes a series of stimulation signals in which trains of baseline beats (SI) are applied before applying the extrastimulation (S2) at incremental S1-S2 coupling intervals. For example, in a first stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of 60 ms following a train of baseline beats (SI); in a second stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of 80 ms following a train of baseline beats (SI); in a third stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of 100 ms following a train of baseline beats (SI); etc. More generally, in a first stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of x ms following a train of baseline beats (SI); in a second stimulation signal in a second stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of (x+y) ms following a train of baseline beats (SI); in a third stimulation signal, the extrastimulation (S2) may be applied at a coupling interval of (x+2y) ms following a train of baseline beats (SI); etc. In some applications, the system automatically executes programmed electrical stimulation protocols, including S1-S2 increments in steps of between 5 and 50 ms (e.g., 10-30 ms), to identify the coupling interval at which local tissue capsule fails, there is a conduction delay, block, or arrhythmia initiation occurs. For some applications, relatively small coupling interval adjustments, as described above, enable precise delineation of local tissue capture failure, conduction delay, decremental response, and repolarization behavior at each electrode site. As described above, for some applications, the stimulation signal is repeatedly applied until the repolarization period of a location within the heart is determined as the longest S1-S2 coupling interval that fails to capture tissue of the heart at the location. For some applications, the train of baseline beats and the extrastimulation are delivered via different electrodes from each other. For some applications, generally similar techniques to those described above are applied, but the extrastimulation signal is applied as an extrastimulation after a train of sinus beats, as an alternative to (or in addition to) being applied after the train of baseline beats. In such cases, the coupling interval between the train of sinus beats and the extrastimulation is varied over the series.

[0144] In some embodiments, the system automatically determines the next stimulation coupling interval based on prior capture response, allowing adaptive pacing sequences that optimize temporal resolution of repolarization recovery.

[0145] For some applications, the stimulation signal includes a series of stimulation signals in which the coupling interval between the baseline beats and the extrastimulation incrementally increases from a minimum coupling interval and incrementally decreases from a maximum coupling interval over the series. For some applications, the train of baseline beats (SI) is applied before applying the extrastimulation (S2) at a maximum (relatively high) S1-S2 coupling interval. In addition, the train of baseline beats (SI) is applied before applying an extrastimulation (S2) at a minimum (relatively low) S1-S2 coupling interval. The system then incrementally decreases the S1-S2 coupling interval from the maximum S1-S2 coupling interval, and incrementally increases the S1-S2 coupling interval from the minimum S1-S2 coupling interval, in order to home in on the coupling interval at which local tissue capsule fails, there is a conduction delay, block, or arrhythmia initiation occurs. For some applications, the train of baseline beats and the extrastimulation are delivered via different electrodes from each other. For some applications, generally similar techniques to those described above are applied, but the extrastimulation signal is applied as an extrastimulation after a train of sinus beats, as an alternative to (or in addition to) being applied after the train of baseline beats. In such cases, the coupling interval between the train of sinus beats and the extrastimulation is varied over the series.

[0146] For some applications, relatively small coupling interval adjustments, as described above, enable precise delineation of local tissue capture failure, conduction delay, decremental response, and repolarization behavior at each electrode site. As described above, for some applications, the stimulation signal is repeatedly applied until the repolarization period of a location within the heart is determined as the longest S1-S2 coupling interval that fails to capture tissue of the heart at the location a given stimulus strength.

[0147] Typically, the repolarization period at a given location within the subject’s heart is derived by determining the longest coupling interval that fails to capture the cardiac tissue at that location in response to a given stimulus strength. In some embodiments, the indication of repolarization is determined by directly determining the refractory period. For some applications, the refractory period is determined by measuring the effective or relative refractory period as the longest S1-S2 coupling interval that fails to capture tissue of the heart at a given stimulus strength (e.g., a multiple of (e.g., twice) the threshold or maximal stimulus strength). In some embodiments, the indication of repolarization is determined by signal analysis including calculating the activation-recovery interval. As mentioned, the frequency and intensity of stimulation signals are typically varied. In some embodiments, conduction and repolarization times are further calculated into arrhythmogenicity metrics.

[0148] Thus, in accordance with some applications, computer processor 28 drives stimulating currents via respective electrodes according to a sequence and pacing parameters, and detect electrical signals at others of the electrodes resulting from the stimulating currents. For some applications, based upon the detected electrical signals, the computer processor derives indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart. For some applications, the computer processor identifies at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality, in response to the indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

[0149] For some applications, the computer processor 28 drives stimulating currents via at least one of the electrodes at varying cycle lengths and / or coupling intervals, and detects electrical signals at others of the electrodes resulting from the stimulating currents. Based upon the detected electrical signals, the computer processor derives indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart. For some applications, the computer processor identifies at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality, in response to the indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

[0150] Reference is now made to Fig. IB, which is a schematic illustration of signals received from array 22 of electrodes 24 in response to automatic sequential stimulation of one or more electrodes within the array, indicating locations exhibiting heterogeneous electrical properties (in conduction and or repolarization), in accordance with some applications of the disclosure. Fig. IB shows an example of how signals are propagated between neighboring electrode locations. As indicated in the example shown in Fig. IB, in some regions the electrical signal propagates in a healthy manner between adjacent electrode locations, while in other regions, the signal is slowed or is blocked. By measuring such signals that indicate conduction and refractory metrics, the computer processor determines an indication of the conduction and / or the repolarization at the locations corresponding to the respective electrodes, thereby distinguishing arrhythmogenic from non-arrhythmogenic sites. Alternatively or additionally, arrhythmogenic sites are distinguished from non-arrhythmogenic sites by detecting the initiation of arrhythmia in response to stimulation.

[0151] In some applications, locations within the heart are identified as being sources (and / or drivers) of a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation) based upon the conduction and / or repolarization indications that are detected (in response to interrogation of the tissue by stimulation) at respective locations. Typically, locations exhibiting heterogeneous electrical properties (in conduction and or repolarization) are identified as being sources of a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation). For some applications, locations having electrical properties (e.g., conduction and / or repolarization) that exhibit local gradients relative to neighboring locations are identified as being sources of a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation). For some applications, locations exhibiting significant repolarization gradients and / or conduction discontinuities are identified as being sources of a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation).

[0152] For some applications, the computer processor is configured to detect the presence (or absence) of tissue capture by a stimulating event through the analysis of electrograms (e.g., electrograms received from electrodes located within or outside the multipolar catheter). This analysis typically includes evaluating signal frequency and depolarization timing between the electrodes.

[0153] For some applications, the computer processor detects the timing interval from the stimulating event (e.g., the driving of a stimulating current via a first one of the electrodes), or a surrogate of the stimulating event, to various signal components recorded by one or more of the electrodes within the patient’s heart. Typically, the computer processor thereby determines depolarization and / or repolarization times, as well as conduction time and the presence of conduction blocks. Typically, by measuring the timing interval, the computer processor determines local electrical properties of the heart tissue, including identifying abnormalities in conduction and / or repolarization that may contribute to a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation).

[0154] In some applications, the identified locations are targeted for ablation to modify the underlying cause of the heart rhythm abnormality. In some applications, the electrodes belonging to the multipolar catheter are used to ablate the identified locations (typically by radiofrequency and / or pulsed-field ablation), typically while maintaining the position of the multipolar catheter with respect to patient’s heart between the procedure for identifying the sources of a heart rhythm abnormality and the ablation of those locations. In this manner, the computer processor is able to ablate the tissue at exactly the set of locations that were identified as the sources of a heart rhythm abnormality.

[0155] In some applications, the computer processor generates a three-dimensional electro- anatomical map of at least a portion of the subject’s heart (e.g., a map of the entire heart or of one or more chambers of the heart) on an output device (such as display 32). The three-dimensional electro-anatomical map typically includes an anatomical shell of the portion of the subject’s heart, and an indication of the locations within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell. Typically, the indicated locations correspond to sites with high reentry vulnerability, representing potential sources or drivers of arrhythmias, and the indication of these sites upon the anatomical shell provides a target for ablation.

[0156] As described hereinabove, in some embodiments, the computer processor drives electrical current through the electrodes according to a predetermined sequence, thereby interrogating cardiac tissue. This sequence is typically designed to optimize the stimulation process by targeting specific regions of the heart, ensuring that the stimulation can detect critical conduction and repolarization properties necessary for accurate diagnosis. The automatic nature of the stimulation process is typically configured to provide an effective and efficient workflow, minimizing manual intervention, and allowing for precise, consistent delivery of electrical currents to the targeted areas.

[0157] In some embodiments, the computer processor drives one or more electrical pulses or trains of electrical pulses through the electrodes at varying frequencies, cycle lengths, coupling intervals, and / or current outputs. Typically, these variations are configured to allow for a comprehensive assessment of the heart's electrical properties. By adjusting the frequency, cycle length, coupling interval, and / or current intensity, the computer processor is configured to effectively probe the heart tissue's response to different stimuli, enhancing the ability to detect and characterize abnormal conduction and repolarization patterns that may contribute to complex rhythm disorders. This flexibility in stimulation parameters typically facilitates the identification of precise sites of arrhythmogenic activity and tailoring of the subsequent treatment.

[0158] As described hereinabove, typically, array 22 of electrodes 24 are disposed on flexible substrate 26, with the flexibility of the substrate maximizing the number of electrodes that are brought into direct contact with cardiac tissue of the patient. For some applications, the computer processor is configured to detect which of the electrodes are in contact with the cardiac tissue of the patient by analyzing signal characteristics, including amplitude, frequency, impedance, temporal and spatial stability. For some such applications, the computer processor subsequently applies current selectively only to those electrodes that are in contact with the cardiac tissue of the patient in order to identify locations that are sources of a heart rhythm abnormality and optionally to then ablate those locations.

[0159] As shown in Fig. 1A, system 10 typically includes display 32. For some applications, computer processor 28 overlays and displays calculated signal data, including repolarization times, repolarization gradients, an indication of locations within the heart with conduction discontinuities, an indication of locations exhibiting heterogeneous electrical properties, an indication of locations within the heart having electrical properties (e.g., conduction and / or repolarization) that exhibit local gradients relative to neighboring locations, and / or other data, directly onto a three-dimensional reconstructed anatomical shell representing the patient’s heart anatomy. For some applications, such locations are indicated as representing potential sources or drivers of heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation).

[0160] For some applications, the computer processor automatically determines a suitable strategy for ablating locations that are identified as potential sources or drivers of a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation). For some applications, the computer processor ablates tissue of the heart by driving an ablative current via a portion of the electrodes that correspond to the identified locations, in accordance with the determined ablation strategy. Alternatively or additionally, the computer processor generates an indication of the determined ablation strategy on display 32.

[0161] Reference is now made to Figs. 2A, 2B, and 2C, which are schematic illustrations of tissue with discontinuous conduction properties, in accordance with some applications of the disclosure. Figure 2A depicts tissue with seemingly normal properties under baseline conduction. However, stimulation of the tissue, in accordance with some applications of the present disclosure, reveals abnormal discontinuous conduction and repolarization (Figure 2B), leading to the initiation of reentrant tachycardia (Figure 2C). As shown, some tissue properties, including conduction and repolarization, may appear normal under baseline rhythm and conditions, concealing abnormalities. However, when the tissue is challenged with stimulation at shorter cycle lengths and / or coupling intervals, as illustrated in Figure 2B, abnormalities in electrical conduction and repolarization are revealed, which can promote arrhythmias. Under normal physiological conditions it may be challenging to identify such locations using conventional methods, because while the tissue is being mapped the physiological sinus rhythm may be sufficiently long that the tissue propagates the signal in a healthy manner. As described hereinabove, in accordance with some applications of the disclosure, the tissue is actively stimulated and the cycle length and / or coupling interval at which the tissue is stimulated and the direction from which the tissue is stimulated is varied, thereby providing a mechanism for detecting locations that act in the manner demonstrated by Figs. 2A-C.

[0162] Figs. 3 A and 3B shows reconstructed anatomical shells of a patient’s left atrium respectively in anterior and posterior projections, as generated using a commercially available electro-anatomical mapping system, with numbers representing the effective repolarization periods measured by pacing at each location, in accordance with some applications of the disclosure. As may be observed in Fig. 3A, there is one region 40 which exhibits a local repolarization gradient, with the effective repolarization period decreasing from 270 ms to 190 ms or from 280 ms to 200 ms over a relatively small distance.

[0163] In some applications, a location at which there is a local gradient in repolarization period and / or activation-repolarization interval that exceeds a threshold is identified as being a source of a heart rhythm abnormality (such as atrial fibrillation, ventricular tachycardia, and / or ventricular fibrillation). For some applications, the threshold repolarization gradient in repolarization period and / or activation-repolarization interval is between 20 ms per 10 mm and 200 ms per 10 mm (e.g., between 40 ms per 10 mm and 100 ms per 10 mm). For some applications, the threshold gradient in repolarization period and / or activation-repolarization interval is approximately 50 ms per 10 ms. In some applications, the system computes and displays spatial maps of the gradient of repolarization period and / or activation-repolarization interval in real-time to assist in identifying sites with abrupt local transitions in repolarization, which correspond to areas with increased vulnerability for reentry and therefore likely sources of a heart rhythm abnormality.

[0164] As noted above, the system identifies locations at which there are local gradients in repolarization period and / or activation-repolarization interval that exceed a threshold as being sources of a heart rhythm abnormality. For some applications, the stimulation protocol that is used to determine the repolarization period and / or activation-repolarization interval is varied from one procedure to another and / or the stimulation protocol is not in accordance with standard clinical protocols. However, since, within a given procedure, the difference in repolarization period and / or activation-repolarization interval between two or more adjacent electrode locations is being measured, the identification of locations as being sources of a heart rhythm abnormality is still effective.

[0165] Reference is now made to Fig. 4A, which shows electrical signals measured at respective cardiac locations after a train of beats and in accordance with certain applications of the disclosure, following extra-stimulation S2. This S2 stimulation at 210 ms after SI (i.e., the end of the train of beats) reveals slow and discontinuous conduction at this location, evident from the long and fractionated signals recorded on the multipolar electrodes after S2 stimulation. These abnormalities are not detected under baseline conditions, including during stimulation at longer coupling intervals. This example underscores the limitations of existing mapping technologies and highlights the advantages of active tissue stimulation that is applied as described herein, in order to expose arrhythmogenic properties. Under normal physiological conditions it may be challenging to identify such locations using conventional methods, because while the tissue is being mapped, the physiological sinus rhythm may be sufficiently long that the tissue propagates the signal in a healthy manner. As described hereinabove, in accordance with some applications of the disclosure, the tissue is actively stimulated and the coupling interval at which the tissue is stimulated and the direction from which the tissue is stimulated is varied, thereby providing a mechanism for detecting locations that act in the manner demonstrated in Fig. 4A.

[0166] Reference is also made to Fig. 4B, which shows electrical signals measured at the same cardiac location as in Fig. 4A but in response to S2 stimulation at a shorter coupling interval from SI of 200 ms. Reducing the coupling interval from 210 ms (Figure 4 A) to 200 ms, in accordance with certain applications of the disclosure, results in the initiation of atrial fibrillation. This is a further example that underscores the limitations of existing mapping technologies and highlights the advantages of active tissue stimulation that is applied as described herein, in order to expose arrhythmogenic properties. Under normal physiological conditions it may be challenging to identify such locations using conventional methods, because while the tissue is being mapped, the physiological sinus rhythm may be sufficiently long that the tissue propagates the signal in a healthy manner. As described hereinabove, in accordance with some applications of the disclosure, the tissue is actively stimulated and the coupling interval at which the tissue is stimulated and the direction from which the tissue is stimulated is varied, thereby providing a mechanism for detecting locations that act in the manner demonstrated in Fig. 4B.

[0167] Fig. 5 is a flow diagram indicating the mechanism of atrial fibrillation initiation triggered by an atrial premature contraction, which is conceptually similar to pacing at a shorter coupling interval (i.e., a shorter S1-S2 interval). Premature stimulation of the tissue leads to slower conduction and shortened recovery of excitability (refractory period), resulting in heterogeneous conduction and refractory properties that promote arrhythmia initiation. As indicated on the right of Fig. 5, as the S1-S2 coupling interval decreases, the combination of conduction slowing or blocking with shortening of the refractory period, leads to reentry and arrythmia. While these characteristics are often challenging to detect under physiological conditions, they can be revealed through targeted tissue stimulation in accordance with certain applications of the disclosure.

[0168] Applications of the disclosure described herein can take the form of a computer program product accessible from a computer-usable or computer-readable medium (e.g., a non-transitory computer-readable medium) providing program code for use by or in connection with a computer or any instruction execution system, such as computer processor 28. For the purposes of this description, a computer-usable or computer readable medium can be any apparatus that can comprise, store, communicate, propagate, or transport the program for use by or in connection with the instruction execution system, apparatus, or device. The medium can be an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system (or apparatus or device) or a propagation medium. Typically, the computer-usable or computer readable medium is a non- transitory computer-usable or computer readable medium.

[0169] Examples of a computer-readable medium include a semiconductor or solid-state memory, magnetic tape, a removable computer diskette, a random-access memory (RAM), a read-only memory (ROM), a rigid magnetic disk and an optical disk. Current examples of optical disks include compact disk-read only memory (CD-ROM), compact disk-read / write (CD-R / W) and DVD.

[0170] A data processing system suitable for storing and / or executing program code will include at least one processor (e.g., computer processor 28) coupled directly or indirectly to memory elements through a system bus. The memory elements can include local memory employed during actual execution of the program code, bulk storage, and cache memories which provide temporary storage of at least some program code in order to reduce the number of times code must be retrieved from bulk storage during execution. The system can read the inventive instructions on the program storage devices and follow these instructions to execute the methodology of the embodiments of the disclosure.

[0171] Network adapters may be coupled to the processor to enable the processor to become coupled to other processors or remote printers or storage devices through intervening private or public networks. Modems, cable modem and Ethernet cards are just a few of the currently available types of network adapters. Computer program code for carrying out operations of the present disclosure may be written in any combination of one or more programming languages, including an object-oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the C programming language or similar programming languages.

[0172] It will be understood that algorithms described herein, can be implemented by computer program instructions. These computer program instructions may be provided to a processor of a general-purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer (e.g., computer processor 28) or other programmable data processing apparatus, create means for implementing the functions / acts specified in the algorithms described in the present application. These computer program instructions may also be stored in a computer-readable medium (e.g., a non-transitory computer-readable medium) that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable medium produce an article of manufacture including instruction means which implement the function / act specified in the flowchart blocks and algorithms. The computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions / acts specified in the algorithms described in the present application.

[0173] Computer processor 28 is typically a hardware device programmed with computer program instructions to produce a special purpose computer. For example, when programmed to perform the algorithms described herein, computer processor 28 typically acts as a special purpose cardiacrhythm-disorder-mapping computer processor. Typically, the operations described herein that are performed by computer processor 28 transform the physical state of a memory, which is a real physical article, to have a different magnetic polarity, electrical charge, or the like depending on the technology of the memory that is used.

[0174] It will be appreciated by persons skilled in the art that the present disclosure is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present disclosure includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description.

Claims

CLAIMS1. Apparatus comprising: a multipolar catheter comprising an array of multiple electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart; and at least one computer processor configured to: drive stimulating currents via respective electrodes according to a sequence and pacing parameters, and detect electrical signals at others of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, derive indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identify at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

2. The apparatus according to claim 1, wherein the computer processor is configured to calculate arrhythmogenicity metrics for respective locations within the subject’s heart based on the indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

3. The apparatus according to claim 1, wherein the apparatus is for use with an output device and wherein the computer processor is configured to generate a three-dimensional electro- anatomical map of at least a portion of the subject’s heart on the output device, the three- dimensional electro-anatomical map comprising: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

4. The apparatus according to any one of claims 1-3, wherein the computer processor is configured to identify at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality by detecting locations that exhibit local gradients in repolarization period and / or activati on-repolarization interval relative to neighboring locations.

5. The apparatus according to claim 4, wherein the computer processor is configured to identify locations at which there is a gradient in repolarization period and / or activation-repolarization interval of between 20 ms per 10 mm and 200 ms per 10 mm as being sources of a heart rhythm abnormality.

6. The apparatus according to any one of claims 1-3, wherein the computer processor is configured to automatically drive the stimulating currents via respective electrodes according to a predetermined sequence and predetermined pacing parameters.

7. The apparatus according to claim 6, wherein the computer processor is configured to automatically drive stimulating currents via respective electrodes according to predetermined pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

8. The apparatus according to any one of claims 1-3, wherein the computer processor is configured to drive the stimulating currents via respective electrodes according to a dynamically determined sequence and pacing parameters.

9. The apparatus according to claim 8, wherein the computer processor is configured to drive stimulating currents via respective electrodes according to dynamically determined pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

10. The apparatus according to any one of claims 1-3, wherein the computer processor is configured to detect one or more signal characteristics and to thereby determine that only some of the electrode are in contact with tissue of the heart.

11. The apparatus according to claim 10, wherein the computer processor is configured to apply the stimulation currents only via electrodes that are in contact with the tissue of the heart.

12. The apparatus according to any one of claims 1-3, wherein the computer processor is configured to receive electrograms and to thereby detect a presence of tissue capture in response to a stimulating current that was driven via one or more of the electrodes.

13. The apparatus according to claim 12, wherein the computer processor is configured to detect the presence of tissue capture by evaluating signal frequency and depolarization timing between the electrodes.

14. The apparatus according to any one of claims 1-3, wherein the computer processor is configured to drive stimulating currents via at least one of the electrodes at varying coupling intervals, and to derive indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals.

15. The apparatus according to claim 14, wherein the computer processor is configured to derive a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

16. The apparatus according to claim 14, wherein the computer processor is configured to derive an indication of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by signal analysis that comprises calculating activationrecovery intervals at the given location.

17. The apparatus according to claim 14, wherein the computer processor is configured to derive an indication of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by directly determining a refractory period at the given location.

18. The apparatus according to claim 17, wherein the computer processor is configured to directly determine the refractory period at the given location by measuring the refractory period as a longest coupling interval that fails to capture tissue of the heart in response to a given stimulus strength.

19. The apparatus according to any one of claims 1-3, wherein the computer processor is configured to drive stimulating currents via respective electrodes by driving a series of stimulation signals via at least one of the electrodes, wherein each of the stimulation signals comprises an extrastimulation following a train of beats and wherein a coupling interval between the train of beats and the extrastimulation varies over the series.

20. The apparatus according to claim 19, wherein the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving a train of baseline beats followed by the extrastimulation, wherein a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

21. The apparatus according to claim 19, wherein the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving the extrastimulation following a train of sinus beats, wherein a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

22. The apparatus according to claim 19, wherein the computer processor is configured to derive a repolarization period at a given location within the subject’s heart by determining alongest coupling interval that fails to capture tissue of the heart at the given location in response to a given stimulus strength.

23. The apparatus according to claim 19, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

24. The apparatus according to claim 19, wherein the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

25. The apparatus according to claim 19, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

26. Apparatus comprising: two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart; and at least one computer processor configured to: drive stimulating currents via at least one of the electrodes at varying coupling intervals, and detect electrical signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, derive indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identify at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

27. The apparatus according to claim 26, wherein the computer processor is configured to calculate arrhythmogenicity metrics for respective locations within the subject’s heart at least partially based on the indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

28. The apparatus according to claim 26, wherein the apparatus is for use with an output device and wherein the computer processor is configured to generate a three-dimensional electro- anatomical map of at least a portion of the subject’s heart on the output device, the three- dimensional electro-anatomical map comprising: an anatomical shell of the portion of the subject’s heart, andan indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

29. The apparatus according to claim 26, wherein the computer processor is configured to derive a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

30. The apparatus according to claim 26, wherein the computer processor is configured to derive indications of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by signal analysis that comprises calculating activationrecovery intervals at the given location.

31. The apparatus according to any one of claims 26-30, wherein the computer processor is configured to identify at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality by detecting locations that exhibit local gradients in repolarization period and / or activati on-repolarization interval relative to neighboring locations.

32. The apparatus according to claim 31, wherein the computer processor is configured to detect locations at which there is a gradient in repolarization period and / or activation- repolarization interval of between 20 ms per 10 mm and 200 ms per 10 mm as being sources of a heart rhythm abnormality.

33. The apparatus according to any one of claims 26-30, wherein the computer processor is configured to derive indications of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by directly determining a refractory period at the given location.

34. The apparatus according to claim 33, wherein the computer processor is configured to directly determine the refractory period at the given location by measuring the refractory period as a longest coupling interval that fails to capture tissue of the heart in response to a given stimulus strength.

35. The apparatus according to any one of claims 26-30, wherein the electrodes comprise an array of multiple electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart.

36. The apparatus according to claim 35, wherein the computer processor is configured to automatically drive stimulating currents via respective electrodes according to a predetermined sequence.

37. The apparatus according to claim 35, wherein the computer processor is configured to automatically drive stimulating currents via respective electrodes according to a dynamically determined sequence.

38. The apparatus according to claim 35, wherein the computer processor is configured to automatically drive stimulating currents via respective electrodes according to pacing parameters that include one or more parameters selected from the group consisting of frequency, cycle length, coupling interval, and current.

39. The apparatus according to any one of claims 26-30, wherein the computer processor is configured to drive stimulating currents via at least one of the electrodes at varying coupling intervals by driving a series of stimulation signals via the at least one of the electrodes, wherein each of the stimulation signals comprises an extrastimulation following a train of beats and wherein a coupling interval between the train of beats and the extrastimulation varies over the series.

40. The apparatus according to claim 39, wherein the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving a train of baseline beats followed by the extrastimulation, wherein a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

41. The apparatus according to claim 39, wherein the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving the extrastimulation following a train of sinus beats, wherein a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

42. The apparatus according to claim 39, wherein the computer processor is configured to derive a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location at the given location in response to a given stimulus strength.

43. The apparatus according to claim 39, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

44. The apparatus according to claim 39, wherein the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

45. The apparatus according to claim 39, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum interval over the series.

46. Apparatus comprising: an output device; two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart; and at least one computer processor configured to: drive stimulating currents via at least one of the electrodes, and detect electrical conduction signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical conduction signals, derive indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; in response thereto, identify at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality; and generate a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three-dimensional electro-anatomical map comprising: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

47. The apparatus according to claim 46, wherein the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell correspond to sites with high reentry vulnerability.

48. The apparatus according to claim 46 or claim 47, wherein the computer processor is configured to automatically determine a suitable strategy for ablating locations that are identified as being sources of the heart rhythm abnormality.

49. The apparatus according to claim 48, wherein the computer processor is configured to generate an indication of the determined ablation strategy on the output device.

50. The apparatus according to claim 46 or claim 47, wherein the computer processor is configured to drive stimulating currents via at least one of the electrodes by driving a series of stimulation signals via the at least one of the electrodes, wherein each of the stimulation signals comprises an extrastimulation following a train of beats and wherein a coupling interval between the train of beats and the extrastimulation varies over the series.

51. The apparatus according to claim 50, wherein the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving a train of baseline beats followed by the extrastimulation, wherein a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

52. The apparatus according to claim 50, wherein the computer processor is configured to drive each of the series of stimulation signals via the at least one of the electrodes by driving the extrastimulation following a train of sinus beats, wherein a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

53. The apparatus according to claim 50, wherein the computer processor is configured to derive a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

54. The apparatus according to claim 50, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

55. The apparatus according to claim 50, wherein the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

56. The apparatus according to claim 50, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

57. A computer software product for use with an array of multiple electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the computer software product comprising a non-transitory computer-readable medium in which program instructions are stored, which instructions, when read by a computer cause the computer to perform the steps of driving stimulating currents via respective electrodes according to a sequence and pacing parameters, and detecting electrical signals at others of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; andin response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

58. The computer software product according to claim 57, wherein deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart comprises calculating arrhythmogenicity metrics for respective locations within the subject’s heart based on the indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

59. The computer software product according to claim 57, wherein the instructions, when read by the computer further cause the computer to perform the step of: generating a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three-dimensional electro-anatomical map comprising: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

60. The computer software product according to any one of claims 57-59, wherein identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality comprises detecting locations that exhibit local gradients in repolarization period and / or activation-repolarization interval relative to neighboring locations.

61. The computer software product according to claim 60, wherein the instructions, when read by the computer cause the computer to perform the step of identifying locations at which there is a gradient in repolarization period and / or activation-repolarization interval of between 20 ms per 10 mm and 200 ms per 10 mm as being sources of a heart rhythm abnormality.

62. The computer software product according to any one of claims 57-59, wherein driving stimulating currents via respective electrodes according to the sequence and pacing parameters comprises automatically driving the stimulating currents via respective electrodes according to a predetermined sequence and predetermined pacing parameters.

63. The computer software product according to claim 62, wherein automatically driving the stimulating currents via respective electrodes according to the predetermined sequence and predetermined pacing parameters comprises automatically driving stimulating currents via respective electrodes according to predetermined pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

64. The computer software product according to any one of claims 57-59, wherein driving stimulating currents via respective electrodes according to the sequence and pacing parameters comprises driving the stimulating currents via respective electrodes according to a dynamically determined sequence and pacing parameters.

65. The computer software product according to claim 64, wherein driving the stimulating currents via respective electrodes according to the dynamically determined sequence and pacing parameters comprises driving stimulating currents via respective electrodes according to pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

66. The computer software product according to any one of claims 57-59, wherein the instructions, when read by the computer further cause the computer to perform the step of detecting one or more signal characteristics and thereby determining that only some of the electrode are in contact with tissue of the heart.

67. The computer software product according to claim 66, wherein driving stimulating currents via respective electrodes according to the sequence and pacing parameters comprises applying the stimulation currents only via electrodes that are in contact with the tissue of the heart.

68. The computer software product according to any one of claims 57-59, wherein the instructions, when read by the computer further cause the computer to perform the step of receiving electrograms, thereby detecting a presence of tissue capture in response to a stimulating current that was driven via one or more of the electrodes.

69. The computer software product according to claim 68, wherein detecting the presence of tissue capture in response to a stimulating current that was driven via one or more of the electrodes comprises evaluating signal frequency and depolarization timing between the electrodes.

70. The computer software product according to any one of claims 57-59, wherein driving stimulating currents via respective electrodes according to the sequence and pacing parameters comprises driving stimulating currents via at least one of the electrodes at varying coupling intervals, and wherein the instructions, when read by the computer further cause the computer to perform the step of deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals.

71. The computer software product according to claim 70, wherein deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respectiveelectrodes contact the tissue of the heart based upon the detected electrical signals comprises deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

72. The computer software product according to claim 70, wherein deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals comprises deriving an indication of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by signal analysis that comprises calculating activation-recovery intervals at the given location.

73. The computer software product according to claim 70, wherein deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals comprises deriving an indication of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by directly determining a refractory period at the given location.

74. The computer software product according to claim 73, wherein directly determining a refractory period at the given location comprises measuring the refractory period as a longest coupling interval that fails to capture tissue of the heart in response to a given stimulus strength.

75. The computer software product according to any one of claims 57-59, wherein driving stimulating currents via respective electrodes comprises driving a series of stimulation signals via at least one of the electrodes, wherein each of the stimulation signals comprises an extrastimulation following a train of beats and wherein a coupling interval between the train of beats and the extrastimulation varies over the series.

76. The computer software product according to claim 75, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving a train of baseline beats followed by the extrastimulation, and wherein a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

77. The computer software product according to claim 75, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving the extrastimulation following a train of sinus beats, wherein a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

78. The computer software product according to claim 75, wherein the instructions, when read by the computer cause the computer to perform the step of deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

79. The computer software product according to claim 75, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

80. The computer software product according to claim 75, wherein the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

81. The computer software product according to claim 75, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

82. A computer software product for use with two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the computer software product comprising a non-transitory computer-readable medium in which program instructions are stored, which instructions, when read by a computer cause the computer to perform the steps of: driving stimulating currents via at least one of the electrodes at varying coupling intervals; detecting electrical signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

83. The computer software product according to claim 82, wherein the computer software product is for use with an array of multiple electrodes and wherein driving stimulating currents via at least one of the electrodes at varying coupling intervals comprises automatically driving stimulating currents via respective electrodes according to a predetermined sequence.

84. The computer software product according to claim 82, wherein the computer software product is for use with an array of multiple electrodes and wherein driving stimulating currents via at least one of the electrodes at varying coupling intervals comprises automatically driving stimulating currents via respective electrodes according to a dynamically determined sequence.

85. The computer software product according to claim 82, wherein the computer software product is for use with an array of multiple electrodes and wherein driving stimulating currents via at least one of the electrodes at varying coupling intervals comprises automatically driving stimulating currents via respective electrodes according to predetermined pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

86. The computer software product according to claim 82, wherein the instructions, when read by the computer further cause the computer to perform the step of calculating arrhythmogenicity metrics for respective locations within the subject’s heart at least partially based on the indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

87. The computer software product according to claim 82, wherein the instructions, when read by the computer further cause the computer to perform the step of generating a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on an output device, the three- dimensional electro-anatomical map comprising: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

88. The computer software product according to claim 82, wherein deriving indications of repolarization at the given location within the subject’s heart at which the respective electrodes contacts the tissue of the heart comprises deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

89. The computer software product according to claim 82, wherein deriving indications of repolarization at the given location within the subject’s heart at which the given electrode contacts the tissue of the heart comprises using signal analysis that comprises calculating activationrecovery intervals at the given location.

90. The computer software product according to any one of claims 82-89, wherein identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality comprises detecting locations that exhibit local gradients in repolarization period and / or activation-repolarization interval relative to neighboring locations.

91. The computer software product according to claim 90, wherein the instructions, when read by the computer cause the computer to perform the step of identifying locations at which there isa gradient in repolarization period and / or activati on-repolarization interval of between 20 ms per 10 mm and 200 ms per 10 mm as being sources of a heart rhythm abnormality.

92. The computer software product according to any one of claims 82-89, wherein deriving indications of repolarization at the given location within the subject’s heart at which the given electrode contacts the tissue of the heart comprises directly determining a refractory period at the given location.

93. The computer software product according to claim 92, wherein directly determining the refractory period at the given location comprises measuring the refractory period as a longest coupling interval that fails to capture tissue of the heart in response to a given stimulus strength.

94. The computer software product according to any one of claims 82-89, wherein driving stimulating currents via at least one of the electrodes at varying coupling intervals comprises driving a series of stimulation signals via the at least one of the electrodes, wherein each of the stimulation signals comprises an extrastimulation following a train of beats and wherein a coupling interval between the train of beats and the extrastimulation varies over the series.

95. The computer software product according to claim 94, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving a train of baseline beats followed by the extrastimulation, and wherein a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

96. The computer software product according to claim 94, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving the extrastimulation following a train of sinus beats, wherein a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

97. The computer software product according to claim 94, wherein the instructions, when read by the computer cause the computer to perform the step of deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

98. The computer software product according to claim 94, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

99. The computer software product according to claim 94, wherein the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

100. The computer software product according to claim 94, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

101. A computer software product for use with two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the computer software product comprising a non-transitory computer-readable medium in which program instructions are stored, which instructions, when read by a computer cause the computer to perform the steps of: driving stimulating currents via at least one of the electrodes, and detecting electrical conduction signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical conduction signals, deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality; and generating a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three-dimensional electro-anatomical map comprising: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

102. The computer software product according to claim 101, wherein the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell correspond to sites with high reentry vulnerability.

103. The computer software product according to claim 101 or 102, wherein the instructions, when read by the computer further cause the computer to perform the step of automatically determining a suitable strategy for ablating locations that are identified as being sources of the heart rhythm abnormality.

104. The computer software product according to claim 103, wherein the instructions, when read by the computer further cause the computer to perform the step of generating an indication of the determined ablation strategy on the output device.

105. The computer software product according to claim 101 or claim 102, wherein driving stimulating currents via at least one of the electrodes comprises driving a series of stimulationsignals via the at least one of the electrodes, wherein each of the stimulation signals comprises an extrastimulation following a train of beats and wherein a coupling interval between the train of beats and the extrastimulation varies over the series.

106. The computer software product according to claim 105, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving a train of baseline beats followed by the extrastimulation, and wherein a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

107. The computer software product according to claim 105, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving the extrastimulation following a train of sinus beats, wherein a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

108. The computer software product according to claim 105, wherein the instructions, when read by the computer cause the computer to perform the step of deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

109. The computer software product according to claim 105, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

110. The computer software product according to claim 105, wherein the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

111. The computer software product according to claim 105, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

112. A method for use with an array of multiple electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the method comprising: using at least one computer processor: driving stimulating currents via respective electrodes according to a sequence and pacing parameters, and detecting electrical signals at others of the electrodes resulting from the stimulating currents,based upon the detected electrical signals, deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

113. The method according to claim 112, wherein deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart comprises calculating arrhythmogenicity metrics for respective locations within the subject’s heart based on the indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

114. The method according to claim 112, further comprising generating a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three- dimensional electro-anatomical map comprising: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

115. The method according to any one of claims 112-114, wherein identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality comprises detecting locations that exhibit local gradients in repolarization period and / or activation- repolarization interval relative to neighboring locations.

116. The method according to claim 115, wherein identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality comprises identifying locations at which there is a gradient in repolarization period and / or activation-repolarization interval of between 20 ms per 10 mm and 200 ms per 10 mm as being sources of a heart rhythm abnormality.

117. The method according to any one of claims 112-114, wherein driving stimulating currents via respective electrodes according to the sequence and pacing parameters comprises automatically driving the stimulating currents via respective electrodes according to a predetermined sequence and predetermined pacing parameters.

118. The method according to claim 117, wherein automatically driving the stimulating currents via respective electrodes according to the predetermined sequence and predetermined pacing parameters comprises automatically driving stimulating currents via respective electrodesaccording to predetermined pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, coupling interval, and current.

119. The method according to any one of claims 112-114, further comprising detecting one or more signal characteristics and thereby determining that only some of the electrode are in contact with tissue of the heart.

120. The method according to claim 119, wherein driving stimulating currents via respective electrodes according to the sequence and pacing parameters comprises applying the stimulation currents only via electrodes that are in contact with the tissue of the heart.

121. The method according to any one of claims 112-114, further comprising receiving electrograms at the at least one computer processor and thereby detecting a presence of tissue capture in response to a stimulating current that was driven via one or more of the electrodes.

122. The method according to claim 121, wherein detecting the presence of tissue capture in response to a stimulating current that was driven via one or more of the electrodes comprises evaluating signal frequency and depolarization timing between the electrodes.

123. The method according to any one of claims 112-114, wherein driving stimulating currents via respective electrodes according to the sequence and pacing parameters comprises driving stimulating currents via at least one of the electrodes at varying coupling intervals, the method comprising deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals.

124. The method according to claim 123, wherein deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals comprises deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

125. The method according to claim 123, wherein deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart based upon the detected electrical signals comprises deriving an indication of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by signal analysis that comprises calculating activation-recovery intervals at the given location.

126. The method according to claim 123, wherein deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heartbased upon the detected electrical signals comprises deriving an indication of repolarization at a given location within the subject’s heart at which a given electrode contacts the tissue of the heart by directly determining a refractory period at the given location.

127. The method according to claim 126, wherein directly determining a refractory period at the given location comprises measuring the refractory period as a longest coupling interval that fails to capture tissue of the heart in response to a given stimulus strength.

128. The method according to any one of claims 112-114, wherein driving stimulating currents via respective electrodes comprises driving a series of stimulation signals via at least one of the electrodes, wherein each of the stimulation signals comprises an extrastimulation following a train of beats and wherein a coupling interval between the train of beats and the extrastimulation varies over the series.

129. The method according to claim 128, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving a train of baseline beats followed by the extrastimulation, and wherein a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

130. The method according to claim 128, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving the extrastimulation following a train of sinus beats, wherein a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

131. The method according to claim 128, wherein deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart comprises deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

132. The method according to claim 128, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

133. The method according to claim 128, wherein the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

134. The method according to claim 128, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

135. A method for use with two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the method comprising: using at least one computer processor: driving stimulating currents via at least one of the electrodes at varying coupling intervals; detecting electrical signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical signals, deriving indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart; and in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality.

136. The method according to claim 135, wherein the method is for use with an array of multiple electrodes and wherein driving stimulating currents via at least one of the electrodes at varying coupling intervals comprises automatically drive stimulating currents via respective electrodes according to a predetermined sequence.

137. The method according to claim 135, wherein the method is for use with an array of multiple electrodes and wherein driving stimulating currents via at least one of the electrodes at varying coupling intervals comprises automatically drive stimulating currents via respective electrodes according to a dynamically determined sequence.

138. The method according to claim 135, wherein the method is for use with an array of multiple electrodes and wherein driving stimulating currents via at least one of the electrodes at varying coupling intervals comprises automatically driving stimulating currents via respective electrodes according to predetermined pacing parameters that include one or more parameters selected from the group consisting of: frequency, cycle length, and current.

139. The method according to claim 135, further comprising calculating arrhythmogenicity metrics for respective locations within the subject’s heart at least partially based on the indications of repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart.

140. The method according to claim 135, further comprising generating a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on an output device, the three- dimensional electro-anatomical map comprising:an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

141. The method according to claim 135, wherein deriving indications of repolarization at the given location within the subject’s heart at which the respective electrodes contact the tissue of the heart comprises deriving a repolarization period at a given location within the subject’s heart by determining a longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

142. The method according to claim 135, wherein deriving indications of repolarization at the given location within the subject’s heart at which the given electrode contacts the tissue of the heart comprises using signal analysis that comprises calculating activation-recovery intervals at the given location.

143. The method according to any one of claims 135-142, wherein identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality comprises detecting locations that exhibit local gradients in repolarization period and / or activation- repolarization interval relative to neighboring locations.

144. The method according to claim 143, wherein identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality comprises identifying locations at which there is a gradient in repolarization period and / or activation-repolarization interval of between 20 ms per 10 mm and 200 ms per 10 mm as being sources of a heart rhythm abnormality.

145. The method according to any one of claims 135-142, wherein deriving indications of repolarization at the given location within the subject’s heart at which the given electrode contacts the tissue of the heart comprises directly determining a refractory period at the given location.

146. The method according to claim 145, wherein directly determining the refractory period at the given location comprises measuring the refractory period as a longest coupling interval that fails to capture tissue of the heart in response to a given stimulus strength.

147. The method according to any one of claims 135-142, wherein driving stimulating currents via at least one of the electrodes comprises driving a series of stimulation signals via the at least one of the electrodes, wherein each of the stimulation signals comprises an extrastimulation following a train of beats and wherein a coupling interval between the train of beats and the extrastimulation varies over the series.

148. The method according to claim 147, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving a train of baseline beats followed by the extrastimulation, and wherein a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

149. The method according to claim 147, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving the extrastimulation following a train of sinus beats, wherein a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

150. The method according to claim 147, wherein deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart comprises deriving a repolarization period at a given location within the subj ect’ s heart at which a given electrode contacts the tissue of the heart by determining the longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

151. The method according to claim 147, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

152. The method according to claim 147, wherein the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

153. The method according to claim 147, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

154. A method for use with an output device and two or more electrodes at least a portion of which are configured to be placed in contact with tissue of a heart of a subject at respective locations within the subject’s heart, the method comprising: using at least one computer processor: driving stimulating currents via at least one of the electrodes, and detecting electrical conduction signals at at least one other of the electrodes resulting from the stimulating currents, based upon the detected electrical conduction signals, deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart;in response thereto, identifying at least some of the locations within the subject’s heart as being sources of a heart rhythm abnormality; and generating a three-dimensional electro-anatomical map of at least a portion of the subject’s heart on the output device, the three-dimensional electro-anatomical map comprising: an anatomical shell of the portion of the subject’s heart, and an indication of the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell.

155. The method according to claim 154, wherein the locations identified within the subject’s heart as being sources of the heart rhythm abnormality overlaid on the anatomical shell correspond to sites with high reentry vulnerability.

156. The method according to claim 154 or claim 155, further comprising automatically determining a suitable strategy for ablating locations that are identified as being sources of the heart rhythm abnormality.

157. The method according to claim 156, further comprising generating an indication of the determined ablation strategy on the output device.

158. The method according to claim 154 or claim 155, wherein driving stimulating currents via at least one of the electrodes comprises driving a series of stimulation signals via the at least one of the electrodes, wherein each of the stimulation signals comprises an extrastimulation following a train of beats and wherein a coupling interval between the train of beats and the extrastimulation varies over the series.

159. The method according to claim 158, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving a train of baseline beats followed by the extrastimulation, and wherein a coupling interval between the train of baseline beats and the extrastimulation varies over the series.

160. The method according to claim 158, wherein driving each of the series of stimulation signals via the at least one of the electrodes comprises driving the extrastimulation following a train of sinus beats, wherein a coupling interval between the train of sinus beats and the extrastimulation varies over the series.

161. The method according to claim 158, wherein deriving indications of conduction and / or repolarization at the locations within the subject’s heart at which respective electrodes contact the tissue of the heart comprises deriving a repolarization period at a given location within thesubj ect’ s heart at which a given electrode contacts the tissue of the heart by determining the longest coupling interval that fails to capture the tissue of the heart at the given location in response to a given stimulus strength.

162. The method according to claim 158, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases over the series.

163. The method according to claim 158, wherein the coupling interval between the train of beats and the extrastimulation incrementally decreases over the series.

164. The method according to claim 158, wherein the coupling interval between the train of beats and the extrastimulation incrementally increases from a minimum coupling interval and decreases from a maximum coupling interval over the series.

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