HK1182979B - Method and device for three-stage atrial cardioversion therapy - Google Patents

Description

Methods and devices for three-stage atrial cardioversion therapy

Technical Field

The present disclosure relates generally to the treatment of atrial arrhythmias, such as atrial fibrillation ("AF") and atrial flutter ("AFl"). In particular, the present disclosure relates to devices and methods for delivering low-energy electrical stimulation using implantable devices that deliver three-stage atrial cardioversion therapy to disrupt and terminate the reentry mechanisms that maintain AF and AFl.

Background

Atrial tachyarrhythmias are the most common atrial arrhythmias and it is currently estimated that approximately 230 million americans are suffering from this disease. There are two main forms of atrial tachyarrhythmia: AF and AFl, respectively, with a rate of incidence of chronic disease forms of about 10: 1. current project studies show that by 2050, 1,200 to 1,500 million americans will suffer from AF. The severity of this problem has been increased by clinical outcomes that have been well documented, such as thromboembolic stroke, congestive heart failure ("CHF"), cognitive dysfunction, and possibly increased mortality.

Many different factors may contribute to the occurrence and persistence of AF and AFl. Certain heart diseases predispose patients to AF, including coronary artery disease, pericarditis, mitral valve disease, congenital heart disease, congestive heart failure, thyrotoxic heart disease, and hypertension. Many of these diseases are thought to promote AF by increasing atrial pressure and/or causing atrial dilation. AF can also occur in individuals without any significant heart disease or systemic disease, a condition known as "solitary AF," which is primarily related to the autonomic nervous system.

AF and AFl are maintained by a reentry mechanism. Specifically, the atrial tissue continues to self-fire, creating reentry, i.e.: cyclic or whirlwind-like excitation. AFl is generally defined as a macro reentrant circuit that is capable of rotating around a functional block or anatomical line. The primary anatomy is typically used to define one or more synchronous reentrant circuits, including the region between the superior and inferior vena cava in the right atrium and the pulmonary vein region in the left atrium. If the reentry cycle time (CL) lasts relatively long, one-to-one conduction can remain throughout the entire atrium and AFl can be observed. However, if the reentry circuit cycle time is short enough, the excitation wave generated by the reentry circuit ends around the atrial tissue and AF ensues. The morphology of the electrogram during AFl or AF depends on the anatomical location and frequency of the arrhythmogenic reentrant circuit.

There is a clear interaction between AF and AFl. AFl is defined as the presence of an independent, persistent and stable reentrant circuit. On the other hand, AF is due to random activation in which a plurality of reentrant microwaves of the main circulation type (mother rotor) are continuously circulated in a direction determined by local excitability, heat resistance and anatomical structure. AF can be converted to AFl and vice versa, either spontaneously or as a result of an intervention, which may be drug administration, direct cardioversion, or atrial pacing.

AF is the most common clinical arrhythmia in the world and is a potential cause of increased morbidity and mortality in the elderly. Although there are some drug treatment options, drug treatment is ineffective for some patients, especially those with sudden AF. In addition, antiarrhythmic drugs have serious proarrhythmic side effects. Thus, there is a need for non-drug treatment of AF.

An alternative to AF medication is cardiac ablation. Despite great advances in ablation techniques, these methods are not without risk. The risks include cardiac perforation, esophageal injury, embolism, phrenic nerve injury, and pulmonary vein stenosis. There are also implantable devices currently on the market for treating atrial tachyarrhythmias. Some of these devices are applied to near-field overdrive pacing, also known as anti-tachycardia pacing ("ATP"); conventional high-energy far-field defibrillation shocks; or a combination of both. As described above, ATP operates on the principle of delivering a burst of stimulated cardiac pacing at an empirically selected frequency at a single pacing point, such as in U.S. patent No. 5,562,708 to Combs et al, to stimulate the excitable gap of the reentry circuit, interrupting and terminating the circuit.

Alternative classes of far field electrodes and ATP, known as far field overdrive pacing delivery, have been proposed for use in implantable devices, such as in U.S. patent No. 5,265,600 to Adams et al, U.S. patent No. 5,676,687 to Ayers, U.S. patent No. 6,510,342 to Park et al, U.S. patent No. 6,813,516 to Ujhelyi et al, and U.S. patent nos. 7,079,891 and 7,113,822 to Kroll. Both U.S. patent No. 5,676,687 to Ayers and U.S. patent No. 6,185,459 to Mehra et al disclose overdrive pacing devices that use near-field electrodes instead of far-field electrode delivery. The overdrive pacing devices disclosed in these patents are used in conjunction with a conventional class of defibrillation treatments in which overdrive pacing is used to prevent the recurrence of AF.

While ATP can work with slower AFl, the effectiveness of ATP decreases when the cycle time is below about 200 microseconds ("ms"), and fails with faster AFl and AF. ATP is disabled when the pacemaker electrode wires are positioned a distance away from the reentry circuit and the pacing-inducing wavefront disappears before reaching the circuit. For faster arrhythmias, the probability of occurrence is extremely high. Further, sustained application of far-field ATP is known to induce ventricular fibrillation, although timed delivery of ATP can reduce the likelihood of inducing ventricular fibrillation and potential recurrence of AF, as disclosed, for example, in U.S. Pat. No. 6,091,991 to Warren, U.S. Pat. No. 6,847,842 to Rodenhiser et al, U.S. Pat. No. 7,110,811 to Wagner et al, and U.S. Pat. No. 7,120,490 to Chen et al.

Another method of treating atrial arrhythmias is to apply a standard external defibrillator to the patient who has been sedated during the delivery of the defibrillation shock. Still other external defibrillation systems, such as those disclosed in U.S. patent No. 5,928,270 to Ramsey, are specifically designed for atrial arrhythmias. However, in order to provide electrodes placed outside the body to an external shock effective to terminate the arrhythmia, the system must provide a higher energy shock than is required by the implantable device. In addition, externally applied shocks must invoke more skeletal muscle groups, which may cause more pain and discomfort to the patient.

Another method of treating patients with periodic sustained AF is implantable atrial defibrillator ("IAD"), such as disclosed in U.S. patent No. 3,738,370 to Charms, and U.S. patent No. 3,942,536 to Mirowski. Although initial clinical experiments showed that IADs have high specificity and sensitivity for AF and are capable of delivering safe and effective shocks, the energy levels required for successful cardioversion may exceed the pain threshold. Intracardiac cardioversion Shock energy levels in excess of 0.1 joules can be uncomfortable for the patient (Ladwig, k.h., Marten-misttag, b., Lehmann, g., Gundel, h.simon, h.alt, e., Absence of an Impact of an experimental disorder on the performance of Intracardiac Shock events, International Journal of behavial Medicine, 2003, 10 (1): 56-65), and patients cannot distinguish higher levels than this and find that these levels all produce the same pain. The pain threshold depends on many factors, including voluntary stress, use of medication, electrode settings, and shock waveforms. In addition, pain thresholds may vary from person to person.

Various approaches are being sought to reduce the energy levels required for effective atrial fibrillation. Many systems, such as U.S. patent No. 5,282,836 to Kreyenhagen et al, U.S. patent No. 5,797,967 to KenKnight, U.S. patent nos. 6,081,746, 6,085,116 and 6,292,691 to Pendekanti et al, and U.S. patent nos. 6,556,862 and 6,587,720 to Hsu et al, disclose the application of atrial pacing pulses to reduce the energy level necessary for an atrial defibrillation shock. In contrast, pacing pulses deliver energy that is notorious for comparison to defibrillation shocks. U.S. patent No. 5,620,468 to monteon et al discloses a method of cyclically shocking the atrium with low energy pulses to terminate atrial arrhythmias. U.S. patent No. 5,840,079 to Warman et al discloses the application of low-rate artificial ventricular pacing prior to delivery of an atrial defibrillation pulse. U.S. patent nos. 6,246,906 and 6,526,317 to Hsu et al disclose delivery of atrial and ventricular pacing pulses prior to delivery of an atrial defibrillation pulse. The use of a biphasic shock in atrial defibrillation is disclosed in U.S. patent No. 5,813,999 to Ayers et al. The use of a multi-step defibrillation waveform is disclosed in U.S. patent nos. 6,233,483 and 6,763,266 to Kroll, while the delivery of two successive defibrillation pulses of decreasing energy instead of one defibrillation pulse of greater energy is disclosed in U.S. patent No. 6,327,500 to Cooper et al.

Other systems have sought ways to reduce the patient's perception of pain perception of an atrial defibrillation shock. For example, U.S. patent No. 5,792,187 to Admas applies electromagnetic stimulation of neural structures within the shocking region to block transmission of shock-induced pain signals. U.S. patent No. 6,711,442 to Swerdlow et al and patent nos. 7,155,286 and 7,480,351 to Kroll et al disclose the use of a "pre-pulse" prior to the application of a high voltage pulse to reduce the pain sensation and panic response caused by the shock pulse. U.S. patent No. 5,925,066 to Kroll et al discloses a drug delivery system in combination with anti-cardiac rapid pacing to suppress pain from atrial fibrillation detection. U.S. patent No. 7,142,927 to Benser measures physical displacement of unconscious patients to different shock levels and programs an arrhythmia treatment device to deliver a shock so that it does not cause undue discomfort.

Despite these efforts, there remains a need in the art for improved methods and devices for treating atrial arrhythmias that can successfully deliver electrical therapy without exceeding any patient's pain threshold and without relying on drug therapy and ablation therapy.

Summary of The Invention

Embodiments of methods and apparatus according to the invention provide a three-stage atrial cardioversion therapy to treat atrial arrhythmias within a patient tolerable pain threshold. Atrial arrhythmia therapy according to various embodiments includes an implantable therapy generator adapted to generate and selectively deliver a three-stage atrial cardioversion therapy and at least two leads operatively connected to the implantable therapy generator, each lead having at least one electrode adapted to be disposed in close proximity to an atrium of a heart of a patient. The atrial arrhythmia treatment device is programmed with a set of treatment parameters, and once an atrial arrhythmia is detected by the atrial arrhythmia treatment device, a three-stage atrial cardioversion is provided to the patient by the far-field configuration and the near-field configuration of the electrodes.

The three-stage atrial cardioversion therapy includes a first stage for unpinning (unpinning) one or more atrial arrhythmia-related abnormalities, a second stage for preventing reimbursement (replanning) of the one or more atrial arrhythmia-related abnormalities, and a third stage for eliminating (extingking) the one or more atrial arrhythmia-related abnormalities. In embodiments, the first stage has at least two and less than ten biphasic atrial cardioversion pulses greater than 10 volts and less than 100 volts with a pulse time of less than 10 milliseconds and a pulse coupling interval between 20 and 50 milliseconds, and the first stage has a total duration of less than the cycle time of two atrial arrhythmias and is triggered by an R-wave and delivered with an energy of less than 0.1 joules per biphasic atrial cardioversion pulse during the ventricular refractory period. The second phase has at least five and less than ten far-field pulses that are less than the ventricular far-field excitation threshold (about 10 volts) with a pulse time greater than 5 and less than 20 milliseconds and a pulse coupling interval that is between 70-90% of the cycle time of the atrial arrhythmia. The third stage has at least five and less than ten near field pulses of less than 10 volts with pulse times greater than 0.2 and less than 5 milliseconds and pulse coupling intervals between 70-90% of the cycle time of the atrial arrhythmia. The three-stage atrial cardioversion therapy is performed in response to detection of atrial arrhythmia with each stage having an intermediate stage delay between 100 and 400 milliseconds, and the conversion of the atrial arrhythmia is not confirmed until after the third stage.

In various embodiments, an atrial arrhythmia treatment device includes at least one electrode adapted to be implanted proximate to an atrium of a patient's heart to provide far field pulses and at least one electrode adapted to be implanted proximate to an atrium of the patient's heart to deliver near field pulses and sense cardiac signals. An implantable therapy generator is operatively coupled to the electrodes and includes a battery system operatively coupled to and providing electrical energy to the sensing, control, and therapy circuits of the implantable therapy generator. The sensing circuitry senses cardiac signals representative of atrial activity and ventricular activity. The detection circuit evaluates a cardiac signal representative of atrial activity to determine an atrial cycle time and detects an atrial arrhythmia based at least in part on the atrial cycle time. A control circuit that controls generation and selective delivery of the three-stage atrial cardioversion therapy to the electrodes with an inter-stage delay of between 100 and 400 milliseconds per stage in accordance with the atrial arrhythmia, and without confirming conversion of the atrial arrhythmia during the three-stage atrial cardioversion therapy. A therapy circuit is operatively connected to the electrodes and the control circuit and includes at least one first stage charge storage circuit selectively connected to at least one far-field electrode that selectively stores energy for a three-stage atrial cardioversion therapy, at least one second stage charge storage circuit selectively connected to the at least one far-field electrode that selectively stores a second stage of the three-stage atrial cardioversion therapy, and at least one third stage charge storage circuit selectively connected to the near-field electrode that selectively stores a third stage of the three-stage cardioversion therapy.

The methods and apparatus of the present invention employ virtual electrode polarization ("VEP") that enables successful treatment of AF and AFl using an implanted system without exceeding any patient's pain threshold. This is achieved by far field excitation of multiple regions of atrial tissue at once, rather than just a small region near the pacing electrode, which is more effective for both AFl and AF. This approach differs from conventional defibrillation therapy, which typically uses only one high-energy (about 1 to 7 joules) monophasic or biphasic shock or two subsequent monophasic shocks from two different vectors of far-field electrical stimulation. To estimate the pain threshold variance of the patient, real-time feedback of the patient is provided to estimate the pain threshold while the implantable device is calibrated and operated.

Methods and devices according to embodiments of the invention can utilize low voltage phase unpinning far field therapy in conjunction with near field therapy to form a three-phase atrial cardioversion therapy to disrupt or terminate the mother rotor core that is anchored to a region of myocardial heterogeneity, such as the intervenal region or the fibrotic region. Energy used to convert atrial arrhythmias can be significantly reduced by this technique of unplugging, anti-retaking, and then eliminating, compared to conventional high-energy defibrillation, so that cardioversion can be successful without exceeding the pain threshold of the patient.

Applying far-field low-energy electric field excitation can break and terminate the foldback loop by selectively exciting the excitable gap near the foldback core, in the appropriate time and frequency domain. By stimulating the excitable gap near the core of the circuit, reentry can be interrupted and terminated. The reentry circuit is anchored to a functionally or anatomically heterogeneous region, which constitutes the core of the reentry. The region near this heterogeneous region (including the folded back core region) will experience greater polarization in response to the applied electric field than the surrounding more uniform tissue. Thus, the area near the reentrant core can be preferentially excited by a very small electric field to disrupt or terminate the fixed reentrant circuit. Once the disruption is successful, subsequent shocks can more easily terminate the arrhythmia and restore normal sinus rhythm.

Virtual electrode excitation can be used to localize regions of anti-heterogeneity, depolarizing critical sites for reentry pathways or excitatory gaps near the reentrant core. In accordance with the present invention, a variety of pulse regimes for three-stage atrial cardioversion therapy are contemplated to terminate atrial arrhythmias. In one aspect, reentry is terminated directly or disrupted by far field pulses delivered in the first and second stages and then terminated by additional stimulation by near field pulses delivered in the third stage of the three-stage atrial cardioversion therapy. The low energy stimulation can be below the pain threshold and therefore does not cause anxiety and uncomfortable side effects in the patient. On the other hand, phased unpinning far field therapy can be administered in response to a detected atrial arrhythmia, with late pacing as a follow-up to phased unpinning far field therapy.

To further optimize the low energy termination method, multiple electric field configurations may be applied to optimize the excitable gap near the excitation foldback core and to interrupt the foldback loop. These field configurations can be achieved by placing a number of defibrillation leads/electrodes in the coronary sinus (including the distal and proximal electrodes), the right atrial appendage, and the superior vena cava. In another embodiment, the electrodes may be placed in the atrial septum. The electric field can be transferred not only between any two or more electrodes, but also between one of these electrodes and the device itself (hot can configuration). Alternatively, segmented electrodes that selectively energize one or more electrodes may be used. The maximum coverage of the entire atrium is then achieved using electric field vector modulation over a set of shock applications or on a trial-to-trial basis. The optimal field of use and the correct field sequence can also be detected on the basis of trial and error tests for each patient.

In another aspect of the invention, a pain threshold regimen is implemented in the treatment. The device and plurality of leads are implanted into a sedated or anesthetized patient. When the patient is fully conscious of the sedation or anesthesia, the device follows the instructions to interrogate the implanted leads by activating stimulation between the two leads and between the "can" and the leads, respectively. The patient is asked to indicate the degree of discomfort for each stimulus. The energy of the stimulation is initially set at a low value and then increased in a ramp-up mode, and the patient is asked to indicate when their pain threshold has been reached. The default maximum stimulation energy level previously stored in the device is replaced with the custom value determined by the protocol, and the device is programmed to limit therapy to energy levels below the custom value.

In another aspect of the invention, external information from a variety of sources prior to treatment, such as a patient electrocardiogram or magnetic resonance imaging, regarding the possible locations of reentry circuits may be used to assist in certain aspects of treatment. This external information can be used to determine patient suitability for the treatment procedure, and to determine lead selection and placement, or to determine an initial lead activation pattern, as compared to other treatments, such as ablation or drug treatments.

In another aspect of the invention, the morphology of the electrogram of the arrhythmia can be recorded, stored and compared to previously stored morphologies. The anatomic location of the reentry circuits may be determined by anatomical and atrial-specific physiological reconstruction models, which are unique to each patient. Embodiments of the present invention utilize observations of multiple atrial arrhythmia modalities that tend to occur with high frequency. Each electrogram modality may be optimized for the electric field configuration and therapeutic pulse sequence, respectively, and stored in memory for future termination of the arrhythmia. When an arrhythmia is detected, it is determined whether the arrhythmia electrogram morphology is known. If so, the optimized treatment plan stored in the memory is applied to convert the arrhythmia.

In one aspect of the invention, a method for disrupting and terminating atrial tachyarrhythmia comprises: detecting initiation of an atrial tachyarrhythmia by sensing atrial electrical activity, estimating a minimum or major cycle time (CL) of the arrhythmia, sensing ventricular electrical activity to detect ventricular R-waves, delivering far-field atrial shocks/stimuli as a pulse sequence of two to ten pulses in one or several AF/AFl cycles synchronized with the detected R-wave, optionally delivering atrial pacing with a cycle time of about 20% to about 90% of the minimum of the sensed atrial fibrillation cycle time ("AFCL"), and (a) using R-wave detection to determine ventricular vulnerable time to prevent or inhibit ventricular fibrillation sensing by atrial shocks, (b) determining an atrial firing threshold by applying atrial shocks with different implanted atrial leads for defibrillation and subsequently sensing atrial activity, (c) during implantation and calibration, and during execution of a device learning algorithm, determining a pain threshold by using a patient-provided feedback circuit, (d) determining a far-field ventricular excitation threshold by applying an atrial shock with a different implanted atrial defibrillation lead and subsequently sensing ventricular activity, (e) delivering far-field stimulation to the atrium by delivering several pulses sequentially with an energy above the atrial excitation threshold.

In another aspect of the invention, an implantable cardiac treatment device for treating an atrium requiring defibrillation includes one or more sensors including one or more implanted electrodes for generating electrogram signals placed at different locations, one or more pacing implanted electrodes for near-field pacing at different atrial locations placed at different locations, one or more implantable defibrillation electrodes for far-field delivery of electrical current placed at different locations, and an implanted or external device capable of providing a series of pulses.

In a typical embodiment, the implantable device is implanted just below the left clavicle. This position places the device approximately in line with the longitudinal anatomical axis of the heart (the axis passing through the center of the heart with the apex intersecting the interventricular septum). When the electrodes are implanted in this manner, the arrangement of the device and electrodes is similar to the umbrella top structure: the device forms the metal ring of the umbrella and the electrode is the tip of the umbrella. The electrodes of the device are sequentially energized to complete the stimulating electric field, similar to the triangular struts of a "stimulating" umbrella, in either a clockwise or counterclockwise direction or in a custom sequence. In one aspect, the right ventricular lead is placed as an implanted portion. On the other hand, without any ventricular lead placement, a lead through the heart valve is no longer needed when implanting the lead. The leads may be actively or passively fixed.

On the other hand, the device may be fully automatic; when an atrial arrhythmia is detected, a shock regimen is automatically implemented. On the other hand, the device can also manually deliver electric shock; the device may prompt the patient for a physician to authorize the device to implement a shock protocol, or the device may prompt the patient to self-control the device to implement a shock protocol to terminate the detected arrhythmia. On the other hand, the device may also be semi-automatic; a "bedside" monitoring station may be used to allow remote control authorization for initiating a shock regimen upon detection of atrial arrhythmia.

Drawings

The invention will be more fully understood from the following detailed description of various examples of the invention taken together with the accompanying drawings, in which:

figure 1A shows a schematic rear view of a human heart and the anatomical locations of an implantable defibrillation lead and sensing electrodes;

FIG. 1B shows a schematic rear view of a human heart with an implanted defibrillation lead and the anatomical location of the sensing electrodes, with an optional lead in the right ventricle;

FIG. 2 shows a flow chart of a method of treatment of a particular embodiment of the present invention;

FIG. 3A is a photograph of an optical image of atrial fluorescence after preparation of ACh-induced AFl and AF from a photodiode array optical imaging view on a Langendorff ex vivo rabbit heart perfusion model;

FIG. 3B depicts an activation map and Optical Action Potential (OAP) during AFL and AF of FIG. 3A;

FIG. 4A is a photograph of a fluorescence optical mapping of the right atrial endocardium prepared with ACh-induced AFl and AF to the canine isolated atrium in an optical mapping field with a photodiode array;

FIG. 4B shows an activation map and OAP during AFL and AF of FIG. 4A;

fig. 5A shows a simplified rear view schematic diagram of a human heart showing the anatomical locations of the implantable defibrillation lead and electrodes, and the orientation of the first shock/pulse sequence;

fig. 5B shows a simplified rear view schematic diagram of a human heart showing the anatomical locations of the implantable defibrillation lead and electrodes, and the orientation of a second shock/pulse sequence;

fig. 5C shows a simplified rear view schematic diagram of a human heart showing the anatomical locations of the implantable defibrillation lead and electrodes, and the orientation of a third shock/pulse sequence;

FIG. 6 shows a flow chart of a method of treatment of a particular embodiment of the present invention;

FIG. 7 shows a simplified schematic diagram of a human heart showing potential locations of arrhythmias;

figure 8 provides a summary of the contents of six ex vivo canine right atrium shock amplitude in vitro experiments;

FIG. 9 provides a list of possible electric field sequences for treating the region of FIG. 7 with the electrodes positioned as shown in FIGS. 5A, 5B and 5C;

FIG. 10 illustrates an embodiment of the steps of FIG. 2 applying stimulation in the form of a three-stage cardioversion therapy;

fig. 11 illustrates an embodiment of a stimulation waveform for the three-phase cardioversion therapy of fig. 10;

FIG. 12 illustrates an embodiment of a first, plucking phase of the waveform of FIG. 11;

FIG. 13 illustrates a second, re-pinning prevention embodiment of the waveform of FIG. 11;

FIG. 14 illustrates an embodiment of a third, cancellation phase of the waveform of FIG. 11;

FIG. 15 illustrates another embodiment of the steps of FIG. 2 applying stimulation in the form of a three-stage cardioversion therapy;

fig. 16 illustrates an embodiment of a stimulation waveform for the three-phase cardioversion therapy of fig. 15;

FIG. 17 illustrates yet another embodiment of the steps of FIG. 2 applying stimulation in the form of a three-stage cardioversion therapy;

FIG. 18 illustrates yet another embodiment of a stimulation waveform for the three-phase cardioversion therapy of FIG. 17;

FIGS. 19A and 19B illustrate block diagrams of embodiments of a three-stage cardioversion therapy device, and its therapy circuitry, respectively;

FIGS. 20A-20H illustrate various portions of a therapy circuit of the device of FIGS. 19A and 19B in greater detail, in accordance with various embodiments;

fig. 21 illustrates EKG waveforms for a subject in a dog undergoing the three-stage cardioversion therapy of fig. 10;

fig. 22 illustrates an EKG waveform for a dog subject undergoing the three-stage cardioversion therapy of fig. 16; and

figure 23 shows four bar graphs summarizing the applied energy during each application of one, two and three phase treatments.

While the invention is amenable to various modifications and alternative forms, specifics thereof have been shown by way of example in the drawings and will be described in detail. It should be understood, however, that the intention is not to limit the invention to the particular embodiments described. On the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.

Detailed Description

Embodiments of the present invention are based on low pressure phase unpinning far field therapy together with near field therapy to form a three-phase atrial cardioversion for the treatment of unstable and subsequently terminating anatomically reentrant tachyarrhythmias. The energy required to convert atrial arrhythmias can be significantly reduced by unplugging, preventing re-pinning, and then eliminating techniques, compared to conventional high-energy defibrillation, thereby enabling successful cardioversion without exceeding the patient's pain threshold.

Myocardial tissue anatomy has an inherent heterogeneity. These even modest proportions of syncytial heterogeneity represent an important mechanism contributing to the far-field excitation process. Fishler, M.G., Vepa K., Spatitemporous Effects of synthetic hetereogenites on Cardiac face-field interactions during Monophasic and Biphasic disks, Journal of Cardiovacular electrophysiology, 1998, 9 (12): 1310-24, incorporated herein by reference.

For the purposes of the present invention, the term "near field" refers to the effect of close proximity of stimulation electrodes, i.e. a distance limited to several spatial constants (λ) of the cardiac tissue, typically up to a few millimeters. The near field effect depends mainly on the distance from the electrodes. The term "far field", on the other hand, refers to an effect that is substantially independent or less dependent on the distance from the electrode. They may occur at distances greater than the spatial constant (λ).

The application of far-field low-energy electric field stimulation over a certain time and frequency domain can interrupt and terminate reentry circuits by selectively stimulating the excitable gap near the reentrant core. Compared with the near-field ATP, the defibrillation success rate of the high-frequency far-field electrical stimulation is remarkably improved. The reentry circuits are capable of anchoring to functionally or anatomically heterogeneous regions of tissue that make up the reentry core. Electric field myocardial excitation virtual electrode theory predicts that more uniform tissue will be present in the region near the core than in the surrounding, with a greater polarization response to the applied electric field. The present invention contemplates a number of different shock methods for terminating atrial arrhythmias. Thus, in one aspect, the area near the reentrant core may be preferentially stimulated with a small electric field to disrupt or terminate a fixed reentrant circuit. Once disturbed, the subsequent shock can more easily drive the trochanter away from the boundary of the myocardial tissue and restore normal sinus rhythm.

In conventional high voltage defibrillation therapies, the biphasic exponential truncated waveform has a lower defibrillation energy than monophasic shocks. However, in the case of a phase of unpinning far-field therapy ("PUFFT"), it has recently been found in a rabbit model that the use of multiple monophasic waveforms more effectively terminates ventricular arrhythmias than multiple biphasic waveforms. This difference exists because the optimal biphasic defibrillation waveform cannot produce VEP due to the asymmetric effect of the membrane polarity inversion. Reference may be made to Efimov, I.R, Cheng, Y., Van Wagoner, D.R., Mazgalev, T., Tchou, P.J., Virtual Electrode-Induced Phase filtration A Basic mechanics of purification Failure, Circulation Research, 1998, 82 (8): 918-25. VEPs are also discussed throughout below: efimov, i.r., Cheng, y.n., Biermann, m., Van Wagoner, d.r., Mazgalev, t.n., Tchou, p.j., fransmembrane Voltage change Produced by Real and visual Electrodes dual ring vibration reduction by implanted Electrode, Journal of Cardiovascular electrolyte, 1997, 8 (9): 1031-45; cheng, Y.N., Mowrey, K.A., Van Wagoner, D.R., Tchou, P.J., Efimov, I.R., Virtual Electrode-Induced regeneration, A Mechanism of defibration, Circulation Research, 1999, 85 (11): 1056-66; and fisher, m.g., synthetic heterogeneous as a Mechanism underscoring cardio-frequency simulation for along-Level clocks. journal of cardio cellular electrodynamics, 1998, 9 (4): 384-94, the entire contents of which are incorporated herein by reference.

The ventricular defibrillation threshold ("DFT") can be significantly reduced by rotating the current field orthogonally. For this reference may be made to Tsukerman, b.m., Bogdanov, KIu, Kon, m.v., Kriukov, v.a., vandianev, g.k., defibrilation of the Heart by a rolling Current Field, kardiologic, 1973, 13 (12): 75-80. By combining two consecutive shocks with one rotating electric field vector, the atrial defibrillation threshold ("ADFT") for a standard lead configuration (right atrium to distal coronary sinus) can be significantly reduced when a subsequent second shock is delivered across the atrial membranes between the proximal coronary sinus and the SVC or Bakerman bundle electrode. For this purpose reference may be made to the literature Zheng, x., Benser, m.e., Walcott, g.p., Smith, W.M, Ideker, r.e., Reduction of the Internal adaptation threshold T with Balanced Orthogonal sequencing disks, Journal of Cardiovascular electrodynamics, 2002; 13(9): 904-9. ADFT can be further reduced by balancing the continuous shock.

Virtual electrode excitation energy is used for local anti-heterogeneity to depolarize an excitable gap near a critical portion or reentry core of the reentry path. Thus, reentry may be terminated directly or after disruption by other stimuli. The techniques may be used in implantable or external devices that, when an atrial tachyarrhythmia is sensed, may apply low-energy stimulation at various intervals until the proper timing is reached and the arrhythmia is terminated. This "trial-and-error" approach is used because atrial arrhythmias are not instantaneously fatal. In addition, low energy stimulation is expected to be below the pain threshold without causing side effects that cause anxiety and discomfort to the patient.

To further optimize this low energy termination method, multiple electric field configurations can be employed to optimize the excitable gap near the excitation foldback core and to interrupt the foldback circuit. Referring to fig. 1A and 1B, the configuration of these fields may be achieved by placing several implantable defibrillation electrodes 11 in the proximal 12 and distal 13 ends of the coronary sinus ("CS"), the right atrial appendage ("RAA") 14, and the superior vena cava ("SVC") 15. In one aspect, the right ventricular lead is provided as part of an implant device (fig. 1B). On the other hand, no ventricular lead is provided (fig. 1A), and the lead need not be implanted through the heart valve. The leads may be actively or passively fixed. As can be seen in fig. 1, no lead is provided on the left side of the heart, thus reducing the time required for implantation.

The electric field can be transferred between any two electrodes and between one electrode and the device 16 itself (hot can configuration). Maximum coverage of the entire atrium can be achieved using electric field vector modulation and the optimal virtual electrode polarization pattern is maintained throughout the arrhythmia cycle to depolarize the largest region of the excitable gap. The optimal electric field and the correct field sequence used can also be achieved on a trial-and-error basis for each patient, or estimated based on external information about the likely location of the reentry circuit, or a combination of both.

Reference is now made to fig. 5A, 5B and 5C, which collectively illustrate the clockwise rotation of the vector in a series of three successive far field pull-out electrical hits. Each shock comprises a series of electrical pulses. In this embodiment, multiple monophasic shocks may be applied at intervals according to the arrhythmia cycle time. In one embodiment, the far-field unpinning shock may be a square wave, and the voltage and vector will change to determine the minimum termination voltage within a 10 millisecond period. In another embodiment, the far field unpinning shock or pulse may be circular, staggered, rising, falling, biphasic, multiphasic, or other variations.

In fig. 5A, a first far-field unpinning shock 40 is applied at the electrode located between electrode (b) and device (a) of the right atrial appendage. In fig. 5B, a second far-field unpinning shock 42 is applied between the electrode located distal to the coronary sinus (e) and the electrode of the superior vena cava (c). In fig. 5C, a third far-field unpinning shock 44 is applied between the device (a) and an electrode located proximal to the coronary sinus (d).

An algorithm can be used to treat AFl and AF. To determine whether the atrium flutters or flutters, the device first estimates the cycle time of the arrhythmia. For example, if the average atrial cardiac cycle time is below 250 milliseconds but above 150 milliseconds, the atrium is considered to be at AFl. The distinguishing characteristics of AF and AFl vary from person to person, so these cycle time parameters can be programmed based on the needs of the patient. An example of distinguishing AF from AFl is shown in U.S. patent No. 5,814,081, the contents of which are incorporated herein by reference. In addition, an algorithm can be used to characterize and classify the morphology of the atrial electrogram to use this information to optimize for patient-specific and morphology-specific phase-extinct far-field therapy.

The optimal timing of the application of this phase of unpinning far field therapy relative to the cardiac cycle may be determined by ventricular sense electrodes including RV or far field R-wave detection. The patent of U.S. patent No. 5,814,081 also describes some examples of finding unsafe opportunities for far-field shocks.

Learning algorithms may also be used to optimize subsequent termination therapy. Once the patient has acquired the best opportunity and field settings to terminate the atrial tachyarrhythmia, these settings are the starting points for terminating the next episode of AFl/AF.

Because AFl/AF is not an immediate fatal arrhythmia, treatment can be optimized with a trial-and-error approach in conjunction with a learning algorithm to tailor the treatment to each patient. This optimization includes two objectives: (a) terminating the arrhythmia, and (b) avoiding the intensity of pain.

As mentioned above, the pain threshold depends on many factors, including voluntary stress, use of medication, electrode location, and shock waveform. Ladwig, k.h., Marten-Mittag, b., Lehmann, g., Gundel, h., Simon, h., Alt, e., Absence of Impact of empirical distribution of the performance of Intracardiac Shock distributions, International Journal of behavior Medicine, 2003, 10 (1): the 0.1 joule values reported in 56-65, the contents of which are incorporated herein by reference, are generally the first to experience pain and/or discomfort as energy values. However, this may also vary from person to person. Thus, real-time feedback can be provided to the patient to estimate his pain threshold when implanting or calibrating the device or executing an optimized learning algorithm.

Referring now to fig. 6, a pain threshold scheme 200 is shown. During surgical procedure 202, an atrial arrhythmia treatment device is implanted in a sedated or anesthetized patient. The implant device includes an implantable therapy generator and at least two leads operatively connected to the implantable therapy generator, each lead having at least two electrodes adapted to be positioned adjacent to an atrium of a heart of a patient. After the surgical procedure is completed, the atrial arrhythmia device is configured when the patient is fully conscious and fully conscious of sedation or anesthesia, step 204. In step 206, the apparatus applies a PUFFT treatment having a first set of treatment parameters to the patient via the far field configuration of the electrodes as instructed in response to detecting the atrial arrhythmia in the patient. An indication of pain sensation for the PUFFT treatment is then provided by the patient, step 208. In step 210, the effectiveness of PUFFT treatment of atrial arrhythmia will be evaluated. In step 212, the PUFFT treatment effect and pain sensation indication are evaluated. In step 214, at least one of the set of therapy parameters and the far field configuration of the electrodes is adjusted based on the indication of pain sensation and the indication of the assessment of the therapy effect. Steps 206 through 212 are repeated until a set of treatment parameters and far field configuration of the electrodes is determined that provides effective atrial arrhythmia treatment for the patient within an acceptable pain sensation range for the patient. The atrial arrhythmia treatment device may then be programmed with the set of treatment parameters and electrode far field configuration determined by steps 206 through 214 for automatically treating the detected atrial arrhythmia with the device in step 216.

Referring to FIG. 2, when implanting the device, first some measurements P101-P103 are made. The field excitation threshold P101 for atrial and ventricular excitation was measured according to each of the aforementioned lead combinations. These values were taken as the minimum and maximum stimulus intensity, respectively, and the changes were tested by the device periodically. The stimulation intensity may also be increased until the patient feels shock and pain. A patient feedback mechanism may be employed to record a maximum shock amplitude that corresponds to a pain threshold for a particular location. These minimum and maximum values delineate the operating range of the device.

After implantation, the device enters a sensing mode 21 for sensing atrial tachyarrhythmias. When an arrhythmia is sensed, all sensing electrodes can determine the minimum AFl/AF cycle time. This minimum AFl/AF cycle time can then be used to calculate stimulation frequency 23b, which can range from about 20% to about 99% of the minimum AFl/AF cycle time. The device then determines whether the arrhythmia is the first round of AFl/AF24 after implantation. If so, first defibrillation trials P103 and 26 may be performed using a combination of default stimulation parameters in combination with the previously measured minimum stimulation intensity. The combination of stimulation parameters 23 may include: stimulation number 23a, stimulation frequency 23b, number of electric field arrangements 23c, electric field arrangement sequence 23d, field strength 23e, waveform form 23f, and cross-phase delay. The default parameter combination may be based on experimental evidence obtained from the AFl/AF of the animal model, previous experience with this technique, or experimental results at the time of implantation for a particular patient. If it is not the first round of AFl/AF after implantation, a first defibrillation trial 25-26 is performed using the stored parameters of the previous stimulation application. To avoid inducing ventricular arrhythmias, the device will wait until the next time that an R-wave is sensed before delivering atrial defibrillation therapy. Appropriate stimulation parameters 28 are then delivered.

After the defibrillation test, sensing may again be used to determine whether the test was successful, step 29. If the trial is unsuccessful and the duration of AFl/AF does not exceed the maximum allowed time, step 30, the stimulation parameters are changed 23 and another defibrillation trial is performed, steps 25-29. Due to the large number of stimulation parameters 23, neural networks can be employed in the device to control the sequence and optimize the parameters. The defibrillation trial continues steps 25-29 until the arrhythmia is terminated or the maximum duration of AFl/AF is reached, step 30. Because prolonged AFl/AF accelerates atrial pathology remodeling (atrial fibrillation with atrial fibrillation), blood clotting and increases the risk of patient stroke and other complications, a higher energy rescue shock can be delivered if needed, step 31, and low energy optimization continues on the next round of AFl/AF.

If a successful set of parameter combinations is found, the stimulation parameters will be saved, steps 36, 25 and used in the next round of AFl/AF. If a particular stimulation parameter combination is found that is successful for many rounds of AFl/AF (i.e. >5 successful terminations), step 33, the device will enter a "continuous optimization algorithm", step 34, to determine if the energy can be reduced further. The stimulation parameters may be varied at lower energies 35, 23 in an attempt to find other successful combinations. If no other such combination can be determined, the device will return to using the successful combination.

In one embodiment, the morphology of the arrhythmia electrogram may be recorded, stored, and compared to previously stored morphologies. The anatomic location of the reentry circuit is determined by the specific anatomic and physiologic reconstruction of the atrium, which is unique to each patient. Thus, the morphology may display a particular anatomical location of the reentry circuit. Pulse sequence optimization of the treatment may be performed separately for each electrogram modality and saved in memory for terminating future arrhythmias.

Referring to fig. 7, different locations 302 where the reentry circuit may be fixed are shown. These locations 302 are divided into 5 regions, indicated by 310, 320, 330, 340, and 350, by dashed lines. In one embodiment, a default treatment sequence may be initiated for the reentry circuits within each zone. For example, if the arrhythmia morphology indicates that the reentry circuit is located in region 310, the sequence of applied electric fields may begin between electrode b and electrode a (on the device) as shown in figure 5. The sequence then continues with the electric field between electrode e and electrode C (fig. 5B), and then between electrode a and electrode d (fig. 5C). The table in fig. 9 provides an example of one possible default treatment order for each of the regions 310, 320, 330, 340, and 350 in fig. 7. If the default treatment sequence within a given region fails to terminate the arrhythmia, another treatment sequence may be subsequently applied.

In some embodiments, conventional implantable pulse generators, such as those commonly used in ICDs, may not be generally suitable for use with the device because the device is capable of delivering a series of electrical field stimuli that are rapidly followed by electrical field stimuli. Conventional implantable pulse generators require a charge time (in seconds) to charge a capacitor and then rapidly discharge the capacitor to administer the shock. The capacitor needs to be charged again before the next shock is delivered. In the present device, several (only 10-100 milliseconds apart) low energy far-field unpinning shocks (2 to 10) are applied in quick succession to each unpinning shock.

Thus, an implantable pulse generator according to embodiments of the device may include several smaller capacitors that are charged before or during a defibrillation trial. For each stimulus delivered, a separate capacitor discharges the appropriate amount of energy, and then another capacitor discharges until the appropriate number of stimuli is delivered. All capacitors are then charged simultaneously prior to the overall defibrillation trial, or alternatively, the capacitors are charged sequentially in groups or individually. In the practice of one embodiment, the capacitor for a subsequently presented plucking shock in a defibrillation trial is charged when another plucking shock is applied earlier in the trial by other capacitors that are pre-charged. In a related embodiment, the capacitor used for the earlier plucking shock is recharged during one or more shocks of a subsequent trial and further reused for the subsequent plucking shock of the same trial. The latter example helps in embodiments where the power supply is able to provide sufficient current drive to charge the capacitor for a sufficient time to allow them to be used again in the same experiment.

In a related embodiment, the device uses multiple capacitors to store the electrotherapy energy, except that, unlike the above-described embodiments, each capacitor has sufficient energy storage to provide more than a continuous single shock.

To generate the appropriate stimulation through the proper lead configuration, a fast switching network is applied between the different capacitors to switch the discharge energy and switch the applied energy to the correct electrode. The pretreatment of the pulses is further discussed in U.S. patent nos. 5,366,485 and 5,314,448, the contents of which are incorporated herein by reference.

Test results

Referring to fig. 3A and 3B, a series of experiments were performed in which the posterior epicardial and Pulmonary Vein (PV) regions of the left and right atria (RA and LA) of the isolated rabbit heart Langendorff perfusion model (n-9) were optically mapped in synchrony, controlled and during ACh perfusion (2.5-100. mu.m). In fig. 3A, the posterior atrial fluorescence optical mapping during ACh-induced AFl and AF in the ex vivo rabbit heart Langendorff perfusion model is shown by a photodiode array optical mapping field of view, in which (1) the original location of the normal sinus rhythm heartbeat is marked with a blue/purple circle, (2) a narrow gray ellipse marks the intervenal conduction block line as an anti-heterogeneity location during identified normal sinus rhythm and during pacing that is likely to be a fixed point of the reentry circuit during atrial flutter or atrial fibrillation, (3) the arrowed black dashed line indicates the location and direction of the reentry circuit, and (4) the white dashed line indicates the ligated blood vessels. In fig. 3B, the activation map and the optical action potential map (OAP) during AF and AFl in fig. 3A are shown, wherein (1) the narrow grey ellipses mark the intervenal conduction block lines, the anti-heterogeneity locations, and (2) the white dotted arrowed lines mark the location and direction of the reentry circuits, and wherein the isochronal maps are plotted in 0.4 millisecond steps.

Arrhythmias are stimulated by either separate pre-stimulation or short pacing. Low-energy shocks are delivered from two large mesh electrodes placed on either side of the heart, oriented parallel to the vertical axis of the heart. To prevent or suppress motion artifacts, blebbistatin (bb) was used. BB is a highly specific myosin TI subtype inhibitor. Under controlled conditions, AF is not triggered, but rather sustained AFl is induced in only one heart. ACh reduced sinus rhythm and stimulated atrial premature beats ("APBs") at 93 ± 7 millisecond coupling intervals from the right atrial appendage, superior pulmonary vein, and inferior vena cava regions. APBs cause spontaneous AF in three hearts. In eight hearts, separate pre-stimulation or burst pacing elicited sustained AFl and AF (> 10 min) at 7 ± 2mu.m and 20 ± 8mu.m Ach, respectively.

Referring again to fig. 3B, AFl and AF are maintained by a single macro reentry circuit or multiple reentry circuits (CL ═ 48 ± 6 milliseconds) around the conduction block region between SVC and IVC (CL ═ 79 ± 10 milliseconds), respectively. In most cases, AF is associated with maternal trochanteric micro-reentry in pectinate muscles of RA (75%) and/or LA (25%). Fig. 3B shows an example of activation during AF. AF is associated with the mother rotor (figure 8) stabilized in the right atrial appendage. Several complete rotations of the additional rotor are observed in the LA, but typically the rotor does not continue to rotate.

To terminate the arrhythmia, a monophasic 5 millisecond shock is delivered from the extranet electrode. Individual shocks are applied at different stages of the AFl, or multiple shocks are applied within one AFl cycle time (3-5). And anti-tachyarrhythmia pacing (ATP, 8 pulses, 50-100% of AFl cycle time) is effected from the right atrial appendage electrode or IVC regional electrode.

A statistically significant phase window was found where a single shock terminated AFl at a defibrillation threshold (DFT) of 0.9 ± 0.4V/cm. In 30% of cases there is a short run (< 1 second) of AF before AFl termination, which demonstrates an example of a disturbance before reentry is completely terminated. Multiple shocks have a lower termination intensity of 0.7 + -0.1V/cm. ATP alone terminated AFl in four of the six hearts, 15% termination was applied after AF, while 11% application resulted in sustained AF. Conventional monophasic shocks, independent of time, terminate sustained AF only at a minimum intensity of 4.7 ± 0.9V/cm. This lower ATP efficacy suggests that low energy field stimulation may be an alternative to ATP for the treatment of AFl.

The experimental protocol was transferred from the rabbit model to the canine AF model. AFl or AF was induced in the isolated, coronary perfused canine right atrium (n-7) in the presence of acetylcholine (3.8 ± 3.2 uM). The cycle times for AFl and AF are 130.7 + -30.7 milliseconds and 55.6 + -7.9 milliseconds, respectively. Referring to fig. 4A and 4B, using optical mapping (a 16 x 16 photodiode array), it was determined whether AFl and AF were maintained by a single macro reentrant circuit or multiple reentrant circuits, respectively, around the sinoatrial node region. Fig. 4A shows a right atrial endocardial fluorescence optical mapping specimen prepared with a photodiode array optical mapping view during ACh-induced AFl and AF in the canine isolated atria, where (1) the sin θ -sinoatrial node, which is anti-heterogeneity and often becomes the fixed location of the reentrant circuit during atrial flutter, is marked by a dark blue/purple ellipse, (2) the white dotted arrowed line marks the reentrant circuit during atrial flutter, and (3) the black dotted arrowed line marks the reentrant circuit during atrial fibrillation (fixed to another anti-heterogeneity region). Fig. 4B shows activation maps and OAPs during AFL and AF, where (1) the white dotted arrowed line marks the reentry circuit during atrial flutter and (2) the black dotted arrowed line marks the reentry circuit during atrial fibrillation (fixed to another region of anti-heterogeneity). From this, the AF reentry core is located in the region of functional and anatomical heterogeneity within the pectinate muscle and SVC/IVC regions. With the rabbit experimental setup, single or multiple monophasic 10 ms shocks were applied by parallel electrode meshes in a tissue bath.

When the super-threshold virtual cathode is introduced to local anti-heterogeneity, the far-field diastolic threshold of excitation reaches 0.14 + -0.12V/cm (0.005 + -0.0001J). The single shock ADFT for AFl is significantly lower (0.2 + -0.06 vs. 7.44 + -3.27V/cm, or 0.018 + -0.001 vs. 2.6 + -0.78J; p < 0.05) than the single shock ADFT for AF. However, the application of delivering 2 or 3 pulses with an optimal coupling interval between pulses can significantly reduce the ADFT of AF: 3.11 + -0.74V/cm and 3.37 + -0.73V/cm for 2 pulses and 3 pulses, respectively, or 0.44 + -0.04 and 0.48 + -0.03J (p < 0.05 to 1 pulse). The coupling interval optimization is performed in the range of 20% to 190% of the AF cycle time. The optimum coupling interval is 87.3 + -18.6% and 91.3 + -17.9% for the two and three pulses, respectively. The table in fig. 8 provides a summary of the results collected from 6 canine atrial preparation specimens.

In addition, low voltage shocks (0.1-1V/cm) convert AF to AFl. Atrial defibrillation is therefore best achieved by a two-step procedure: (a) converting AF to AFL, and (b) terminating AFL. Both steps are performed by multiple pulses with an energy range of 0.02-0.1J.

Similar ADFT values for AF and AFl were found in both models, indicating correlation between rabbit models and dog trials, among other applications. Lower ADFT can be achieved when multiple field directions are used, and when properly timed shocks or multiple shocks are used.

The above method is an example of a method according to an aspect of the present invention. The above method may be accomplished by an internal implant device. The above-described methods may be implemented to deliver electrical cardiac stimulation according to the present invention using any number and configuration of electrode devices, such as endocardial, epicardial, intravenous implantable devices or external devices, or any combination thereof. The use of multipath electrode configurations is contemplated in some embodiments of the present invention, for example, as shown in U.S. patent nos. 5,306,291 and 5,766,266, which are incorporated herein by reference in their entirety.

The methods of the present invention can be used with or separate from other pacing and defibrillation therapies. For example, the present invention can be implemented as part of an ICD that can deliver a high voltage defibrillation shock in the event that the method of the present invention is not successful in converting cardiac arrhythmias. Alternatively, the present invention may be implemented as part of a conventional cardiac pacemaker for providing an emergency response to a patient's VT/VF condition to increase the patient's chances of survival.

The methods of the present invention also contemplate the use of a number of electrical stimulation pulse waveform configurations and devices. Known monophasic, biphasic, triphasic and cross-phase stimulation pulses may be employed. In one embodiment, the present invention contemplates the use of a rising ramp waveform, as described in the literature: qu, f., Li, l., Nikolski, v.p., Sharma, v., Efimov, i.r., mechanics of preference of Ascending Ramp waves: new instruments of Shock-induced Vulnerability and Defibrillation, American Journal of Physiology- -Heart and Circulatory Physiology, 2005, 289: H569-H577, the entire contents of which are incorporated herein by reference.

The method of the present invention also contemplates the use of a number of devices and configurations that produce phase unpinning of far-field electrical stimulation pulses. While conventional high voltage capacitive discharge circuits may be utilized to generate lower energy stimulation pulses consistent with the present invention, it would be desirable to be able to utilize alternative devices that include lower voltage capacitive devices, such as the stacked, switched, or secondary capacitors, rechargeable batteries, charge pumps, and boost circuits described, for example, in U.S. patent nos. 5,199,429, 5,334,219, 5,365,391, 5,372,605, 5,383,907, 5,391,186, 5,405,363, 5,407,444, 5,413,591, 5,620,464, and 5,674,248, the entire contents of which are incorporated herein by reference. Phased unpinning far field therapy according to embodiments of the present invention may be accomplished by a number of methods, including known methods of generating pacing pulses. Likewise, many known cardiac arrhythmia detection techniques may be used in accordance with the methods of the present invention.

Three-stage atrial cardioversion therapy

According to one embodiment, PUFFT treatment is performed as part of a three-stage atrial cardioversion therapy. As shown in fig. 10, in one embodiment, the treatment 28 implemented by the method shown in fig. 2 includes a three-stage atrial cardioversion therapy implemented on a patient responsive to detection of atrial arrhythmia, the three-stage atrial cardioversion therapy having a set of therapy parameters and having a first stage 400 and a second stage 402 implemented by a far-field configuration of electrodes, and a third stage 404 implemented by a near-field configuration of electrodes.

Referring to fig. 11, a combined illustration of all three phases of a three-phase atrial cardioversion therapy is shown. The first stage 400 is used to pluck out one or more abnormalities associated with atrial arrhythmia. The second stage 402 is used to prevent one or more abnormalities associated with atrial arrhythmia from being pinned again. The third stage 404 is used to eliminate one or more abnormalities associated with atrial arrhythmia. In various embodiments, the first phase 400 has at least two and less than ten biphasic atrial cardioversion pulses greater than 10 volts and less than 100 volts, in some embodiments accompanied by a pulse time of about 3-4 milliseconds, or more generally in various other embodiments accompanied by a pulse time of less than 10 milliseconds, accompanied by a pulse coupling interval of between 20 and 50 milliseconds. In some embodiments, the first phase 400 has a total duration of less than the cycle time of two atrial arrhythmias and is delivered with an energy of less than 0.1 joules per biphasic atrial cardioversion pulse. There is an inter-stage delay I1 of between 100 and 400 milliseconds before the second stage 402. In some embodiments, the second phase 402 has at least five and less than ten far-field pulses that are less than the ventricular far-field excitation threshold (10 volts) with a pulse time greater than 5 and less than 20 milliseconds and a pulse coupling interval that is between 70-90% of the cycle time of the atrial arrhythmia. There is an inter-stage delay I2 of between 100 and 400 milliseconds before the third stage 404. In some embodiments, the third stage 404 has at least five and less than ten near-field pulses of less than 10 volts with pulse times greater than 0.2 and less than 5 milliseconds and pulse coupling intervals between 70-90% of the cycle time of the atrial arrhythmia. A three-stage atrial cardioversion therapy is implemented based on the atrial arrhythmia detected for each stage (400, 402, and 404), and the conversion of the atrial arrhythmia is not confirmed until after the third stage 404 is implemented.

Referring to fig. 12, one embodiment of a first stage 400 is shown. In this embodiment, each of the four biphasic cardioversion pulses is delivered from a separate output capacitor configuration, wherein the H-bridge output switching device reverses the polarity of the far field electrodes at some time during discharge of the output capacitance device. In an alternative embodiment, few output capacitance means are available for delivering a later cardioversion pulse from the same output capacitance means that is used to deliver an earlier cardioversion pulse and that has completed recharging before the later cardioversion pulse. In other embodiments, each phase of the biphasic cardioversion pulses may be delivered from a separate output capacitive device. In other embodiments, a switched capacitor network may be used in combination with an output capacitor device to deliver cardioversion pulses of the first stage 400. It will be appreciated that the range of pulse parameters provided for the first stage 400, the original output voltage, the inversion voltage, the duration and the coupling interval between pulses may be the same or different for all or some of the pulses. It will also be appreciated that the pulses of the first stage 400 shown in fig. 12 may all be delivered by the same far-field electrode configuration, and that in other embodiments the pulses may be delivered as part of delivering a rotated set of PUFFT pulses by a different far-field electrode configuration.

Referring to FIG. 13, one embodiment of a second stage 402 is shown. In this embodiment, each of the six single-phase far-field low-voltage pulses is delivered from the same output capacitance arrangement that recharges between successive pulses, although the pulses may be delivered from separate output capacitance arrangements or from fewer than the total number of pulses for the second stage 402. Alternatively, the pulses may be delivered directly from a charge pump, voltage booster, or other such charge storage device driven by the battery system. As with the first stage 400, it will be appreciated that the original output voltage, the inversion voltage, the duration, and the coupling interval between pulses in the second stage 402 may be the same or different for all or some of the pulses within the parameters of the pulses provided for the second stage 402. It will also be appreciated that the pulses of the second stage 402 shown in fig. 13 may all be delivered by the same far-field electrode configuration, and that in other embodiments the pulses may be delivered as part of delivering a rotated set of PUFFT pulses by a different far-field electrode configuration. The far field electrode configuration for the second stage 402 may be the same as or different from the far field electrode configuration for the first stage 400.

Referring to fig. 14, one embodiment of the third stage 404 is shown. In this embodiment, each of the eight single-phase near-field low-voltage pulses is delivered from the same output capacitance device that recharges between successive pulses, although the pulses may each be delivered from a separate output capacitance device or from fewer than the total number of pulses for the third stage 404. Alternatively, the pulses may be delivered directly from a charge pump, voltage booster, or other such charge storage device driven by the battery system. In one embodiment, the same output capacitance arrangement is used to deliver the second stage pulse and the third stage pulse. As with the first stage 400 and the second stage 402, it is to be understood that the original output voltage, the inversion voltage, the duration, and the coupling interval between pulses in the third stage 404 may be the same or different for all or some of the pulses within the parameters of the pulses provided for the third stage 404. It will also be appreciated that the pulses of the third stage 404 shown in fig. 14 may all be delivered by the same near-field electrode configuration, and that in other embodiments the pulses may be delivered as part of delivering a rotated set of PUFFT pulses by a different near-field electrode configuration. In some embodiments, the near field electrode configuration may be a monopolar electrode arrangement, and in other embodiments, the near field electrode configuration may be a bipolar electrode arrangement.

Referring to fig. 15 and 16, an alternative embodiment of a three-stage atrial cardioversion therapy is shown. In this embodiment, the pluck phase one 400 and the prevent re-pinning phase two 402 are repeated in sequence as part of the overall atrial cardioversion therapy 28 before the ablation phase three 404 is performed. As with the embodiment shown in fig. 11, the parameters for each phase, and the pulses within each phase, may be the same or different from the different phases and/or the different pulses within each phase.

Referring to fig. 17 and 18, an alternative embodiment of a three-stage atrial cardioversion therapy is shown. In this embodiment, the plucking phase one 400 and the preventing re-pinning phase two 402 are repeated in sequence, with the elimination phase three 404 as part of the overall atrial cardioversion therapy 28, and then all three phases are repeated before the atrial cardioversion therapy 28 is completed. As with the embodiment shown in fig. 11, the parameters for each phase, and the pulses within each phase, may be the same or different from the different phases and/or the different pulses within each phase.

Referring now to fig. 19A-19B and 20, the structure of one embodiment of a three-stage atrial cardioversion system is shown in detail. In an embodiment depicted at a high level in fig. 19A, an atrial arrhythmia treatment device 500 includes a plurality of electrodes 502 adapted to be implanted proximate to an atrium of a heart of a patient to deliver far field pulses and a plurality of electrodes 504 adapted to be implanted proximate to the atrium of the heart of the patient to deliver near field pulses and detect signals of the heart. The housing of apparatus 500 may serve as one of far-field electrode 502 or near-field electrode 504. Furthermore, in some embodiments, far-field electrode 502 and near-field electrode 504 may share at least one common electrode. An implantable therapy generator 506 is operatively coupled to the electrodes and includes a battery system 508 (or other suitable on-board energy source such as a supercapacitor) and one or more power circuits 510 that are operatively coupled to and provide electrical energy to the implantable therapy generator's sensing circuit 512, sensing circuit 514, control circuit 516, and therapy circuit 51. In one class of embodiments, the therapy circuit 518 includes a dedicated power supply that is supplied directly from the battery system 508, bypassing the power circuit 510. Sensing circuitry 512 senses cardiac signals representative of atrial and ventricular activity. The detection circuit 514 evaluates the cardiac signal representative of atrial activity to determine atrial cycle time and detects atrial arrhythmias based at least in part on the atrial cycle time. In response to the atrial arrhythmia, the control circuit 516 controls the generation and selective delivery of a three-stage atrial cardioversion therapy to the electrodes 502 and 504 with an inter-stage delay of between 100 and 400 milliseconds per stage without confirming conversion of the atrial arrhythmia during the three-stage atrial cardioversion therapy. In various embodiments, the detection circuitry 514, control circuitry 516, and therapy circuitry 518 may share components. For example, in one embodiment, a common microcontroller may be part of the detection circuit 514, the control circuit 516, and the therapy circuit 518.

A therapy circuit 518 is operatively connected to the electrodes 502 and 504 and the control circuit 516. Fig. 19B illustrates an exemplary arrangement of a therapy circuit 518 according to one class of embodiments. The therapy circuit 518 includes its own power circuit 602 that is powered by the battery system 508. The power circuit 602 may be a simple voltage regulator or it may be a current limiting circuit that functions to prevent the therapeutic circuit (which has the greatest power demand among all the circuits in the device) from drawing too much power and thereby causing the supply voltage to drop to a level low enough not to supply the controller and other critical components. Alternatively, the power supply circuit 602 may be applied to the power supply circuit 510; alternatively, in one class of embodiments, the power supply circuit 602 may be omitted entirely, such that the charging circuit 604 is powered directly by the battery system 508.

The charging circuit 604 is a voltage conversion circuit that generates the voltage at the level required by the stimulus waveform. The voltage input to the charging circuit is at or near the voltage of the battery system 508, and in one embodiment is between 3 and 12 volts. Because the stimulus waveform, particularly the first phase, is at a very high voltage (up to about 100 volts), the charging circuit 604 employs a boosted voltage topology. Any suitable boost circuit may be used including a switching regulator that utilizes one or more inductive elements (e.g., a transformer, an inductor, etc.), or a switching regulator that utilizes a capacitive element (e.g., a charge pump).

Fig. 20A-20F illustrate various known layouts for a boost circuit that may be used as part of the charging circuit 604, according to various embodiments. Fig. 20A shows a basic boost converter topology. The boost converter of fig. 20A stores energy with a single inductor indicated at L1 at each cycle of switch SW. When switch SW is closed, inductor L1 is excited and a self-induced magnetic field is generated. When switch SW is opened, the voltage at node L1-SW-D1 is raised due to the collapse of the magnetic field in inductor L1. The related current passes through the blocking diode D1 and the charging energy storage capacitor C_outTo a voltage greater than the input voltage V_inThe voltage value of (2).

Fig. 20B shows a flyback converter topology. The flyback converter utilizes a transformer T1 as an energy storage device and a step-up transformer. When switch SW is closed, the primary winding of transformer T1 is energized in a manner similar to inductor L1 in fig. 20A. When the switch SW is opened, the voltage across the primary coil is reversed and increased due to the initial collapse of the magnetic field. The varying voltage of the primary coil is magnetically connected to the secondary coil, which typically has a larger coil to further increase the voltage of the secondary side. In some embodiments, a typical turns ratio for defibrillator signal applications is about Np: ns is about 1: 15 where Np is the primary turns and Ns is the secondary turns. The high voltage passing through the secondary coil is rectified by a diode and stored in a capacitor C_outIn (1).

Fig. 20C illustrates a single-ended primary coil inductive converter ("SEPIC") that provides certain advantages over other power converter topologies. For example, SEPIC converters have the advantage that no significant energy storage in the transformer is required. This reduces the required gap width of the transformer, since most of the energy in the transformer is stored in its gap. Battery voltage applied to VIN and switching elementSwitching is done at a fixed frequency and duty cycle, which varies according to the feedback of battery current into the power converter and output voltage. The voltage output from the step-up transformer T1 is rectified by a diode D1 to generate C_outAn output voltage of the voltage converter.

Fig. 20D illustrates a variation of the SEPIC converter of fig. 20C. The SEPIC layout of fig. 20D has an additional inductive component L1. The additional inductor L1 may be applied separately or may be magnetically integrated with the high voltage transformer into a single magnetic structure, as shown in fig. 20D.

Fig. 20E illustrates a Cuk converter topology. The Cuk converter comprises two inductors L1 and L2, and two capacitors C1 and C_outA switch SW and a diode D1. The capacitor C is used to transfer energy and is alternately connected to the input and output of the converter by commutation of the transistor and the diode. Two inductors L1 and L2 are used to convert the input voltage source Vi and the capacitor C, respectively_outThe output voltage of (2) enters a current source. Similar to the voltage conversion circuit described above, the ratio of the output voltage to the input voltage is related to the duty cycle of the switch SW. Alternatively, inductors L1 and L2 may be magnetically coupled, as indicated by T1.

Fig. 20F illustrates a basic charge pump layout for multiplying the input voltage. The embodiment shows a Cockcroft-Walton multiplication circuit. Three capacitors C_A、C_BAnd C_CEach capacitor C is connected in series and the capacitance C is connected_AIs connected to a supply voltage V_DD. In thatDuring the phase, the capacitor C is connected₁Is connected to C_AAnd charged to a voltage V_DD。

When the switch is in the next cycleWhile changing position, capacitor C₁To-be-connected capacitor C_BShare the electricity and both will be if they have equal energyCharging to V_DD/2. In the next cycle, C is added₂And C_BConnecting and distributing V_DDA potential of/4, and C₁Is charged again to V_DD. When this method is continued for several cycles, charge will be transferred to all capacitors until 3V is generated_DDOver the output voltage V_out. Additional stages may be added to increase the voltage factor.

Referring again to fig. 19B, the pulse energy storage circuit 606 may take various forms. Generally, the pulse energy storage circuit has sufficient energy storage capacity to store all three phases of atrial cardioversion therapy, or a portion of the energy of therapy, provided that the energy storage circuit 606 and the means of the charging circuit 604 are able to support recharging of a portion of the energy storage circuit 606 when other portions of the energy storage circuit 606 are or are about to be discharged during the application of the electrical therapy. Fig. 20G illustrates a basic embodiment of an energy storage circuit 606, in which there are three separate reservoirs for the three phases of electrotherapy. The storage tank 606a stores energy for the first stage; reservoir 606b for the second stage; and 606c for the third stage. Each tank may have one or more storage elements. In a class of embodiments, each tank has a plurality of storage element groups, each storage element group being selectively available for charging and discharging, respectively, in an openable manner. The memory element may take any suitable form including capacitors of suitable technology such as electrolytic, tantalum thin film, ceramic sheet, super capacitors and the like.

The reservoirs 606a-606c are connected to the charging circuit 604 through a selector switch 607. The selection switch 607 may be implemented using an analog multiplexer, a transmission gate, or any other suitable electronic switching device. The selection switch 607 is controlled by the control circuit 614 in this embodiment.

Referring again to fig. 19B, the wave shaping circuit 608 regulates the application of the electrotherapy by selecting and controlling the discharge of the energy stored in the energy storage circuit 606. In one embodiment, wave shaping circuit 608 is in the form of an H-bridge layout, as shown in FIG. 20G. Switches S1-S4 are controlled by control circuit 614, respectively. The H-bridge arrangement facilitates steering, or reversing the polarity of the electrotherapy signals, ensuring that a biphasic shock can be applied from a unipolar energy storage container. Other forms of switchable coupling are also contemplated for other embodiments. For example, a set of analog transmission gates may be used, thereby making each tank 606a-606c individually selectable. In the latter embodiment, separate capacitors of opposite polarity are used to store the charge for each phase of the biphasic plucking waveform of the first electrotherapy phase.

Referring again to fig. 19B, the electrode coupling circuit 610 operates to select sets of patient electrodes 612 that are connected to the output of the wave shaping circuit 608. In one embodiment, the electrode coupling circuit 610 may be implemented using a set of analog multiplexers controlled by the control circuit 614.

In various other embodiments, the functions of the charging circuit 604 and the pulse energy storage circuit 606 may be combined into a single circuit 620, such as a charge pump device, in which certain capacitors are also used to charge and store pulse energy for electrotherapy. In another variation, the pulse energy storage circuit 606 may be the same circuit, such as the wave shaping circuit 608 shown at 622, for example, where a plurality of different capacitors are used to store each individual pulse, and where the electrode coupling circuit has the ability to individually select which capacitor is switched on to which electrode. Furthermore, in yet another variation, the charging circuit 604, the pulse energy storage circuit 606, and the wave shaping circuit 608 may be combined into a single circuit arrangement 624, which may be implemented as a combination of circuits 620 and 622.

Referring now to fig. 21 and 22, an exemplary EKG output is displayed over the three-stage atrial cardioversion therapy to demonstrate how the three-stage atrial cardioversion therapy successfully converts atrial arrhythmias. FIG. 21 shows two curves, the upper curve showing the signal of an EKG lead measurement; and the lower curve shows the signal measured at another lead in the atrium. Electrotherapy is applied to the RAA to LAA. As shown, in the first phase, two plucking biphasic shocks of 30V are applied at 40ms intervals. Then, in the second stage, eight 3V single-phase shocks to prevent re-pinning were applied at 100ms intervals, using the same electrodes as in the first stage. Next, in a third phase, eight pacing stimuli are applied at 100ms intervals. The third stage is performed by RA epicardial pacing electrodes. Atrial fibrillation is restored to normal sinus rhythm by administration of this therapy, as shown by the lower curve. Figure 22 shows a similar pair of curves, except that three-stage electrotherapy was applied in three trials. In the first experiment, the first phase, carried out at 20ms intervals, had five plucking biphasic shocks of 20V. In the second phase of the first trial, eight 3V, re-pinning prevention, monophasic shocks were applied at 100ms intervals from the same electrodes as in the first phase. In the third phase of the first trial, eight pacing stimuli were applied at 100ms intervals from the pacing electrodes on the epicardium of the RA.

The second and third trials of the three-stage treatment were conducted in a similar manner except that five 30V plucking biphasic shocks were applied at 20ms intervals during the first phase of trials 2 and 3. As shown in the lower curve in fig. 22, following the performance of three experiments, atrial EKG indicated restoration of normal sinus rhythm.

Referring now to FIG. 23, experimental results showing a comparison of results for a shock-only procedure, a shock followed by ATP, and for a three-stage atrial cardioversion therapy are shown, according to the energy required for successful conversion of AF for three different electrode configuration vectors, in accordance with one embodiment of the present invention.

In the first part of the study, eight mongrel dogs were used. Two 1 "diameter disk electrodes were placed on the Right Atrial Appendage (RAA) and Left Atrial Appendage (LAA), respectively. AF is induced by rapid atrial pacing with bilateral vagus nerves stimulated at a frequency of 4-20 Hz. AF lasting >5 minutes was defined as persistent AF. A 1 to 4 monophasic (MP, 10 ms) or biphasic (BP, 6-4 ms) shock is applied from the disc electrode, followed by application from the atrial epicardial-pacing electrode at either w/o ATP. All shocks are triggered by the right ventricular R-wave and are delivered within 80-100 milliseconds to avoid VF induction. In six dogs, sustained AF with a primary frequency of 11.0 + -1.7 Hz was observed with vagus nerve stimulation at 12.0 + -4.4 Hz. For AF (95% case), the DFT of 1BP is lower than the DFT of 1MP (0.73 ± 0.43 versus 1.68 ± 0.98J, p =. 008). The DFT of 2BP is lower than that of 2MP (0.37 ± 0.14 vs. 0.93 ± 0.59J, p =.01). The DFT of 2BP is lower than that of 1BP (0.37 + -0.14 vs. 0.73 + -0.43J, p =. 04). There is no significant difference in the DFTs of 2BP, 3BP and 4BP, while the DFT of 4BP is higher than that of 3BP (0.53 + -0.41 vs. 0.39 + -0.36J, ns). The DFT of 2BP following 6 ATP pulses is significantly lower than the DFT of 2BP (0.23 ± 0.05 vs. 0.5 ± 0.08J, p =.001). Atrial flutter (5% of cases with a dominant frequency of 7.7 ± 0.4 Hz) can be easily transformed by multiple shocks of 0.0003 ± 0.0001j.

In the second part of the study, eight mongrel dogs were used. Three 0.5 "diameter disk electrodes were placed on the RAA, LAA and Superior Vena Cava (SVC). A 3F lead having two 1 "coils is inserted into the coronary sinus. The distal coil is called the coronary sinus end (CSd) and the proximal coil is called the coronary sinus proximal (CSp). We performed a DFT test of the shock, from three vectors: SVC to CSd, LAA to CSp, and LAA to RAA. Three different combinations of three stages were randomly tested: only the first phase, followed by the second phase, and three phases together are named treatment 1, treatment 2, and treatment 3, respectively. In six of eight dogs, a primary frequency of 9.77 ± 0.88Hz induced persistent AF. Of all three vectors, treatment 3 had the lowest DFT among the three treatments. Treatment 1 had the highest DFT of the three treatments. The DFTs for treatment 1, treatment 2, and treatment 3 were 0.53 + -0.14 versus 0.35 + -0.26 versus 0.12 + -0.070J across the vectors SVC to CSd. The DFT for treatment 1, treatment 2 and treatment 3 was 0.52 + -0.14 vs 0.27 + -0.27 vs 0.12 + -0.074J at vectors LAA to CSp. The DFT for the vectors RAA to LAA, treatment 1, treatment 2 and treatment 3 was 0.37. + -. 0.13 vs 0.27. + -. 0.26 vs 0.097. + -. 0.070J. There is no significant difference in the DFT of the three vectors.

The above embodiments are intended to be illustrative and not limiting. Other embodiments are within the scope of the following claims. Moreover, although aspects of the present invention have been described with reference to particular embodiments, workers skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention, as defined by the claims.

One of ordinary skill in the relevant art will recognize that the invention may include fewer features than the individual embodiments described above. The embodiments described herein are not intended to be exhaustive or to combine the various features of the invention. Thus, the embodiments are not a combination of mutually exclusive features; rather, the invention may comprise a combination of different individual features selected from different individual embodiments, as understood by a person skilled in the art.

Any reference cited above is limited in that it does not introduce subject matter that is contrary to what is explicitly disclosed herein. Any of the above-cited references are also limited by the claims not incorporated by reference into these references. Any document cited by reference above is further limited in that any definition provided in the document is not incorporated by reference herein unless explicitly stated otherwise.

For the purposes of the claims to explain the present invention, it is expressly stated that the provisions of chapter six, 112 of U.S. patent law USC35 should not be recalled unless the claims refer to the specific terms "means for … …" or "step for … …".

Claims (20)

1. An atrial arrhythmia treatment device, comprising:

at least one electrode adapted to be implanted near an atrium of a heart of a patient to provide far-field pulses;

at least one electrode adapted to be implanted near an atrium of a heart of a patient to provide near field pulses and sense cardiac signals;

an implantable therapy generator adapted to be implanted in a patient and operatively connected to the electrodes, comprising:

sensing circuitry to sense cardiac signals representative of atrial and ventricular activity;

a detection circuit operably connected to the sensing circuit to evaluate a cardiac signal representative of atrial activity to determine an atrial cycle time and detect an atrial arrhythmia based at least in part on the atrial cycle time;

a control circuit, operatively connected to the sensing circuit, for controlling the generation and delivery of a three-stage atrial cardioversion therapy to the electrodes in response to the atrial arrhythmia with an inter-stage delay of between 100 and 400 milliseconds per stage and without confirmation of conversion of the atrial arrhythmia during the three-stage atrial cardioversion therapy; and

a therapy circuit operatively connected to at least one electrode providing far field pulses and at least one electrode providing near field pulses and sensing cardiac signals and a control circuit, comprising:

at least one first-stage charge storage circuit connected to at least one far-field electrode that stores energy for a first stage of a three-stage atrial cardioversion therapy having at least two and less than ten biphasic atrial cardioversion pulses of greater than 10 volts and less than 100 volts with a pulse time of less than 10 milliseconds and a pulse coupling interval between 20 and 50 milliseconds, wherein the first stage has a total duration of less than the cycle time of two atrial arrhythmias and is delivered within a ventricular refractory period at an energy of less than 0.1 joules per biphasic atrial cardioversion pulse to extirpate one or more reentrant circuits associated with atrial arrhythmia;

at least one second stage charge storage circuit connected to the at least one far-field electrode that stores energy for a second stage of the three-stage atrial cardioversion therapy having at least five and less than ten far-field pulses that are less than a ventricular far-field excitation threshold with a pulse time greater than 5 and less than 20 milliseconds and a pulse coupling interval between 70-90% of the cycle time of the atrial arrhythmia, wherein the second stage prevents re-pinning of one or more reentry circuits associated with the atrial arrhythmia that were pulled through the first stage; and

at least one third-stage charge-storage circuit connected to the near-field electrodes that stores energy for a third stage of the three-stage cardioversion therapy having at least five and less than ten near-field pulses of less than 10 volts with a pulse time greater than 0.2 and less than 5 milliseconds and a pulse coupling interval between 70-90% of the cycle time of the atrial arrhythmia, wherein the third stage eliminates one or more reentry circuits associated with the atrial arrhythmia that are pulled out by the first stage and prevented from being repinned by the second stage; and

a battery system operatively connected to and providing power to the sensing circuit, the detection circuit, the control circuit, and the therapy circuit.

2. The apparatus of claim 1, wherein the first stage charge storage circuit comprises at least one output capacitor configuration and a high voltage transformer electrically coupled to the battery system to charge the at least one output capacitor configuration.

3. The apparatus of claim 1, wherein the first stage charge storage circuit comprises at least one output capacitor configuration and a charge pump electrically coupled to the battery system to charge the at least one output capacitor configuration.

4. The apparatus of claim 1, wherein the second stage charge storage circuit and the third stage charge storage circuit comprise separate low voltage output capacitance configurations and switching circuits between the separate low voltage output capacitance configurations and the far field and near field electrodes.

5. The apparatus of claim 1, wherein the control circuit comprises an H-bridge switching circuit connected to at least one electrode providing far-field pulses and at least one electrode providing near-field pulses and sensing cardiac signals to ensure delivery of biphasic pulses.

6. The apparatus of claim 1, wherein the control circuit controls delivery of a three-stage atrial cardioversion therapy to deliver the first stage once, the second stage once, and the third stage once in a sequence.

7. The apparatus of claim 1, wherein the control circuit controls delivery of the three-stage atrial cardioversion therapy to deliver the first stage once, the second stage once, and the third stage once in a sequence.

8. The apparatus of claim 1, further comprising at least two leads operatively connected to an implantable therapy generator, wherein the apparatus and the at least two leads comprise at least four far-field electrodes, and the control circuit is configured to excite a combination of the far-field electrodes to generate a plurality of different electric fields between the different far-field electrodes to provide a cyclical electric field as a phased unpinned far-field therapy generated by the at least one first-stage charge storage circuit and the at least one second-stage charge storage circuit.

9. The device of claim 1, wherein the control circuit delivers treatment in each of the first, second and third phases in accordance with a set of treatment parameters for the pulses of each phase, which is programmed in accordance with feedback from the patient implanted with the device to provide the patient with effective treatment of atrial arrhythmia within the patient's tolerable pain sensation.

10. The apparatus of claim 9, wherein the control circuitry comprises a microprocessor programmed with a heuristic learning algorithm that dynamically modifies settings of the set of therapy parameters for the pulses of each phase based on the effect of the three-phase atrial cardioversion therapy.

11. An atrial arrhythmia treatment device, comprising:

an implantable therapy generator adapted to be implanted in a patient, comprising:

means for detecting an atrial arrhythmia and determining a cycle time of the atrial arrhythmia;

apparatus for generating a three-stage atrial cardioversion therapy, comprising:

a device for generating a first phase of a three-phase atrial cardioversion therapy having at least two and less than ten biphasic atrial cardioversion pulses of greater than 10 volts and less than 100 volts with a pulse time of less than 10 milliseconds and a pulse coupling interval of between 20 and 50 milliseconds for pulling out one or more reentrant circuits associated with atrial arrhythmias, wherein the first phase has a total duration of less than the cycle time of the two atrial arrhythmias and is delivered within a ventricular refractory period at an energy of less than 0.1 joules per biphasic atrial cardioversion pulse;

a device for generating a second phase of a three-phase atrial cardioversion therapy having at least five and less than ten far-field pulses less than a ventricular far-field excitation threshold with a pulse time greater than 5 and less than 20 milliseconds and a pulse coupling interval between 70-90% of the cycle time of the atrial arrhythmia for preventing re-pinning of one or more reentry circuits associated with the atrial arrhythmia; and

a device for generating a third stage of a three-stage cardioversion therapy having at least five and less than ten near-field pulses of less than 10 volts with a pulse time greater than 0.2 and less than 5 milliseconds and a pulse coupling interval between 70-90% of the cycle time of the atrial arrhythmia for ablating one or more abnormalities associated with the atrial arrhythmia; and

means for controlling delivery of the three-stage atrial cardioversion therapy in response to detection of the atrial arrhythmia with each stage having an inter-stage delay of between 100 and 400 milliseconds and without confirming conversion of the atrial arrhythmia until after delivery of the third stage; and

at least two leads adapted to be operably connected to the implantable therapy generator, each lead having at least one electrode adapted to be positioned proximate to an atrium of a heart of the patient, through which a three-stage atrial cardioversion therapy is delivered to the atrium of the heart,

whereby the means for producing the first phase and the means for producing the second phase are connected by means for controlling the far field configuration delivered to the electrodes and the means for producing the third phase is connected by means for controlling the near field configuration delivered to the electrodes.

12. The apparatus of claim 11, wherein the means for controlling the three-stage atrial cardioversion therapy delivers the first stage once, the second stage once, and the third stage once in sequence.

13. The apparatus of claim 11, wherein the means for controlling delivery of the three-stage atrial cardioversion therapy delivers the first stage once, the second stage once, and the third stage once in sequence.

14. The apparatus of claim 11, wherein the apparatus and the at least two leads comprise at least four far-field electrodes and the means for controlling delivery of the three-stage atrial cardioversion therapy is configured to excite a combination of the far-field electrodes to produce a plurality of different electric fields between different far-field electrodes to deliver a circulating electric field as a phased unpinning far-field therapy produced by the means for producing the first stage and the means for producing the second stage.

15. The apparatus of claim 11, wherein the means for controlling delivery of the three-stage atrial cardioversion therapy delivers therapy in each of the first, second and third stages according to a set of therapy parameters for the pulses of each stage programmed to provide effective treatment of atrial arrhythmia to the patient in response to feedback from the patient implanted with the apparatus within the patient's tolerable pain sensation.

16. The apparatus of claim 15, wherein the means for controlling delivery further comprises a heuristic learning algorithm that dynamically modifies settings of the set of therapy parameters for the pulses of each phase based on an effect of the three-phase atrial cardioversion therapy.

17. The apparatus of claim 11, wherein the means for generating a three-stage atrial cardioversion therapy comprises a battery system and the means for generating a first stage comprises at least one output capacitance arrangement and a high voltage transformer electrically coupled to the battery system to charge the at least one output capacitance arrangement.

18. The apparatus of claim 11, wherein the means for generating a three-stage atrial therapy includes a battery system and the means for generating a first stage includes at least one output capacitive configuration and a charge pump electrically coupled to the battery system to charge the at least one output capacitive configuration.

19. The apparatus of claim 18, wherein the means for generating the first phase comprises a plurality of output capacitor configurations, one for each biphasic atrial cardioversion pulse, and the charge pump selectively charges each of the plurality of output capacitor configurations.

20. The apparatus of claim 11, wherein the at least two leads comprise a first lead having at least one far-field electrode and a second lead having at least one near-field electrode, and wherein the implantable pulse generator comprises at least a portion of a housing of the implantable pulse generator as a far-field electrode.