WO2011159641A1 - Stimulation waveform and system for polarity-independent cardiac resynchronization - Google Patents

Abstract

Systems and methods for cardiac rhythm management using a plurality of electrodes are provided, where at least one of the plurality of electrodes is in contact with a cardiac site. In the system and method, at least one sequence of electrical pulses is generated for electrically stimulating cardiac tissues using either of cathodal stimulation and anodal stimulation. Further, the at least one sequence of electrical pulses is applied to the cardiac tissue. In the system and method, the pulse widths in at least a portion of the at least one sequence of electrical pulses are configured to be less than about 1us and to have an amplitude and a frequency so that a threshold for the cathodal stimulation of the cardiac tissues and a threshold for the anodal stimulation of the cardiac tissues are substantially the same.

Description

STIMULATION WAVEFORM AND SYSTEM FOR POLARITY -INDEPENDENT

CARDIAC RESYNCHRONIZATION

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Serial No. 61/354,316, entitled "STIMULATION WAVEFORM AND SYSTEM FOR POLARITY- INDEPENDENT CARDIAC RESYNCHRONIZATION", filed June 14, 2010, which is herein incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to cardiac resynchronization by electrical stimulation, and more specifically to systems and methods for providing polarity independent cardiac resynchronization.

BACKGROUND

[0003] Cardiac resynchronization by electrical stimulation can increase heart performance and avoid the need for heart transplantation for patients with heart failure. Resynchronization is typically achieved by using an implantable device that generates electric pulses delivered via multiple electrodes in multiple regions of the heart. In such devices, the pulse waveforms typically result in the threshold (in terms of voltage amplitude) for anodal cardiac stimulation being much higher than the threshold for cathodal cardiac stimulation. Generally, this is a difference of approximately at least 2x to 5x higher. Thus with such conventional pulse waveforms, stimulation via two electrodes placed in the heart requires that the generator output of the device be set to a level higher than the threshold for anodal cardiac stimulation to ensure occurrence of such stimulation. As a result, this output will far exceed the threshold needed for cathodal stimulation. Accordingly, when conventional cardiac stimulation pulse waveforms are used, the anodal electrode is less efficient and has higher stimulation threshold than the cathodal electrode.

[0004] The use of such conventional waveforms therefore results in either: ( 1) a higher stimulation strength setting in order to exceed the higher anodal threshold required if the generator is attached in bipolar mode in order to use both electrodes to stimulate two regions of the heart; or (2) a wasted application of energy if the generator is attached in unipolar mode with one of the electrodes at a remote location where thai electrode does not stimulate the heart. [0005] If a configuration is used in which only the cathodal electrode is placed in the heart and the body of the implantable device or a remote electrode is used as the anodal electrode, then the generator may be set to exceed just the threshold for ca thodal stimulation. However, such an arrangement is still inefficient for cardiac resynchronization. First, such an arrangement will only result one region of the heart being stimulated, thus the arrangement has limited, functionality. Further, the anodal electrode remote from the heart cannot be used to effectively stimulate cardiac tissue, although it will use energy. Accordingly, the energy efficiency of the system will be decreased.

SUMMARY

[0006] As noted, above, conventional cardiac resynchronization devices and. techniques are generally inefficient and result in limited battery lifetimes for implantable

resynchronization devices. As a result, such devices require frequent replacement. However, a higher efficiency during stimulation of mu ltiple regions of the heart, and hence increased battery life in an implanted cardiac resynchronization system, can be achieved if the system can be configured such that a threshold for the anodal stimulation (anodal threshold) of the cardiac tissues and the threshold for the cathodal stimulation (cathodal threshold) are substantially equal.

[0007] As used herein, the term "substantial equal" with respect to the comparison of two quantities, values, or the like, refers to quantities, values, or the like in having a relative difference of about 15% or less. Further, the term "cathodal stimulation", as used herein, refers to a stimulation of cardiac tissues in contact with an electrode so that current flows from the cardiac tissues into the electrode. Conversely, the term "anodal stimulation", as used herein, refers to a stimulation of cardiac tissues in contact with an electrode so that current fiow^rs into the cardiac tissues from the electrode.

[0008] In such a configuration, two electrodes could then be used to stimulate different regions of the heart, depending on the polarity of the electrodes. Accordingly, such a device would operate with greater efficiency than existing implantable devices. Further, a single low generator current setting could be used instead of requiring a setting that exceeds the typically higher anodal threshold and greatly exceeds the typically lower cathodal threshold.

[0009] Accordingly, the various embodiments provide systems and methods for managing cardiac rhythm. In the various embodiments, systems and. methods are provided which utilize a cardiac stimulation pulse waveform that produces the same threshold for the anodal and cathodal electrodes. Further, the various embodiments provide for the delivery of the pulses to the heart so that both the anodal and cathodal electrodes stimulate different regions of the heart with a single generator having a low current setting. In particular, a pulse waveform for stimulating cardiac tissues is provided that is polarity-independent and occurs by a cellular mechanism that is different from the mechanism of stimulation with

conventional pulses. In particular, a waveform is provided that provides stimulation via efectroporation and electrostimulation.

[0010] In a first embodiment of the invention, a cardiac rhythm management system is provided. The system can include a stimulation device configured for generating at least one sequence of electrical pulses for electrically stimulating cardiac tissues using either of cathodal stimulation and anodal stimulation. The system also includes a plurality of electrodes coupled to the pulse generator and providing at least one pair of electrodes for applying the at least one sequence of electrical pulses. In the system, the pair of electrodes is configured so that at feast one electrode is in contact with a cardiac site. Further, the system is configured so that the pulse widths in at least a portion of the at least one sequence of electrical pulses are less than about lus and have an amplitude and a frequency so that a threshold for the cathodal stimulation of the cardiac tissues and a threshold for the anodal stimulation of the cardiac tissues are substantially the same.

[0011] In a second embodiment of the invention, a method, for cardiac rhythm

management using a plurality of electrodes is provided, where at least one of the plurality of electrodes is in contact with a cardiac site. The method includes generating at least one sequence of electrical pulses for electrically stimulating cardiac tissues using either of cathodal stimulation and anodal stimulation. The method further includes applying the at least one sequence of electrical pulses using a plurality of electrodes. In the method, the pulse widths in at least a portion of the at least one sequence of electrical pulses are configured, to be less than about lus and to have an amplitude and a frequency so that a threshold for the cathodal stimulation of the cardiac tissues and a threshold for the anodal stimulation of the cardiac tissues are substantially the same.

BRIEF DESCRIPTION OF TFIE DRAWINGS

[0012] FIG. 1 is a simplified diagram illustrating an exemplary implantable stimulation device for carrying out the various embodiments:

[0013] FIG. 2 is a functional block diagram of an exemplary implantable stimulation device illustrating basic elements that are configured to provide cardioversion, defibrillation,pacing stimulation and/or other tissue stimulation in accordance with the various embodiments;

[0014] FIG. 3 is a schematic diagram of the experimental setup used for confirming electroporation- induced currents as a result of the new waveform in accordance with the various embodiments:

[0015] FIG, 4 is a plot showing a shock pulse in accordance with the various

embodiments delivered, to the hearts;

[0016] FIG. 5 is a plot showing the extracellular electrogram of a heart used for testing the new waveform in accordance with the various embodiments;

[0017] FIG. 6 is a plot showing monophasic action potential of a heart used for testing the new waveform in accordance with the various embodiments;

[0018] FIG. 7 is a plot showing the enlarged image of the extracellular voltage difference before and after a shock using the new waveform in accordance with the various

embodiments.

[0019] FIG. 8 is a plot showing the image of the extracellular voltage difference before and after a shock using the new waveform in accordance with the various embodiments;

[0020] FIG. 9 is a image of a goldfish heart at an electrode site having a fluorescent dye for showing electroporated portions of the heart; and

[0021] FIG. 10 is a schematic illustration of the electrical circuit formed as a result of applying a waveform in accordance with the various embodiments.

DETAILED DESCRIPTION

[0022] The present invention is described with reference to the attached figures, wherein like reference numerals are used throughout the figures to designate similar or equivalent elements. The figures are not drawn to scale and they are provided merely to illustrate the instant invention. Several aspects of the invention are described below with reference to example applications for illustration. It should be understood that numerous specific details, relationships, and methods are set forth to provide a full understanding of the invention. One having ordinary skill in the relevant art, however, will readily recognize that the invention can be practiced without one or more of the specific details or with other methods. In other instances, well-known structures or operations are not shown in detail to avoid obscuring the invention. The present invention is not limited by the illustrated ordering of acts or events, as some acts may occur in different orders and/or concurrently with other acts or events. Furthermore, not all illustrated acts or events are required to implement a methodology in accordance with the present invention.

[0023] The various embodiments can be implemented in connection with, any stimulation device that is configured or configurable to delivery cardiac therapy and/or sense information germane to cardiac therapy. Such a stimulation device is described below with respect to FIGs. 1 and 2,

[0024] FIG. 1 shows an exemplary stimulation device 100 in electrical communication with a patient's heart 102 by way of one or more leads, such as leads 104, 106, 108, suitable for delivering multi-chamber stimulation and shock therapy. The leads 104, 106, 108 are optionally configurable for delivery of stimula tion pulses suitable for stimulation of nerves or other tissue. In addition, the device 100 includes a fourth lead. 1 10 suitable for stimulation. However, in some implementations, the lead can have multiple electrodes, such as electrode 144, 144', 144" that are suitable for stimulation and sensing of physiologic signals. In the various embodiments, this lead may be positioned in or near a patient's heart. Alternatively, the lead can be placed in a position remote from the heart.

[0025] The right atrial lead 104, as the name implies, is positioned in and/or passes through a patient's right atrium. The right atrial lead 104 can optionally sense atrial cardiac signals and/or provide right atrial chamber stimulation therapy. As shown in FIG. 1, the stimulation device 100 is coupled to an implantable right atrial lead 104 having, for example, an atrial tip electrode 120, which typically is implanted in the patient's right atrial appendage. The lead 104, as shown in FIG. .1 , also includes an atrial ring electrode 121. Of course, the lead 104 may have other electrodes as well. For example, the right atrial lead can optionally include a distal bifurcation having electrodes suitable for stimulation and/or sensing.

[0026] To sense atrial cardiac signals, ventricular cardiac signals and/or to provide chamber pacing therapy, particularly on the left side of a patient's heart, the stimulation device 100 can be coupled to a coronary sinus lead 106 designed for placement in the coronary sinus and/or tributary veins of the coronary sinus. Thus, the coronary sinus lead 106 is optionally suitable for positioning at least one distal electrode adjacent to the left ventricle and/or additional electrode(s) adjacent to the left atrium. In a normal heart, tributary veins of the coronary sinus include, but may not be limited to, the great cardiac vein, the left marginal vein, the left posterior ventricular vein, the middle cardiac vein, and the small cardiac vein.

[0027] Accordingly, an exemplary coronary sinus lead 106 can be optionally designed, to receive atrial and ventricular cardiac signals and to deliver left ventricular pacing therapy using, for example, at least a left ventricular tip electrode 122, left atria! pacing therapy using at least a left atrial ring electrode 124, and shocking therapy using at least a left atrial coil electrode 126. For a complete description of a coronary sinus lead, the reader is directed to U.S. Pat. No. 5,466,254, "Coronary Sinus Lead with Atrial Sensing Capability" (Helland), which is incorporated herein by reference. The coronary sinus lead 106 further optionally includes electrodes for stimulation of nerves or other tissue. Such a lead may include bifurcations or legs. For example, an exemplary coronary sinus lead includes pacing electrodes capable of delivering pacing pulses to a patient's left ventricle and at least one electrode capable of stimulating an autonomic nerve.

[0028] The stimulation device 100 is also shown in electrical communication with the patient's heart 102 by way of an implantable right ventricular lead 108 having, in this exemplary implementation, a right ventricular tip electrode 128, a right ventricular ring electrode 130, a right ventricular (RV) coil electrode 132, and an SVC coil electrode 134, Typically, the right ventricular lead 108 is transvenously inserted into the heart 102 to place the right ventricular tip electrode 128 in the right ventricular apex so that the RV coil electrode 132 will be positioned in the right ventricle and the SVC coil electrode 134 will be positioned in the superior vena cava. Accordingly, the right ventricular lead 108 is capable of sensing or receiving cardiac signals, and delivering stimulation in the form of pacing and shock therapy to the right ventricle. An exemplar}' right ventricular lead may also include at least one electrode capable of stimulating other tissue; such an electrode may be positioned on the lead or a bifurcation or leg of the lead,

[0029] Although the leads 104, 106, 108 are shown in FIG. 1 as being be placed and contacting portions of the heart 102 transvenously, the various embodiments are not limited in this regard. For example, in some embodiments, the leads 104, 106, 108 can also placed to contact the tissues of the heart 102 through its outer surfaces.

[0030] FIG. 2 shows an exemplary, simplified block diagram depicting various components of stimulation device 100. The stimulation device 100 can be capable of treating both fast and slow arrhythmias with stimulation therapy, including cardioversion, defibrillation, and pacing stimulation. While a particular mufti-chamber device is shown, it is to be appreciated and understood that this is done for illustration purposes only. Thus, the techniques, methods, etc., described below can be implemented in connection with any suitably configured or configurable stimulation device. Accordingly, one of skill in the art could readily duplicate, eliminate, or disable the appropriate circuitry in any desired combination to provide a device capable of treating the appropriate chamber(s) or regions of a patient's heart. [0031 ] Housing 200 for the stimulation device 100 is often referred to as the "can", "case" or "case electrode", and may be programmably selected to act as the return electrode for all "unipolar" modes. Housing 200 may further be used as a return electrode alone or in combination with one or more of the coil electrodes 126, 132 and 134 for shocking or other purposes. Housing 200 farther includes a connector (not shown) having a plurality of terminals 201 , 202, 204, 206, 208, 212, 214, 216, 218, 221 (shown schematically and, for convenience, the names of the electrodes to which they are connected are shown next to the terminals).

[0032] To achieve right atrial sensing, pacing and/or other stimulation, the connector includes at least a right atrial tip terminal (AR TIP) 202 adapted for connection to the atrial tip electrode 120. A right atrial ring terminal (AR RING) 201 is also shown, which is adapted for connection to the atrial ring electrode 121. To achieve left chamber sensing, pacing, shocking, and/or autonomic stimulation, the connector includes at least a left ventricular tip terminal (VL TIP) 204, a left atrial ring terminal (AL RING) 206, and a left atrial shocking terminal (AL COIL) 208, which are adapted for connection to the left ventricular tip electrode 122, the left atrial ring electrode 124, and the left atrial coil electrode 126, respectively. Connection to suitable stimulation electrodes is also possible via these and/or other terminals (e.g., via a stimulation terminal S ELEC 221). The terminal S ELEC 221 may optionally be used for sensing. For example, electrodes of the lead 110 may connect to the device 100 at the terminal 221 or optionally at one or more other terminals.

[0033] To support right chamber sensing, pacing, shocking, and/or autonomic nerve stimulation, the connector further includes a right ventricular tip terminal (VR TIP) 212, a right ventricular ring terminal (VR RING) 214, a right ventricular shocking terminal (RV COIL) 216, and a superior vena cava shocking terminal (SVC COIL) 218, which are adapted for connection to the right ventricular tip electrode 128, right ventricular ring electrode 130, the RV coil electrode 132, and the SVC coil electrode 134, respectively.

[0034] At the core of the stimulation device 100 is a programmable microcontroller 220 that controls the various modes of cardiac or other therapy. As is well known in the art, microcontroller 220 typically includes a microprocessor, or equivalent control circuitry, designed specifically for controlling the delivery of stimulation therapy, and may further include RAM or ROM memory, logic and timing circuitry, state machine circuitry, and I/O circuitry. Typically, microcontroller 220 includes the ability to process or monitor input signals (data or information) as controlled by a program code stored in a designated block of memory . The type of microcontroller is not critical to the described implementations. Rather, any suitable microcontroller 220 may be used that is suitable to carry out the functions described herein. The use of microprocessor-based control circuits for performing timing and data analysis functions are well known in the art.

[0035] Representative types of control circuitry that may be used in connection with the described embodiments can include the microprocessor-based control system of U.S. Pat. No. 4,940,052, the state-machine of U.S. Pat. Nos. 4,712,555 and 4,944,298, all of which are incorporated by reference herein. For a more detailed description of the various timing intervals used within the stimulation device and their inter-relationship, see U.S. Pat. No. 4,788,980, also incorporated herein by reference.

[0036] FIG. 2 also shows an atria! pulse generator 222 and a ventricular pulse generator 224 that generate pacing stimulation pulses for delivery by the right atrial lead 104, the coronary sinus lead 106, and/or the right ventricular lead 108 via an electrode configuration switch 226. It is understood that in order to provide stimulation therapy in each of the four chambers of the heart (or to autonomic nerves) the atrial and ventricular pulse generators, 222 and 224, may include dedicated, independent pulse generators, multiplexed pulse generators, or shared pulse generators. The pulse generators 222 and 224 are controlled by the microcontroller 220 via appropriate control signals 228 and 230, respectively, to trigger or inhibit the stimulation pulses.

[0037] Microcontroller 220 further includes timing control circuitry 232 to control the timing of the stimulation pulses (e.g., pacing rate, atrio-ventricular (AV) delay, interatrial conduction (AA) delay, or interventricular conduction (VV) delay, etc.) as well as to keep track of the timing of refractory periods, blanking intervals, noise detection windows, evoked response windows, alert intervals, marker channel timing, etc., which is well known in the art.

[0038] Microcontroller 220 further includes an arrhythmia detector 234. The detector 234 can be utilized by the stimulation device 100 for determining desirable times to administer various therapies. The detector 234 may be implemented in hardware as part of the microcontroller 220, or as software/firmware instructions programmed into the device and executed on the microcontroller 220 during certain modes of operation.

[0039] Microcontroller 220 further includes a morphology discrimination module 236, a capture detection module 237 and an auto sensing module 238. These modules are optionally used to implement various exemplary recognition algorithms and/or methods presented below. The aforementioned components may be implemented in hardware as part of the microcontroller 220, or as software/firmware instructions programmed into the device and executed on the microcontroller 220 during certain modes of operation. The capture detection module 237, as described herein, may aid in acquisition, analysis, etc., of information relating to IEGMS and, in particular, act to distinguish capture versus non-capture versus fusion.

[0040] The microcontroller 220 further includes an optional motion detection module 239. The module 239 may be used for purposes of acquiring motion information, for example, in conjunction with a device (internal or external) that may use body surface patches or other electrodes (internal or external). The microcontroller 220 may initiate one or more algorithms of the module 239 in response to a signal detected by various circuitry or information received via the telemetry circuit 264. Instructions of the module 239 may cause the device 100 to measure potentials using one or more electrode configurations where the potentials correspond, to a potential field generated by current delivered to the body using, for example, surface patch electrodes. Such a module may help monitor cardiac mechanics in relationship to cardiac electrical activity and may help to optimize cardiac resynchronization therapy. The module 239 may operate in conjunction with various other modules and/or circuits of the device 100 (e.g., the impedance measuring circuit 278, the switch 226, the A/D 252, etc.).

[0041 ] The electronic configuration switch 226 includes a plurality of switches for connecting the desired electrodes to the appropriate I/O circuits, thereby providing complete electrode programmability. Accordingly, switch 226, in response to a control signal 242 from the microcontroller 220, determines the polarity of the stimulation pulses (e.g., unipolar, bipolar, etc.) by selectively closing the appropriate combination of switches (not shown) as is known in the art.

[0042] Atrial sensing circuits 244 and ventricular sensing circuits 246 may also be selectively coupled to the right atrial lead 104, coronary sinus lead 106, and the right ventricular lead 108, through the switch 226 for detecting the presence of cardiac activity in each of the four chambers of the heart. Accordingly, the atrial and ventricular sensing circuits, 244 and 246, may include dedicated sense amplifiers, multiplexed amplifiers, or shared amplifiers. Switch 226 determines the "sensing polarity" of the cardiac signal by selectively closing the appropriate switches, as is also known in the art. In this way, the clinician may program the sensing polarity independent of the stimulation polarity. The sensing circuits (e.g., 244 and 246) are optionally capable of obtaining information indicative of tissue capture.

[0043] Each sensing circuit 244 and 246 preferably employs one or more low power, precision amplifiers with programmable gain and/or automatic gain control, bandpass filtering, and a threshold detection circuit, as known in the art, to selectively sense the cardiac signal of interest. The automatic gain control enables the device 100 to deal effectively with the difficult problem of sensing the low amplitude signal characteristics of atria! or ventricular fibrillation.

[0044] The outputs of the atrial and ventricular sensing circuits 244 and 246 are connected to the microcontroller 220, which, in turn, is able to trigger or inhibit the atrial and ventricular pulse generators 222 and 224, respectively, in a demand fashion in response to the absence or presence of cardiac activity in the appropriate chambers of the heart. Furthermore, as described herein, the microcontroller 220 is also capable of analyzing information output from the sensing circuits 244 and 246 and/or the data acquisition system, A/D 252, to determine or detect whether and to what degree tissue capture has occurred and to program a pulse, or pulses, in response to such determinations. The sensing circuits 244 and 246, in turn, receive control signals over signal lines 248 and 250 from the microcontroller 220 for purposes of controlling the gain, threshold, polarization charge removal circuitry (not shown), and the timing of any blocking circuitry (not shown) coupled to the inputs of the sensing circuits, 244 and 246, as is known in the art.

[0045] For arrhythmia detection, the device 100 may utilize the atrial and ventricular sensing circuits, 244 and 246, to sense cardiac signals to determine whether a rhythm is physiologic or pathologic. Of course, other sensing circuits may be available depending on need and/or desire. In reference to arrhythmias, as used herein, "sensing" is reserved for the noting of an electrical signal or obtaining data (information), and "detection" is the processing (analysis) of these sensed signals and noting the presence of an arrhythmia or of a precursor or other factor that may indicate a risk of or likelihood of an imminent onset of an arrhythmia.

[0046] The exemplary detector module 234. optionally uses timing intervals between sensed events (e.g., P-waves, R-waves, and depolarization signals associated with fibrillation which are sometimes referred to as "F-waves") and to perform one or more comparisons to a predefined rate zone limit (i.e., bradycardia, normal, low rate VT, high rate VT, and fibrillation rate zones) and/or various other characteristics (e.g., sudden onset, stability, physiologic sensors, and morphology, etc.) in order to determine the type of remedial therapy (e.g., anti-arrhythmia, etc.) that is desired or needed (e.g., bradycardia pacing, anti- tachycardia pacing, cardioversion shocks or defibrillation shocks, collectively referred to as "tiered therapy"). Similar rules can be applied to the atrial channel to determine if there is an atrial tachyarrhythmia or atrial fibrillation with appropriate classification and intervention. [0047] Cardiac signals are also applied to inputs of an analog-to-digital (A/D) data acquisition system 252. The data acquisition system 252 is configured to acquire intracardiac electrogram (TEGM) signals or other action potential signals, convert the raw analog data into a digital signal, and store the digital signals for later processing and/or telemetric

transmission to an external device 254. The data acquisition system 252 is coupled to the right atrial lead 104, the coronary sinus lead 106, the right ventricular lead 108 and/or the nerve stimulation lead through the switch 226 to sample cardiac signals across any pair of desired electrodes. A control signal 256 from the microcontroller 220 may instruct the A/D 252 to operate in a particular mode (e.g., resolution, amplification, etc.).

[0048] Various exemplary mechanisms for signal acquisition are described herein that optionally include use of one or more analog-to-digital converter. Various exemplary mechanisms allow for adjustment of one or more parameter associated with signal acquisition.

[0049] The microcontroller 220 is further coupled, to a memory 260 by a suitable data/address bus 262, wherein the programmable operating parameters used by the microcontroller 220 are stored and modified, as required, in order to customize the operation of the stimulation device 100 to suit the needs of a particular patient. Such operating parameters define, for example, pacing pulse amplitude, pulse duration, electrode polarity, rate, sensitivity, automatic features, arrhythmia detection criteria, and the amplitude, waveshape, number of pulses, and vector of each shocking pulse to be delivered to the patient's heart 102 within each respective tier of therapy. One feature of the described embodiments is the ability to sense and store a relatively large amount of data (e.g., from the data acquisition system 252), which data may then be used for subsequent analysis to guide the programming of the device,

[0050] Advantageously, the operating parameters of the implantable device 100 may be non-invasively programmed into the memory 260 through a telemetry circuit 264 in telemetric communication via communication lint 266 with the external device 254, such as a programmer, transtelephonic transceiver, or a diagnostic system analyzer. The

microcontroller 220 activates the telemetry circuit 264 with a control signal 268. The telemetry circuit 264 advantageously allows intracardiac electrograms (IEGM) and other information (e.g., status information relating to the operation of the device 100, etc., as contained in the microcontroller 220 or memory 260) to be sent to the external device 254 through an established communication link 266. [005] ] The stimulation device 100 can further include one or more physiologic sensors 270. For example, the device 100 may include a "rate-responsive" sensor that may provide, for example, information to aid in adjustment of pacing stimulation rate according to the exercise state of the patient. However, the one or more physiological sensors 270 may further be used to detect changes in cardiac output (see, e.g., U.S. Pat. No. 6,314,323, entitled "Heart stimulator determining cardiac output, by measuring the systolic pressure, for controlling the stimulation", to Ekwall, issued Nov. 6, 2001, which discusses a pressure sensor adapted to sense pressure in a right ventricle and to generate an electrical pressure signal corresponding to the sensed pressure, an integrator supplied with the pressure signal which integrates the pressure signal between a start time and a stop time to produce an integration result that corresponds to cardiac output), changes in the physiological condition of the heart, or diurnal changes in activity (e.g., detecting sleep and wake states). Accordingly, the microcontroller 220 responds by adjusting the various pacing parameters (such as rate, A V Delay, V-V Delay, etc.) at which the atrial and ventricular pulse generators, 222 and 224, generate stimulation pulses.

[0052] While shown as being included within the stimulation device 100, it is to be understood that one or more of the physiologic sensors 270 may also be external to the stimulation device 100. yet still be implanted within or carried by the patient. Examples of physiologic sensors that may be implemented in device 100 include known sensors that, for example, sense respiration rate, pH of blood, ventricular gradient, cardiac output, preload, afterload, contractility, and so forth. Another sensor that may be used is one that detects activity variance, wherein an activity sensor is monitored diurnaliy to detect the low variance in the measurement corresponding to the sleep state. For a complete description of the activity variance sensor, the reader is directed to U.S. Pat, No. 5,476,483, which patent is hereby incorporated by reference.

[0053] The one or more physiological sensors 270 optionally include sensors for detecting movement and minute ventilation in the patient. Signals generated by a position sensor, a MV sensor, etc., may be passed to the microcontroller 220 for analysis in determining whether to adjust the pacing rate, etc. The microcontroller 220 may monitor the signals for indications of the patient's position and activity status, such as whether the patient is climbing upstairs or descending downstairs or whether the patient is sitting up after lying down.

[0054] The stimulation device 100 additionally includes a battery 276 that provides operating power to all of the circuits shown in FIG. 2. For the stimulation device 100, which employs shocking therapy, the battery 276 is capable of operating at low current drains for long periods of time, and is capable of providing high-current or high-voltage pulses when the patient requires a shock pulse. The battery 276 also desirably has a predictable discharge characteristic so that elective replacement time can be detected.

[0055] The stimulation device 100 can further include magnet detection circuitry (not shown), coupled to the microcontroller 220, to detect when a magnet is placed over the stimulation device 100. A magnet may be used by a clinician to perform various test functions of the stimulation device 100 and/or to signal the microcontroller 220 that the external programmer 254 is in place to receive or transmit data to the microcontroller 220 through the telemetry circuits 264.

[0056] The stimulation device 100 further includes an impedance measuring circuit 278 that is enabled by the microcontroller 220 via a control signal 280. The known uses for an impedance measuring circuit 278 include, but are not limited to, lead impedance surveillance during the acute and chronic phases for proper lead positioning or dislodgement; detecting operable electrodes and automatically switching to an operable pair if dislodgement occurs; measuring respiration or minute ventilation; measuring thoracic impedance for determining shock thresholds; detecting when the device has been implanted; measuring stroke volume; and. detecting the opening of heart valves, etc. The impedance measuring circuit 278 is advantageously coupled to the switch 226 so that any desired electrode may be used.

[0057] In the case where the stimulation device 100 is intended to operate as an implantable cardioverter/defibrillator (ICD) device, it detects the occurrence of an arrhythmia, and automatically applies an appropriate therapy to the heart aimed, at terminating the detected arrhythmia. To this end, the microcontroller 220 further controls a shocking circuit 282 by way of a control signal 284. The shocking circuit 282 generates shocking pulses controlled by the microcontroller 220. Such shocking pulses are applied to the patient's heart 102 through at least two shocking electrodes, and as shown in this embodiment, selected from the left atrial coil electrode 126, the RV coil electrode 132, and/or the SVC coil electrode 134. As noted above, the housing 200 may act as an active electrode in combination with the RV electrode 132, or as part of a split electrical vector using the SVC coil electrode 134 or the left atrial coil electrode 126 (i.e., using the RV electrode as a common electrode),

[0058] Cardioversion level shocks are generally considered to be of low to moderate energy level (so as to minimize pain felt by the patient), and/or synchronized with an R-wave and/or pertaining to the treatment of tachycardia. Defibrillation shocks are generally of moderate to high energy level (e.g., corresponding to thresholds in the range of

approximately 5 J to 40 J), delivered asynchronously (since R-waves may be too

disorganized), and pertaining exclusively to the treatment of fibrillation. Accordingly, the microcontroller 220 is capable of controlling the synchronous or asynchronous delivery of the shocking pulses.

[0059] As already mentioned, the implantable device 100 includes impedance measurement circuitry 278. Such a circuit may measure impedance or electrical resistance through use of various techniques. For example, the device 100 may deliver a low voltage (e.g., about 10 mV to about 20 mV) of alternating current between the RV tip electrode 128 and the case electrode 200. During delivery of this energy, the device 100 may measure resistance between these two electrodes where the resistance depends on any of a variety of factors. For example, the resistance may vary inversely with respect to volume of blood along the path.

[0060] In another example, resistance measurement occurs through use of a four terminal or electrode technique. For example, the exemplary device 100 may deliver an alternating current between one of the RV tip electrode 128 and the case electrode 200. During delivery, the device 100 may measure a potential between the RA ring electrode 121 and the RV ring electrode 130 where the potential is proportional to the resistance between the selected potential measurement electrodes.

[0061] With respect to two terminal or electrode techniques, where two electrodes are used to introduce current and the same two electrodes are used to measure potential, parasitic electrode-electrolyte impedances can introduce noise, especially at low current frequencies: thus, a greater number of terminals or electrodes may be used. For example, aforementioned four electrode techniques, where one electrode pair introduces current and another electrode pair measures potential, can cancel noise due to electrode-electrolyte interface impedance. Alternatively, where suitable or desirable, a two terminal or electrode technique may use larger electrode areas (e.g., even exceeding about 1 cm.sup.2) and/or higher current frequencies (e.g., above about 10 kHz) to reduce noise.

[0062] Although FIGs. 1 and 2 show a specific configuration for a stimulation device, this represents but one exemplary architecture for a device capable of carrying out the various embodiments of the invention. However, the various embodiments are not limited in this regard. Rather, any other type of stimulation device including more or less features than shown in FIGs. 1 and 2 can be used to carry out the various embodiments of the invention. [0063] As noted above, a stimulation device, such as that described above with respect to FIGs. 1 and 2, can be configured in the various embodiments to deliver pulses to the heart such that both the cathodal threshold and the anodal threshold are substantially equal.

Further, such a configuration would also allow a set of electrodes to be used to stimulate different parts of a heart without needing discrete sets of anode and cathode electrodes for each part to be stimulated. To provide such functionality, the various embodiments provide a new waveform configuration for providing cardiac resynchronization.

[0064] The new waveform in accordance with the various embodiments consists of a sequence of high voltage, sub-microsecond electrical pulses that can be delivered anodally or cathodally. In the new waveform, each of the electrical pulses can have a pulse duration from about 1 ns to about 1 us. In one embodiment, the duration of the electrical pulses can be about 300 ns, such as from about 270ns to about 330ns. Further, each of the electrical pulses can have an amplitude in the range of about 100V to about 1000V. In some embodiments of the invention, the amplitude of the pulses can be in the range of about 300V to about 600V. Additionally, the frequency of the electric pulses in the sequence can be selected to correspond to a normal heartbeat frequency for a patient. For example, in the case of human patients, the frequency can correspond to a range of about 50 beats per minute to about 150 beats per minute, depending on the patient.

[0065] As noted above, the new waveform is believed by the present inventors to provide stimulation by mechanisms different that those associated with conventional pulse waveform. A first mechanism of the new waveform is believed, to be electroporation. That is, the short duration and high voltage pulses generated by the electrode are believed to induce a difference in transmembrane potential in the cardiac tissues in and around the contacting electrode. The difference in transmembrane potential caused by the electroporation is then believed to generate a current in the cardiac tissues and thus stimulate the heart. The electroporation-induced current then travels through the heart to non-electroporated regions and causes stimulation of the heart. A second mechanism is believed to be

electrostimulation. That is, the pulses provide stimulation by directly depolarizing cardiac tissue cells to activate sodium channels in the ceil membrane.

[0066] A significant aspect of all the various embodiments is that the electrode current that flows through the interface between an electrode and the heart tissue that is contacted by the electrode is likely carried by the charge displacement effect that is sometimes described as capaeitive current at the interface. Since the pulse is very brief, current carried by chemical reactions of oxidation or reduction involving the electrode's metal ions that occur when a long-duration pulse is used are probably small or nonexistent with the pulses in these embodiments. This provides the advantages of avoiding electrochemical corrosion of metal electrodes and allowing more freedom in the choice of the electrode material since chemical reactions at the electrode tissue interface are not likely to play a role in stimulation with the present embodiments.

[0067] Another significant aspect of the ultrashort pulses in the various embodiments is that impedance and overpotentiai are believed to be low at the electrode tissue interface when the charge displacement current occurs. This is because the current is believed to be mainly capacitive current at the interface. This is advantageous over pulse waveforms used for conventional heart stimulation that have durations in the millisecond range. In such stimulation, ohmic impedance and overpotentials of electrode interfaces that occur with the conventional pulses produce waste of energy due to joule heating at the interface. As a result they typically require the generator voltage to exceed the overpotentiai of the interface before useful stimulation current can flow.

[0068] Still another aspect is that by using the submicrosecond duration pulses the amount of charge that flows to the heart is smaller than it would be for a longer duration pulse since the charge is defined by the integration of current over the pulse duration. A smaller charge can result in a battery life of a device that produces these pulses can be extended. Accordingly, implantable devices with a smaller battery are possible. More importantly, the size of the implanted device can also be reduced.

[0069] The new waveform can be used with a stimulation device in several

configurations. For example, referring back to FIG. 1, the stimulation device 100 can be configured for stimulating the patient's heart 102 via the use of lead 108 and lead 1 10. That is, to provide a first electrode contacting cardiac tissues directly and a second electrode in a remote location. Alternatively, the second electrode can be provided by the can of the stimulation device 100. Such a configuration is similar to the conventional cathodal stimulation configuration described above. However, using a conventional pulse waveform, only cathodal stimulation would, be possible with such a configuration or. In contrast, the new waveform in accordance with the various embodiments permits the conventional cathodal stimulation configuration to be utilized for performing both cathodal and anodal stimulation of chosen cardiac tissues, as further described below.

[0070] The new waveform can also be utilized in the various embodiments to provide anodal stimulation and cathodal stimulation using the pulse waveform and produce simultaneous stimulation of different regions of the heart. Such a configuration is advantageous in that it allows greater control and efficiency for synchronizing the heart's mechanical contractions in different regions. To use the new waveform in such a configuration, first and second leads, such as leads 106 and 108 are placed inside of the heart of the patient, as described above with respect to FIG, 1. Lead 108 can contact tissues in the right ventricle, such as the endocardial surface, and Lead 106 is placed inside a vein within the left ventricle, as described above. Since there is dispersion of current as it passes through the wall of the vein, the exposed metallic area of the electrode in lead 106 may need to be larger than that of lead in order to produce the same stimulation current density in the right ventricular muscle tissue contacting Lead 108 as occurs in the left ventricular muscle tissue surrounding the vein tha t contains Lead 106, A particular ratio of these areas can be determined, in various ways. For example, via experimental data or with a computer model.

[0071] As described above, the leads 106, 108 are attached to the stimulation device 100, which may be located anywhere in the body or outside of the body. In this configuration, there are two possible cases of lead, polarities for the electrodes that depend on the polarity setting of the stimulation device 100. in one case, lead 106 provides the anode electrode while lead. 108 provides the cathode electrode. In the other case, lead 108 provides the anode electrode while lead 106 provides the cathode electrode. In either case, both an anodal and. cathodal electrode are located at different regions of the heart and are attached to a single generator, ensuring that the current is delivered simultaneously to both electrodes which is an advantage for synchronization of the heart.

[0072] In order for both electrodes to successfully stimulate these two regions of the heart, stimulation device 100 must produce a pulse voltage magnitude that exceeds the thresholds for both electrodes provided by leads 106 and. 108. With conventional pulse waveforms, the anodal threshold is greater than the cathodal threshold, in which case the successful stimulation by the anodal electrode would, require that the output of the stimulation device 100 be much greater than the cathodal threshold. That is a disadvantage of conventional pulses, and may cause faster battery depletion in an implantable stimulation device. However, since the new waveform in accordance with the various embodiments produces the same threshold for anodal and cathodal stimulation, the output of the stimulation device only needs to exceed one of these thresholds in order for the electrodes provided by leads 106 and 108 to successfully stimulate the two regions.

[0073] Although the description above is directed to stimulation using two electrodes, the various embodiments are not limited in this regard. In other embodiments, any number of pairs of electrodes can be defined, using any number of leads so that each pair can stimulate with the same anodal and cathodal thresholds using the new waveform in accordance with the various embodiments. Accordingly, the leads and electrodes defined therein can be used in the invention to act upon different regions of the heart.

[0074] A significant aspect of the various embodiments is that the combination anodal and cathodal stimulation can be provided using a single generator, as the same waveform can be applied to the various electrodes. Thus, the amount of battery power needed can be significantly reduced. Additional advantages are that since the same waveform can be applied, the electrodes can be connected to the single generator in multiple ways to maintain efficiency. For example, in some embodiments, pairs of anodal and cathodal electrodes in the heart can be attached in parallel arrangement to a single pulse generator. This can decrease the number of pulse generators needed to be included in the implanted system. In another embodiment, pairs of anodal and cathodal electrodes in the heart can be attached in series arrangement to a single pulse genera tor. This can decrease the number of pulse generators needed to be included in the implanted system. It can also decrease the lengths of electrode leads that need to be implanted.

[0075] A series arrangement of the electrodes located at different regions of the heart tissue can stimulate multiple regions of the heart without requiring that each region's electrode have an electrode lead, attached, to it that is also attached to the stimulation pulse generator. Instead, a pair of electrodes within a series can be formed by using a metallic conductor that has two areas of the conductor simultaneously contacting two different regions of the heart but does not have a lead, attaching either area of the conductor to the stimulation pulse generator.

[0076] Such embodiments with series connection of electrodes can be effective for heart stimulation therapies that seek to stimulate multiple regions of the heart. When there is an electric field present in the heart, a metallic conductor that is placed on the heart and is not attached to the generator stimulates regions of the heart, causing stimulatory current to flo w through areas of the interlace of the conductor with the heart. This can lower electrical defibrillation thresholds as has been shown existing studies of rabbit hearts and in computer models for other types of stimulation waveforms.

[0077] A parallel arrangement provides many of the same advantages of a serial arrangement. However, in the parallel arrangement, the amount of voltage required for the stimulation can be lower for the parallel connection embodiment than for the serial connection. Thus, an advantage of the parallel embodiment is that the stimulation pulse generator circuitry may be smaller because it needs only to produce a smaller pulse voltage. [0078] Although the preceding description of stimulation has been described generally with respect to unipolar stimulation systems (i.e., one electrode per lead), the various embodiments are not limited, in this regard. In some embodiments, one or more bipolar stimulation systems can be used.. That is, leads with multiple electrodes can be provided. In such a configuration, each system can have anodal and cathodal electrodes located in the heart and are separated (by at least one or more centimeters) that they stimulate different regions of the heart. For each bipolar stimulation system, the anodal and cathodal electrodes can be attached to a single pulse generator. This reduces the energy used compared with unipolar stimulation systems in which more than one generator is used for different unipolar electrodes in the heart, or in which a single generator is attached to multiple electrodes with, at least one electrode located remote from the heart. Since the anodal and cathodal electrodes have the same threshold when the cardiac stimulation waveform in this invention is used, the generator output will not need to be set above an anodal threshold, that exceeds the cathodal threshold as it would for conventional waveforms. Accordingly, ^synchronization of the heart by the anodal and cathodal electrodes can be produced with a lower current setting, a smaller number of electrodes and. leads, and. smaller number of generators as compared with conventional methods. These advantages will increase efficiency of the ^synchronization, increase the battery lifetime of implantable devices, simplify implantation and can also eliminate need for a canister or another implanted object located remotely from the heart to serve as an electrode.

[0079] A stimulation device configured to apply the new waveform in accordance with the various embodiments can be used, for several types of pacing modes. For example, in some embodiments, the stimulation device can operate in an "on demand'^' mode. That is, the stimulation device, together with a sensor, can detect the heart rate of a patient. If the detected heart rate fails outsid e a target heart rate range, a sequence of pulses at a target heart rate can be provided, in other embodiments, the stimulation device can also operate in a rate- responsive mode. That is, the stimulation device, together with one or more sensors, can also detect the activity level of the patient, if the detected heart rate falls outside a target heart rate range for the detected activity , a sequence of pulses at a target heart rate for the detected activity can be provided. Other types of pacing modes can also be implemented using a waveform in accordance with the various embodiments.

[0080] Further, although the preceding description refers generally to a sequence of identically configured pulses, the various embodiments are not limited in this regard. Rather, since the pulses in new waveform operate based on a combination of electroporation and. electrostimulation, a sequence of different pulses can be provided in the various

embodiments. That is, in some embodiments, the pulses can have different amplitudes. For example, the sequence can have a strong initial pulse can be provided with a high voltage (greater than about 300V) followed by one or more weaker pulses (less than about 300V). In such a configuration, the initial pulse would generate electropores in the cardiac tissues being stimulated. Thereafter, the weaker pulses, via a combination of el ectroporation and electrostimulation, would provide a sufficient current thereafter to provide stimulation of the cardiac tissues.

[0081 ] It is generally believed that in nerves the summation of currents from more than one current source can produce stimulation, even when the current from either source alone is insufficient to stimulate. Accordingly, a configuration using different pulses in accordance with the various embodiments can exploit this phenomena. That is, a current induced by efectroporation can be established using one or more of the sub microsecond pulses, as described above. That current may be strong enough to excite the heart, or may have insufficient strength to excite the heart, depending on the degree of eiectroporation produced and the geometry of the heart regions that are electroporated and those not electroporated. When an efectroporation current is not strong enough to excite the heart, it still may contribute to excitation. This current will remain for a time that may be I0s of seconds or e v en minutes after the sub microsecond pulse is turned off because the electropores remain for a certain time. During that time, the eiectroporation current would driven by the heart cells and not by the artificial pulse generator.

[0082] One result is that the sustained electropores can be used to avoid sustained battery depletion. However, the other result is that the sustained eiectroporation current will sum with the current from a second and weaker stimulation pulse (with amplitudes of 1/10 less as compared to a first pulse). The pulse duration of the weak pulse can be approximately one ms or several ms so that the current provided by this pulse and with the eiectroporation current both remain on long enough for the sodium channels in the cell membranes to become activated. The cellular mechanism for this type of stimulation would be the summation of direct excitation current from the weak pulse with the eiectroporation current.

[0083] That weak pulse may provide a small current that by itself is insufficient to excite the heart but when summed with the eiectroporation current is sufficient to excite the heart. This allows the weak pulse to stimulate and control the heartbeat timing for

resynchronization or pacing while having current that is weaker than that which would be required if it were used alone with no accompanying eiectroporation current. With the weak pulse being sufficient in the presence of electroporation current, the control of the heart may thus be accomplished using the weak pulse with less energy, smaller batteries, and a smaller generator, which are advantages for an implanted system.

[0084] This same advantage would apply for additional pulses that are similar to the weak pulse and given while the electroporation current exists, enabling repeated heart stimulation and thus repetitive pacing or resynchronization of the heart with weak pulses. In an embodiment that can be envisioned, the eventual closure of electropores and thus the removal of the electroporation current may be sensed using an automatic algorithm as a failure of the weak pulses to continue to pace the heart. Then the system would apply another sub microsecond pulse in order to again produce electroporation current, and the weak pulses would then again be able to pace the heart. This process could be repeated, any number of times.

[0085] EXAMPLES

[0086] The following non-limiting Examples serve to illustrate some aspects of the various embodiments. It will be appreciated that variations in proportions and alternatives in elements of the components shown will be apparent to those skilled in the art and are within the scope of various embodiments.

[0087] Methods and Materials

[0088] Individual goldfish hearts were used to show the effects of the new waveform in accordance with the various embodiments. A standard anesthetic solution consisting of tricane methanesulfonate (MS-222) was used to properly anesthetize the test subjects. Animal protocols require the dosage of the anesthetic to be 200 -300 mg/L. This concentration was sufficient to completely anesthetize the fish within two to three minutes, depending on the size of the goldfish. The conditions required to determine complete paralysis of the fish were a cessation of movement in the fish except for the gills. The motion of the gills was necessary to ensure that the animal remained alive. After the goldfish were submerged in the anesthesia, the goldfish were rinsed under cool water to remove the anesthetic solution. Directly following rinsing, the hearts were surgically removed. Using standard dissection tools, the heart was removed from the body cavity and secured in a custom containment dish. The dish was coated in silicone to provide a medium in which to secure the goldfish hearts using minutia pins.

[0089] Prior to securing the hearts to the dish, a physiological saline solution was added to the container. The physiological solution used in the study consisted of 3 mM KCL, 0.5 mM CaCl₂, 114 mM NaCf, and 2 mM NaHCCK. This solution was equilibrated with air at room temperature. Two fish hearts were secured to the dish at one time and were completely bathed in the physiological saline solution.

[0090] Referring now to FIG. 3, there is shown a schematic of the configuration used for verifying the existence of an electroporation-- induced current as a result of the new waveform in accordance with the various embodiments.

[0091] The dish 300 containing a heart 302 was placed under a Nikon SMZ-10A microscope 304. The maximum magnification of the Microscope was 50x. The lens of a Nikon CoolPix P5100 digital camera 306 was inserted into the viewing piece of the microscope in order to capture the magnified image of the fish hearts. The camera was then connected to a Samsung SyncMaster 510 mp TV monitor 308 so that the enlarged image of the heart could be viewed, on the monitor 308. In this way, the fish hearts were observed while they were beating freely in the saline solution. The images were recorded using the Nikon camera 306.

[0092] A high- voltage generator 310 was used to deliver the electrical stimulation to the fish hearts. The generator 310 was calibrated to deliver 500 V (dc) to the heart tissue. In these experiments, 500 V was a sufficient amount to cause the heart to beat in response to the shock pulse. The high-voltage generator 310 was connected to a custom-made pulsed power coil 312. The pulsed power coil controlled the duration of the shock pulse. The coil was calibrated to deliver pulses of 300 nanosecond duration. The shock pulse was verified using a Tektronix TDS 220, 100 MHz digital oscilloscope 314. Figure 4 shows a graph of the 500V, 300 ns pulse.

[0093] A switch 316 was inserted in the shock circuit to control the delivery of the high- voltage shocks. By pressing the switch 316, the desired voltage was delivered to the submerged heart 302 using two electrodes. The first electrode, called the shock electrode 318, was a Ag-AgCT wire encased in an insulating material except for the tip of the electrode, which was exposed to the heart. This shock electrode 318 was mounted using a three- dimensional manipulator (not shown). The manipulator allowed the electrode to be accurately adjusted so that the tip of the Ag-AgCl electrode contacted the surface of the fish heart 302. The second electrode, or return probe 320, was inserted into the bath near the edge of the dish. This return probe completed the shock circuit.

[0094] In addition to the shock electrode 318 and return electrode 320, two more electrodes were used. These electrodes measured the extracellular potential difference across the heart. These measuring electrodes 322 and 324 were made of 0.010 inch Ag wire and both were mounted using a second three-dimensional manipulator (not shown). Using a double-pole-double-throw switch, the two measuring electrodes 322, 324, could be connected to either an Analog Devices AD210N isolation amplifier 326 or to a separate ground (not shown). During the shock delivery, the inputs to the amplifier 326 were grounded to avoid damage to the amplifier due to excess input differential voltages. The isolation amplifier 326 was configured to have a gain of 10 so that the extracellular voltage difference of the heart was more easily observed on a second digital oscilloscope. The output signal of the isolation amplifier 326 was connected to a Tektronix 3032B, 300 MHz digital phosphor oscilloscope 328 to observe and record the voltage potentials of the hearts. A custom low-pass filter (not shown) with a cutoff frequency of 1 kHz was connected to the output signal of the amplifier 326 to reduce background noise.

[0095] This experimental setup allowed an excitation voltage to be delivered to the heart 302 via the Ag-AgCl probe while the 0.010 inch Ag probes measured the voltage potential difference between the electroporated and non-electroporated regions of the heart. The measuring electrode closest to the shock site, or proximal probe, was arranged l-2mm away from the shock electrode. The measuring electrode located away from the shock site, or distal probe, was situated on the opposite side of the heart away from the shock probe. After the shock was administered, the isolation amplifier 326 increased the differential potential of the proximal and distal probes by a factor of 10. The results of these shocks are shown below with respect to FIGs. 4-9.

[0096] FIG. 4 is shock pulse for a waveform in accordance with the various

embodiments. FIG. 5 is a plot showing the extracellular eleetrograph of a heart and FIG. 6 shows the monophasic action potential of the heart. The beats observed in FIGs 5 and 6 represent the depolarization and subsequent repolarization of the heart. FIG. 7 is a plot showing the extracellular voltage difference before and after a shock. FIG. 8 is a reduced image of FIG. 7 showing the extracellular voltage difference before and after a shock.

[0097] The results in FIGs. 5-8 show that the potential difference in the hearts could be measured reliably. Moreover, the results show that the high voltage, sub-microsecond pulses result in baseline shifts, as observed in FIG.s 7 and 8. As shown in FIGs. 7 and 8 this observed baseline shift was from about 0.2mV to about 0.3mV for the goldfish hearts. This shift in baseline potential thus supports the assumption that a current was induced. A shift in baseline potential indicates a change in transmembrane potential, resulting in current flow. The observed baseline shifts in the goldfish hearts support the assumption that a current was induced across the heart. Consequently, FIGs. 7 and 8 provide evidence of an electroporation- induced current. [0098] The shift in the baseline is a direct indication that the difference between the potentials of the two 0.010 inch measuring electrodes (322 and 324 in FIG 3) changed when the pulse was applied.. For example, in FIG 8, the baseline can be seen during the first 4 seconds of the recording and occurs at the voltage that is arbitrarily labeled as zero mV. The zero can be interpreted to mean simply that the difference between the potentials of the two 0,010 inch measuring electrodes (322 and 324 in FIG 3) was exactly the same as the prepulse baseline. Then at about 8 s, in FIG 8, the graph deflects upward, suddenly which was produced when the amplifier was grounded to protect it. The 300 ns pulse was delivered within the next second, and after that pulse the graph deflects downward just after 9 s when the amplifier was ungrounded.

[0099] The significant aspect of these plots is that the baseline that occurred after the pulse was different from zero, was more negative as seen in FIGs 7 and 8. This demonstrates that the difference between the potentials of the two 0.010 inch measuring electrodes (322 and 324 in FIG. 3) was not exactly the same after the pulse as the pre-pulse baseline. This change of the baseline after the pulse cannot be interpreted as an effect of electrochemical polarization of the two 0.010 inch measuring electrodes (322 and 324 in FIG, 3) by the 300 ns pulse because those electrodes were not used, to deliver the 300 ns pulse. R ather, the change of the baseline after the pulse is interpreted, as a change in d ifference between the potentials of the two 0.010 inch measuring electrodes (322 and 324 in FIG. 3}. That it is interpreted as an indication thai current was flowing after the pulse in the heart.

[0100] Ohms law states that when there is a potential difference between two locations in a conductive object, a current will flow between the locations. For a resistor, the current and potential difference are related by the resistance of the object according to the expression, V = IR, where V is the potential difference measured in Volts, I is the current measured, in amperes and. R is the resistance measured in ohms where 1 ohm = 1 Volt divided by 1 ampere. The geometry of the heart and saline solution is more complex than in a simple resistor so that a more complex analysis such as a finite element analysis would be required to know the precise distributions of current in the heart.

[0101] The change in potential difference after the pulse of the regions of the heart tissue where the two 0.010 inch measuring electrodes (322 and 324 in FIG. 3) were located indicates a change in the current between these locations. On first glance, this might indicate the pulse decreased a preexisting current, but this is ruled out since that hearts do not have a preexisting DC current, as evident from lack of a DC electrocardiographic potential. Instead, the interpretation that fits the available information is that that the pulse produced a DC current. This interpretation is further supported by the observed direction of the change in poteiUial difference. This direction is exactly as would occur if the heart tissue region nearer the 300 us pulse electrode which is near where the sensing electrode (324 in FIG. 3) was, became electroporated while the distal region of the heart near sensing electrode 322 (FIG. 3} did not become electroporated. The presence of electroporation was farther confirmed via the used of fluorescent dyes. For example, as shown in FIG. 9 shows an image of a location of goldfish heart near and electrode, dyed with propidium iodide dye. As shown in FIG. 9, the cellular uptake of the propidium iodide dye, which is typically taken into electroporated cells, was observed in these hearts. In particular, the dye was taken into the hearts at or near the 300 ns pulse delivery electrode.

[0102] A schematic of the conceptualized, circuit for the electroporation current is shown FIG 10. The theorized driving force for the current is a difference in the transmembrane potentials in the electroporated and non-eiectroporated regions. At rest, heart cell membrane potentials have a non-zero transmembrane potential in non-eiectroporated tissue (-80mV). The membrane voltage in a nonelectroporated region is depicted by V_m in FIG. 10. When electroporated, the transmembrane potential becomes some level close to 0 mV in the electroporated tissue. The two tissue regions in a heart are coupled electrically by the gap junctions and cytoplasm of the cells that can pass current between the insides of adjacent cells. This is called the intracellular current and its path is represented in FIG. 10 by R¾. The return current needed to complete a circuit is through the fluid outside of the cells, called the extracellular current. The path of the extracellular current is represented in FIG. 10 by R_o.

[0103] The 300 ns shock delivered to the heart in the various experiments described above acts by producing electropores in the electroporated region, which is represented by a short circuit or zero mV across the membrane of the electroporated region, as represented in the bottom part of FIG. 10. The use of a short circuit there represents the most extreme effect of electropores that would cause the membrane potential to become zero. An intermediate effect of electropores is also conceivable in which the membrane potential in the

electroporated region becomes some value between V_m and zero. The distal and proximal sensing electrodes are placed across the extracellular resistor R₀. These represent the two sensing electrodes that were touching the heart in the electroporated and nonelectroporated regions, as described above. Since the potential baseline was observed as shifting downward, this indicates that the proximal electrode became more negative than the distal electrode. In other words, this indicates that a current, /, that traveled in the direction from the distal electrode to the proximal electrode. As shown in FIG. 10. Accordingly, in the experiments shown in FIGs 4-8, the two sensing electrodes (322 and 324 in FIG. 3) were outside of the cells and thus indicated just the part of the current that was extracellular.

[0104] To show that heartbeats were the results of electroporation-induced currents and electrostimulation, further study of such goldfish hearts were performed. In particular, the present inventors note that as the resting transmembrane potential of cardiac cells is altered by a depolarizing agent or a voltage damp setup to be slightly less negative that -80 mV, the stimulation threshold for providing depolarization of cardiac cells, and thus

electrostimulation, should be lower. This is because the resting membrane potential would be closer to the membrane threshold for activating the sodium channels. At the same time, if the transmembrane potential of cardiac cells is increased, the stimulation threshold for providing eiectroporation would be increased, as a greater potential would have to be overcome by the applied pulse in order to reach the membrane threshold for activating the sodium channels. Accordingly, to verify the presence of this mechanism, the present inventors note that applying pulses in accordance with the various embodiments while adding potassium would confirm the presence of such mechanism. That is, since an elevation of the potassium concentration is known to produce a depolarization of the resting cell transmembrane potential, the membrane voltage will be closer to the threshold for sodium channel activation, and. thus closer to the threshold for electrostimuiation and heart excitation can be achieved, using a weaker pulse.

[0105] Accordingly, a similar configuration to that shown in FIG. 3 was tested.

However, the hearts in this configuration were test using three solutions: (1) a control solution -- 3 mM/L KCl, 0.5CaCl₂, 1 14NaCl, 2NaHC0₃; (2) a high potassium Solution - 10KCl, 0.5CaCl₂, 1 14NaCl, 2NaHC0₃ (to enhance electrostimulation and increase osmotic strength); and (3) a high Potassium, low Sodium solution - 10KCl, 0.5CaCl₂, 107NaCl, 2NaHC0₃ (to enhance electrostimulation and reduce or maintain osmotic strength). For each of the solutions, the hearts were stimulated by starting with a 300ns, 400V pulse. If no beat was observed within a second of the initial pulse, one or more additional pulses with a 20- 100V increase were provided until a beat was observed. Thereafter, a 10V decrease was provided. If no beat was observed within a second of the initial pulse, one or more additional pulses with, a 20V decrease were provided, until a beat was not observed. Thereafter, a 10V increase was provided. The results for four hearts are shown below in Table 1. Table 1 : Anodal and Cathodal Thresholds (in Volts) for Solutions (l)-(3)

[0106] The results in Table 1 show various results. First, these show that the anodal and cathodal thresholds using pulses in accordance with the various embodiments are substantially equal. Second, comparing the results of the control solution (solution 1) to the high potassium solution (solution 2) shows that these thresholds were lowered. Therefore, since the addition of potassium, which depolarizes resting transmembrane potential and increases osmotic strength, results in lower and substantially equal anodal and cathodal thresholds, this supports the hypothesis that electrostimulation produces the stimulation provided by the new waveform in accordance with the various embodiments. Third, comparing the results of the control solution (solution 1 ) to the high potassium, low sodium solution (solution 3) shows that the thresholds were increased. Therefore, since the addition of potassium, which depolarizes resting transmembrane potential, while maintaining osmotic strength by removing an equal amount of sodium, results in higher and substantially equal anodal and cathodal thresholds, this supports the hypothesis that electrostimulation does not produce the stimulation when osmotic strength is held constant. This supports the hypothesis that in the cases of constant osmotic strength, eiectroporaiion produces the stimulation provided by the new waveform in accordance with the various embodiments. Osmotic strength is often maintained, constant in people by the body's control of electroiytes, and thus eiectroporaiion current would apply to those people. It is possible that osmotic strength alters in certain diseases. Results suggest that patients with high electrolytes might respond, less to eiectroporaiion current. [0107] While various embodiments of the present invention have been described above, it should be understood that they have been presented by way of example only, and not limitation. Numerous changes to the disclosed embodiments can be made in accordance with the disclosure herein without departing from the spirit or scope of the invention. Thus, the breadth and scope of the present invention should not be limited by any of the above described embodiments. Rather, the scope of the invention should be defined in accordance with the following claims and their equivalents.

[0108] Although the invention has been illustrated and described with respect to one or more implementations, equivalent alterations and modifications will occur to others skilled in the art upon the reading and understanding of this specification and the annexed drawings. In addition, while a particular feature of the invention may have been disclosed with respect to only one of several implementations, such feature may be combined with one or more other features of the other implementations as may be desired and advantageous for any given or particular application.

[0109] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as w^rell, unless the context clearly indicates otherwise. Furthermore, to the extent that the terms "including", "includes", "having", "has", "with", or variants thereof are used in either the detailed description and/or the claims, such terms are intended to be inclusive in a manner similar to the term "comprising."

[0110] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used, dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

Claims

CLAIMS What is claimed is:

1. A cardiac rhythm management system, comprising:

a stimulation device configured for generate at least one sequence of electrical pulses for electrically stimulating cardiac tissues using either of cathodal stimulation and anodal stimulation; and

a plurality of electrodes coupled to the pulse generator and providing at least one pair of electrodes for applying the at least one sequence of electrical pulses,

wherein the plurality of electrodes comprise at least one electrode contacting at least one cardiac site and, wherein pulse widths in at least a portion of the at least one sequence of electrical pulses are configured to be less than about lus and to have an amplitude and a frequency so that a threshold for the cathodal stimulation of the cardiac tissues and a threshold for the anodal stimulation of the cardiac tissues are substantially the same.

2. The system of claim 1 , wherein the plurality of electrodes comprise at least one other electrode contacting at least one other cardiac site.

3. The system of claim 1, wherein the amplitude is in the range of about 100 V to about 1000V.

4. The system of claim 1 , wherein the amplitude is in the range of about 300V to about 600V.

5. The system of claim 1 , wherein the amplitude for at least a first pulse in the at least one sequence of electrical pulses is greater the amplitude for subsequent pulses in the at least one sequence of electrical pulses.

6. The system of claim 5, wherein a pulse duration for the subsequent pulses is greater than about lms.

7. The system of claim 1, further comprising a pulse sensor communicatively coupled to the stimulation device and configured for detecting a pulse rate of the cardiac tissues to y ield a detected pulse rate, and wherein the pulse generator system is configured for applying the at least one sequence of electrical pulses based on the detected pulse rate.

8. The system of claim 7, wherein the frequency is based on a target pulse rate, and. wherein the pulse generator system is configured for applying the at least one sequence of electrical pulses if the detected pulse rate falls below the target pulse rate.

9. The system of claim 7, wherein the stimulation device is configured for setting the frequency for the at least one sequence of electrical pulses to substantially correspond to the detected pulse rate.

10. The system of claim 1, wherein the duration of the pulses is in the range of about Ins to about 1 us.

1 1. The system of claim 1 , wherein the duration of the pulses is in the range of about 270ns to about 330ns.

12. The system of claim 1, wherein the stimulation device comprises:

at least one pulse generator for generating the at least one sequence of electrical pulses; and

a controller for defining the at least one pair of electrodes to yield at least one defined pair of electrodes and for controlling the at least one pulse generator based on the at least one defined pair of electrodes.

13. The system of claim 12, wherein the at least one defined pair of electrodes comprises two or more pair of electrodes coupled to the at least one pulse generator in series.

14. The system of claim 13, wherein at least one of the electrode is not directly connected to the at least one pulse generator.

15. The system of claim 12, wherein the at least one defined pair of electrodes comprises two or more pair of electrodes coupled to the at least one pulse generator in parallel.

16. A method for cardiac rhythm management using a plurality of electrodes, wherein at least one of the plurality of electrodes contacts at least one cardiac site, the method comprising:

generating at least one sequence of electrical pulses for electrically stimulating- cardiac tissues using either of cathodal stimulation and anodal stimulation; and

applying the at least one sequence of electrical pulses to the cardiac tissues, wherein pulse widths in at least one portion of the at least one sequence of electrical pulses are configured to be less than about 1 us and to have an amplitude and a trequency so that a threshold for the cathodal stimulation of the cardiac tissues and a threshold for the anodal stimulation of the cardiac tissues are substantially the same.

17. The method of claim 16, wherein the step of generating further comprises selecting the amplitude to be in the range of about 100V to about iOOOV.

18. The method of claim 16, wherein the step of generating further comprises selecting the amplitude to be in the range of about 320V to about 360V.

19. The method of claim 16, wherein the step of generating further comprises selecting the amplitude for at least a first pulse in the at least one sequence of electrical pulses is greater the amplitude for subsequent pulses in the at least one sequence of electrical pulses.

20. The system of claim 19, wherein the step of generating farther comprises selecting a pulse duration for the subsequent pulses to be greater than about 1ms.

21. The method of claim 16, further comprising detecting a pulse rate of the cardiac tissues to yield a detected pulse rate, and wherein the step of generating further comprises selecting the frequency to substantially correspond to the detected pulse rate.

22. The method of claim 16, further comprising:

detecting a pulse rate of the cardiac tissues to yield a detected pulse rate, comparing the detected pulse rate to a target pulse rate; and

performing the steps of generating and applying if the detected pulse rate is substantially less than the target pulse rate,

wherein the frequency is selected to substantially correspond to the target pulse rate.

23. The method of claim 16, wherein the step of generating further comprises selecting the duration of the pulses to be in the range of about I ns to about lus,

24. The method of claim 16, wherein the step of generating further comprises selecting the duration of the pulses to be in the range of about 270ns to about 330ns.