Cardiac contractility modulation for atrial arrhythmia patients

Abstract

To provide a therapy to patients with atrial fibrillation (AF), for example, to increase cardiac output, and to treat and / or prevent AF, AF symptoms, and / or other diseases.SOLUTION: A cardiac treatment device 200 includes: stimulation circuitry 204 configured to generate a non-excitatory electrical signal which, when applied to ventricular tissue during a ventricular refractory period thereof, improves a condition of heart failure in human patients; atrial arrhythmia detection circuitry 208; and decision circuitry 202 which controls the stimulation circuitry 204 to deliver the signal also when the atrial arrhythmia detection circuitry 208 detects an atrial arrhythmia.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63 / 042,061, filed June 22, 2020 (Attorney Specification No. 79078), U.S. Provisional Patent Application No. 62 / 924,776, filed October 23, 2019 (Attorney Specification No. 79063), U.S. Provisional Patent Application No. 63 / 001,343, filed March 29, 2020 (Attorney Specification No. 79080), and U.S. Provisional Patent Application No. 62 / 924,782, filed October 23, 2019 (Attorney Specification No. 79062), the contents of which are incorporated herein by reference in their entireties.

[0002] This application is part of the following concurrently filed PCT applications, filed on the same day by the same applicant: Attorney Docket No. 85056 to PRUTCHI David et al., entitled "ENHANCEMENT OF PEAK VO2 IN HF PATIENTS USING CARDIAC CONTROL MODULATION (CCM) STIMULATION"; Attorney Docket No. 85069 to PRUTCHI David et al., entitled "METHOD FOR PLANNING AND DELIVERING CARDIAC ELECTRICAL STIMULATION"; and Attorney Docket No. 85070 to PRUTCHI David et al., entitled "CARDIAC CONTROL MODULATION IN RELATION TO RESPIRATION."

[0003] The contents of the above applications are all incorporated by reference as if fully set forth herein in their entirety.

[0004] The present invention, in some embodiments thereof, relates to providing electrical stimulation, e.g., non-excitatory stimulation, e.g., cardiac contractile modulation stimulation (C2MS) therapy, to patients with atrial arrhythmia (AA), e.g., atrial fibrillation (AF), e.g., to increase cardiac output, treat and / or prevent AF, AF symptoms, and / or other disorders. [Background technology]

[0005] US Patent US9713723B2 describes using a refractory signal from the right ventricle to affect the left ventricle: "A method is provided for use in a human subject. The method includes accessing a site of the heart via an aorta of the subject, and alleviating heart failure in the subject by applying a refractory signal to the site of the heart during a refractory period of the site that affects the left ventricle of the subject's heart. Other embodiments are also described."

[0006] US Patent US6480737 teaches the use of a method for arrhythmia detection based on a ventricular lead, and discloses therein "an apparatus for applying a non-excitatory signal to the heart, comprising at least one electrode, a power source, a wide-range ECG sensor for receiving a wide-range ECG signal containing contributions from non-localized portions of the heart, a controller for selectively charging the at least one electrode with a non-excitatory signal from the power source, and a safety filter for suppressing charging in response to the wide-range ECG signal" and "in an exemplary embodiment of the invention, the wide-range ECG sensor covers a portion of the right ventricle and a portion of the left ventricle (near the apex), and the temporal portion used for alignment is between a right ventricular sensed event and the most recent valid left ventricular ECG applied event. When pacing in the right ventricle, the tracing may start shortly after the pacing event. Optionally, the template also includes a portion from after the application of the ETC signal."

[0007] US Patent US9713723B2 discusses the use of a type of C2MS therapy to reduce the prevalence of arrhythmias, particularly ventricular arrhythmias, in claim 1: "A method of applying a plurality of cardiac contractility-modulating electrical signals to a heart, the method comprising: calculating an arrhythmia prevalence level by counting a plurality of arrhythmia episodes in the heart for a given period of time; comparing the arrhythmia prevalence level with a value representing the arrhythmia prevalence level of the arrhythmia to be treated; and applying one or more of the plurality of cardiac contractility-modulating electrical signals to the heart in response to a result of the comparison to reduce the arrhythmia prevalence level, wherein the cardiac contractility-modulating electrical signals can increase the contractility of cardiac myocytes."

[0008] US Patent US8977353B2 discusses short-term and long-term effects in claim 1: "A method for modifying the behavior of cardiac tissue at a first site by application of an electric field to cardiac tissue at a second site, comprising: determining a desired non-acute modification of protein activity and / or gene activity in cardiac tissue at the first site; selecting electric field parameters including one or more of a second site, a duration of application of the electric field, and an electric field power level that have the expected effect of producing the desired non-acute modification of protein activity and / or gene activity at the first site, but which does not cause significant acute effects at the first site; and applying an electric field having the selected parameters to cardiac tissue at the second site to produce the selected non-acute modification at the first site, wherein the first site is sufficiently remote from the second site so that no significant acute effects at the first site occur."

[0009] The 2019 FDA approval of the Impulse Dynamics Optimizer® device with C2MS listed persistent or persistent long-standing atrial fibrillation or atrial flutter as a contraindication and precaution, and AF is considered an off-label indication for the use of C2MS.

[0010] The paper "Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond" by C. Tschope et al, European Journal of Heart Failure, (2018), doi:10.1002 / ejhf.1349, describes various possible mechanisms for the operation of C2MS.

[0011] US Pat. No. 4,554,922 apparently suggests that an electrical signal applied during the relative refractory period will prolong the refractory period and make the tissue less prone to arrhythmias.

[0012] The disclosures of all of the above documents are incorporated herein by reference. Summary of the Invention [Means for solving the problem]

[0013] Below is a non-exhaustive list including some examples of embodiments of the present invention. The present invention also includes embodiments that include fewer than all of the features in the examples and embodiments, even if not explicitly listed below.

[0014] Example 1. A cardiac treatment device, a stimulation circuit configured to generate a non-excitatory electrical signal that, when applied to ventricular tissue during the ventricular refractory period, ameliorates a condition of heart failure in a human patient; atrial arrhythmia detection circuit; and a decision circuit that controls the stimulation circuit to deliver the signal when the atrial arrhythmia detection circuit detects an atrial arrhythmia.

[0015] Example 2. The apparatus of Example 1, wherein the decision circuitry alters at least one parameter of the signal in response to detecting the atrial arrhythmia.

[0016] Example 3. The device of Example 2, wherein said modifying comprises increasing the range of tissues stimulated by said signal.

[0017] Example 4. The device of any of Examples 1-3, wherein the decision circuitry is configured to prevent the delivery if a ventricular arrhythmia is detected.

[0018] Example 5. The device of any of Examples 1-4, wherein the decision circuitry is configured to allow the delivery if a supraventricular arrhythmia is detected.

[0019] Example 6. The device of any of Examples 1-5, wherein the device includes a memory containing instructions for the dose and duration of application of the signal to be applied, and wherein the decision circuitry is configured to modify the actual duration of signal application in accordance with the actual delivery of the signal.

[0020] Example 7. The device of any of Examples 1-6, wherein the device includes a data logger configured to record the effect of the application on the detected atrial arrhythmia.

[0021] Example 8. The device of any of Examples 1-7, wherein the device is configured to apply the signal also during non-refractory periods in the atrium of the patient.

[0022] Example 9. The device of any of Examples 1-8, wherein the device does not have an atrial lead.

[0023] Example 10. The device of any of Examples 1-8, wherein the device does not have a ventricular stimulation lead.

[0024] Example 11. The device of any of Examples 1-10, wherein the device includes pacing circuitry and the decision circuitry is programmable to selectively prefer to apply a non-excitatory signal over applying increased pacing when cardiac demand increases.

[0025] Example 12. The device of Example 11, wherein the selective preference is in response to a cardiac parameter sensed by the device.

[0026] Example 13. A device described in any of Examples 1 to 12, wherein the decision circuit defines an inhibit window of the number of beats within which the signal is not applied after an arrhythmia is detected, the window being one or zero.

[0027] Example 14. The device of any of Examples 1-13, wherein the atrial arrhythmia detection circuit detects atrial arrhythmia from signals measured by one or more ventricular leads.

[0028] Example 15. A method of planning treatment for a patient, comprising: (a) Identifying a patient as having or at risk of developing atrial arrhythmia; (b) in response to said identifying, planning a treatment schedule for the patient with an implantable device that generates a non-excitatory electrical signal when applied to ventricular tissue during the ventricular refractory period, which improves the condition of heart failure in the human patient.

[0029] Example 16. The method of Example 15, wherein said planning includes programming said device to apply said signal also during atrial arrhythmias.

[0030] Example 17. The method of Example 15, comprising selecting said patient and implementing said plan with the goal that said treatment will ameliorate the symptoms of said atrial arrhythmia.

[0031] Example 18 The method of Example 16 or 17, wherein said ameliorating comprises preventing abnormal ventricular activation due to said atrial arrhythmia.

[0032] Example 19. The method of any of Examples 16-18, wherein said improving comprises reducing said atrial arrhythmia.

[0033] Example 20. The method of any of Examples 15-19, wherein the atrial arrhythmia comprises transient AF.

[0034] Example 21 The method of any of Examples 15-20, wherein said planning comprises planning to apply said non-excitatory signal within 20 mm of the ventricular septum.

[0035] Example 22 The method of any of Examples 15-20, wherein said planning comprises planning to apply said non-excitatory signal within an atrium of the heart.

[0036] Example 23. The method of any of Examples 15-22, wherein said planning includes selecting power levels and application sites for stimulating cardiac tissue in both the atria and ventricles.

[0037] Example 24 The method of any of Examples 15-23, wherein said identifying comprises selecting a patient with transient AF for treatment.

[0038] Example 25 The method of any of Examples 15-23, wherein said identifying comprises selecting for treatment patients who have a greater than 20% risk of developing AA in the next year.

[0039] Example 26 The method of any of Examples 15-24, wherein said identifying comprises selecting a patient with chronic AF for treatment.

[0040] Example 27 The method of any of Examples 15-26, wherein said identifying comprises selecting a patient with NYAH Class II or Class III heart failure for treatment.

[0041] Example 28 The method of any of Examples 15-26, wherein said identifying comprises selecting for treatment patients with heart failure who are asymptomatic at rest.

[0042] Example 29 The method of any of Examples 15-26, wherein said identifying comprises selecting a patient with NYAH Class IV heart failure for treatment.

[0043] Example 30 The method of any of Examples 15-27, wherein said identifying comprises selecting for treatment patients with at least 30% oxygenated oxygen flow, a potential for increased acceptable cardiac output.

[0044] Example 31 The method of any of Examples 15-28, wherein said identifying comprises selecting for treatment patients in which at least 50% of beats are treatable using the device used to apply the treatment.

[0045] Example 32. The method of any of Examples 15-31, wherein said planning comprises setting device parameters to apply said signal to more than 20,000 treated beats per day averaged over a month.

[0046] Example 33. The method of any of Examples 15-32, wherein the planning includes planning to treat using one or more application parameters, and the one or more application parameters include which leads to use among several leads.

[0047] Example 34 The method of any of Examples 15-33, wherein said planning comprises planning with the goal of improving VO2 max in said patient.

[0048] Example 35 The method of any of Examples 15-34, wherein said planning comprises planning with the goal of reducing episodes of AF in said patient.

[0049] Example 36. The method of any of Examples 15-35, wherein said planning includes programming the device to apply said signal also during beats and periods when the signal is excitatory for the atrium.

[0050] Example 37. The method of any of Examples 15-36, wherein said planning comprises programming the device to apply said signal during a portion of said ventricular refractory period that is sufficiently slow so that said refractory period is prolonged.

[0051] Example 38. The method of any of Examples 15-36, wherein said planning includes programming the device to also apply said signal during a time between 40 and 100 ms from the local excitation time.

[0052] Example 39. A method of treating a patient, comprising: (a) identifying the patient as having a cardiac dysfunction including atrial arrhythmia or reduced cardiac output and an additional cardiac dysfunction; (b) in response to said identifying, planning a treatment schedule for the patient with an implantable device that generates a non-excitatory electrical signal when applied to ventricular tissue that ameliorates heart failure in the human patient, wherein said applying ameliorates both of said dysfunctions.

[0053] Example 40. The method of claim 39, wherein said improving comprises improving two dysfunctional chambers using the same applied signal.

[0054] As can be appreciated, treatment is applied according to a plan.

[0055] Example 41. A method of treating a patient, comprising planning to apply a C2MS signal to a patient with an atrial arrhythmia or reduced cardiac output when the atrial arrhythmia is active.

[0056] Example 42. A method of treating a patient, comprising administering a C2MS signal to a patient with a possible atrial arrhythmia, thereby reducing the probability of the patient developing an atrial arrhythmia by at least 10% over the next hour. Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of embodiments of the present invention, exemplary methods and / or materials are described below. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and are not necessarily intended to be limiting.

[0057] As will be appreciated by those skilled in the art, some embodiments of the present invention may be embodied as a system, method, or computer program. Accordingly, some embodiments of the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, microcode, etc.), or an embodiment combining software and hardware aspects, all of which may be generally referred to herein as a "circuit," "module," or "system." Furthermore, some embodiments of the present invention may take the form of a computer program embodied in one or more computer-readable medium(s) having computer-readable program code embodied thereon. Implementation of the methods and / or systems of some embodiments of the present invention may involve performing and / or completing selected tasks manually, automatically, or a combination thereof. Furthermore, according to the instrumentation and apparatus of some embodiments of the methods and / or systems of the present invention, some selected tasks may be implemented by hardware, software, or firmware, and / or a combination thereof, e.g., using an operating system.

[0058] For example, hardware for performing selected tasks according to some embodiments of the present invention may be implemented as a chip or circuit. As software, selected tasks according to some embodiments of the present invention may be implemented as software instructions executed by a computer using a suitable operating system. In exemplary embodiments of the present invention, one or more tasks according to some exemplary embodiments of the methods and / or systems as described herein are performed by a data processor, such as a computer platform executing instructions. Optionally, the data processor includes volatile memory for filtering instructions and / or data, and / or non-volatile storage, e.g., a magnetic hard disk and / or removable media for filtering instructions and / or data. Optionally, a network connection is also provided. Optionally, a display and / or a user input device, such as a keyboard or mouse, are also provided.

[0059] Combinations of one or more computer-readable medium(s) may be utilized in some embodiments of the present invention. The computer-readable medium may be a computer-readable signal medium or a computer-readable storage medium. The computer-readable storage medium may be, for example, but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any suitable combination of the foregoing. More specific examples (a non-exhaustive list) of computer-readable storage media include the following: an electrical connection having one or more cables, a portable floppy disk, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the foregoing. In the context of this document, a computer-readable storage medium may be any tangible medium that contains or can store a program for use by or in connection with an instruction execution system, apparatus, or device.

[0060] A computer-readable signal medium may include, for example, a propagated data signal with computer-readable program code embodied therein, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electromagnetic, optical, or any suitable combination thereof. A computer-readable signal medium may also be a computer-readable medium that is not a computer-readable storage medium and that can carry, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.

[0061] The program code embodied in the computer readable medium and / or data used thereby may be transmitted using any suitable medium, including but not limited to wireless, wired, fiber optic cable, RF, etc., or any suitable combination of the foregoing.

[0062] Computer program code for carrying out operations for some embodiments of the present invention may be written in any combination of one or more programming languages, including, for example, object-oriented programming languages ​​such as Java, Smalltalk, C++, etc., and conventional procedural programming languages ​​such as the "C" programming language or similar programming languages. The program code may execute entirely on the user's computer, partially on the user's computer, as a stand-alone software package, partially on the user's computer and partially on a remote computer, or entirely on a remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer via any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be to an external computer (e.g., via the Internet using an Internet Service Provider).

[0063] Some embodiments of the present invention may be described below with reference to flowchart illustrations and / or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the present invention. It will be understood that each block of the flowchart illustrations and / or block diagrams, and combinations of blocks in the flowchart illustrations and / or block diagrams, can be implemented by computer program instructions. The computer program instructions may be provided to a general-purpose computer, a processor of a special-purpose computer, or a programmable data processing device that makes a machine, such that the instructions, executing via the computer's processor or other programmable data processing device, create means for performing the function(s) / acts indicated in the block(s) of the flowchart and / or block diagrams.

[0064] These computer program instructions may be stored on a computer-readable medium that can direct a computer, other programmable data processing apparatus, or other device to function in a particular manner, such that the instructions stored on the computer-readable medium create an article of manufacture that includes instructions that implement the functions / acts indicated in the flowchart and / or block diagram blocks.

[0065] The computer program instructions may be loaded into a computer, other programmable data processing apparatus, or other device to produce a series of operational steps that are executed on the computer, other programmable data processing apparatus, or other device to create a computer-implemented process such that the instructions executing on the computer or other programmable apparatus provide a process for performing the function(s) / acts indicated in the block(s) of the flowcharts and / or block diagrams.

[0066] Some of the methods described herein are generally designed for computational use only and may not be feasible or practical for purely manual performance by a human expert. For example, a human expert wishing to manually perform similar tasks, such as controlling a cardiac stimulation device and / or processing cardiac signals in real time, may be expected to use an entirely different method, e.g., a method that uses the expert's knowledge and / or the pattern recognition capabilities of the human brain, which may be much more efficient than manually experiencing the method steps described herein, but which likely cannot operate on the required time scales.

[0067] Several embodiments of the present invention are described herein, by way of example only, with reference to the accompanying drawings. With specific reference now to the detailed drawings, it is emphasized that the matter shown is by way of example and for purposes of illustrative discussion of embodiments of the present invention. In this regard, the description taken in conjunction with the drawings will make apparent to those skilled in the art how embodiments of the invention may be practiced. [Brief explanation of the drawings]

[0068] [Figure 1] FIG. 1 is a schematic diagram of a heart showing various tissue and electrode / lead locations according to some embodiments of the present invention. [Figure 2] FIG. 1 is a schematic block diagram of a cardiac therapy device according to some embodiments of the present invention. [Figure 3] FIG. 1 is a schematic diagram of a heart showing the spatial extent of non-excitable regions according to some embodiments of the present invention. [Figure 4] 1 is a timeline illustrating the timing of non-excitable regions related to various cardiac events, according to some embodiments of the present invention. [Figure 5] 1 is a graph showing the results of a study in which C2MS improved VO2 parameters in patients with AF, according to some embodiments of the present invention. [Figure 6] FIG. 1 is a schematic diagram of a heart showing the spatial extent of non-excitable regions from the right atrium according to some embodiments of the present invention. [Figure 7] FIG. 1 is a schematic diagram of a heart showing the spatial extent of a non-excitable region from the left atrium according to some embodiments of the present invention. [Figure 8] 1 is a flowchart of a method for patient selection and treatment of a patient with atrial arrhythmia problems, according to some embodiments of the present invention. [Figure 9] 1 is a flowchart of a method of patient selection and treatment for patients with cardiac output and additional cardiac dysfunction, according to some embodiments of the present invention. [Figure 10] 1 is a flowchart of the operation of a cardiac controller, according to some embodiments of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0069] The present invention, in some embodiments thereof, relates to providing electrical stimulation, e.g., non-excitatory stimulation, e.g., cardiac contractility modulation therapy, to patients with atrial arrhythmia (AA), e.g., atrial fibrillation (AF), to increase cardiac output, treat and / or prevent AF, symptoms of AF, and / or other disorders.

[0070] A broad aspect of some embodiments of the present invention relates to planning for and / or treating patients with atrial arrhythmias. While atrial arrhythmias may previously have been considered off-label for the application of C2MS therapy, the inventors have discovered that not only can C2MS be safely applied to AF patients, but that such therapy appears to be useful as well. In some embodiments of the present invention, patients are generally treated despite a diagnosis of AA. Optionally, or in addition, patients are treated during an AA event. In some embodiments, such AA events are detected and not terminated (or, in some embodiments, result in and / or otherwise alter therapy). In some embodiments of the present invention, such AA events are not detected, or are detected and ignored during the application of therapy.

[0071] A broad aspect of some embodiments of the present invention relates to using a strong, non-excitatory signal applied to the heart to provide two or more distinct therapeutic effects with the same signal. Optionally, one or more signal application parameters are optimized for such multiple desired effects. In some embodiments, such effects include both increasing cardiac contractility and ameliorating arrhythmia conditions.

[0072] Aspects of some embodiments of the present invention relate to treating patients with atrial arrhythmias (and / or generating treatment plans for such patients) with cardiac contractility modulation stimulation (C2MS) signals, e.g., non-excitatory signals, applied to the heart during the heart's relative and / or absolute refractory periods. In some embodiments of the present invention, the signals are selected to enhance cardiac ventricular contractility when the signal's electric field stimulates such ventricular tissue, e.g., the left ventricle, right ventricle, and / or interventricular septum. In some embodiments of the present invention, contractility modulation is provided by signal-induced phosphorylation of phospholamban. In some embodiments of the present invention, contractility modulation is caused by signal-induced changes in protein transcription and / or mRNA production, optionally in the form of reversal of a fetal genetic program. The term "C2MS" is used herein as a general term for all such signals, unless otherwise specified. It is noted that in some embodiments, C2MS signals may be excitatory to tissues other than the tissue to which they are applied. Various mechanisms by which C2MS signals may operate are described, for example, in “Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond” by C. Tschope et al, European Journal of Heart Failure, (2018), doi:10.1002 / ejhf.1349, the disclosure of which is incorporated herein by reference, and may help guide selection of signal application parameters to utilize and / or follow one or more of these mechanisms.

[0073] It is understood that patients who do not have AA may also be selected for treatment, and / or that selection for treatment may optionally disregard the patient's AA status or risk.

[0074] In some embodiments of the invention, patients are selected for treatment based on having atrial arrhythmia comorbidities, e.g., atrial flutter, paroxysmal AF, episodic and / or chronic AF, atrial tachycardia (AT), and / or based on anticipation of the onset of such arrhythmias. While some of the following examples focus on atrial fibrillation, it is recognized that they may also be usefully applied to other atrial arrhythmias.

[0075] In some embodiments of the invention, patients are selected for treatment without a specific treatment goal. In others, such a treatment goal is selected based on, for example, an expected outcome (e.g., an improvement of at least one in NYHA functional class in more than 50%, 60%, 70%, 80%, or the median percentage of cases).

[0076] In some embodiments of the invention, patients are selected based on a desire (and / or ability) to increase their NYHA class by at least 0.5, 0.75, 1, 1.5, or mid-class or greater. In some embodiments of the invention, patients are selected if they have class III and / or class IVa heart failure.

[0077] In some embodiments of the invention, patients are selected based on their desire (and / or ability) to increase their peak VO2, e.g., between 5 and 300%, e.g., between 10 and 50%. In some embodiments of the invention, it is desired that peak VO2 be increased by 1 to 10 mlO2 / min / kg, e.g., 3 to 7 mlO2 / min / kg. Optionally, patients with a pre-existing peak VO2 of 5 to 25 mlO2 / min / kg, e.g., 9 to 20 mlO2 / min / kg, are selected. Optionally, this excludes some patients, e.g., patients with no or reduced respiratory reserve (e.g., no or reduced ability to increase lung throughput).

[0078] In some embodiments of the invention, the dose of C2MS therapy is selected based on the desired amount of improvement in peak VO2, e.g., a reduced dose for patients for whom a lesser improvement in peak VO2 is desired (fewer beats per day, fewer hours per day, and / or less tissue directly stimulated), or to trade off the challenges associated with C2MS treatment with the increased clinical health provided by C2MS. In one example, if a patient is less likely to improve in C2MS, e.g., has less respiratory reserve, less C2MS is applied. In some embodiments of the invention, it is assumed that patients with a higher peak VO2 have more pulmonary reserve.

[0079] In some specific embodiments of the invention, C2MS is applied without the use of an atrial lead, e.g., using a device with only one or two ventricular leads. Optionally, atrial arrhythmias are detected by analyzing signals from only one or more ventricular leads (e.g., detecting activation signals when activation is not expected from the ventricle and / or activation signals that fall within an expected atrial activation window, e.g., based on a cardiac timing model, e.g., based on an expected range of delay between atrial and ventricular activation and / or an expected ventricular refractory window). While accuracy and sensitivity may be reduced, in some embodiments of the invention, all that is required may be an indication that AA is in progress. In some embodiments, such analysis may include multiple heartbeats, so that while AA may be detected, detection may take longer than one heartbeat. In some embodiments, one or all leads are atrium (e.g., as described below), and the timing of stimulation from such stimulation leads uses measured or estimated ventricular activation times based on sensing from the atrium (e.g., atrial activation plus an expected and / or programmable AV delay).

[0080] In some embodiments of the present invention, C2MS is applied using logic that only excludes some or all ventricular abnormal heartbeats from such application, but not all supraventricular abnormal heartbeats from application of C2MS. A potential advantage is the ability to apply effective C2MS therapy even if most or all of the heartbeats have atrial arrhythmias.

[0081] Aspects of some embodiments of the present invention relate to reducing the prevalence of ventricular arrhythmias, e.g., reducing the occurrence and / or length of AF episodes, optionally reducing the severity of an existing AF condition and / or preventing such a condition from occurring and / or worsening and / or becoming further functionally symptomatic.

[0082] In some embodiments of the invention, application of a C2MS signal uses suitable parameters to reach the atria and affect conduction properties therein, and AF may be reduced at its source in at least a portion of the atria (e.g., left and / or right), optionally in the portion that conducts to the rest of the heart.

[0083] In some embodiments of the invention, application of the C2MS signal to the atrium is by a lead in the atrium.

[0084] In some embodiments of the invention, application of the C2MS signal uses parameters suitable to reach the AV node and / or ventricular tissue that carries the activation signal to the rest of the ventricle, e.g., the His bundle, the left and / or right bundle branches of the ventricle, and / or one or more of the Purkinje fibers. Optionally, this reduces the functional symptoms of AF, e.g., because excess atrial activation is not propagated at and / or to the ventricle by increasing the refractory period (relative and / or absolute) in such tissue.

[0085] In some embodiments of the invention, if desired, one or more application parameters, such as amplitude, delay from local activation and / or electrode location, may be modified according to the desired effect (e.g., effect on the atrium).

[0086] In some embodiments of the invention, application is selected according to a desired effect of reducing the probability of atrial arrhythmia occurring in the next 10 beats, next 50 beats, next 100 beats, next 300 beats, next 1200 beats, next 3600 beats, next 5000 beats, or even smaller intermediate or larger number of beats by at least 10%, 30%, 50%, 70%, 80%, or an intermediate or large percentage. Various desired effects may be selected (e.g., and / or monitored for) based on, for example, the severity of the patient's disease, the patient's stability, and / or the amount of extra C2MS application required, while taking into account side effects of such C2MS application (e.g., pain) or available battery life. For example, if pain is less of a problem, a more aggressive reduction may be desired.

[0087] In some embodiments of the invention, the estimated probability of prevention is estimated based on a table querying information from multiple tests. Optionally, or in addition, the information is personalized, for example, the implanted device (or an external processor receiving records) tracks the duration and / or magnitude of the effect of the C2MS signal on the occurrence of subsequent AF episodes. This data may be used, for example, to program the device, to update the table, and / or to set automatic device parameters, such as parameters that trade off power consumption resulting from C2MS application versus effectiveness in alleviating AA. It is known that an overall therapeutic effect should be expected in some patients, and that the overall prevalence and / or duration and / or severity of AA episodes can be expected to decrease for such patients as treatment progresses. Optionally, this is used to set parameters for the implanted therapeutic device, for example, to reduce the amount and / or duration and / or modify the application site, and / or update other C2MS parameters.

[0088] An aspect of some embodiments of the present invention relates to applying C2MS to the ventricles using electrodes placed in the atrium. In some embodiments of the present invention, application is between an electrode in the atrium and an electrode outside the atrium, e.g., in the ventricle. In some embodiments of the present invention, application uses bipolar electrodes in the atria (e.g., left and / or right). It is known that even if such application causes an arrhythmia in the atrium, it will not be fatal, since the risk of fatal arrhythmia may be reduced by the fact that atrial arrhythmias do not usually propagate fatally to the ventricles (e.g., due to the AV node spreading the frequency and / or the ventricles responding as quickly as the refractory rate). It is further known that in patients with AF, because atrial arrhythmias are already present, C2MS signals applied during the non-refractory period of the atrium are not expected to cause further dysfunctional arrhythmias. In some cases, such signals are not expected to increase the ventricular heart rate.

[0089] In some embodiments of the invention, the signal may be applied when there is no refractory period in the atrium (absolute refractory period) while there is an absolute refractory period in the ventricle.

[0090] In some embodiments of the invention, such an atrial electrode is used to apply other therapies, for example, anti-arrhythmia pacing to the atrium.

[0091] An aspect of some embodiments of the present invention relates to applying a C2MS with parameters suitable for terminating an ongoing AF episode. In some embodiments of the present invention, the parameters of the C2MS are set such that they have the effect of cardioversion, for example, by forcing a significant portion of the atrium into a refractory state and / or exciting such portions. In some embodiments of the present invention, after such treatment, the parameters are changed (e.g., lowering the amplitude), for example, such that the AF episode is assumed to end and / or restart as soon as AF is detected again. In some embodiments of the present invention, the therapy device tracks which signals appear to have a more favorable effect on AF for that particular patient and / or for various atrial arrhythmia episodes, so that such signals can be applied automatically as needed.

[0092] A potential benefit of using C2MS during an AF episode and / or for AF patients is to increase cardiac output, at least partially compensating for the reduced cardiac output caused by AF. For example, increasing contractility may allow for a smaller LV end-systolic volume, which may allow for better left atrial filling, at least partially overcoming the loss of left atrial contraction in AF. This potential benefit is optionally realized even if C2MS has no effect on the current or subsequent atrial arrhythmia episode.

[0093] In some embodiments of the invention, the amplitude of the signal applied to treat an ongoing AA episode may be greater than in chronic applications (e.g., between 10% and 500%, e.g., between 10% and 60%, between 60% and 150%, between 150% and 300%, between 300% and 500%, or greater or intermediate percentages). This may be due, for example, to pain or other side effects that are less significant to the patient, provided the patient is aware that the increase in treatment is temporary and / or is intended to treat an acute medical condition.

[0094] An aspect of some embodiments of the present invention relates to the relationship between the number of stimulations and improvement in peak VO2, which can optionally lead to improvement in heart failure symptoms. In some embodiments of the present invention, at least for AF patients, increasing the number of treated beats on a monthly basis increases the health benefit to the patient. In some embodiments of the present invention, the number of treated beats (per day) is increased to greater than 15,000, e.g., greater than 17,000, e.g., greater than 20,000, optionally up to 25,000, optionally up to 35,000, and / or greater than and / or to an intermediate number.

[0095] According to some embodiments, the effect of the treated pulsatility increase may be monotonic and at least over a particular range and / or may be otherwise known, which may be used to trade off the amount of treatment (and therefore effect) against potential side effects and / or power usage.

[0096] Aspects of some embodiments of the present invention relate to treating two conditions in the heart using the application of a single non-excitatory signal, for example, treating heart failure and atrial arrhythmia using a single C2MS signal, optionally applied in a single chamber.

[0097] In some embodiments of the invention, one of the conditions is heart failure and the other condition is one of atrial arrhythmias, valvular insufficiency and HOCM.

[0098] In some embodiments of the invention, two conditions are treated in different cardiac chambers, e.g., one in the atrium and one in the ventricle, by a non-excitatory signal originating in one of the chambers and reaching the other chamber.

[0099] In some embodiments of the present invention, one or more application parameters of the signal application are optimized to provide a better trade-off between the two conditions being treated. In one example, the application time, power level, and / or site (e.g., within the atrium and / or atrioventricular or other site) of the C2MS signal application may be modified so that the charge hits the desired tissue (e.g., atrium, AV node, conduction fibers, healthy tissue, diseased tissue, sensitive tissue) at the desired time, even if the improvement in contractility is reduced. In one example, the C2MS signal is applied earlier to ensure that it hits the atrium at the correct time, for example, for cardioversion or AF prevention. In another example, a suboptimal electrode site for cardiac output is selected to ensure sufficient coverage of the atrium.

[0100] In some embodiments of the present invention, other conditions treated may be structural heart disease and / or implants. For example, the site of C2MS application may be optimized to improve fixation of prosthetic heart valves and / or modified to reduce the amount of regurgitation (e.g., in mitral valve implantation, with or without a clip or valve, or implant). Such valves may be, for example, the mitral, pulmonary, aortic, and / or tricuspid valves.

[0101] In an example of reducing regurgitation, C2MS is optionally applied in a manner that reduces heart rate. For example, using C2MS to increase cardiac output instead of increasing HR may reduce regurgitation if regurgitation is heart rate dependent. For example, if a patient has demand-type pacing, this type of logic may be used. For example, C2MS may be used in place of some or all of the increase in pacing frequency. In another example, a sensor in the atrium or atrioventricular chamber may be used to detect regurgitation and trigger C2MS application. In another example, such a sensor (e.g., a pressure sensor) may be used to detect increased demand and apply C2MS so that the heart meets such demand without having to increase its heart rate. In another example, high heart rates may be associated with a higher risk of AA and should therefore be avoided (e.g., by suitable thresholds or other logic programmed into the device). In another example, if AA is detected, heart rate is reduced (e.g., using an electrical activity sensor).

[0102] While C2MS signals are described herein and in other embodiments, it is understood that acute changes in contractility need not be provided. Rather, unless otherwise indicated, C2MS is used to refer to non-excitatory signals that cause an immediate and / or ultimate increase in cardiac output and / or an alteration in the fetal genetic program.

[0103] An aspect of some embodiments of the present invention relates to shortening the inhibitory period after a suspected arrhythmia when applying C2MS. In one example, a suspected ventricular arrhythmia beat results in an inhibitory window of only one beat, or optionally no beats. Potentially, this allows the next C2MS to operate on tissue that is still recovering from the abnormal heartbeat. Presumably, this reduces the arrhythmogenic tendency of the abnormal heartbeat and / or otherwise improves the function and / or potential healing of tissue in heart failure or other dysfunction. In some embodiments of the present invention, the length of the inhibitory window depends on the number of abnormal heartbeats (and / or the duration of the ventricular arrhythmia episode). In some embodiments of the present invention, there is no inhibitory window for atrial abnormal heartbeats, even if there is a window for ventricular abnormal heartbeats. In some embodiments of the present invention, a C2MS signal is applied even when the atrium is excitable.

[0104] In some embodiments of the invention, the inhibit window is shortened and / or C2MS is applied during the atrial excitability time even in hearts without atrial arrhythmia and / or even when there is no active atrial arrhythmia.

[0105] In some embodiments of the invention, a relatively low threshold for heart rate is used, for example, between about 90 or about 100 to about 110 beats per minute (BPM), which may prevent wasting energy at higher heart rates (as they have more beats in the simultaneous window and an exemplary treatment is 7 hours per day) and direct more applied energy to lower heart rates at the body's resting state.

[0106] In other embodiments, even higher heart rate thresholds may be used, for example, 120, 130, 140 heart rates or intermediate heart rates.

[0107] It is known that the heart rate may be measured approximately and / or not at a threshold, and some kind of fuzzy decision-making or hypothesis may be used to determine inhibition. For example, a signal may be inhibited with a probability that depends on the heart rate. In another example, once the heart rate drops, the threshold may be higher or lower than the threshold for stopping therapy when the heart rate is high.

[0108] In some embodiments of the invention, there are different inhibiting windows for different heart rates, for example, an arrhythmia-free inhibiting window is applied between about 80 and 110, and / or a one beat long inhibiting window is applied between 100 and 130, and a two beat long inhibiting window is applied between 120 and 160.

[0109] An aspect of some embodiments of the present invention relates to detecting atrial arrhythmias from ventricular electrodes. In some embodiments of the present invention, AA, e.g., AF, is detected based on the absence of P waves, optionally in conjunction with a high heart rate. In some embodiments of the present invention, if the system includes two leads in the ventricle, the two leads are used together as a bipolar ECG sensor. In some embodiments of the present invention, the distance between the ventricular leads (if two are used) increases the distance over which electrical activity can be sensed using the leads. Optionally, during a calibration phase, various pairings of electrodes and casings on the leads may be examined, and a pairing that better detects P waves (or atrial arrhythmias directly) may be selected for use in detecting AF. Optionally, or in addition, each lead is used to separately detect the absence of P waves. Optionally, a threshold for P wave detection is set for each lead. Optionally, if one or both leads (depending on the desired reliability and / or sensitivity of the particular lead) do not detect P waves, the P wave is said to be absent. Optionally, a score for AA is calculated based on the number of leads detecting P waves, the certainty of detection, the high heart rate, and / or a comparison with the patient's measured baseline.

[0110] An aspect of some embodiments of the present invention relates to a patient planning process. In some embodiments of the present invention, a patient with AA or at risk for AA, who may have heart failure, is presented. Such a patient is optionally treated using a C2MS, for example, by implanting a therapeutic device and / or reprogramming an already implanted device. Treating a patient using electrical stimulation may cause side effects and may require a trade-off between different outcomes, for example, between pain level and reduction of AA. In some embodiments of the present invention, an initial treatment is set, and treatment parameters are modified (and the implanted device reprogrammed) according to the effectiveness of the treatment. Such reprogramming may be required even if the initial treatment plan was complete, for example, due to changes in the patient's physiological condition.

[0111] In some embodiments of the present invention, the caregiver takes into account multiple considerations (e.g., as described herein), including the level of pain, the desired anti-AA effect, the desired heart failure-related effect, potential sites for electrodes and leads, and / or the type of existing cardiac arrhythmia (e.g., ventricular) in the patient.

[0112] In some embodiments of the invention, a computer or table is used to determine the initial treatment. For example, the computer may contain rules or tables that dictate parameters and their expected effects, and the caregiver may select or be provided with a treatment plan that meets various requirements. Optionally, or in addition, the caregiver may input such a proposed treatment plan and have such a computer evaluate it.

[0113] In some embodiments of the invention, a computer is programmed with a dataset that collates one or more treatment effects of one or more treatment regimens by one or more parameters for patients with one or more characteristics. In some embodiments of the invention, machine learning methods are used to analyze such datasets to generate a parametric model (or other model) that can be queried to assess the expected range of treatment effects for the patient, or that can be used to automatically or semi-automatically search for suggested treatments.

[0114] In some embodiments, if the patient has an implant capable of providing cardiac contractility modulation therapy, in addition to any other therapies the implant may provide, a plan is provided to provide cardiac contractility modulation therapy based on the patient's cardiac condition and / or the patient's pulmonary condition.

[0115] In some embodiments, the patient's AA condition and / or other conditions (e.g., pulmonary condition) are evaluated for suitability for providing cardiac contractility modulation to improve such conditions. For example, such improvement may be an increase in peak VO2. In some embodiments, the patient's pulmonary condition is evaluated for the presence of pulmonary limitation. If the patient's pulmonary condition is such that the patient would benefit from an improvement in peak VO2, it is planned to provide cardiac contractility modulation therapy in conjunction with or on its own with additional cardiac therapy(ies). Such additional therapy may include, for example, one or more of pharmaceutical therapy, mechanical implants, electrical stimulation, ablation, and / or surgery. The parameters of the C2MS therapy may depend on such additional therapy, for example, C2MS is known to be used to compensate for or function synergistically with such other therapy.

[0116] In some embodiments, the patient's cardiac condition is assessed to determine whether a cardiac therapy should be provided in addition to cardiac contractility modulation. If the patient's cardiac condition is such that the patient could benefit from an improvement in peak VO2 or other physiological parameter, then a plan is generated to provide cardiac contractility modulation therapy. If the patient's cardiac condition indicates that an additional cardiac therapy is desirable, then a plan is generated to provide cardiac contractility modulation therapy along with the additional cardiac therapy(ies), optionally with modification of one or more C2MS parameters.

[0117] In some embodiments, a treatment plan is selected for the patient that may include providing cardiac contractility modulation therapy alone; providing cardiac contractility modulation therapy in conjunction with treatment of the patient's cardiac condition; or not providing cardiac contractility modulation therapy.

[0118] In some embodiments, potential patients are identified, tests are performed to assess and / or quantify one or more of the patient's pulmonary or other physiological condition and cardiac condition, and a suitable, potentially most suitable, cardiac contractility modulation treatment is optionally selected for the patient.

[0119] Such a computer used for planning may be provided as part of a programmer. In some embodiments of the invention, the computer is a cloud instance or a remote server evaluated by a local interface.

[0120] Before describing at least one embodiment of the present invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and arrangement of components and / or methods set forth in the following description and / or illustrated in the drawings and / or examples, as the invention is capable of other embodiments or of being practiced or carried out in various ways.

[0121] Exemplary cardiac electrification Referring now to the drawings, FIG. 1 is a schematic diagram of a heart 100 showing the location of various tissues and electrodes / leads according to some embodiments of the present invention.

[0122] Referring first to the heart, the following are shown: left ventricle 104 with LV free wall 102, interventricular septum 106, aortic valve 108, mitral valve 110, left atrium 112, aorta 114, interatrial septum 116, pulmonary artery 118, right atrium 120, AV node 122 at the bottom of interatrial septum 116, right ventricle 124 with RV free wall 126, tricuspid valve 136, and pulmonary valve 138.

[0123] Also shown is a first stimulation lead 130 contacting the ventricular septum 106 with an electrode 134, and a second stimulation lead contacting the ventricular septum 106 at a second location thereon with an electrode 132. In some embodiments, a single lead including two spaced apart stimulation electrodes will be used. Optionally, or in addition, the lead may include one or more sensing electrodes.

[0124] While contact electrodes are known, other types of electrodes, such as screw electrodes, suture electrodes, and floating electrodes, may be used as well.

[0125] In some embodiments of the invention, stimulation is bipolar with electrodes 132, 134 (e.g., a pair), each of which is a bipolar electrode, e.g., in the form of a tip surface and a ring electrode surface, and / or operating themselves as a bipolar pair (e.g., one on each lead). Optionally, or in addition, a remote electrode operates (e.g., the device can operate) as a second electrode, e.g., for unipolar stimulation. In some embodiments of the invention, two leads are used, with each lead operating as one pole of the bipolar stimulation.

[0126] In some embodiments of the invention, C2MS is applied simultaneously and / or alternately and / or sequentially on both leads (or optionally on more than two leads, if there are more than two leads). The two C2MS signals may be identical, or they may differ, e.g., in delay, phase length, interphase delay, amplitude, and / or other parameters. This may be useful, for example, if each lead is to affect a different tissue type and / or have a potentially different therapeutic effect. In some embodiments, it is known that stimulation of a lead is avoided if that stimulation results in an unpleasant sensation. However, in some embodiments of the invention, such sensation is acceptable, e.g., for the acute treatment of AA.

[0127] In some embodiments of the invention, the C2MS is applied in contact with or within the ventricular tissue, e.g., from a distance of 0-5 mm, 5-10 mm, 10-20 mm, 20-30 mm, or an intermediate or even greater distance from the ventricular tissue.

[0128] Leads 128 and / or 130 may be dual-use, for example, providing pacing, cardioversion and / or defibrillation signals in addition to non-excitatory signals such as C2MS signals.

[0129] In some embodiments of the invention, leads 128 and / or 130 may be used for sensing electrical activity, optionally using the same electrodes used for stimulation. In some embodiments, only one lead and / or only one electrode is used for therapy. For example, a single ventricular or atrial lead may be used. Optionally, or in addition, in addition to or instead of leads within the chambers, leads are used outside the chambers, e.g., in the coronary sinus or other blood vessels outside the heart (e.g., on / attached to its outer surface and / or on the left side of the heart, e.g., left ventricle 104 and / or left atrium 112).

[0130] Note that this view is schematic and flattened. For example, in a real heart, the left atrium 112 and the right atrium 120 both border the interatrial septum 116.

[0131] Exemplary Cardiac Therapy Device 2 is a schematic block diagram of a cardiac therapy device 200 according to some embodiments of the present invention. While existing devices such as the Optimizer4 sold by Impulse Dynamics may be used, other device designs may be used as well and may require special setup or reprogramming.

[0132] Device 200, as shown, includes one or more leads 216 (optionally two leads) that can optionally be coupled to device 200 at one or more CAN connectors (not shown).

[0133] For example, a pulse generator 204 (eg, an example of a stimulation circuit) including a power circuit, eg, one or more storage capacitors, is optionally used to generate the signal.

[0134] In some embodiments of the present invention, a ventricular detector 206 is provided and used to detect atypical ventricular activation that may be contraindicated for signal application.

[0135] In some embodiments of the present invention, an atrial detector 208 (as an example of an atrial arrhythmia circuit) is provided and used to detect atypical atrial activation, which may be used as an input into decision making by device 200.

[0136] The sensor input 214 may receive data from one or more sensors, such as electrical sensors or other sensors, such as flow sensors, pressure sensors, and / or acceleration sensors. The data from the sensors is optionally further processed (e.g., by the controller 202 and / or the detectors 206, 208) and optionally used as input to a decision-making process in the device 200.

[0137] A controller 202 (as an example of a decision circuit) is optionally provided, implementing one or more logic circuits that determine, for example, the timing and / or other parameters of a signal and / or whether a signal should be applied.

[0138] Memory 218 is optionally provided to store, for example, logic, past effects, treatment plans, adverse events, and / or pulse parameters.

[0139] A data logger 210 is optionally provided to store device 200 and / or patient activity. Such logging and / or programming uses a communications module 21 (e.g., of a type known in the art) to send data and / or receive data, e.g., programming, e.g., pulse parameters, from device 200 to, e.g., a programmer (not shown).

[0140] It should be understood that the methods described herein may, in some embodiments, be implemented as methods for controlling the operation of device 200 via its circuitry (e.g., controller 202, memory 218) and / or as methods for programming the device and / or selecting patients that the device may implement as a therapy and / or that the device may use as a therapy and / or to plan (and optionally set) parameters of a therapy for a patient. Any such method may functionally terminate with device 200 being instructed by the circuitry to apply current to the leads. Device 200 may also be used to investigate these methods on a test bench without a human subject present.

[0141] It should be noted that when planning a therapy, the planning may include one or more goals, which may be trade-offs that consider, for example, the patient's quality of life and device features. Various goals and settings that may be used to approach the goals and various trade-offs that may be required are described in this application (not always in the same embodiment), and one or more of these may be used in the actual planning activity of a single therapy that may use the goals and settings described in the context of a different embodiment.

[0142] In some embodiments of the present invention, planning includes planning using a planning system (e.g., a local client and a cloud server) that indicates an expected treatment effect for the patient. Such expected effect may be determined, for example, using rules as described herein and / or using datasets of previous (and / or current) patients and the effects of treatment on them. Such datasets may be processed using machine learning methods to extract relationships between one or more patient characteristics, one or more stimulation parameters, and one or more clinical and / or quality of life effects. Such relationships may be provided, for example, in the form of rules, tables, neural networks, and / or other software components, optionally provided in a tangible form, such as, for example, computer memory.

[0143] Exemplary stimuli FIG. 3 is a schematic diagram of the heart similar to FIG. 1, also showing the spatial extent of non-excitable regions according to some embodiments of the present invention.

[0144] While the heart is 3D and the schematic diagram is not spatially accurate, circle 302 is used to schematically indicate the range over which the amplitude of the signal applied by lead 130 is sufficient (e.g., amplitude) to have a contractility-modulating effect on cardiac tissue (and / or other therapeutic effect, such as reversal of a genetic program and / or other physiological effect, such as a functionally meaningful increase in phosphorylation of phospholamban). Note also that the diagram shows the lead entering from the inferior vena cava. In some embodiments of the invention, the lead enters the right atrium via the superior vena cava (e.g., inserted via the subclavian vein) or via a different location (e.g., through the heart wall or remaining intracardiac and / or extrapericardially).

[0145] Circle 304 shows the same range for lead 128. For example, the amplitude of the signal affects the size of the circle (stronger amplitudes reach further). In addition, the interaction between the signal and the tissue may be affected by other parameters, such as timing and tissue type relative to local excitation.

[0146] As can be seen, different leads can reach different tissues with the same signal amplitude. For example, circle 302 can include a portion of the LV free wall 102, while circle 304 can include a portion of the RA 120, AV node 122, and / or LA 112.

[0147] In some embodiments of the invention, the location of the electrifying lead and / or pulse parameters are selected according to the desired effect on one or more of these tissues and / or trade-offs between those effects.

[0148] It is known that if there are actually two leads in the heart, some signals may be applied to one lead and some to the other lead to provide multiple types of effects and / or tradeoffs.

[0149] 3, both leads are shown at RV 124 relative to the interventricular septum 106. However, one or more stimulation leads may be in other locations, resulting in different circles of effect (e.g., 302, 304) and / or different tissues targeted. In some embodiments of the invention, the lead is optionally placed intracardially on its right side to take advantage of two potential advantages: (a) less extracardiac tissue to stimulate; and (b) less invasive access and / or presence than the left side of the heart.

[0150] With reference to circle 302, note that primarily ventricular tissue is affected. Such effects may include lengthening the refractory period of tissues that conduct electrical impulses from the AV node 122, with the potential benefit of preventing atrial arrhythmias from causing ventricular arrhythmias. Optionally, the timing of stimulation is selected to lengthen the refractory period of the relevant conducting tissues.

[0151] Such effects may also include significant modulatory effects on both the septum 106 and free wall 102 and / or other portions of the left ventricle 104 (eg, due to remodeling of fetal genetic programs).

[0152] Referring to circle 304, note that the AV may be stimulated by the C2MS region. Potentially, this would reduce the tendency of atrial activation to propagate, potentially reducing the symptoms of AF by preventing mistiming of ventricular beats.

[0153] Potentially, atrial tissue (right and / or left) is stimulated by the signal, which may potentially attenuate AA, for example, stopping paroxysmal AF episodes.

[0154] Example Pulse Parameters While not limited to a single pulse sequence, the term C2MS is used to describe any family of signals that have a clinically significant effect on cardiac contractility in an acute and / or chronic manner, including a significant component applied during the absolute refractory period, and / or that cause reversal of fetal genetic programming and / or increase phosphorylation of phospholamban. In some embodiments, the signal is potentially excitatory to one portion of the heart but non-excitatory to another. For example, the signal can be excitatory in the atria but not in the ventricles (relative to ventricular activation) when applied.

[0155] In some embodiments of the invention, the signal is potentially excitatory during the refractory period of the cardiac cycle, yet non-excitatory due to its timing, particularly the signal is applied during, and optionally within, the absolute refractory period of the tissue affected thereby.

[0156] In some embodiments of the invention, the absolute refractory period of the atria is assumed to be approximately 0.15 seconds, followed by a relative refractory period of approximately 0.03 seconds. In some embodiments of the invention, the absolute refractory period of the ventricles is assumed to be between 0.25 and 0.3 seconds, with an additional relative refractory period of 0.05 seconds. It is known that these times can vary between hearts and under various conditions, such as, for example, medication intake, anatomical excitation level, heart rate, recent arrhythmias, and / or exercise, and may be measured (e.g., by device 200). In some embodiments of the invention, stimulation factors are pre-programmed with parameters that take such refractory periods into account. Optionally, different numbers (e.g., stored in memory 218) are used for different conditions (e.g., different heart rates).

[0157] This may allow the signal to have a high amplitude without causing dangerous arrhythmias. For example, the amplitude of the signal may be at least 2, 4, 10, or an intermediate multiple of the cardiac activation threshold. Optionally, the level at which cardioversion occurs is used as an upper limit, or some fraction of that limit, e.g., 0.1, 0.3, 0.5, 0.9, or an intermediate fraction.

[0158] In some embodiments of the present invention, the following families of pulse parameters are optionally used in C2MS signals for use as described herein.

[0159] In the following tests, the following C2MS signal was used: a train of two bipolar pulses with a duration of 5.14 ms (milliseconds) per pulse phase, a voltage of 4.5 V to 7.5 V, and a delay of 30 to 35 ms (using bipolar leads) after local excitation at the applied site, followed by a 40 ms charge balance phase. It is known that local excitation often occurs immediately after the onset of ventricular activation. In the balance pulse, the active electrodes are all short-circuited together. The voltage is reduced until there is likely a lack of sensation.

[0160] This signal can be modified, and in some embodiments of the invention, the equilibration phase can be omitted or can be of varying lengths, e.g., between 1 and 200 ms, e.g., between 10 and 50 ms, e.g., between 20 and 41 ms, or intermediate lengths.

[0161] The top voltage can be increased from 7.5 V to, for example, 8 V, 9 V, 10 V, 12 V, 20 V, 40 V, 100 V or intermediate or even smaller values. It is known that arrhythmias, especially ventricular arrhythmias, may need to be avoided, but as an acute effect sensations may not be considered a problem.

[0162] The delay can be even shorter, for example, between 1 ms and 30 ms, between 5 and 20 ms, between 10 and 25 ms, or intermediate delays. The delay can be even longer, for example, between 35 and 50 ms, between 50 and 70 ms, or intermediate, smaller, or larger delays. It is known that even longer delays may be tolerable in AA patients (due to C2MS applied outside the absolute atrial refractory period) as causing arrhythmias in the atria, but may not be an issue in patients with atrial fibrillation. It is known that this may allow patients with long AV delays to be treated beneficially (e.g., by ignoring atrial effects).

[0163] The number of phases may also be varied, e.g., as few as 1, 2, or 3, or as many as 5, 10, 20, 50, or an intermediate or even greater number. The length of the phases may also be varied, e.g., between 1 and 100 ms, e.g., 2, 3, 5, 6, 6.6, 10, 15, 25, 50 ms, or an intermediate length. Also, not all of the phases need to be the same length and / or voltage. In addition, while square pulses are optionally used, other pulse shapes, e.g., curved, bent, triangular, and / or symmetrical and / or asymmetrical shapes, may be provided. In some embodiments, there is an inter-phase delay, e.g., 1, 2, 4, 5, 6, 10, 20 ms, or an intermediate or shorter or longer delay.

[0164] The energy delivered to the pulse may be, for example, 0.01, 0.1, 0.5, 1 J, 5 J, 10 J or intermediate or even smaller or larger energy levels.

[0165] The duration during which pulses are applied to the heart in one beat can be, for example, 5 ms, 10 ms, 20 ms, 30 ms, 40 ms, or an intermediate or even longer duration.

[0166] In some embodiments of the invention, any of the above numbers are varied, for example, by 5%, 10%, 20% or intermediate values.

[0167] The delay may be a calculated delay (if the patient is paced) or an approximation, and if two leads are used as bipolar electrodes, it is known to optionally use the minimum or average activation time to calculate the delay.

[0168] In some embodiments of the present invention, C2MS treatment is applied for, for example, 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 24 hours a day or for an intermediate period, for example, 1, 2, 3, 4, 5, 8, 12, 24 weeks or for an intermediate period or more weeks. During the treatment period, each heartbeat is optionally treated or intended to be treated. In other schemes, treatment may be administered per day, for example, according to the heart rate target as described herein.

[0169] It is known that C2MS signals may not be applied to a heartbeat for reasons other than medication. For example, a heartbeat may be deemed unsafe in the sense that applying a C2MS signal during that beat could cause arrhythmia. Optionally, or in addition, the heart may be allowed to "recover" from the abnormal heartbeat for one or more "prohibited" beats.

[0170] In some embodiments of the invention (e.g., in the tests described herein), the following algorithm is used to determine whether to apply a C2MS signal during a given beat:

[0171] A first optional section of the algorithm is to avoid stimulation with C2MS where the heart rate is too high, e.g., above a cutoff threshold, e.g., 90, 100, 110, 120, 130, 140, 145, 160, or any value in between. Optionally, this may prevent application of C2MS during VT or incipit CT and / or other arrhythmias, which may be detected as high heart rates.

[0172] A second optional section of the algorithm is to avoid stimulation if the delay between the two ventricular leads exceeds a certain threshold, e.g., 30 ms, although other numbers, e.g., 10 ms, 20 ms, 40 ms, 50 ms, and / or intermediate or even larger thresholds may be used. The threshold may be condition-dependent (e.g., heart rate or other cardiac parameter). This delay may indicate multiple foci and / or irregular propagation directions in the ventricles.

[0173] The concrete algorithm of the example is - Sensing ventricular contractions in both ventricular leads - Determine if your heart rate is below 110 bpm - A detected systolic delay between the two leads greater than 30 ms is defined as an inappropriate beat. -For each detected inappropriate beat, not providing C2MS stimulation during the current and subsequent ventricular contractions (in some embodiments, C2MS may be provided on the next beat, but in other embodiments the delay may be more than 1 beat, e.g., between 3 and 10 beats, or may be a time delay such as, e.g., 5 to 60 seconds or more). -Detection of an inappropriate beat followed by consecutive detection of ventricular contractions in two leads. Once two appropriate beats (less than 3 ms delay) are detected, a C2MS stimulus is delivered to that contraction with a preset delay.

[0174] In some embodiments of the invention, irregular beats are detected based on AV delay and / or based on the morphology of the electrogram signal detected at one or more of the electrodes. Other methods of detecting potentially unsafe beats (e.g., beats in which the ventricle may be stimulated outside of its absolute refractory period) may be used as well.

[0175] Safety and Efficacy of Exemplary Atrial Stimulation FIG. 4 is a time chart that schematically illustrates the timing of non-excitable regions associated with various cardiac events, according to some embodiments of the present invention.

[0176] Figure 4 includes three time-ordered charts (402, 404, 406) showing atrial activation as "A", AV activation as "AV", and ventricular activation as "V". Each timeline shows two beats.

[0177] Referring first to time chart 402, AV excitation occurs after atrial excitation and before ventricular excitation. This reflects excitation in the heart, which begins at the SA node, encompasses the right atrium, is conducted by the AV node, is delayed there, and then reaches and propagates into the ventricles. The two beats are shown to be identical.

[0178] Referring to time chart 404, in the first beat (time chart read from left to right), the C2MS signal is optionally applied after ventricular activation, with a short delay during the ventricular absolute refractory period. This can be seen by referring to time chart 406, where the absolute refractory period in the atria is indicated by 414 (and its termination by 416), and the absolute refractory period in the ventricles is indicated by 418 and its termination by 420. These refractory periods are shown as if the C2MS signal itself does not affect their duration. As shown in the time chart, it may be desirable to apply C2MS at a time when the atria are also in their absolute refractory period. In other embodiments, as noted herein, C2MS is applied when the atria are not refractory.

[0179] The second beat in chart 404 contains an atrial arrhythmia. The first possibility is marked as "A?", which is when the atria tend to produce arrhythmic activation. According to some embodiments of the present invention, application of a C2MS signal reaches the atria and prolongs the refractory period therein, as indicated by 422. This can prevent such arrhythmic activation from occurring and / or prevent it from propagating to the AV node (e.g., if it is the AV nodal refractory period that is prolonged).

[0180] The second possibility is marked as "AV / V?", where abnormal activation is present in the AV node. However, according to some embodiments of the present invention, the refractory period of the conduction tissue near the AV node is extended 424 by the C2MS signal, so such activation cannot propagate. According to some embodiments of the present invention, the refractory period of the tissue in the ventricle itself is extended, so that even if activation begins programming, it is stopped by addressing the refractory tissue of the ventricle.

[0181] These time charts demonstrate several possibilities by which C2MS signals may actually prevent ventricular activation from exhibiting significant dysfunction due to atrial arrhythmias. Additionally, C2MS signals are thought to entrain tissues to resist arrhythmic behavior.

[0182] The time chart 406 shows that the ventricular refractory period prolongation 424 is likely to be less than the atrial refractory period prolongation 422. This may be due, for example, to the relative timing of the C2MS signal and tissue excitation. It is believed that the refractory period prolongation increases when applied toward the end of the refractory period. For example, U.S. Pat. No. 7,991,469 shows how a non-excitatory signal applied during the refractory period can prolong the refractory period. In some embodiments of the present invention, the application of C2MS is selected to target the AV node and / or fast conduction pathways, such as, for example, Purkinje fibers.

[0183] In some embodiments of the invention, the timing of C2MS is modified, e.g., delayed, to a greater or lesser extent depending on the desired effect, particularly those related to improving AA. Optionally, or in addition, the site of application of the C2MS signal is modified and / or the amplitude of the signal is altered to select which tissue should be affected by the C2MS signal. Because cardiac tissue moves during the cardiac cycle, such changes in C2MS signal parameters optionally take physical distance into account as they depend on the cardiac cycle. For example, applying C2MS late in systole (from the interventricular septum) can affect the left ventricular free wall for a longer period of time than a similar signal applied before the ventricle significantly contracts. In some embodiments of the invention, the duration of the signal is varied (or the C2MS signal is split into two or more time-separated components) so that different parts of the ventricle are stimulated for different periods of time. This allows the total power delivered to be reduced (e.g., if a target threshold application level has been reached in the treated tissue). Such modifications may be particularly important if the C2MS signal is selected to be suboptimal for C2MS application due to other desired effects.

[0184] Tradeoffs may be made between various desired effects. For example, as mentioned above, a preferred electrode location in the right atrium may result in less coverage of the ventricle. This may result in a reduced ventricular effect, but from a clinical perspective, the patient's overall condition may be improved. Similarly, if two stimulation parameter settings exist, one of which covers more ventricular tissue but causes more mitral regurgitation, a different parameter setting may reduce regurgitation and perhaps be more desirable overall, even if it has a reduced or delayed therapeutic effect. In one example, various stimulation regimens are tested on a patient, and the regimen having the desired effect (e.g., on atrial and / or mitral regurgitation, or HOCM-type blockage of atrial outflow) is selected. In some embodiments of the invention, the regimen is determined by modeling the heart and its response to stimulation and / or by matching one or more cardiac parameters to known patients and their responses to C2MS. Modeling may be preferred prior to implanting device 200 to determine whether to implant device 200 and / or to determine when to modify parameters in the implanted device.

[0185] In some embodiments of the invention, more than one lead may be used, and selective activation of such leads may be practiced if some effects are chronic, e.g., using more atrial leads if AF is anticipated or detected (e.g., using an atrial detector), or more ventricular leads otherwise (e.g., and / or to meet any desired therapeutic dose).

[0186] For example, in the case of paroxysmal AF, upon detection of the onset of AF, device 200 may deliver C2MS therapy. The stimulation lead may be, for example, in the RV and / or LV, and delivery may be during its refractory period, and / or delivery may be from the atrium if the stimulation has not reached the ventricle, and delivery may be optional and at any time.

[0187] Optionally, in another example, during an ongoing AF episode in a chronic AF patient, device 200 may be used to prolong the ventricular refractory period (by delivering a C2MS signal to the ventricles) and / or may be used to deliver a C2MS signal to the atria that may inhibit induction of AF.

[0188] Referring back to the extended refractory periods 422, 424, according to some embodiments of the present invention, even if the C2MS signal itself provides an indication of atrial arrhythmia, for example, by directly causing abnormal activation, this may not be an overall problem if it prevents such activation from reaching the ventricles. The overall therapeutic balance may allow for such a deterioration in atrial function due to an overall increase in cardiac output and / or health.

[0189] Exemplary stimulus variations Figure 3 is depicted using a methodology where only the ventricular lead is present and no atrial sensing is provided. Because the ventricles are in a refractory state when the C2MS signal is applied, this has the potential advantage of ignoring the AA while maintaining the safety of ventricular application.

[0190] In some embodiments of the invention, an atrial sensing configuration is used, for example, by adding an atrial lead (e.g., along with one or two ventricular leads). In some embodiments of the invention, such a configuration may be used to detect AA and treat it and / or its symptoms, for example, using a C2MS signal as described herein or other electrical therapy, such as atrial antiarrhythmia pacing. Alternatively, if AA is detected, an additional check is performed to determine whether there is a ventricular irregularity. As mentioned herein, some such ventricular irregularities can be prevented and / or inhibited by a C2MS signal. In some embodiments of the invention, such arrhythmias are detected by measuring the delay between atrial activation and ventricular activation, for example, by determining whether the ratio is 1:1 and / or by detecting the relative delay.

[0191] In some embodiments of the invention, arrhythmias (at the current beat or ongoing) are detected using one or more of the following methods: (1) Based on heart rate. If the heart rate exceeds a set threshold, it is considered tachycardia. If it falls below a lower threshold, the heart condition may be considered bradycardia. (2) If the origin of the trigger is not from the AN node, this can be detected by a change in the time interval between the two ventricular septal leads and / or a change in the shape of the QRS detected by the ventricular lead. (3) Heart Rate Variability (HRV). If HRV is high (e.g., above a threshold), this may indicate a ventricular arrhythmia.

[0192] In some embodiments of the invention, safety / irregularity detection methods such as those described in one or more of the following U.S. Patent Nos. 6,233,487, 6,597,952, 6,263,242, 6,370,430, 6,993,385, 7,953,481, and 6,480,737 may be used, and have been used. Other methods may be used as well.

[0193] Exemplary Evaluation In some embodiments of the present invention, sensor input 214 and / or controller 202 are used to close the treatment loop.

[0194] In one example, sensors can provide indicators of cardiac output or patient activity, which can be used to automatically identify that a treatment protocol is working and should be continued.

[0195] In another example, acute changes in arrhythmia, heart rate and / or cardiac output are used to identify whether application parameters are acceptable.

[0196] In another example, a sensor is used to detect the need for higher cardiac output, and in such cases, stimulation parameters are provided that increase cardiac output at the expense of the therapeutic goal, e.g., long-term suppression of AF.

[0197] In another example, changes in heart rate may indicate a need to modify parameters of the C2MS signal. For example, changes in heart rate may alter the relative timing of activation in the two chambers and / or the timing of refractory periods in the atria and ventricles. In some embodiments of the invention, the timing of application of the C2MS signal is altered (e.g., to enter or not enter the atrial refractory period) to maintain the desired arrhythmia mitigation effect.

[0198] Simultaneous drug delivery In some embodiments of the present invention, C2MS signals are used to provide some antiarrhythmic effect by lengthening the refractory period and / or by other means. As a result, the dosage of such antiarrhythmic drugs may be modified. For example, the dosage of one or more of the following drug families may be modified (e.g., allowed to be reduced and / or increased): antiarrhythmic drugs such as amiodarone, flecainide, procainamide, and / or sotalol; beta-blockers; calcium channel blockers; and / or ACE inhibitors.

[0199] In some embodiments of the invention, the application of C2MS is timed according to the drug dosing time to provide greater C2MS antiarrhythmic effect during times when blood levels (or other indicators of drug efficacy) are low.

[0200] In some embodiments of the present invention, the timing of C2MS is selected according to the expected effect of a cardiac drug on the refractory period, for example, to ensure that stimulation occurs throughout the refractory period. A signal applied near the end of the refractory period may have the effect of preventing subsequent activation, which is known in some indications to have an anti-arrhythmic effect. Timing such activation may depend, for example, on the drug's dosage and / or expected effect. Optionally, such effects are programmed into memory 218.

[0201] Possible mechanisms of C2MS Without necessarily being limited to any particular explanation, one or more of the following physiological explanations may be helpful in providing some understanding of how various parameters of treatment may be modified for use in some embodiments of the present invention.

[0202] As discussed, for example, in Heart Fail Rev. 2016;21(6):645-660, "Cardiac contractility modulation: a novel approach for the treatment of heart failure," C2MS signaling may have a contractility-improving effect through a direct effect on phospholamban phosphorylation and / or other direct effects on cellular function (e.g., other proteins). This may trigger a cascade that reverses the fetal genetic program and causes functional remodeling of the affected cardiac tissue. In some embodiments of the present invention, the amount of phosphorylation (or other cellular effect as described therein) and / or the amount of program reversal is used as a guideline to describe what amount of C2MS signaling is desired.

[0203] With respect to the atria, C2MS signals may, for example, synchronize the tissue and entrain atrial tissue by preventing fluctuations in activity, which may also cause long-term remodeling of the electrical behavior of such tissue.

[0204] At the acute level, U.S. Patent No. 4,554,922, for example, suggests that an electrical signal applied apparently within the relative refractory period prolongs the refractory period, rendering the tissue less prone to arrhythmia. Such prolongation may block propagation without generally affecting muscle activity. In some cases, the effect is to block electrical activity for longer than the duration between activations, which reduces muscle functionality.

[0205] Improved VO2 FIG. 5 is a graph showing the results of a study in which C2MS improved VO2 parameters in patients with AF, according to some embodiments of the present invention.

[0206] In the study, 60 patients were selected and implanted with a C2MS device, a two-lead Optimizer Smart System by Impulse Dynamics. Nine of these patients had atrial fibrillation, and the effects of the treatment on them are described herein. The patients were selected (and may be selected for treatment and / or therapy for such patients planned according to some embodiments of the present invention based on one or more or all of the criteria, inclusion criteria, and / or exclusion criteria described herein below).

[0207] Methods: Patients were eligible for inclusion if they had NYHA III / IVa symptoms despite adequate medical therapy, had a LVEF of 25-45%, and were ineligible for CRT. All subjects who received an Optimizer2 lead implant were followed up at weeks 12 and 24. Device verification provided a number of effectively delivered C2MS signals.

[0208] Sixty subjects were enrolled from seven medical centers in the United States and one medical center in Germany. Subjects were evaluated at baseline and again at 12 and 24 weeks after implantation. Inclusion and exclusion criteria are summarized in Table 1. Key criteria included: adult subjects with an LVEF of ≥ 25% and ≤ 45% by echocardiography (assessed by a core laboratory); NYHA III or ambulatory IV symptoms that were stable for 30 days prior to enrollment despite 90 days of guideline-indicated heart failure medical therapy (including an ICD if indicated), and no indication for cardiac resynchronization therapy (CRT). Patients were excluded if they had been hospitalized for heart failure requiring intravenous loop diuretics, inotropes, or hemofiltration within 30 days; if they had received any form of inotropic therapy within 30 days prior to enrollment; if their peak VO2 on cardiopulmonary stress testing (CPX) was <9 or >20 mlO2 / min / kg (as assessed by a core laboratory); if they had a potentially treatable cause of heart failure (e.g., valvular heart disease or congenital heart disease); if their exercise tolerance was limited by a condition other than heart failure; or if they were scheduled for or had recently undergone CABG, PCI, or MI. Notably, patients with atrial fibrillation may be enrolled, compared with all previous trials in the United States. [Table 1]

[0209] The timeline of events is summarized in Table 2. Following eligibility assessment, subjects underwent implantation of a 2-lead Optimizer Smart System. After device programming, subjects were generally discharged from the hospital the same day as implantation or the next day. Approximately 2 weeks later, subjects returned for routine wound checks and device checks (when C2MS signal parameters were checked and optimized). Study follow-up visits for clinical evaluation occurred at 12 and 24 weeks (± 2 weeks) after device implantation. In addition to interim safety assessments, on-site clinicians assessed NYHA and repeated CPX testing at these visits. [Table 2]

[0210] General results (not including AF) included 60 subjects, 88% male, 66 ± 9 years old, with a LVEF of 34 ± 6%, including 68% with ischemic cardiomyopathy and 15% with atrial fibrillation. C2MS delivery did not differ between the two-lead and three-lead systems (19,892 ± 3472 vs. 19,583 ± 4998 beats / day). The change in peak VO2 from baseline to week 24 was greater in the two-lead device group compared with the control group, 1.72 ml / kg / min (95% Bayesian confidence interval [BCI]: 1.02, 2.42). Adverse events did not differ between groups, except for a reduction in Optimizer-related adverse events in the two-lead group compared with the three-lead group (8% vs. 0%, p = 0.03).

[0211] Additionally, NYHA improved by at least one functional class in 83.1% of subjects treated with the 2-Lead Optimizer System at 24 weeks compared to only 42.7% in the FIX-HF-5C control group (p<0.001).

[0212] Further details regarding the test may be found in co-filed application with attorney specification 79062.

[0213] Generally, patients were selected for the study if they had systolic heart failure with an ejection fraction of 25% to 45% of NYHA Class III (although Class IVa is also acceptable and / or may be used in some embodiments of the present invention as Class II). In some embodiments of the present invention, patients may be selected with an EF between 25% and 55%, e.g., between 33% and 45%. In addition, patients had a peak VO2 of 9 to 25 mL / kg / min. In some embodiments of the present invention, patients were selected if they had a peak VO2 between 9 to 12, 12 to 15, 15 to 20, 20 to 25, or intermediate values, e.g., between 9 and 12, 12 to 15, 15 to 20, 20 to 25, or intermediate values. In some embodiments of the present invention, patients with a high peak VO2 are expected to have a greater likelihood of taking advantage of any cardiac improvements provided by the treatment.

[0214] As can be seen in Figure 5, when applied to patients with heart failure and atrial fibrillation, C2MS increases peak VO2 compared to baseline for most patients, averaging 0.844 mL / kg / min across all nine patients with a slope level of 0.0025 (e.g., after several months, e.g., 12 or 24 weeks); improvement compared to controls is also expected, as control patients typically deteriorate. It is known that improvement increases if only patients with high treated heart rates are selected. Non-AF patients showed a mean improvement of 1.09 mL / kg / min, STD 1.48 mL / kg / min, with no apparent positive effect of treated heart rate. In comparison, when using a three-lead device, there is a substantial lack of increase in peak VO2 for non-AF patients (but also no decrease, which would be expected for such patients). This suggests a synergistic effect between patients with AF and those who benefit from treatment. As noted, this synergistic effect likely exceeds and exceeds the basic potential benefit of using C2MS signals to treat AF patients, even though AF is a contraindication.

[0215] In some embodiments of the invention, AF patients are selected for treatment with a target improvement in VO2 of at least 0.5 mlO2 / min / kg, at least 1 mlO2 / min / kg, at least 2 mlO2 / min / kg, at least 3 mlO2 / min / kg, or at least 7 mlO2 / min / kg, or intermediate values.

[0216] In some embodiments of the present invention, patients are selected for treatment based on indications where peak VO2 is limited by cardiac considerations.

[0217] It is known that increasing VO2 may require patients to have some pulmonary reserve. Optionally, patients are selected if their ventilatory reserve (potential increase in lung effectiveness) is at least 10%, at least 20%, at least 30%, at least 50%, or intermediate or higher values. A BR below 30 or 33 is often considered low and indicates pulmonary impairment that may limit improvement in peak VO2. BR may be defined as the difference between maximal voluntary ventilation (MVV) and the maximum ventilation measured during an exercise test (e.g., BR% = (MVV-VE / MVV) × 100).

[0218] In some embodiments of the invention, a patient is considered to potentially have useful pulmonary reserve based on the patient's oxygen uptake efficiency slope (OUES) being below, for example, 95%, 90%, 89%, 85%, 70%, or an intermediate value.

[0219] In some embodiments of the invention, a patient is considered to potentially have useful pulmonary reserve based on the patient's peak RER being above, for example, 1, 1.05, 1.1, 1.15, or an intermediate value.

[0220] In some embodiments of the present invention, patients are considered to potentially have useful pulmonary reserve based on their AT being low rather than normal or crossing.

[0221] In some embodiments of the invention, a patient is considered to potentially have useful pulmonary reserve based on the patient's VE / VCO2 ratio being above, for example, 25, 30, 35, or an intermediate value.

[0222] In some embodiments of the invention, a patient is considered to potentially have useful pulmonary reserve based on the patient's O2 saturation not declining and / or not declining rapidly during exercise, e.g., declining by less than 20%, 10%, 5% or an intermediate value over a 20 minute period of exercise.

[0223] Alternatively (or additionally), improved cardiac function may be reflected in ways other than improved VO2, e.g., reversal of fetal genetic programming as evidenced by normalization of one, two, three or more indices of mRNA, protein levels, and / or circulating peptides. In some embodiments of the invention, patients are selected if they have AF (or other AA, e.g., atrial tachycardia, atrial flutter, sinus tachycardia, supraventricular tachycardia (SVT), Wolff-Parkinson-White (WPW) syndrome) and heart failure (e.g., reduced cardiac output), even if, or particularly if, they are not expected to have useful pulmonary reserve.

[0224] As can be seen in Figure 5, the degree of improvement appears to increase as a function of the number of beats actually treated. In particular, above about 17,000 beats there is an average improvement, and this improvement increases as the number of beats treated increases to 20,000 and 25,000 beats.

[0225] In some embodiments of the present invention, this suggests selecting AF patients based on the predicted likelihood of treating more beats. For example, the surface ECGs of such patients may be interpreted and processed to stimulate the C2MS application algorithm and select treatment patients where a sufficient number of beats may cause C2MS to be applied.

[0226] It is known that in some patients, C2MS is not applied based on beat. For example, in AF patients in which C2MS is applied to the atria, there may not be a meaningful definition of beat, and application may not be synchronized to an actual beat. In other patients, application is synchronized to an actual or desired beat. Optionally, paced beats are treated. In some cases, synchronization occurs in one chamber (e.g., the ventricle) while timing is ignored in another chamber (e.g., the atrium), and in some cases, stimulation reaches the other chamber, and in other cases, it does not. In some embodiments, the timing is selected so that application occurs when both the atria and the atria are in their refractory periods, even if the heart rates are not synchronized.

[0227] In some embodiments of the invention, the duration of treatment (e.g., greater than 7 hours based on estimated heart rates per hour or by heart rate, e.g., 8 or 9 hours of treatment is permitted) is selected to increase the treated heart rate.

[0228] In some embodiments of the invention, one or more of the blocking parameters, e.g., heart rate, may be moderated so that pulsation can be treated at higher heart rates. For example, heart rates between 110 and 150 or between 110 and 130 may be treated.

[0229] In some embodiments of the invention, device parameters are modified in response to actual measurements of applied pulsation (e.g., as detected during or after implantation, e.g., at 1 day, 1 week, 1 month, 3 months, or intermediate periods).

[0230] In some embodiments of the invention, pacemaker settings are modified to allow treatment of more beats per day (eg, increasing the basal heart rate).

[0231] In some embodiments of the invention, the parameters are adjusted to increase the number of heart beats per day in response to the effectiveness of the lack of treatment rather than in response to the number of heart beats applied, for example, to 30,000, 40,000, 50,000, or intermediate or higher heart beats per day. In some embodiments of the invention, the parameters may reach such a number and are modified to stop stimulation for that day once the desired number is reached.

[0232] In some embodiments of the present invention, such selection of the dose of beats per day is specifically applied to AF patients, while in other embodiments, it is applied to non-AF patients.

[0233] In some embodiments of the invention, the heart rate is increased in response to detecting that the application of C2MS is reducing the number of atrial abnormal beats. In some cases, such a determination may indicate that the C2MS is not having sufficient antiarrhythmic effect, and the application of C2MS is reduced and / or altered so that it is applied primarily for other effects, such as increasing cardiac output.

[0234] In another example, if an atrial (or other) sensor detects increased electrical activity in the atrium, AA is envisioned and delivery of C2MS affecting the atrium and / or AV node and / or ventricular conduction from the AV node is increased and / or timing and / or other parameters are altered to better accommodate AA.

[0235] In another example, during an AA episode, if the ventricular heart rate increases and actual demand does not increase (e.g., based on an accelerometer or other activity sensor), an increased and / or modified C2MS is applied to the atrium.

[0236] Exemplary impulses from the atrium FIG. 6 is a schematic diagram of a heart 100 illustrating the spatial reach 602 of non-excitable regions from the right atrium according to some embodiments of the present invention.

[0237] Although the drawing is distorted, it is understandable, and it should be noted that the parameters of the stimulation signal may be set so that a significant portion of the interventricular septum, as well as significant portions of the right atrium, left atrium, and AV node, are affected by the C2MS signal. It is known that such an effect may reduce AA in one or both atria. Optionally, pulse parameters are selected so that the C2MS signal reaches the junction of the pulmonary veins with the left atrium, which may reduce some types of atrial arrhythmias.

[0238] A potential benefit is that applying a C2MS signal in a manner asynchronous with atrial self-pacing and / or timed to induce an arrhythmic episode may not be as dangerous as such extra atrial beats may not affect the ventricles (for reasons noted herein) or may at most act as "natural" atrial arrhythmias that are not immediately life-threatening in themselves. In some embodiments of the invention, electrodes 606 of leads 604 are used to detect signals indicative of ventricular timing to allow timing of stimulation in the atria at short delays (e.g., 1-70 ms) after ventricular activation.

[0239] FIG. 7 is a schematic diagram of a heart showing the spatial reach 702 of a non-excitable region from an electrode 707 of a lead 704 in the left atrium according to some embodiments of the present invention.

[0240] In the illustrated example, lead 704 is provided in a transseptal approach, with dotted line 708 indicating the hidden portion of the lead and noting that the drawing is distorted. In the illustrated example, lead 704 passes through the interatrial septum (e.g., the foramen ovale) and has a curved (optionally pre-shaped) section 710 (e.g., to aid in fixation and / or tip placement). Optionally, as shown, tip 706 is placed facing downward, close to the ventricle. In some embodiments, tip placement is selected to "reach" the entrance to the pulmonary vein where the C2MS region 702 is located. In some embodiments of the invention, electrode location and / or signal strength and / or timing are selected to minimize or avoid potential effects, if any, in the ventricle other than the effect of contractility enhancement. A potential benefit of placing an electrode in the atrium is that such an electrode can be used to apply a signal of defibrillation strength, even though its amplitude limits its reach to the relevant atrium. Optionally, the timing of such signals is selected to fall during the absolute refractory period of the relevant ventricle (eg, a ventricle that may be directly stimulated by such region).

[0241] It is known that when stimulating from the atrium, it may be necessary to use stronger amplitudes and / or different timing to ensure delivery of the applied C2MS field to the desired non-atrial tissue.

[0242] In some embodiments of the invention, one lead is placed in the atrium and one lead is placed in the ventricle, and both are used to apply C2MS, or C2MS is applied between the two leads.

[0243] In some embodiments of the invention, the amplitude of the C2MS signal is selected based on the cardiac cycle. For example, if the C2MS signal is applied not during the absolute refractory period of the ventricle, the amplitude may be reduced (or the electrode location selected) so that dangerous levels of electrical charge do not reach the ventricle. If stimulating from the ventricle during the ventricular refractory period and / or with precise timing, a higher amplitude (e.g., voltage) may be used, even if it "covers" both a portion of the atrium and a portion of the ventricle. For example, as mentioned above, inducing arrhythmia in the atrium may not be an issue in arrhythmia patients and / or may be less life-threatening than if the ventricle were so stimulated.

[0244] In some embodiments of the invention, both C2MS and CRT are administered to the same patient, and while such dual administration may share electrodes (e.g., left ventricular and / or right ventricular electrodes), in some embodiments of the invention, an atrial electrode is used to administer C2MS (optionally with parameters that provide meaningful stimulation to the ventricles).

[0245] In some embodiments of the invention, C2MS is used to treat and / or prevent AA. Optionally, or additionally, or alternatively, C2MS is used to treat the ventricles for heart failure, the latter of which may also be applied to hearts without AA.

[0246] In some embodiments of the invention, sensing in the atria (or other parts of the heart and / or the rest of the body) is used to estimate levels of AA, e.g., the presence of acute episodes of AA and / or the general prevalence of AA. Treatment may be modified accordingly, e.g., activating the atrial electrode (or electrodes near the atria) and / or activating the ventricular electrode at higher amplitudes in response to acute and / or chronic increases in AA.

[0247] Some results from dogs In a series of experiments, two healthy dogs were treated with C2MS and it was discovered that C2MS applied to the ventricular septum could reduce AA and / or susceptibility to AA.

[0248] More specifically, two dogs were subjected to rapid atrial pacing to induce AF (by mimicking AA). Such induction was easily achieved. The dogs maintained AF even after such rapid pacing was discontinued, for example, for at least 10 minutes. It is known that in a typical heart, repeated and sustained bouts of AF tend to increase the propensity to spontaneously develop an AF event and / or initiate AF, even if such AF is induced.

[0249] When C2MS (in the ventricle) was applied, AF was terminated within less than 1 minute. This process of inducing and terminating AF using C2MS was repeated several times.

[0250] Once C2MS was applied for several days (approximately 1 week, 5 hours / day), AF could not be induced using rapid pacing. Several attempts to induce AF were made with delays ranging from 1 minute to 3 hours (the exact number is unknown) after the end of C2MS application. Such attempts failed after multiple attempts in both animals and on multiple occasions. Manual injection of proarrhythmic drugs into dogs, which are expected to increase the atria's susceptibility to arrhythmia induction, also failed to initiate AF using rapid pacing.

[0251] Generally, AF can be induced by rapid pacing of the atrium before relying on C2MS therapy. However, activation of C2MS quite rapidly caused reversion to NSR (normal sinus rhythm). Even when the animals were given proarrhythmic drugs, they were simply not inducible after receiving C2MS for several hours or weeks, even though they were under the same conditions (anesthesia and rapid pacing).

[0252] In some embodiments of the invention, C2MS therapy is used to help reduce episodes of AA by being applied for periods of, for example, 20 minutes, 40 minutes, 1 hour, 2 hours, or for intermediate or longer periods. On an acute basis (e.g., if an AA episode is detected), C2MS may be applied, optionally with some type of antiarrhythmia pacing, for example, 1 second, 10 seconds, 1 minute, 10 minutes, 20 minutes, or for intermediate or longer periods.

[0253] It is known that higher power levels and / or more sensitive electrodes can be used for acute treatments because patients may be willing to accept temporary discomfort if treatment is required acutely. It is also known that while power consumption may increase with signal amplitude, this may be less of a consideration for acute treatments (e.g., less than 20%, 10%, 5% or intermediate percentages of applied beats per day).

[0254] Optionally, the C2MS is applied to the ventricular septum. Optionally, or in addition, the C2MS is applied to the atrium.

[0255] In some embodiments of the present invention, the C2MS is applied before and / or after the onset of an AA episode.

[0256] In some embodiments of the invention, specific physiological parameters, such as high heart rate or exercise, are used to determine the application of C2MS and / or based on the timing of antiarrhythmic medication. Such application of C2MS may reduce the risk of AA episodes induced by these or other proarrhythmic conditions.

[0257] In some embodiments of the invention, C2MS is administered as a preventative treatment, for example, on a schedule of 1-20 minutes every hour. Such treatment may be scheduled to cover a full 24-hour period, for example, to prevent AF from occurring during "off" times.

[0258] In some embodiments of the invention, C2MS is applied after an AA episode has been treated (e.g., by cardioversion), e.g., for 1 to 20 minutes, e.g., for 5 to 60 minutes, particularly to potentially maintain a non-arrhythmic state despite the pro-arrhythmic state caused by the treated AA episode and / or its treatment.

[0259] In some embodiments of the invention, C2MS is applied over a similar time range to prevent AF after defibrillation is applied, e.g., to prevent AA from occurring. More generally, in some embodiments of the invention, upon detection or estimation of high levels of atrial pro-arrhythmia, device 200 is used to provide C2MS to suppress such pro-arrhythmia.

[0260] If the C2MS is applied after treatment, the onset of C2MS application is optionally delayed, for example, for 1 to 300 seconds, for 30 to 200 seconds, or for an intermediate or longer period of time.

[0261] By "apply C2MS for XX minutes," what is meant is that the controller logic is configured to apply the C2MS signal for that period of time every beat (or perhaps according to another schedule, e.g., every other beat), although it is known that some beats will not be treated due to, e.g., irregularities in ventricular activation.

[0262] In some embodiments of the present invention, the heart rate limit above which C2MS does not apply is increased.

[0263] Exemplary AF Patient Selection and Treatment FIG. 8 is a flowchart of a method for patient selection and treatment of a patient with atrial arrhythmia issues according to some embodiments of the present invention; note that in some embodiments, the actions described may be performed in parallel and / or in other orders.

[0264] At 802, patients are identified who have a cardiac condition, e.g., as described herein, and who may benefit from treatment. For example, patients with NYHA stage II (or higher) heart failure, optionally with AF, may be identified. For example, such patients may be selected to have an ejection fraction (EF) between 20% and 50%, e.g., between 25% and 40% or 45%. Optionally, or in addition, such patients may have chronic angina (e.g., angina pectoris). Optionally, or in addition, such patients may have a 6-minute walk test of less than 800 meters, 600 meters, 400 meters, and / or intermediate values. In some embodiments of the invention, the patient has significant pulmonary reserve (acceptable cardiac output), e.g., predicted to allow an increase in oxygenated blood flow by between 5% and 20%, 20% and 40%, 40% and 60%, 60% and 100%, 100% and 200%, and / or intermediate or even greater percentages compared to the patient at rest. In some embodiments of the invention, the patient has a peak VO2 between 8 and 20 mlO2 / min / kg.

[0265] In some embodiments of the invention, patients are selected based on the amount of beats that can be treated, for example, patients in which at least 20%, 40%, 50%, 80% or any intermediate percentage of their heart rate can be treated using C2MS when considering patient safety.

[0266] At 804, the patient's atrial arrhythmia status is determined; for example, the patient may be identified as having paroxysmal AF. In some embodiments, patients who do not have AF but may be at risk for developing AF (e.g., have sleep apnea) are selected. In some embodiments of the invention, the patient spends between 0% and 10% of their time (e.g., averaged over a month) in AA, between 10% and 30% in AA, between 30% and 50% in AA, greater than 50% in AA, and perhaps up to 90% or 100% in AA. An increasing percentage may indicate increasing severity of AA. In some embodiments of the invention, the patient has an estimated risk of 5%, 10%, 20%, 30%, 50%, 70%, or an intermediate or even greater risk level of developing AF, such as transient AF or progression to chronic AF, in the next year (e.g., using clinical and / or diagnostic methods known in the art).

[0267] At 806, the patient's heart failure status is optionally determined. Optionally, HF status is defined according to a cardiac output lower than a desired cardiac output. In some embodiments, patients without significant heart failure (e.g., NYHA stage I or below) are known to be treated. In other embodiments, patients with acceptable resting symptoms (NYHA II or II) are treated. In some embodiments of the invention, patients with NYHA IV are treated.

[0268] The status of pulmonary reserve is optionally determined at 808. In some cases, C2MS therapy is provided regardless of respiratory status and / or availability of respiratory reserve.

[0269] At 810, the patient's suitability for treatment is determined, for example, based on expected improvement, based on the presence of a treatable disease, and / or based on a desired preventative effect, and / or based on an expected cardiac response (e.g., the expected number of treated beats). In particular, it is known that patients may be selected because they have atrial fibrillation (or other AA) or despite such AA.

[0270] At 812, initial stimulation settings are optionally determined, such as desired lead location, tissue that the C2MS will affect (and therefore signal amplitude and / or timing), and / or application logic.

[0271] In some embodiments of the invention, a combination of timing and amplitude is used to determine which tissues are within range of the signal from the leads at what time and for how long. Planning may involve setting desired ranges for such values ​​and running a stimulation or other solver to determine the parameters of signal application that meet the requirements.

[0272] At 814, one or more leads are implanted in or near the heart, for example, in the right atrium and / or right ventricle. Optionally, existing leads (e.g., from a pacemaker and / or defibrillator) are reused or used in parallel for C2MS applications.

[0273] In some embodiments of the invention, the lead location (e.g., not septal) is selected to, for example, reduce charging of nerves or nerve plexuses within or outside the heart and / or reduce stimulation of other chest tissues.

[0274] In some embodiments of the invention, the electrode is an external lead or other non-implanted lead, e.g., an electrode(s) on a catheter, for use in short therapy, e.g., for illustrative cardioversion. Optionally, the charge is via a needle used to penetrate the skin or other outer layer of the body.

[0275] At 816, the electrodes to be stimulated are optionally selected.

[0276] At 818, the effect of the first signal parameter is optionally monitored.

[0277] At 820, application parameters and logic circuits are optionally programmed and / or reprogrammed (eg, in response to such monitoring), for example, using an external controller.

[0278] It is understood that such methods as described herein may include a treatment planning phase (e.g., through 812, 88, 820) followed by a treatment phase (e.g., 814, 816), one of which may optionally be omitted.

[0279] Exemplary Non-AF Patient Selection and / or Treatment 9 is a flowchart of a method of patient selection and treatment planning and optionally treatment administration for patients with cardiac output and additional cardiac dysfunctions, according to some embodiments of the invention, in which both dysfunctions are treated using the same C2MS signal.

[0280] At 902, patients with heart failure and / or AA and additional existing or underlying cardiac dysfunction are considered.

[0281] At 904, the heart failure and / or AA status is determined, for example, as described with reference to FIG.

[0282] Additional impairments (one or more) are determined at 906. Exemplary impairments include HOCM, valves (e.g., mitral, aortic, tricuspid), implants such as clips (e.g., mitral or tricuspid), diseased and / or weakened tissue, and such impairments may be pre-existing (e.g., diseased cardiac tissue) or latent (e.g., a clip that has not yet been implanted).

[0283] At 910, initial settings for C2MS therapy are determined. In some embodiments of the invention, such settings are selected to provide a trade-off between maximizing the therapeutic effect on one dysfunction versus maximizing the therapeutic effect on another. For example, a lead location may be selected that does not significantly enhance cardiac output, while at the same time providing a satisfactory level of AF prevention / therapy and / or avoiding stimulating diseased or diseased tissue and / or reducing mechanical challenges in the heart.

[0284] At 912, one or more leads are optionally implanted in the heart.

[0285] At 914, optionally after implantation, treatment begins.

[0286] At 916, the effectiveness of such treatment is monitored.

[0287] At 918, stimulation parameters are optionally reset.

[0288] Exemplary manipulation of implants FIG. 10 is a flowchart of the operation of a cardiac therapy device (eg, device 200) according to some embodiments of the present invention.

[0289] At 1002, an atrial event (eg, the onset of arrhythmia activity or the presence of arrhythmia) is optionally detected.

[0290] At 1004, a ventricular event (eg, the onset of arrhythmia activity or the presence of arrhythmia) is optionally detected.

[0291] These detected events are optionally used as inputs for either or both of the decision to apply the therapy and / or the decision whether to apply the therapy. In some embodiments of the invention, the order is reversed from that shown here, with the decision about the potential therapy being made first, followed by the decision of one or more events (if any).

[0292] At 1006, the protocol to be used is optionally considered (e.g., selected from a set or calculated), such as "apply C2MS for 7 hours," or "apply C2MS in response to AF," or "apply C2MS to alter cardiac activation so HOCM is less likely to block the aortic outlet," each of which are exemplary possible application protocols.

[0293] At 1008, a specific desired effect is optionally considered, e.g., a reduction in AA. This can be the case, for example, when 1002 detects an atrial arrhythmia or when an acute need for increased cardiac output is detected.

[0294] At 1010, it is optionally contemplated to provide a general dose of C2MS to have a general effect, for example, to reverse the genetic programming of the fetus.

[0295] At 1012, trade-offs between various effects are considered, for example, selecting application parameters that treat AF at the expense of minor improvements in cardiac output.

[0296] At 1014, signal parameters that achieve such a tradeoff are selected. In some cases, it is known that such parameters are selected prior to or in conjunction with the tradeoff. In some embodiments of the invention, such parameters are selected based on what may be expected to apply to the heart at the current beat or a nearby beat.

[0297] At 1016, in response to passing the safety test, a signal is applied to the heart.

[0298] At 1018, the effectiveness of the application is monitored, and the goals and / or protocols used in subsequent applications may be modified. For example, if the signal is not sufficient to stop AF, an increase in signal may be used (e.g., up to a threshold parameter value).

[0299] overview It is anticipated that numerous related non-excitable cardiac therapies will be developed between the filing of this application and the life of the maturing patent; the scope of the term non-excitable is intended to include such new pioneering technologies.

[0300] When used herein in reference to an amount or value, the term "about" means "within ±10% of."

[0301] The terms "comprises," "comprising," "includes," "including," "has," "having," and their cognates mean "including but not limited to."

[0302] The term "consisting of" means "including and limited to."

[0303] The term "consisting essentially of" means that a composition, method, or structure may include additional components, steps, and / or moieties, but only if the additional components, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0304] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the terms "a compound" or "at least one compound" may include multiple compounds, including mixtures thereof.

[0305] Throughout this application, embodiments of the invention may be presented with reference to a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, a description of a range should be construed as including all specifically disclosed possible subranges, as well as individual numerical values ​​within that range. For example, a description of a range such as "1 to 6" should be construed as including specifically disclosed subranges, such as "1 to 3," "1 to 4," "1 to 5," "2 to 4," "2 to 6," "3 to 6," etc., as well as individual numerical values ​​within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of fractional ranges.

[0306] Whenever a numerical range is given herein (e.g., "10-15," "10 to 15," or any pair of numbers connected by another such range designator), it is intended to include any number (fractional or integer) within the indicated range limits, inclusive of the range limits, unless the content clearly dictates otherwise. The phrases "range / ranging / ranges between" a first number and a second number, and "range / ranging / ranges" from a first number to a second number "to," "up to," "up to," or "between" (or another such range term) indicate that the numbers are used interchangeably herein and are intended to include the first and second numbers and all decimal and integer values ​​therebetween.

[0307] Unless otherwise indicated, numbers used herein and any numerical ranges based thereon are approximations within the accuracy and reasonable measurement and rounding errors as understood by one of ordinary skill in the art.

[0308] As used herein, the term "method" refers to ways, means, techniques and procedures for accomplishing a given task, including, but not limited to, ways, means, techniques and procedures known to or readily developed from known ways, means, techniques and procedures by the practitioner of the chemical, pharmacological, biological, biochemical and medical arts.

[0309] As used herein, the term "treating" includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating the clinical or cosmetic symptoms of a condition, or substantially preventing the appearance of clinical or cosmetic symptoms of a condition.

[0310] It is to be appreciated that certain features of the invention that are described for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any suitable subcombination, or as preferred, in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be construed as essential features of those embodiments, unless the embodiment is inoperable without those elements.

[0311] While the present invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0312] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. To the extent section headings are used, they should not be construed as necessarily limiting. Additionally, the priority document(s) of this application are incorporated herein by reference in their entirety.

Claims

1. A cardiac treatment device, comprising: a stimulation circuit configured to generate a non-excitatory electrical signal that, when applied to ventricular tissue during the ventricular refractory period, ameliorates a condition of heart failure in a human patient; an atrial arrhythmia detection circuit; a decision circuit that controls the stimulation circuit to deliver the signal when the atrial arrhythmia detection circuit detects an atrial arrhythmia.

2. 10. The device of claim 1, wherein the decision circuitry modifies at least one parameter of the signal in response to detecting the atrial arrhythmia.

3. The device of claim 2 , wherein the modification comprises increasing the range of tissue stimulated by the signal.

4. The device of any of claims 1 to 3, wherein the decision circuitry is configured to prevent the delivery if a ventricular arrhythmia is detected.

5. The device of any one of claims 1 to 4, wherein the decision circuitry is configured to allow the delivery if a supraventricular arrhythmia is detected.

6. 6. The device of any preceding claim, wherein the device comprises a memory containing an indication of the dose and duration of application of the signal to be applied, and wherein the decision circuitry is configured to modify the actual duration of signal application in accordance with the actual delivery of the signal.

7. The device of any preceding claim, wherein the device includes a data logger configured to record the effect of the application on the detected atrial arrhythmia.

8. The device of any preceding claim, wherein the device is configured to apply the signal also during non-refractory periods in the atrium of the patient.

9. The device of any one of claims 1 to 8, wherein the device does not have an atrial lead.

10. The device of any one of claims 1 to 8, wherein the device does not have a ventricular stimulation lead.

11. 11. The device of any of claims 1 to 10, wherein the device includes pacing circuitry, and the decision circuitry is programmable to selectively prefer applying a non-excitatory signal to applying increased pacing when cardiac demand increases.

12. 12. The device of claim 11, wherein the selective preference is in response to a cardiac parameter sensed by the device.

13. The device according to any one of claims 1 to 12, wherein the decision circuit defines an inhibit window of the number of beats within which the signal is not applied after an arrhythmia is detected, the window being one or zero.

14. 14. The device of claim 1, wherein the atrial arrhythmia detection circuit detects atrial arrhythmias from signals measured by one or more ventricular leads.

15. 1. A method of planning treatment for a patient, comprising: (a) identifying a patient as having or at risk of developing an atrial arrhythmia; (b) in response to said identifying, planning a treatment schedule for the patient with an implantable device that generates a non-excitatory electrical signal when applied to ventricular tissue during the ventricular refractory period, which ameliorate a condition of heart failure in the human patient.

16. 16. The method of claim 15, wherein said planning includes programming said device to apply said signal also during atrial arrhythmias.

17. 16. The method of claim 15, comprising selecting the patient and implementing the plan with the goal that the treatment will ameliorate symptoms of the atrial arrhythmia.

18. 18. The method of claim 16 or 17, wherein said ameliorating comprises preventing abnormal ventricular activation due to said atrial arrhythmia.

19. The method of any of claims 16 to 18, wherein said ameliorating comprises reducing said atrial arrhythmia.

20. The method of any of claims 15 to 19, wherein the atrial arrhythmia comprises transient AF.

21. 21. The method of any of claims 15 to 20, wherein said planning comprises planning to apply said non-excitatory signal within 20 mm of the interventricular septum.

22. The method of any of claims 15 to 20, wherein said planning comprises planning to apply said non-excitatory signal within an atrium of the heart.

23. The method of any of claims 15 to 22, wherein said planning includes selecting power levels and application sites for stimulating cardiac tissue in both the atria and ventricles.

24. The method of any of claims 15 to 23, wherein said identifying comprises selecting a patient with transient AF for treatment.

25. 24. The method of any of claims 15-23, wherein said identifying comprises selecting for treatment patients who have a greater than 20% risk of developing AA in the next year.

26. The method of any of claims 15 to 24, wherein said identifying comprises selecting a patient with chronic AF for treatment.

27. 27. The method of any of claims 15-26, wherein said identifying comprises selecting a patient with NYAH class II or class III heart failure for treatment.

28. 27. The method of any of claims 15-26, wherein said identifying comprises selecting for treatment patients with heart failure who are asymptomatic at rest.

29. 27. The method of any of claims 15-26, wherein said identifying comprises selecting a patient with NYAH Class IV heart failure for treatment.

30. 28. The method of any of claims 15-27, wherein said identifying comprises selecting for treatment patients with at least 30% increased oxygen flow, a potential increase in acceptable cardiac output.

31. 29. The method of any of claims 15-28, wherein said identifying comprises selecting for treatment patients in which at least 50% of their beats are treatable using the device used to apply the treatment.

32. 32. The method of any of claims 15-31, wherein said planning comprises setting device parameters to apply said signal to more than 20,000 treated beats per day averaged over a month.

33. 33. The method of any of claims 15-32, wherein the planning comprises planning to treat using one or more application parameters, the one or more application parameters comprising which leads of a number of leads to use.

34. 34. The method of any of claims 15 to 33, wherein said planning comprises planning with the goal of improving VO2max in said patient.

35. 35. The method of any of claims 15-34, wherein said planning comprises planning with the goal of reducing episodes of AF in said patient.

36. 36. The method of any of claims 15 to 35, wherein said planning comprises programming the device to apply said signal also at beats and times when the signal is excitable for the atria.

37. 37. The method of any of claims 15 to 36, wherein said planning comprises programming a device to apply said signal during a portion of said ventricular refractory period that is sufficiently slow so that said refractory period is prolonged.

38. 37. The method of any of claims 15 to 36, wherein said planning comprises programming the device to also apply the signal during a time between 40 and 100 ms from the local excitation time.

39. 1. A method of treating a patient, comprising: (a) identifying a patient as having a cardiac dysfunction including atrial arrhythmia or reduced cardiac output and an additional cardiac dysfunction; (b) in response to said identifying, planning a treatment schedule for the patient with an implantable device that generates a non-excitatory electrical signal that, when applied to ventricular tissue, ameliorates heart failure in the human patient, wherein said applying ameliorates both of said dysfunctions.

40. 40. The method of claim 39, wherein said improving comprises improving two dysfunctional chambers using the same applied signal.

41. 10. A method of treating a patient, comprising planning to apply a C2MS signal to a patient having an atrial arrhythmia or reduced cardiac output when the atrial arrhythmia is active.

42. A method of treating a patient, comprising administering a C2MS signal to a patient having a possible atrial arrhythmia, thereby planning to reduce the probability of the patient developing an atrial arrhythmia by at least 10% in the next hour.

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