Regulation of cardiac contractility in patients with atrial arrhythmias

Abstract

A cardiac therapy device includes a stimulation circuit configured to generate a non-excitatory electrical signal that improves a condition of heart failure in a human patient when the non-excitatory electrical signal is applied to ventricular tissue during a ventricular refractory period of the ventricular tissue; an 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.

Description

Technical Field

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

[0002] This application is part of a joint filing of PCT applications filed on the same day by the same applicants: Agent File No. 85056, entitled "Increasing Peak VO2 in Patients with HF Using Cardiac Contractile Modulation (CCM) Stimulation", David Pruch et al.; Agent File No. 85069, entitled "Methods for Planning and Implementing Cardiac Electrical Stimulation", David Pruch et al.; and Agent File No. 85070, entitled "Respiratory-Related Cardiac Contractile Modulation", David Pruch et al.

[0003] The contents of the above applications are all incorporated herein by reference. Background Technology

[0004] In some embodiments of the invention, the invention relates to providing electrical stimulation, such as non-excitatory stimulation, such as cardiac contractility modulation stimulation (C2MS), to patients with atrial arrhythmias (AA), such as atrial fibrillation (AF), to increase cardiac output in order to treat and / or prevent AF, AF symptoms, and / or other diseases.

[0005] US Patent 9713723B2 describes using a refractory period signal from the right ventricle to influence the left ventricle, “providing a method for use in a human subject. The method includes accessing the heart site via the subject's vena cava and alleviating the subject's heart failure by applying a refractory period signal that influences the left ventricle of the subject's heart during the refractory period of the heart site. Other embodiments are also described.”

[0006] US Patent 6480737 teaches a method for detecting arrhythmias using ventricular leads, disclosing "an apparatus for applying a non-excitatory signal to the heart, comprising: at least one electrode, a power source, a wide-field ECG sensor receiving a wide-field ECG signal including contributions from a non-localized portion of the heart, a controller for selectively energizing the at least one electrode using the non-excitatory signal from the power source, and a safety filter suppressing the energization in response to the wide-field ECG signal" and "In an exemplary embodiment of the invention, the wide-field ECG sensor covers a portion of the right ventricle and a portion of the left ventricle (e.g., near the apex), and the timing portion for matching is between a right ventricular sensing event and a most recent reasonable left ventricular ETC application event. When the right ventricle is paced, tracking may begin slightly after the pacing event. Optionally, the template also includes portions from after the application of the ETC signal."

[0007] US Patent 9713723B2, in claim 1, discusses the use of a cardiac systolic modulation stimulation therapy to reduce the incidence of arrhythmias (obviously ventricular arrhythmias): "A method of applying a plurality of cardiac systolic modulation electrical signals to a heart, the method comprising: calculating an arrhythmia prevalence level by counting a plurality of arrhythmia episodes in the heart during a given period; comparing the arrhythmia prevalence level with a value representing an arrhythmia prevalence level of a to be treated arrhythmia; and, in response to the result of the comparison, applying one or more of the plurality of cardiac systolic modulation electrical signals to the heart to reduce the arrhythmia prevalence level, wherein the cardiac systolic modulation electrical signals are capable of increasing the contractility of cardiac cardiomyocytes."

[0008] US Patent 8977353B2 discusses short-term and long-term effects in claim 1: “A method of altering the behavior of cardiac tissue at a first location by applying an electric field to cardiac tissue at a second location, comprising: determining a desired non-acute modification of protein activity and / or gene activity in cardiac tissue at the first location; selecting electric field parameters including one or more of a second location, a duration of application of the field, and a power level of the field, the field having an intended effect of producing the desired non-acute modification of protein activity and / or gene activity at the first location, but without causing a significant acute effect at the first location; applying an electric field having the selected parameters to cardiac tissue at the second location to produce the selected non-acute modification at the first location, wherein the first location is remote from the second location so that no significant acute effect occurs at the first location.”

[0009] In 2019, the FDA approved the use of ImpulseDynamics, a pulse dynamics device that utilizes cardiac systolic modulation stimulation. In the context of equipment, permanent or persistent long-term atrial fibrillation or flutter is listed as a contraindication and precaution. AF is considered a contraindication for the application of cardiac contractile modulation stimulation.

[0010] The paper “Cardiosystolic regulation: a mechanism of action in heart failure with reduced ejection fraction and above” by C. Tschope et al., European Journal of Heart Failure (2018), doi:10.1002 / ejhf.1349, describes various possible mechanisms of cardiac systolic regulation stimulation.

[0011] U.S. Patent No. 4,554,922 clearly demonstrates that an electrical signal applied during the relative refractory period prolongs the refractory period and reduces pro-arrhythmic activity in tissues.

[0012] The full contents of the aforementioned documents are incorporated herein by reference. Summary of the Invention

[0013] The following is a non-exclusive list of some examples including embodiments of the present invention. Unless otherwise expressly listed below, the present invention also includes embodiments that include fewer than all features in one example and embodiments that use features from multiple examples.

[0014] Example 1. A cardiac treatment device comprising:

[0015] A stimulation circuit configured to generate a non-excitatory electrical signal that, when applied to ventricular tissue during a ventricular refractory period, improves the condition of heart failure in human patients.

[0016] Atrial arrhythmia detection circuit; and

[0017] The determination circuit controls the stimulation circuit to transmit the signal when the atrial arrhythmia detection circuit detects an atrial arrhythmia.

[0018] Example 2. The apparatus according to Example 1, wherein the determination circuit modifies at least one parameter of the signal in response to the detection of the atrial arrhythmia.

[0019] Example 3. The apparatus according to Example 2, wherein the modification includes increasing the tissue extent stimulated by the signal.

[0020] Example 4. An apparatus according to any one of Examples 1-3, wherein the determination circuit is configured to prevent the transmission when a ventricular arrhythmia is detected.

[0021] Example 5. An apparatus according to any one of Examples 1-4, wherein the determination circuit is configured to allow the transmission when a supraventricular arrhythmia is detected.

[0022] Example 6. An apparatus according to any one of Examples 1-5, wherein the apparatus includes a memory having an indication of a dose of the signal to be applied and an indication of a duration of application, and wherein the determination circuit is configured to modify an actual duration of signal application based on an actual delivery of the signal.

[0023] Example 7. An apparatus according to any one of Examples 1-6, wherein the apparatus includes a recorder configured to record the effect of the applied force on the detected atrial arrhythmia.

[0024] Example 8. A device according to any one of Examples 1-7, wherein the device is configured to also apply the signal during a non-responsive time in one atrium of the patient.

[0025] Example 9. A device according to any one of Examples 1-8, wherein the device does not have an atrial lead.

[0026] Example 10. A device according to any one of Examples 1-8, wherein the device does not have a ventricular stimulation lead.

[0027] Example 11. An apparatus according to any one of Examples 1-10, wherein the apparatus includes a pacing circuit, and wherein the determination circuit is programmable to selectively and preferably apply a non-excitatory signal rather than an increase in pacing in the event of increased cardiac demand.

[0028] Example 12. The device according to Example 11, wherein the selectivity is preferably responsive to a cardiac parameter sensed by the device.

[0029] Example 13. An apparatus according to any one of Examples 1-12, wherein the determination circuit defines a control window of several beats in which no signal is applied after an arrhythmia is detected, and wherein the window is one or zero.

[0030] Example 14. An apparatus according to any one of Examples 1-13, wherein the atrial arrhythmia detection circuit detects atrial arrhythmia from signals measured from one or more ventricular leads.

[0031] Example 15. A method for planning the treatment of a patient, comprising:

[0032] (a) Identify a patient who has an atrial arrhythmia or is at risk of developing an atrial arrhythmia; and

[0033] (b) In response to the identification, a treatment schedule is planned for the patient using an implantable device that generates a non-excitatory electrical signal, which improves the patient’s heart failure condition when the non-excitatory electrical signal is applied to the ventricular tissue during a ventricular refractory period.

[0034] Example 16. The method according to Example 15, wherein the planning includes programming the device to also apply the signal during atrial arrhythmias.

[0035] Example 17. The method according to Example 15 includes selecting the patient and executing the plan to improve the symptoms of the atrial arrhythmia through the treatment.

[0036] Example 18. The method according to Example 16 or Example 17, wherein the improvement includes preventing abnormal ventricular excitation caused by the atrial arrhythmia.

[0037] Example 19. The method according to any one of Examples 16-18, wherein the improvement includes reducing the atrial arrhythmia.

[0038] Example 20. The method according to any one of Examples 15-19, wherein the atrial arrhythmia includes paroxysmal atrial fibrillation (AF).

[0039] Example 21. The method of any one of Examples 15-20, wherein the planning includes planning to apply the non-excitatory signal within 20 mm of a ventricular septum.

[0040] Example 22. The method of any one of Examples 15-20, wherein the planning includes planning to apply the non-excitatory signal in one atrium of the heart.

[0041] Example 23. The method according to any one of Examples 15-22, wherein the planning includes selecting a power level and an application location to stimulate cardiac tissue in an atrium and a ventricle.

[0042] Example 24. The method according to any one of Examples 15-23, wherein the identification includes selecting a patient with paroxysmal atrial fibrillation for treatment.

[0043] Example 25. The method according to any one of Examples 15-23, wherein the identification includes selecting patients who have a greater than 20% risk of developing atrial arrhythmias in the coming year for treatment.

[0044] Example 26. The method according to any one of Examples 15-24, wherein the identification includes selecting patients with chronic atrial fibrillation for treatment.

[0045] Example 27. The method according to any one of Examples 15-26, wherein the identification includes selecting patients with heart failure of New York Heart Association (NYHA) class II or III for treatment.

[0046] Example 28. The method of any one of Examples 15-26, wherein the identification includes selecting patients with rest-asymptomatic heart failure for treatment.

[0047] Example 29. The method according to any one of Examples 15-26, wherein the identification includes selecting patients with heart failure of New York Heart Association class IV for treatment.

[0048] Example 30. The method according to any one of Examples 15-27, wherein the identification includes selecting patients who have the potential to increase oxygen flow rate with oxygen content by at least 30% when cardiac output permits for treatment.

[0049] Example 31. The method according to any one of Examples 15-28, wherein the identification includes selecting at least 50% of patients whose pulsations can be treated using a device for applying treatment.

[0050] Example 32. The method according to any one of Examples 15-31, wherein the planning includes setting multiple device parameters to apply the signal to the pulses of a process that averages more than 20,000 times per day over a month.

[0051] Example 33. The method according to any one of Examples 15-32, wherein the planning includes planning to use one or more application parameters for treatment, and wherein the one or more application parameters include which of the several leads to be used.

[0052] Example 34. The method of any one of Examples 15-33, wherein the planning includes a plan aimed at improving the patient's maximum oxygen uptake (VO2 max).

[0053] Example 35. The method of any one of Examples 15-34, wherein the planning includes a plan aimed at reducing the incidence of atrial fibrillation in the patient.

[0054] Example 36. The method according to any one of Examples 15-35, wherein the planning includes programming the device so that the signal can be applied even when the beating and the signal excites an atrium.

[0055] Example 37. The method according to any one of Examples 15-36, wherein the planning includes programming the device to apply the signal during a sufficiently late portion of the ventricular refractory period, such that the refractory period is prolonged.

[0056] Example 38. The method according to any one of Examples 15-36, wherein the planning includes programming the device to also apply the signal for a period of time starting from a local excitation time, said period of time being between 40 and 100 milliseconds.

[0057] Example 39. A method of treating a patient, comprising:

[0058] (a) Identify a patient with one cardiac dysfunction and an additional cardiac dysfunction, said cardiac dysfunction including an atrial arrhythmia or a reduced cardiac output; and

[0059] (b) In response to the identification, a treatment schedule is planned for the patient using an implantable device that generates a non-excitatory electrical signal, which improves heart failure in the human patient when the non-excitatory electrical signal is applied to ventricular tissue, and the application improves both functional impairments.

[0060] Example 40. According to the method of Example 39, the improvement includes improving the two dysfunctional chambers using the same applied signal.

[0061] It is understood that, in some embodiments, treatment is applied according to the plan.

[0062] Example 41. A method of treating a patient, comprising: planning to apply a cardiac systolic modulation stimulation (C2MS) signal to a patient suffering from an atrial arrhythmia and reduced cardiac output when the atrial arrhythmia is active.

[0063] Example 42. A method of treating a patient, comprising: planning to apply a cardiac contractile modulation stimulation signal to a patient with the potential for atrial arrhythmia, thereby reducing the probability of atrial arrhythmia occurring in the next hour by at least 10%.

[0064] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. While similar or equivalent methods and materials to those described herein may be used in the implementation or testing of embodiments of the invention, exemplary methods and / or materials are also described below. In case of conflict, the patent specification, including definitions, shall prevail. Furthermore, the materials, methods, and examples described are for illustrative purposes only and are not intended to be limiting.

[0065] As those skilled in the art will understand, some embodiments of the present invention can be embodied as systems, methods, or calculator program products. Therefore, some embodiments of the present invention may take the form of entirely hardware embodiments, entirely software embodiments (including firmware, resident software, microcode, etc.), or embodiments combining software and hardware aspects, which are generally referred to herein as “circuits,” “modules,” or “systems.” Furthermore, some embodiments of the present invention may take the form of calculator program products containing calculator-readable program code on one or more calculator-readable media. Implementation of the methods and / or systems of some embodiments of the present invention may involve manually, automatically, or in combination thereof, performing and / or completing selected tasks. Furthermore, actual instruments and devices according to some embodiments of the methods and / or systems of the present invention can implement multiple selected tasks through hardware, software, or firmware and / or combinations thereof (e.g., using an operating system).

[0066] For example, according to some embodiments of the invention, the hardware for performing a selected task can be implemented as a chip or circuit. As software, the selected task according to some embodiments of the invention can be implemented as a plurality of software instructions executed by a calculator using any suitable operating system. In exemplary embodiments of the invention, one or more tasks according to some exemplary embodiments of the methods and / or systems described herein are performed by a data processor, such as a computing platform for executing a plurality of instructions. Optionally, the data processor includes volatile and / or non-volatile memory for storing instructions and / or data, such as a disk and / or removable media. Optionally, a network connection is also provided. A display and / or a user input device such as a keyboard or mouse are also provided.

[0067] Any combination of one or more calculator-readable media can be used in some embodiments of the present invention. A calculator-readable medium can be a calculator-readable signal medium or a calculator-readable storage medium. A calculator-readable storage medium can be, for example, but not limited to, electronic, magnetic, optical, electromagnetic, infrared, or semiconductor systems, devices, or apparatuses, or any suitable combination thereof. Examples of specific calculator-readable storage media (a non-exhaustive list) will include the following: an electrical connection having one or more wires, a portable calculator disk, a hard disk, random access memory (RAM), read-only memory (ROM), erasable programmable read-only memory (EPROM or flash memory), optical fiber, portable optical disc read-only memory (CD-ROM), optical storage devices, magnetic storage devices, or any suitable combination thereof. In the context of this document, a calculator-readable storage medium can be any tangible medium that can contain or store a program used or connected to an instruction execution system, apparatus, or device.

[0068] Calculator-readable signal media may include propagated data signals, such as calculator-readable program code in baseband or as part of a carrier wave. Such propagated signals may take any of a variety of forms, including but not limited to electromagnetic, optical, or any suitable combination thereof. Calculator-readable signal media may be any calculator-readable medium that is not a calculator-readable storage medium but can communicate, propagate, or transmit programs for use by or associated with an instruction execution system, apparatus, or device.

[0069] The program code embodied on the calculator's readable medium and / or the data used therefrom can be transmitted using any suitable medium, including but not limited to wireless, wired, cable, radio frequency, or any suitable combination thereof.

[0070] The calculator program code used to perform operations according to some embodiments of the present invention can be written in any combination of one or more programming languages, including object-oriented programming languages ​​such as Java, Smalltalk, C++, etc., and conventional programming languages ​​such as the "C" programming language or similar programming languages. The program code can execute entirely on the user's calculator, partially on the user's calculator as a standalone software package, partially on the user's calculator, partially on a remote calculator, or entirely on a remote calculator or server. In the latter case, the remote calculator can be connected to the user's calculator via any type of network including a local area network (LAN) or a wide area network (WAN), or it can be connected to an external calculator (e.g., via the Internet provided by an Internet service provider).

[0071] Some embodiments of the present invention will now be described with reference to flowchart illustrations and / or block diagrams of methods, apparatus (systems), and calculator program products according to embodiments of the present invention. It should 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 calculator program instructions. These calculator program instructions can be provided to the processor of a general-purpose calculator, special-purpose calculator, or other programmable data processing device to generate a machine that, when executed by the processor of the calculator or other programmable data processing device, creates the functions / actions specified in the flowchart illustrations and / or block diagrams for implementation.

[0072] These calculator program instructions can also be stored in a calculator-readable medium that can instruct a calculator, other programmable data processing device or other device to operate in a particular manner, such that the instructions stored in the calculator-readable medium produce an article of art including instructions that implement the functions / actions specified in the flowchart and / or block diagram.

[0073] Calculator program instructions may also be loaded onto a calculator, other programmable data processing device or other device to cause a series of operational steps to be performed on the calculator, other programmable device or other device, thereby producing a process implemented by the calculator, such that the instructions executed on the calculator or other programmable device provide a process for implementing the functions / actions specified in the flowchart and / or block diagram.

[0074] Some of the methods described in this article are typically designed for use with calculators only and may be infeasible or impractical for human experts to perform purely manually. Human experts who wish to perform similar tasks manually (e.g., controlling cardiac stimulation devices and / or processing multiple cardiac signals in real time) may use entirely different approaches, such as leveraging expert knowledge and / or the pattern recognition capabilities of the human brain, which would be more efficient than manually executing the steps of the methods described in this article; however, they may not work within the required timeframe. Attached Figure Description

[0075] Some embodiments of the invention are described herein by way of example only, with reference to the accompanying drawings. Referring now specifically to the drawings, it is emphasized that the details shown are by way of example and for the purpose of illustrative discussion of embodiments of the invention. In this regard, the description taken in conjunction with the drawings will be apparent to those skilled in the art to how embodiments of the invention can be practiced.

[0076] In the attached diagram:

[0077] Figure 1 This is a schematic diagram of the heart, illustrating various tissue and electrode / lead locations according to some embodiments of the present invention;

[0078] Figure 2 This is a schematic block diagram of a cardiac treatment device according to some embodiments of the present invention;

[0079] Figure 3 This is a schematic diagram of the heart, illustrating the spatial extent of a non-excitatory field according to some embodiments of the present invention;

[0080] Figure 4 This is a time plot showing a non-excitatory field relative to the timing of various cardiac events according to some embodiments of the present invention;

[0081] Figure 5 This is a graph showing the results of a study on the improvement of VO2 parameters in patients with atrial fibrillation (AF) by cardiac contractile modulation stimulation according to some embodiments of the present invention;

[0082] Figure 6 This is a schematic diagram of the heart, illustrating the spatial extent of a non-excitatory field from the right atrium according to some embodiments of the present invention;

[0083] Figure 7 This is a schematic diagram of the heart, illustrating the spatial extent of a non-excitatory field from the left atrium according to some embodiments of the present invention;

[0084] Figure 8 This is a flowchart of a method for selecting and treating patients with atrial arrhythmia according to some embodiments of the present invention;

[0085] Figure 9 This is a flowchart of a method for patient selection and treatment of patients with heart failure and additional cardiac dysfunction according to some embodiments of the present invention; and

[0086] Figure 10 This is an operation flowchart of a cardiac controller according to some embodiments of the present invention. Detailed Implementation

[0087] In some embodiments of the invention, the invention relates to providing electrical stimulation, such as non-excitatory stimulation, such as cardiac contractile modulation therapy, to patients with atrial arrhythmias (AA) such as atrial fibrillation (AF) to increase cardiac output in order to treat and / or prevent AF, AF symptoms, and / or other conditions.

[0088] A broad aspect of some embodiments of the present invention relates to the planning and / or treatment of patients with atrial arrhythmias. While atrial arrhythmias may previously have been considered an adverse indication for the application of cardiac systolic modulation stimulation (CMS), the inventors have found that CMS can not only be safely applied to patients with atrial fibrillation, but this treatment also appears to be useful. In some embodiments of the invention, patients are generally treated despite a diagnosis of atrial arrhythmia. Optionally or additionally, patients are treated during atrial arrhythmia events. In some embodiments, such atrial arrhythmia events are detected and not stopped (or, in some embodiments, treatment is triggered and / or otherwise modified). In some embodiments of the invention, such atrial arrhythmia events are not detected, or are detected and ignored during treatment application.

[0089] 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 different therapeutic effects having the same signal. Optionally, one or more signal application parameters are optimized for such multiple desired effects. In some embodiments, such effects include increased cardiac contractility and improved arrhythmia conditions.

[0090] One aspect of some embodiments of the present invention relates to treating patients with atrial arrhythmias (and / or generating treatment plans for such patients) with cardiac contractility modulation stimulation (C2MS) signaling, for example, by applying a non-excitatory signal to the heart during the relative and / or absolute refractory period of the heart. In some embodiments of the invention, the signal is selected to increase ventricular contractility when the electric field of the signal stimulates ventricular tissues such as the left ventricle, right ventricle, and / or ventricular septum. In some embodiments of the invention, contractility modulation is provided by phosphorylation of phosphoproteins induced by the signal. In some embodiments of the invention, contractility modulation is caused by changes in protein transcription and / or mRNA production induced by the signal, optionally in the form of reversal of fetal genetic programs. Unless otherwise stated, the term “cardiac contractility modulation stimulation (C2MS)” is used herein as a generic placeholder for all such signals. It should be noted that in some embodiments, the cardiac contractility modulation stimulation signal may be excitatory to tissues other than the tissue to which it is applied. Various mechanisms by which cardiac systolic regulation stimulation signals may function are described, such as “C. Tschope et al., “Cardiosystolic regulation: Mechanism of action in heart failure with reduced and excessive ejection fraction,” European Journal of Heart Failure (2018), doi:10.1002 / ejhf.1349, the contents of which are incorporated herein by reference and may be used to guide the selection of signal application parameters in order to utilize and / or comply with one or more of these mechanisms.

[0091] Note that patients without atrial arrhythmias may also be selected for treatment and / or treatment may be chosen where the patient’s atrial arrhythmia status or risk can be optionally ignored.

[0092] In some embodiments of the invention, treatment is selected based on whether the patient has comorbidities of atrial arrhythmia, such as atrial flutter, paroxysmal atrial fibrillation, episodic atrial fibrillation and / or chronic atrial fibrillation, atrial tachycardia (AT), and / or based on the anticipated development of such arrhythmia. While some of the examples below focus on atrial fibrillation, it is worth noting that they can also be effectively applied to other atrial arrhythmias.

[0093] In some embodiments of the invention, patients are selected for treatment without a specific treatment goal. In other cases, such treatment goals are selected, for example, based on expected outcomes (e.g., an improvement of at least 1 in the New York Heart Association functional grade in more than 50%, 60%, 70%, 80%, or intermediate percentages of cases).

[0094] In some embodiments of the invention, patients are selected based on the expectation (and / or potential) of increasing their New York Heart Association grade by at least 0.5, 0.75, 1, 1.5, or an intermediate or greater number of grades. In some embodiments of the invention, patients with grade III and / or IV heart failure are selected.

[0095] In some embodiments of the invention, patients are selected based on the expectation (and / or potential) of increasing their peak oxygen uptake by, for example, 5-300%, or, for example, 10-50%. In some embodiments of the invention, the expected increase in peak oxygen uptake is 1 to 10 ml O2 / min / kg, for example, 3 to 7 ml O2 / min / kg. Optionally, patients with an existing peak oxygen uptake between 5 and 25 ml O2 / min / kg, for example, between 9 and 20 ml O2 / min / kg, are selected. Optionally, this excludes some patients, for example, those with no respiratory reserve or reduced respiratory reserve (e.g., no ability to increase lung capacity or reduced ability to increase lung capacity).

[0096] In some embodiments of the invention, the dosage of cardiac systolic modulation stimulation (CMP) is selected based on the desired improvement in peak oxygen uptake. For example, reducing the patient's dosage (fewer beats per day, fewer hours per day, and / or less direct tissue stimulation) requires a smaller improvement in peak oxygen uptake, or weighs the problems associated with CMP treatment against the increased clinical health provided by CMP. In one example, less CMP is applied if the patient has a lower potential improvement with CMP, for example, if lung reserve is low. In some embodiments of the invention, it is assumed that patients with higher peak oxygen uptake have greater lung reserve.

[0097] In certain embodiments of the invention, cardiac contractility modulation stimulation is applied without the use of atrial leads, for example, 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 no ventricular activity is expected and / or when the expected atrial activation window is encountered, for example, based on a time-based cardiac model, such as the expected delay range between atrial and ventricular activation and / or the expected refractory window of the ventricle). While this may reduce accuracy and sensitivity, in some embodiments of the invention, what may be desired is an indication that an atrial arrhythmia is in progress. In some embodiments, such analysis may include multiple heartbeats, so while an atrial arrhythmia can be detected, detection may require a time longer than one heartbeat. In some embodiments, one or all leads are in the atrium (e.g., as described below), and the stimulation timing from such stimulation leads uses sensing from the atrium (e.g., atrial activation plus an expected and / or programmable AV delay).

[0098] In some embodiments of the invention, cardiac systolic modulation stimulation is applied using logic that excludes only some or all ventricular arrhythmic beats from such applications, but does not exclude all supraventricular arrhythmic beats from the application of cardiac systolic modulation stimulation. A potential advantage is that effective cardiac systolic modulation stimulation therapy can be applied even if most or all beats have atrial arrhythmias.

[0099] One aspect of some embodiments of the present invention relates to reducing the prevalence of atrial arrhythmias, such as reducing the incidence and / or duration of atrial fibrillation episodes, optionally reducing the severity of existing atrial fibrillation symptoms and / or preventing the occurrence and / or worsening and / or becoming more functional.

[0100] In some embodiments of the invention, the application of the cardiac contractility modulation stimulation signal uses parameters suitable for reaching the atria and affecting the conduction characteristics therein. Atrial fibrillation can be reduced at its source, in at least a portion of the atrium (e.g., left and / or right), and optionally conducted to the remainder of the heart.

[0101] In some embodiments of the present invention, cardiac contractility modulation stimulation signals are applied to the atria via leads in the atria.

[0102] In some embodiments of the invention, the application of the cardiac contractility modulation stimulation signal uses parameters suitable for reaching the AV node and / or ventricular tissues that transmit the excitation signal to the remainder of the ventricle, such as one or more of the His bundle, left and / or right ventricular bundles, and / or Purkinje fibers. Optionally, this reduces the functional symptoms of atrial fibrillation because the additional atrial excitation does not propagate into and / or to the ventricles, for example, by increasing the refractory period (relative and / or absolute) in such tissues.

[0103] In some embodiments of the invention, one or more application parameters, such as amplitude, delay from local excitation and / or electrode location, can be modified as needed to achieve the desired effect (e.g., effect on the atria).

[0104] In some embodiments of the invention, application is selected based on the desired effect of reducing the probability of atrial arrhythmias by at least 10%, 30%, 50%, 70%, 80%, or a greater percentage in a series of smaller, intermediate, or larger number of beats, including the next 10 beats, the next 50 beats, the next 100 beats, the next 300 beats, the next 1200 beats, the next 3600 beats, the next 5000 beats, or smaller, intermediate, or larger number of beats. Different desired effects can be selected (e.g., and / or monitored), such as the underlying patient disease severity, patient stability, and / or the amount of additional cardiac contractility modulation stimulation required, while taking into account the side effects of such cardiac contractility modulation stimulation (e.g., pain) or available battery power. For example, if pain is a minor problem, a more aggressive reduction may be required.

[0105] In some embodiments of the invention, the estimated probability of prevention is estimated based on a table compiling information from multiple studies. Optionally or additionally, the information is personalized; for example, the implanted device (or an external processor receiving the logs) tracks the duration and / or magnitude of the effect of cardiac contractile modulation stimulation signals on subsequent atrial fibrillation episodes. This data can be used, for example, to program the device, to update the table, and / or to set automatic parameters of the device, such as parameters weighing the power consumed due to the application of cardiac contractile modulation stimulation against the effectiveness of reducing atrial arrhythmias. It should be noted that an overall cure can be expected in some patients, and as treatment progresses, a decrease in the overall prevalence and / or duration and / or severity of such patients can be expected. Optionally, this is used to update (optionally automatically) the parameter settings of the implanted therapeutic device, for example, reducing the amount and / or duration and / or modifying the application location and / or other parameters of the cardiac contractile modulation stimulation.

[0106] One aspect of some embodiments of the invention relates to applying cardiac contractile modulation stimulation to the ventricles using electrodes located in the atria. In some embodiments of the invention, the stimulation is applied between an electrode located within the atria and an electrode located outside the atria, such as within the ventricles. In some embodiments of the invention, bipolar electrodes are used for the application to the atria (e.g., left and / or right). It is noteworthy that the fact that atrial arrhythmias typically do not propagate fatally to the ventricles may reduce the risk of fatal arrhythmias (e.g., because the AV junction filtering frequency and / or the ventricular response rate is only as fast as its refractory rate), so even if such application results in an atrial arrhythmia, it will not be fatal. Further note that in patients with atrial fibrillation, atrial arrhythmias are already present, so a cardiac contractile modulation stimulation signal applied during the non-refractory period of the atria is not expected to lead to further dysfunctional arrhythmias. In some cases, such a signal is not expected to increase the ventricular rate.

[0107] In some embodiments of the invention, the signal can be applied at a time that is not the refractory period (or absolute refractory period) in the atrium but is the absolute refractory period in the ventricle.

[0108] In some embodiments of the invention, such atrial electrodes are used to apply other therapies, such as antiarrhythmic pacing of the atrium.

[0109] One aspect of some embodiments of the invention relates to applying cardiac contractile modulation stimulation with parameters suitable for stopping an ongoing atrial fibrillation episode. In some embodiments of the invention, the cardiac contractile modulation stimulation parameters are set such that they have a cardioversion effect, for example, by forcing important parts of the atrium into an inappropriate state and / or activating these parts. In some embodiments of the invention, after such treatment, for example, once it is assumed that the atrial fibrillation episode has ended and / or if atrial fibrillation is detected again, the parameters are changed (e.g., amplitude is reduced). In some embodiments of the invention, the treatment device tracks which signals appear to be more effective for atrial fibrillation for the particular patient and / or for different atrial arrhythmia events, so that these signals can be automatically applied when needed.

[0110] A potential benefit of using cardiac systolic modulation stimulation during and / or in patients with atrial fibrillation is increased cardiac output to at least partially compensate for the reduced cardiac output due to atrial fibrillation. For example, increased contractility may result in a smaller left ventricular end-systolic volume, which allows for better filling from the left atrium, potentially at least partially overcoming the loss of atrial contraction during atrial fibrillation. This potential benefit may be selectively realized even if cardiac systolic modulation stimulation does not affect current or future atrial arrhythmia episodes.

[0111] In some embodiments of the invention, the signal amplitude used to treat an ongoing episode of atrial arrhythmia is allowed to be greater than (e.g., between 10% and 60%, between 60% and 150%, between 150% and 300%, between 300% and 500%, or higher or moderate percentages) the amplitude of chronic medication. For example, if a patient perceives the increased treatment as transient and / or as being used to treat an acute medical condition, this may be because pain or other side effects are less important to the patient.

[0112] One aspect of some embodiments of the invention relates to the relationship between the number of stimulations and improvements in peak oxygen uptake, which may optionally lead to improvements in heart failure symptoms. In some embodiments of the invention, at least for patients with atrial fibrillation, increasing the number of treatment beats per month increases the health benefits for the patient. In some embodiments of the invention, the number of treated beats (per day) is increased to more than 15,000, for example, more than 17,000, for example, more than 20,000, optionally up to 25,000, optionally up to 35,000 and / or more and / or an intermediate number.

[0113] According to some embodiments, it has been noted that the effect of increased pulsation from treatment can be monotonous, at least within a certain range, and / or can be known in other ways, and this can be used to weigh the amount of treatment (and therefore the effect) against potential side effects and / or power consumption.

[0114] One aspect of some embodiments of the present invention relates 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 cardiac contractile modulation stimulation signal, optionally applied in a single chamber.

[0115] In some embodiments of the invention, one condition is heart failure, and another condition is one of atrial arrhythmia, regurgitation, and HOCM.

[0116] In some embodiments of the invention, the two conditions are treated in different cardiac chambers, such as an atrium and a ventricle, with non-excitatory signals traveling from one chamber to the other.

[0117] In some embodiments of the invention, one or more application parameters of the signal application are optimized to provide a better trade-off between the two diseases being treated. In one example, the application time, power level, and / or the location of the cardiac contractility modulation stimulation signal (e.g., within a chamber and / or which chamber or other location) can be modified such that even if contractility improvement is reduced, the electrochemical stimulation hits the desired tissue (e.g., atrium, atrioventricular node, conduction fibers, healthy tissue, diseased tissue, sensitive tissue) at the desired time. In one example, the cardiac contractility modulation stimulation signal is applied earlier to ensure it reaches the atrium at the correct time, for example, for cardiac version or atrial fibrillation prevention. In another example, a suboptimal electrode location for cardiac output is selected to ensure adequate atrial coverage.

[0118] In some embodiments of the invention, other conditions being treated may be structural heart disease and / or implants. For example, the location of cardiac contractility modulation stimulation application can be optimized to improve and / or modify the artificial heart valve anchorage, thereby reducing regurgitation (in mitral valve implants, such as clips or valves, or even in the absence of an implant). Such a valve may be, for example, the mitral valve, pulmonary valve, aortic valve, and / or tricuspid valve.

[0119] In an example of reducing regurgitation, cardiac systolic regulation stimulation is optionally applied in a manner that lowers the heart rate. For example, if regurgitation is rate-dependent, using cardiac systolic regulation stimulation to increase cardiac output rather than increasing heart rate may reduce the occurrence of regurgitation. This type of logic can be used, for example, if a patient requires pacing. For example, cardiac systolic regulation stimulation can be chosen instead of a partial or complete increase in pacing rate. In another example, a sensor in the atrium or ventricle can be used to detect regurgitation and trigger the application of cardiac systolic regulation stimulation. In yet another example, such a sensor (e.g., a pressure sensor) can be used to detect increased demand and provide cardiac systolic regulation stimulation so that the heart will not need to increase its own heart rate to meet that demand. In yet another example, a higher heart rate may be associated with an increased risk of atrial arrhythmias and should therefore be avoided (e.g., by using an appropriate threshold or other logic programmed into the device). In yet another example, if an atrial arrhythmia is detected (e.g., using an electrical activity sensor), the heart rate is reduced.

[0120] Note that while cardiac contractility modulation stimulation signals are described here and in other embodiments, it is not necessary to provide abrupt changes in contractility. Instead, unless otherwise stated, cardiac contractility modulation stimulation is used to represent non-excitatory signals that result in an immediate and / or eventual increase in cardiac output and / or changes in fetal genetic programming.

[0121] One aspect of some embodiments of the invention relates to shortening the prohibition period after suspected arrhythmia when applying cardiac systolic modulation stimulation. In one example, a suspected ventricular arrhythmia beat results in a control window with only one or optionally no beats. Potentially, this allows the next cardiac systolic modulation stimulation to act on tissue still recovering from the arrhythmia beat. Possibly, this reduces the proarrhythmic tendency of the arrhythmia beat and / or otherwise improves function and / or potential healing of tissue with heart failure or other dysfunctions. In some embodiments of the invention, the length of the control window depends on the number of arrhythmia beats (and / or the duration of the ventricular arrhythmia episode). In some embodiments of the invention, there is no window prohibiting atrial arrhythmia beats, even if there is a window for ventricular arrhythmia beats. In some embodiments of the invention, cardiac systolic modulation stimulation signals are applied even during atrial excitation.

[0122] In some embodiments of the invention, even in the absence of atrial arrhythmias and / or when there are no active atrial arrhythmias, the control window during atrial excitation time is shortened and / or cardiac contractile modulation stimulation is applied.

[0123] In some embodiments of the invention, a relatively low heart rate threshold is used, for example, between approximately 90 or 100 and 110 BPM. Potentially, this can prevent energy from being wasted at high heart rates (because they have more beats in the same time window and an exemplary treatment is 7 hours per day) and / or direct more applied energy to the body at a low heart rate at rest.

[0124] In other embodiments, higher heart rate thresholds, such as 120, 130, 140, or moderate heart rates, may be used.

[0125] Note that heart rate can be approximated and / or replaced by a threshold, and some type of fuzzy decision or hysteresis decision can be used to determine prohibition. For example, a signal might be prohibited with a probability dependent on heart rate. In another example, the threshold might be higher or lower than a threshold that stops treatment as heart rate increases, once the heart rate drops.

[0126] In some embodiments of the invention, different prohibition windows exist for different heart rates. For example, no arrhythmia control window is applied between approximately 80 and 110 and / or there is a one-beat length control window between 100 and 130 and a two-beat prohibition window between 120 and 160.

[0127] One aspect of some embodiments of the present invention relates to the detection of atrial arrhythmias from ventricular electrodes. In some embodiments of the invention, atrial arrhythmias, such as atrial fibrillation, are detected based on the absence of a P wave, optionally along with an elevated heart rate. In some embodiments of the invention, if the system includes two leads in the ventricle, the two leads together serve as a bipolar ECG sensor. In some embodiments of the invention, the distance between the ventricular leads (if two are used) increases the distance at which electrical activity can be sensed using the leads. Optionally, during the calibration phase, various electrode pairings on the leads and housing are tested, and pairings that better detect P waves (or directly detect atrial arrhythmias) can be selected for detecting atrial fibrillation. Optionally or additionally, each lead is used to detect the absence of a P wave individually. Optionally, a P wave sensing threshold is set for each lead. Optionally, if one or both leads (depending on the required reliability and / or sensitivity of a particular lead) do not detect a P wave, it is termed the absence of a P wave. Optionally, the score of atrial arrhythmia can be calculated based on the number of leads in which P waves were detected, the certainty of detection, the increased heart rate, and / or a comparison with the patient's baseline measurements.

[0128] One aspect of some embodiments of the present invention relates to a planning process for a patient. In some embodiments of the invention, a patient is presented with atrial arrhythmias or at risk of atrial arrhythmias and may have heart failure. Such a patient may optionally be treated with cardiac contractile modulation stimulation, for example, by implanting a treatment device and / or by reprogramming an already implanted device. Treating a patient with electrical stimulation may produce side effects, and a trade-off may need to be made between different outcomes, such as the degree of pain and a reduction in atrial arrhythmias. In some embodiments of the invention, an initial treatment is set and the treatment parameters are changed (and the implanted device is reprogrammed) based on the treatment effect. It is noteworthy that even if the initial treatment plan is perfect, such reprogramming may be necessary, for example due to changes in the patient's physiological state.

[0129] In some embodiments of the invention, caregivers consider a variety of factors (e.g., as described herein), including, for example, the degree of pain, the desired anti-atrial arrhythmic effect, the desired heart failure-related effect, the potential location and leads of the electrodes, and / or the type of existing cardiac arrhythmia (e.g., ventricular arrhythmia) in the patient.

[0130] In some embodiments of the invention, a computer or form is used to determine the initial treatment. For example, the computer may include rules or forms indicating parameters and their expected effects, and caregivers may select or be provided with treatment plans that meet various sets of requirements. Optionally or additionally, caregivers may input such proposed treatment plans and evaluate them via such a computer.

[0131] In some embodiments of the invention, a computer is programmed using a dataset that compares one or more treatment outcomes of one or more treatment plans with one or more parameters of a patient having one or more characteristics. In some embodiments of the invention, machine learning methods are used to analyze such datasets to generate parametric models (or other models) that can be queried to assess the expected range of effects of treatment on the patient or can be used to automatically or semi-automatically search for suggested therapies.

[0132] One aspect of some embodiments of the present invention relates to a planning process for a patient. In some embodiments of the invention, a patient is presented with atrial arrhythmias or at risk of atrial arrhythmias and may have heart failure. Such a patient may optionally be treated with cardiac contractile modulation stimulation, for example, by implanting a treatment device and / or by reprogramming an already implanted device. Treating a patient with electrical stimulation may produce side effects, and a trade-off may need to be made between different outcomes, such as the degree of pain and a reduction in atrial arrhythmias. In some embodiments of the invention, an initial treatment is set and the treatment parameters are changed (and the implanted device is reprogrammed) based on the treatment effect. It is noteworthy that even if the initial treatment plan is perfect, such reprogramming may be necessary, for example due to changes in the patient's physiological state.

[0133] In some embodiments of the invention, caregivers consider a variety of factors (e.g., as described herein), including, for example, the degree of pain, the desired anti-atrial arrhythmic effect, the desired heart failure-related effect, the potential location and leads of the electrodes, and / or the type of existing cardiac arrhythmia (e.g., ventricular arrhythmia) in the patient.

[0134] In some embodiments of the invention, a computer or form is used to determine the initial treatment. For example, the computer may include rules or forms indicating parameters and their expected effects, and caregivers may select or be provided with treatment plans that meet various sets of requirements. Optionally or additionally, caregivers may input such proposed treatment plans and evaluate them via such a computer.

[0135] In some embodiments, if the patient has an implant capable of providing cardiac systolic modulation therapy in addition to any other treatments that the implant can provide, a plan for providing cardiac systolic modulation therapy based on the patient’s cardiac condition and / or the patient’s lung condition is provided.

[0136] In some embodiments, the patient's atrial arrhythmia status and / or other conditions (e.g., pulmonary status) are assessed to determine if cardiac contractility modulation is appropriate to improve such conditions. For example, such improvement might be an increase in peak oxygen uptake. In some embodiments, the patient's pulmonary status is assessed to determine if there are pulmonary limitations. If the patient's pulmonary status allows the patient to benefit from an improvement in peak oxygen uptake, myocardial contractility modulation therapy is planned, including additional cardiac treatment or cardiac contractility modulation therapy alone. Such additional treatment may include one or more of, for example, pharmacological therapy, mechanical implantation, electrical stimulation, ablation, and / or surgery. It should be noted that the parameters of the cardiac contractility modulation stimulation treatment may depend on such additional treatment; for example, the cardiac contractility modulation stimulation may be used to compensate for or synergize with such other treatments.

[0137] In some embodiments, the patient's cardiac condition is assessed to determine whether cardiac therapy should be provided in addition to cardiac systolic modulation. If the patient's cardiac condition allows the patient to benefit from improvements in peak oxygen uptake or other physiological parameters, a plan to provide cardiac systolic modulation therapy is developed. If the patient's cardiac condition indicates the need for additional cardiac therapy, a plan may be developed to provide cardiac systolic modulation therapy and additional cardiac therapy, and one or more cardiac systolic modulation stimulation parameters may be modified accordingly.

[0138] In some embodiments, a treatment plan may be selected for the patient, which may include providing only cardiac contractility modulation therapy; providing cardiac contractility modulation therapy in combination with treatment for the patient's cardiac condition; or not providing cardiac contractility modulation therapy.

[0139] In some embodiments, potential patients are identified, tests are performed to assess and / or quantify one or more of the patient’s lung or other physiological and cardiac conditions, and optionally, appropriate and possibly most suitable cardiac contractility modulation therapy is selected.

[0140] Such a computer for planning can be provided as part of the programmer's workflow. In some embodiments of the invention, the computer is a cloud instance or a remote server accessed via a local interface.

[0141] Before explaining at least one embodiment of the invention in detail, it should be understood that the invention is not necessarily limited in its application to the details of the construction and arrangement of the components and / or methods set forth in the following description and / or illustrated in the drawings and / or embodiments. The invention can have other embodiments or can be practiced or performed in various ways.

[0142] Exemplary cardiac electrification

[0143] Now refer to the diagram, Figure 1This is a schematic diagram of the heart 100, illustrating various tissue and electrode / lead locations according to some embodiments of the present invention;

[0144] First, referring to the heart section, the following information is provided: Left ventricle 102 has 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 has RV free wall 126, tricuspid valve 136, and pulmonary valve 138.

[0145] The diagram also shows a second position thereon, where a first stimulation lead 130 contacts the interventricular septum 106 with electrode 134, and a second stimulation lead 128 contacts the interventricular septum 106 with electrode 132. In some embodiments, a single lead comprising two spaced-apart stimulation electrodes will be used. Optionally or additionally, the lead may comprise one or more sensing electrodes.

[0146] While contact electrodes are noted, other types of electrodes can also be used, such as screw-in electrodes, suture electrodes, and free-floating electrodes.

[0147] In some embodiments of the invention, the stimulation is bipolar, with electrodes 132 and 134 each being a bipolar electrode (e.g., a pair), for example in the form of a pointed surface and a ring electrode surface, and / or as a bipolar pair (e.g., a pair on each lead). Optionally or additionally, a remote electrode (e.g., a device) may be used as a second electrode, for example, for unipolar stimulation. In some embodiments of the invention, two leads are used, each acting as one pole of the bipolar stimulation.

[0148] In some embodiments of the invention, cardiac contractile modulation stimulation is applied to two leads (or, optionally, more than two leads if there are more than two), for example, simultaneously and / or alternately and / or sequentially. The two cardiac contractile modulation stimulation signals may be the same or different, for example, in terms of delay, phase length, interphase delay, amplitude, and / or other parameters. This may be useful, for example, if each lead is to affect different tissue types and / or have potentially different therapeutic effects. Note that in some embodiments, stimulation at the lead is avoided if it causes an unpleasant sensation. However, in some embodiments of the invention, some sensation is permitted, for example, for the acute treatment of atrial arrhythmias.

[0149] In some embodiments of the invention, the cardiac contractile modulation stimulus is applied in contact with or within the ventricular tissue. In some embodiments of the invention, the application distance from the ventricular tissue is 0-5 mm, 5-10 mm, 10-20 mm, 20-30 mm, or a distance greater than this.

[0150] Leads 128 and / or 130 can be dual-purpose, for example, providing pacing, cardioversion, and / or defibrillation signals in addition to non-excitatory signals (such as cardiac contractile modulation stimulation signals).

[0151] In some embodiments of the invention, leads 128 and / or 130 may be used to sense electrical activity, optionally using the same electrodes used for stimulation. In some embodiments, only one lead and / or only one electrode is used for treatment. For example, a single ventricle or atrial lead may be used. Optionally or additionally, an outdoor lead may be used in addition to or in place of an indoor lead, for example, in the coronary sinus or other vessels, outside the heart (e.g., on its outer surface / attached thereto and / or on the left side of the heart, such as left ventricle 104 and / or left atrium 112).

[0152] It is worth noting that the diagram is schematic and has been flattened. For example, in a real heart, the left atrium 112 and the right atrium 120 are both adjacent to the interatrial septum 116.

[0153] Exemplary cardiac treatment device

[0154] Figure 2 This is a schematic block diagram of a cardiac treatment device 200 according to some embodiments of the present invention. While existing devices such as the Optimizer 4 sold by Pulse Dynamics can be used, other device designs and / or special settings or reprogramming may be required.

[0155] As shown, device 200 includes one or more leads 216 (optionally two leads) that are optionally coupled to device 200 at one or more can connectors (not shown).

[0156] The pulse generator 204 (as an example of a stimulation circuit) may optionally be used to generate signals, for example, including power circuitry, for example, including one or more storage capacitors.

[0157] In some embodiments of the invention, a ventricular detector 206 is provided for detecting atypical ventricular excitation, which may be a contraindication to signal application.

[0158] In some embodiments of the invention, an atrial detector 208 (as an example of an atrial arrhythmia circuit) is provided for detecting atypical atrial excitation, which can be used as a decision input for device 200.

[0159] Sensor input 214 may receive data from one or more sensors, such as electrical sensors or other sensors, such as flow, pressure, and / or acceleration sensors. The data from the sensors may optionally be further processed (e.g., by controller 202 and / or detectors 206, 208) and may optionally be used as input to the decision-making process in device 200.

[0160] Optionally, a controller 202 (as an example of a decision circuit) is provided and performs one or more logic to determine, for example, the timing of a signal and / or other parameters and / or whether a signal is applied.

[0161] For example, memory 218 may optionally be provided to store logic, past effects, treatment plans, adverse events, and / or pulse parameters.

[0162] Optionally, a recorder 210 may be provided to store the activities of the device 200 and / or the patient. Such logging and / or programming may be performed using a communication module 21 (e.g., of a type known in the art) to send data from the device 200, for example, to a programmer (not shown), and / or to receive data, such as programming, for example, pulse parameters.

[0163] It should be understood that, in some embodiments, the methods described herein are implemented as methods of operating the control device 200, through its circuitry (e.g., controller 202, memory 218) and / or methods of programming and / or selecting a patient, the device being used to treat and / or plan (and optionally set) patient treatment parameters. Any such method may be functionally terminated at a stage where the circuitry indicates that the device 200 is energized. The device 200 can also be used to test these methods on a test bench without human subjects.

[0164] It should be noted that when planning treatment, the planning may include one or more objectives that can be traded off, for example, taking into account the patient's quality of life and device characteristics. Various objectives and settings that can be used to approach these objectives, as well as various trade-offs that can be taken (not always in the same embodiment), are described in this application, and one or more of these can be used in the actual planning activities for a single treatment, which may utilize the objectives and settings described in the context of different embodiments.

[0165] In some embodiments of the invention, planning includes using a planning system (e.g., a local client and a cloud server) that displays the expected effects of treatment on the patient. For example, such expected effects can be determined using the rules described herein and / or using datasets of previous (and / or current) patients and the effects of treatment on them. Machine learning methods can be used to process such datasets to extract relationships between one or more patient characteristics, one or more stimulus parameters, and one or more clinical and / or quality-of-life effects. Such relationships can be provided, for example, in the form of rules, tables, neural networks, and / or other software components, optionally in a tangible form, such as computer memory.

[0166] Exemplary Stimuli

[0167] Figure 3 Similar to Figure 1 A schematic diagram of the heart is shown, and the spatial extent of a non-excitatory field according to some embodiments of the present invention is also illustrated.

[0168] Although the heart is three-dimensional and the schematic diagram does not accurately represent space, circle 302 is used to schematically show a range within which the amplitude of the signal applied by lead 130 is sufficient (e.g., amplitude) to produce a contractile modulatory effect on cardiac tissue (and / or other therapeutic effects, such as reversal of genetic programs and / or other physiological effects, such as a functionally meaningful increase in phosphorylase phosphorylation). It is also noteworthy 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., via the subclavian vein) or through different locations (e.g., through the heart wall or remaining within the cardiac vessels and / or epicardium).

[0169] Circle 304 shows the same range as lead 128. The size of the circle is influenced by factors such as signal amplitude (the larger the amplitude, the greater the effect). Furthermore, the interaction between the signal and tissue may be affected by other parameters, such as timing relative to local excitation and tissue type.

[0170] It can be seen that different leads can reach different tissues with the same signal amplitude. For example, circle 302 includes a portion of LV free wall 102, while circle 304 may include a portion of RA 120, AV node 122 and / or LA 112.

[0171] In some embodiments of the invention, the location of the energized leads and / or pulse parameters are selected based on the desired effect on one or more of these tissues and / or a trade-off between these effects.

[0172] It is important to note that if there are actually two leads in the heart, some signals may be applied to one lead and others to the other, in order to provide multiple types of effects and / or trade-offs.

[0173] It should also be noted that, Figure 3 In the diagram, both leads are shown in RV 124, opposite the interventricular septum 106. However, one or more stimulating leads may be located in other locations, thus having different effect loops (e.g., 302, 304) and / or targeting different tissues. In some embodiments of the invention, the leads are located inside the heart, optionally on the right side, to take advantage of two potential benefits: a. less extracardiac tissue is stimulated; b. less invasiveness and / or presence compared to the left ventricle.

[0174] Referring to circle 302, note that primarily the ventricular tissue is affected. This effect may include prolonging the refractory period of the tissue conduction electrical impulse from AV node 122, with the potential benefit of preventing atrial arrhythmias from causing ventricular arrhythmias. Optionally, the timing of the stimulation is chosen to prolong the refraction period of the relevant conduction tissue.

[0175] This effect may also include significant regulatory effects on the septum 106 and free wall 102 and / or other parts of the left ventricle 104 (e.g., on fetal genetic program remodeling).

[0176] Referring to circle 304, note that AV can be stimulated by a cardiac contractility-modulated stimulation field. This may reduce its tendency to transmit atrial excitation, and by preventing ventricular dysregulation, may reduce the symptoms of atrial fibrillation.

[0177] The atrial tissue (left and / or right) may be stimulated by signals. This may suppress atrial arrhythmias, such as stopping paroxysmal atrial fibrillation episodes.

[0178] Exemplary pulse parameters

[0179] While not limited to a single pulse sequence, the term cardiac contractile modulation stimulation is used to describe any of a range of signals that include important components applied during the absolute refractory period, have clinically significant effects on acute and / or chronic cardiac contractility, and / or lead to reversal of fetal genetic programs and / or increased phosphoprotein phosphorylation. In some embodiments, the signal is potentially excitatory to one part of the heart but non-excitatory to others. For example, the signal may be excitatory in the atria but applied at a time when it is not excitatory in the ventricles (relative to ventricular activation).

[0180] In some embodiments of the invention, the signal, while potentially stimulating during the receptive period of the cardiac cycle, is applied due to its temporal rather than excitatory nature. Specifically, the signal is applied during the refractory period of the affected tissue and (optionally) during its absolute refractory period.

[0181] In some embodiments of the invention, the absolute refractory period of the atria is assumed to be about 0.15 seconds, followed by a relative refractory period of about 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 time of 0.05 seconds. It is worth noting that these times can vary between hearts and under different conditions, such as drug intake, anatomical excitation levels, heart rate, recent arrhythmias and / or exercise and / or can be measured (e.g., via device 200). In some embodiments of the invention, the stimulator is pre-programmed with parameters that take into account such refractory periods. Optionally, different numbers (e.g., stored in memory 218) are used for different conditions (e.g., different heart rates).

[0182] This may result in a high-amplitude signal without causing dangerous arrhythmias. For example, the signal amplitude may be at least 2, 4, 10, or an intermediate multiple of the cardiac excitation threshold. Alternatively, the level at which cardiac cardioversion occurs may be used as an upper limit or a portion of the aforementioned limit, such as 0.1, 0.3, 0.5, 0.9, or an intermediate portion.

[0183] In some embodiments of the invention, the following family of pulse parameters may be optionally used for cardiac contractility modulation stimulation signals for use as described herein.

[0184] In the study below, the following cardiac systolic modulation stimulation signal was used: a series of two biphasic pulses, each pulse phase lasting 5.14 milliseconds (ms), with a voltage of 4.5V–7.5V, followed by a 30–35 ms delay (using bipolar leads) after local activation at the application site, followed by a 40 ms charge-balancing phase. Notably, the local activation typically occurs shortly after the onset of ventricular activation. During the balancing pulse, all activating electrodes are shorted together. The voltage may decrease until it becomes imperceptible.

[0185] This signal can be modified. In some embodiments of the invention, the balancing phase can be omitted or provided with different lengths, for example, between 1 and 200 milliseconds, for example, between 10 and 50 milliseconds, for example, between 20 and 41 milliseconds, or an intermediate length.

[0186] For example, the maximum voltage can be increased from 7.5V to 8V, 9V, 10V, 12V, 20V, 40V, 100V, or medium or lower values. It is worth noting that, as an acute effect, sensation may not be considered a problem, but it may be necessary to avoid arrhythmias, especially ventricular arrhythmias.

[0187] The delay can be shorter, for example, between 1 and 30 milliseconds, between 5 and 20 milliseconds, between 10 and 25 milliseconds, or an intermediate delay. The delay can also be longer, for example, between 35 and 50 milliseconds, between 50 and 70 milliseconds, or an intermediate or smaller or larger delay. It is noteworthy that longer delays may be tolerable for patients with atrial arrhythmias because the arrhythmia caused by intraatrial arrhythmias (due to the application of cardiac systolic regulatory stimuli outside the absolute refractory period of the atria) may not be a problem for patients with atrial fibrillation. It is also noteworthy that this may allow for effective treatment of patients with long-term atrioventricular delays (e.g., by ignoring atrial effects).

[0188] The number of phases can also be modified, for example, from as few as 1, 2, or 3 to as many as 5, 10, 20, 50, or a number in between or greater. The phase length can be modified, for example, between 1 and 100 milliseconds, such as 2, 3, 5, 6, 6.6, 10, 15, 25, 50 milliseconds, or an intermediate length. Furthermore, not all phases need to have the same length and / or voltage. Additionally, while square pulses can optionally be used, other pulse shapes can be provided, such as sinusoidal, curved, triangular, and / or symmetrical or asymmetrical. In some embodiments, there is an inter-phase delay, for example, 1, 2, 4, 5, 6, 10, 20 milliseconds, or an intermediate or smaller or larger delay.

[0189] The energy transferred during the jump can be, for example, 0.01, 0.1, 0.5, 1J, 5J, 10J or medium or smaller or larger energy levels.

[0190] The duration of the pulse applied to the heart during a single beat can be, for example, 5 milliseconds, 10 milliseconds, 20 milliseconds, 30 milliseconds, 40 milliseconds, or a duration in between or longer.

[0191] In some embodiments of the invention, any of the above numbers are changed by, for example, 5%, 10%, 20%, or intermediate values.

[0192] Note that the delay can be a calculated delay (e.g., if the patient has pacing) or an approximation. For example, if the two leads are used as bipolar electrodes, the lowest or average activation time can be selected to calculate the delay.

[0193] In some embodiments of the invention, cardiac contractility modulation stimulation therapy is applied, for example, for 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 24 hours or an intermediate number of hours per day, or for example, for 1, 2, 3, 4, 5, 8, 12, 24 weeks or an intermediate number of weeks or more. Within a treatment period, each heartbeat can be selectively treated or is intended to be treated. In other embodiments, for example, as described herein, treatment can be set according to a target number of heartbeats to be treated per day.

[0194] It is important to note that sometimes, for reasons beyond dosage, a cardiac contractility modulation stimulation signal is not applied at the heartbeat. For example, the heartbeat may be considered unsafe because applying a cardiac contractility modulation stimulation signal during said beating could lead to arrhythmias. Optionally or additionally, the heart may be allowed to “restore” one or more “prohibited” beatings from arrhythmias.

[0195] In some embodiments of the invention (e.g., in the study described herein), the following algorithm is used to determine whether a cardiac contractility modulation stimulation signal should be applied during a given beat:

[0196] A first optional part of the algorithm is to avoid stimulation with cardiac contractile modulation stimulation, i.e., stimulation with excessively high heart rates, for example, above a cutoff threshold, such as 90, 100, 110, 120, 130, 140, 145, 160, or intermediate values. (Optional) This may prevent the application of cardiac contractile modulation stimulation during VT or initial VT and / or other arrhythmias, which could be detected as high heart rates.

[0197] A second optional part of the algorithm is to avoid stimulation if the delay between the two ventricular leads exceeds a certain threshold, such as 30 milliseconds, although other numbers can be used, such as 10 milliseconds, 20 milliseconds, 40 milliseconds, 50 milliseconds, and / or intermediate or larger thresholds. The threshold may also depend on conditions (such as heart rate or other cardiac parameters). This delay may indicate multiple lesions in the ventricles and / or irregular propagation directions.

[0198] Example specific algorithms include:

[0199] - Detecting ventricular contraction through the two ventricular leads

[0200] - Determine your heart rate is below 110 BPM

[0201] - If a contraction delay greater than 30 milliseconds is detected between the two leads, it is defined as an incorrect bounce.

[0202] - For each detected incorrect beat, no cardiac contractile modulation stimulation is provided during the current and subsequent ventricular systole (although in some embodiments, cardiac contractile modulation stimulation may be provided at the next beat, while in other embodiments, the delay may be more than one beat, such as between 3 and 10 beats, or a time delay, such as 5 to 60 seconds or longer).

[0203] - After an abnormal beat is detected, ventricular contraction is continued to be detected via lead 2. Once two appropriate beats are detected (with a delay of less than 30 milliseconds), a cardiac contractility modulation stimulus is provided during the cardiac contraction with a preset delay.

[0204] In some embodiments of the invention, irregular beats are detected based on AV delay and / or on the morphology of electrocardiographic signals detected on one or more electrodes. Other methods for detecting potentially unsafe beats (e.g., beats whose central ventricle may be stimulated outside its absolute refractory period) may also be used. Safety and effectiveness of exemplary atrial stimulation.

[0205] Figure 4 This schematically illustrates a time plot of a non-excitatory field relative to the timing of various cardiac events according to some embodiments of the present invention.

[0206] Figure 4 Includes three time-aligned charts (402, 404, 406), where atrial activation is represented by "A", AV activation by "AV", and ventricular activation by "V". Each time row shows two beats.

[0207] Referring first to timeline 402, the AV excitation occurs after the atrial excitation and before the ventricular excitation. This reflects that the excitation in the heart begins at the sinoatrial node, travels around the right atrium, is conducted and delayed by the atrioventricular node, and then reaches the ventricle and propagates within it. The two beats appear identical.

[0208] Referring to timeline 404, during the first beat (read from left to right), within the absolute refractory period of the ventricle, a cardiac contractile modulation stimulation signal can be selectively applied at a short delay after ventricular excitation. This can be seen by referring to timeline 406, where the absolute refractory period of the atrium is indicated by 414 (its end by 416), the absolute refractory period of the ventricle by 418, and its end by 420. These refractory periods are shown as the cardiac contractile modulation stimulation signal itself does not affect its duration. As can be seen from the timeline, applying cardiac contractile modulation stimulation when the atrium is also in its absolute refractory period is desirable. In other embodiments, for example, as described herein, cardiac contractile modulation stimulation is applied when the atrium is not refractory.

[0209] The second beat in Figure 404 includes atrial arrhythmias. The first possibility is marked "A?", meaning the atria are prone to arrhythmias. According to some embodiments of the invention, the application of a cardiac contractility modulation stimulus signal reaches the atria and prolongs the refractory period in the atria, as shown in 422. This can prevent such arrhythmic excitation from occurring and / or prevent its propagation to the atrioventricular node (e.g., if the refractory period of the atrioventricular node tissue is prolonged).

[0210] The second possibility is labeled "AV / V?", where abnormal excitation exits the AV node. However, according to some embodiments of the invention, the refractory period of the conduction tissue near the AV node is prolonged 424 by the cardiac contractility modulation stimulation signal, and this excitation fails to propagate. According to some embodiments of the invention, the refractory period of the ventricular tissue itself is prolonged, so even if excitation begins to propagate, it will stop upon encountering the ventricular refractory tissue.

[0211] These timescales illustrate several possibilities that cardiac systolic modulation stimulation signals can effectively prevent ventricular excitation from exhibiting significant functional impairment due to atrial arrhythmias. Furthermore, it is believed that cardiac systolic modulation stimulation signals can entrain tissue to resist arrhythmic behavior.

[0212] Timing diagram 406 shows the likelihood that ventricular refractory period prolongation 424 is less than atrial refractory period prolongation 422. This could be due, for example, to the relative timing of the cardiac contractile modulation stimulus signal and tissue excitation. When used near the end of the refractory period, the prolongation of the refractory period can be expected to increase. For example, US7991469 shows how applying a non-excitatory signal during the refractory period can prolong it. In some embodiments of the invention, the application of the cardiac contractile modulation stimulus is selected to target AV nodes and / or fast conduction pathways, such as Purkinje fibers.

[0213] In some embodiments of the invention, the timing of the cardiac contractile modulation stimulation is altered, for example, by more or less delay, depending on the desired effect, particularly the desired effect associated with improving atrial arrhythmias. Optionally or additionally, the location of the cardiac contractile modulation stimulation signal application and / or the signal amplitude are altered to select which tissue will be affected by the cardiac contractile modulation stimulation signal. It is noteworthy that cardiac tissue moves during the cardiac cycle, so such variations in cardiac contractile modulation stimulation signal parameters can selectively take into account physical distance, as it depends on the cardiac cycle. For example, applying cardiac contractile modulation stimulation late in systole (starting from the interventricular septum) can affect more of the left ventricular free wall over a longer period compared to a similar signal applied before significant ventricular contraction. In some embodiments of the invention, the duration of the signal is altered (or the cardiac contractile modulation stimulation signal is divided into two or more time-separated components) to stimulate different parts of the ventricle at different times. This may reduce the total power delivered (e.g., if the goal is to reach a threshold application level for therapeutic tissue). This modification may be particularly important if the cardiac contractile modulation stimulation signal is selected as a suboptimal cardiac contractile modulation stimulation application due to other desired effects.

[0214] Trade-offs can be made between various desired effects. For example, as mentioned above, an electrode placement suitable for the right atrium may cover less of the ventricle. This may reduce ventricular effects, but from a clinical perspective, the patient's overall condition may improve. Similarly, if there are two sets of stimulation parameters, one of which covers more ventricular tissue but also results in more mitral regurgitation, a different set of parameters may be needed to reduce regurgitation, even if it has a therapeutic effect of reducing or mitigating the effect. In one example, various stimulation protocols are tested on the patient, and the protocol with the desired effect is selected (e.g., for atrial and / or mitral regurgitation or HOCM-type atrial outflow obstruction). In some embodiments of the invention, the protocol 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 cardiac contractility modulation stimulation. Modeling can be performed before implantation of the device 200 to determine whether and / or when to change which parameters in the implanted device.

[0215] In some embodiments of the invention, selective activation of the leads can be implemented if two or more leads are used and some effects are chronic. For example, if atrial fibrillation is anticipated or detected (e.g., using an atrial detector), more atrial leads are used; otherwise (e.g., and / or to meet certain desired therapeutic doses), more ventricular leads are used.

[0216] For example, in the case of paroxysmal atrial fibrillation, the device 200 can provide cardiac systolic modulation stimulation therapy upon detection of the onset of atrial fibrillation. For example, the stimulation lead may be located in the RV and / or LV, and delivery and / or transmission during its refractory period may form the atria, and selective delivery may be made at any time if the stimulation does not reach the ventricles.

[0217] In another example during an ongoing atrial fibrillation episode, optionally, for a patient with chronic atrial fibrillation, the device 200 can be used to prolong the ventricular refractory period (by transmitting a cardiac contractile modulation stimulation signal to the ventricle) and / or to transmit a cardiac contractile modulation stimulation signal in the atrium to suppress atrial fibrillation triggering.

[0218] Returning to the extended refractory period 422, 424, it should be noted that, according to some embodiments of the invention, even if the cardiac contractile regulatory stimulation signal itself leads to the direction of atrial arrhythmia, for example, by directly causing abnormal excitation, this may not be an overall problem if such excitation is prevented from reaching the ventricles. The overall therapeutic balance may lead to this degeneration of atrial function due to the overall increase in cardiac output and / or health status.

[0219] Exemplary stimulus changes

[0220] Figure 3A method is described that uses only ventricular leads without providing atrial sensing. This has the potential advantage of ignoring atrial arrhythmias while still maintaining the safety of ventricular application, since the ventricles are in a refractory state when cardiac contractile modulation stimulation signals are applied.

[0221] In some embodiments of the invention, a setup with atrial sensing is used, for example, by adding atrial leads (e.g., having one or two ventricular leads). In some embodiments of the invention, such a setup is used to detect atrial arrhythmias and potentially treat atrial arrhythmias and / or their symptoms, for example, using cardiac contractility modulation stimulation signals, as described herein, or using other electrical therapies, such as atrial antiarrhythmic pacing. Alternatively, if an atrial arrhythmia is detected, additional checks are performed to see if ventricular irregularities are present. As described herein, some such ventricular irregularities can be prevented and / or blocked by cardiac contractility modulation stimulation signals. In some embodiments of the invention, such arrhythmias are detected by measuring the delay between atrial and ventricular activation and detecting, for example, whether their ratio is 1:1 and / or their relative delays.

[0222] In some embodiments of the present invention, one or more of the following methods are used to detect cardiac arrhythmias (in the current beat or during):

[0223] 1. Based on heart rate. If the heart rate exceeds a set threshold, it is considered tachycardia. If it is below a lower threshold, the heart condition can be considered bradycardia.

[0224] 2. If the trigger source is not from the AN node, it can be detected by changing the time interval between the two ventricular septal leads and / or the QRS shape detected by the ventricular leads.

[0225] 3. Heart rate variation (HRV). If HRV is high (e.g., above the threshold), it may indicate the presence of ventricular arrhythmia.

[0226] In some embodiments of the present invention, security / irregularity detection methods as described in one or more of the following U.S. patents, US6,233,487, US6,597,952, US6,263,242, US6,370,430, US6,993,385, US7,953,481, and US6,480,737, may be used. Other methods may also be used.

[0227] Exemplary assessment

[0228] In some embodiments of the present invention, sensor input 214 and / or controller 202 are used to shut down the treatment circuit.

[0229] In one example, the sensor could provide an indication of cardiac output or patient activity. Such indications could be used to automatically determine whether a treatment plan is effective and whether it should continue.

[0230] In another example, acute changes in arrhythmias, heart rate, and / or cardiac output (or surrogate) are used to determine whether the application of procedural parameters is acceptable.

[0231] In another example, sensors are used to detect whether an increase in cardiac output is needed. In this case, stimulation parameters that increase cardiac output are provided at the expense of achieving a therapeutic goal, such as long-term suppression of atrial fibrillation.

[0232] In another example, changes in heart rate may indicate a need to modify parameters of the cardiac contractile modulation stimulus signal. For instance, changes in heart rate may alter the relative timing of activation in the two ventricles and / or the duration of the atrial and ventricular refractory periods. In some embodiments of the invention, the timing of the application of the cardiac contractile modulation stimulus signal (e.g., whether it falls within the atrial refractory period) is varied to maintain the desired arrhythmia relief effect.

[0233] Simultaneous drug delivery

[0234] In some embodiments of the invention, cardiac contractility modulation stimulation signals are used to provide some antiarrhythmic effect by prolonging the refractory period and / or by other means. Therefore, the dosage of such antiarrhythmic drugs can be modified. For example, the dosage of one or more of the following drug families can be modified (e.g., reduced and / or allowed to be increased): antiarrhythmic drugs such as amiodarone, flecainamide, procainamide and / or sotalol; beta-blockers; calcium channel blockers; and / or Ace inhibitors.

[0235] In some embodiments of the invention, the application of cardiac contractile modulation stimulation is timed according to the time of drug administration, for example, to provide greater cardiac contractile modulation stimulation antiarrhythmic effect during periods of lower blood levels (or other efficacy indicators of DAG).

[0236] In some embodiments of the invention, the timing of cardiac contractile modulation stimulation is selected based on the expected effect of the cardiac drug on the refractory period, for example, to ensure that the stimulation occurs during the refractory period. It is noteworthy that there are indications that a signal applied at the end of the refractory period may prevent the next activation, which could have an antiarrhythmic effect. For example, the timing of such activation may depend on the drug dosage and / or the expected effect. Alternatively, such effects may be programmed in memory 218.

[0237] Possible mechanisms of cardiac contractile regulation stimulation

[0238] Without being limited to any particular interpretation, one or more of the following physiological explanations may be used to provide some intuition about how to modify various parameters of treatment for some embodiments of the present invention.

[0239] As described in the Heart Failure Review, 2016;21(6):645–660, “Cardiac Contractile Modulation: A Novel Approach to Treating Heart Failure,” cardiac contractile modulation stimulation signals may have contractile-improving effects by directly influencing phosphoprotein phosphorylation and / or other direct effects on cellular function (such as other proteins). This could lead to a cascade of effects, reversing fetal genetic programming and resulting in functional remodeling of affected cardiac tissue. In some embodiments of the invention, the amount of phosphorylation (or other cellular effects described therein) and / or the amount of program reversal are used as guidelines for describing the desired amount of cardiac contractile modulation stimulation signal.

[0240] Regarding the atria, cardiac contractile regulatory stimuli may entrain atrial tissue, for example, by synchronizing tissue and preventing changes in activity, and such changes may also lead to long-term remodeling of the electrical behavior of such tissue.

[0241] For example, at the acute level, U.S. Patent No. 4,554,922 clearly demonstrates that an electrical signal applied during the relative refractory period prolongs the refractory period, reducing the proarrhythmic factors in the tissue. This extension may impede propagation without affecting muscle activity. In some cases, its effect is to prevent the duration of electrical activity from exceeding the duration between excitations, which does indeed reduce muscle function.

[0242] Improved oxygen uptake

[0243] Figure 5 This is a graph showing the results of a study on the improvement of oxygen uptake parameters in patients with atrial fibrillation by cardiac contractile modulation stimulation according to some embodiments of the present invention.

[0244] In one study, 60 patients were selected and implanted with a 2-lead optimizer intelligent system and a cardiac contractility modulation stimulation device via pulse dynamics. Nine of these patients had atrial fibrillation, and the effects of treatment on them are described herein. Patient selection (and may be based on one or more of the criteria described below, including and / or exclusion, for the treatment and / or treatment of such patients planned according to some embodiments of the invention):

[0245] Methods: Patients who still exhibited New York Heart Association III / IVa symptoms, had an LVEF of 25-45%, and did not meet the criteria for CRT were eligible for treatment. All subjects received an Optimizer 2 lead implant and were observed at 12 and 24 weeks. Device interrogation provided a large number of effectively transmitted cardiac contractile modulation stimulation signals.

[0246] Sixty participants were drawn from seven medical centers in the United States and one in Germany. Participants were assessed at baseline and again at 12 and 24 weeks post-implantation. Table 1 summarizes the inclusion and exclusion criteria. The primary criteria included: ≥25% LVEF and ≤45% echocardiographically (assessed by a core laboratory); New York Heart Association III or dynamic IV symptoms, despite guideline-guided medical treatment for heart failure (including ICD, if indicated) for 90 days, and stable within 30 days prior to enrollment; and, not eligible for cardiac resynchronization therapy (CRT). Patients were excluded if they were hospitalized for heart failure and required intravenous diuretics, inotropic agents, or hemofiltration within 30 days; if they received any form of positive inotropic support within 30 days prior to enrollment; if their peak oxygen uptake on cardiopulmonary stress testing (CPX) was <9 or >20 mL O2 / min / kg (assessed by a core laboratory); if they had a chance of correcting the cause of heart failure (such as valvular heart disease or congenital heart disease); if their exercise tolerance was limited by conditions other than heart failure; or if they were on schedule or had recently undergone CABG, PCI, or MI. Notably, patients with atrial fibrillation were included compared to all previous studies in the United States.

[0247] Table 1. Inclusion and Exclusion Criteria.

[0248]

[0249]

[0250] Table 2 summarizes the event timeline. After eligibility was confirmed, subjects underwent implantation of the 2-lead optimizer intelligent system. After device programming, subjects were typically discharged on the day of implantation or the day after. Approximately 2 weeks later, subjects returned for routine wound and device examinations (when examining and optimizing cardiac contractility modulation stimulation signal parameters). Study follow-up included clinical evaluations at 12 and 24 weeks (±2 weeks) post-implantation. In addition to interim safety assessments, CPX testing was repeated at these visits by the NYHA (New York Heart Association) and determined by the field clinician.

[0251] Table 2. Timeline of the research on the event

[0252]

[0253]

[0254] * Results of 12-lead EKG and echocardiography tests (from a study-qualified laboratory) obtained within 30 days prior to informed consent and performed in accordance with protocol, testing, and data collection requirements may be used for eligibility determination and baseline testing.

[0255] **Prior to the issuance of a PMA order by the FDA, an access should be conducted every 6 months to inquire about and report any SAEs (if any) related to the optimizer device.

[0256] General outcomes (excluding atrial fibrillation) included: 60 participants, 88% male, aged 66 ± 9 years, LVEF 34 ± 6%, 68% with ischemic cardiomyopathy, and 15% with atrial fibrillation. There was no difference in cardiac systolic modulation of stimulation delivery between the 2- and 3-lead systems (19892 ± 3472 vs 19583 ± 4998 pulses / day). Compared with the control group, the change in peak oxygen uptake from baseline to 24 weeks in the 2-lead group was 1.72 (95% Bayesian credible interval [BCI]: 1.02, 2.42) mL / kg / min. There was no difference in adverse events between the groups, except that the 2-lead group had a reduction in optimizer-related adverse events compared to the 3-lead group (0% vs 8%, p = 0.03).

[0257] Furthermore, compared to 42.7% in the FIX-HF-5C control group, the New York Heart Association reported at least one improvement in functional grade in subjects treated with the 2-lead optimizer system at 24 weeks (p<0.001).

[0258] For more details about the study, please refer to the application filed together with the agent, case number 79062.

[0259] Generally, patients are selected for the study if they have NYHA Class III systolic heart failure with an ejection fraction between 25% and 45% (although Class IVa, as with Class II, is also permitted and / or may be used in some embodiments of the invention). In some embodiments of the invention, patients with an ejection fraction between 25% and 55% (e.g., between 33% and 45%) may be selected. Furthermore, the patient's peak oxygen uptake is between 9 and 25 ml / kg / min. In some embodiments of the invention, patients are selected if their peak oxygen uptake is between 9 and 12 ml / kg / min, between 12 and 15 ml / kg / min, between 15 and 20 ml / kg / min, between 20 and 25 ml / kg / min, or an intermediate value. In some embodiments of the invention, it is assumed that patients with higher peak oxygen uptake have a greater potential to benefit from any cardiac improvement provided by the treatment.

[0260] like Figure 5As shown, when cardiac systolic modulation stimulation was applied to patients with heart failure and atrial fibrillation, peak oxygen uptake increased in most patients, with a mean of 0.844 mL / kg / min for all nine patients and a slope of 0.0025 (e.g., after several months, such as 12 or 24 weeks), relative to baseline; since the condition of control patients would typically worsen, improvement was also expected compared to the control group. Notably, the improvement was increased if only patients receiving high-volume treatment were selected. The mean improvement rate in non-atrial fibrillation patients was 1.09, with a STD of 1.48 mL / kg / min, and the number of beats treated apparently had no positive effect. In contrast, when a three-lead device was used, peak oxygen uptake in non-atrial fibrillation patients was essentially not increased (but not decreased either, which is to be expected for such patients). This suggests a synergistic effect between patients with atrial fibrillation and those who benefited from the treatment. As previously mentioned, although atrial fibrillation is a contraindication, this synergistic effect may outweigh the basic potential benefits of treating patients with atrial fibrillation using cardiac systolic modulation stimulation signals.

[0261] In some embodiments of the invention, patients with atrial fibrillation are selected for treatment with a target of at least 0.5 ml O2 / min / kg, at least 1 ml O2 / min / kg, at least 2 ml O2 / min / kg, at least 3 ml O2 / min / kg, or at least 7 ml O2 / min / kg, or an intermediate improvement in oxygen uptake.

[0262] In some embodiments of the invention, patients are selected for treatment based on indications that peak oxygen uptake is limited by cardiac factors.

[0263] It is important to note that an increase in oxygen uptake may require some lung reserve in the patient. Patients may be selected if their respiratory reserve (e.g., a potential increase in lung effectiveness) is at least 10%, at least 20%, at least 30%, at least 50%, and / or an intermediate value or greater. A BR below 30 or 33 is generally considered low, indicating that lung disease may limit improvements in peak oxygen uptake. BR can be defined as the difference between maximum spontaneous ventilation (MVV) and the maximum ventilation measured during exercise testing (e.g., BR% = (MVV - VE / MVV) x 100).

[0264] In some embodiments of the invention, a patient is considered to have a useful lung reserve based on the patient’s oxygen uptake efficiency slope (OUES), for example, if it is below 95%, 90%, 89%, 85%, 70%, or an intermediate value.

[0265] In some embodiments of the invention, a patient is considered to have potentially useful lung reserve based on their peak RER, for example, values ​​above 1, 1.05, 1.1, 1.15, or intermediate values.

[0266] In some embodiments of the invention, the patient is considered to have potentially useful lung reserve based on the fact that the patient's atrial tachycardia is low, rather than normal or crossed.

[0267] In some embodiments of the invention, a patient is considered to have a useful lung reserve based on a VE / VCO2 ratio that is higher than, for example, 25, 30, 35 or an intermediate value.

[0268] In some embodiments of the invention, a patient is considered to have potentially useful lung reserve based on the fact that the patient's O2 saturation does not decrease and / or does not decrease rapidly during exercise, for example, by less than 20%, 10%, 5%, or an intermediate value during 20 minutes of exercise.

[0269] In alternative (or additional) approaches, it should be noted that improvements in cardiac function may be reflected in ways other than improvements in oxygen uptake, such as reversal of fetal genetic programs, such as normalization of one, two, three or more mRNAs, protein level indicators, and / or blood peptides. In some embodiments of the invention, patients may be selected if they have atrial fibrillation (or other atrial arrhythmias, such as 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 the patient appears to have no useful lung reserve.

[0270] like Figure 5 As shown, the degree of improvement appears to increase with the number of actual treated beats. In particular, there is an average improvement above 17,000 beats, and this improvement increases further as the number of treated beats increases to 20,000 and 25,000 beats.

[0271] In some embodiments of the invention, this suggests selecting atrial fibrillation patients based on the predicted likelihood of treating more beats. For example, surface ECGs of such patients can be obtained and processed using simulations of algorithms for applying cardiac contractile modulation stimulation, and a sufficient number of beats can be selected for treatment of patients to whom cardiac contractile modulation stimulation can be applied.

[0272] It is noteworthy that in some patients, cardiac systolic modulation stimulation is not applied based on the beat rate. For example, in atrial fibrillation patients receiving cardiac systolic modulation stimulation at the atrium, there may be no meaningful definition of the beat rate and / or the application may be out of sync with the actual beat rate. In other patients, the application procedure is synchronized with the actual or desired beat rate. Optionally, a rhythmic beat rate is treated. In some cases, synchronization refers to what occurs in one chamber (e.g., the ventricle) while ignoring timing in another chamber (e.g., the atrium); in some cases, the stimulus reaches the other chamber; in some cases, the stimulus does not reach the other chamber. In some embodiments, timing is chosen so that application occurs when both the atrium and the chamber are in their refractory period, even if the beat rates are out of sync.

[0273] In some embodiments of the invention, the treatment duration is selected (e.g., based on an estimated number of beats per hour or by quantity, e.g., allowing 8 or 9 hours of treatment) to increase the number of treatment beats.

[0274] In some embodiments of the invention, one or more blocking parameters, such as heart rate, are relaxed so that the beating can be treated at a higher heart rate. For example, treatment may be allowed for heart rates between 110 and 150 or between 110 and 130.

[0275] In some embodiments of the invention, device parameters are modified in response to actual measurements of the applied jump (e.g., detected during or after implantation, such as a day, a week, a month, three months, or an intermediate period).

[0276] In some embodiments of the invention, pacemaker settings are modified (e.g., baseline heart rate is increased) to allow for more daily treatments.

[0277] In some embodiments of the invention, parameters are adjusted to increase the number of beats per day in response to treatments that lack efficacy, rather than in response to the number of beats applied. For example, the number of beats may be increased to 30,000, 40,000, 50,000, or a moderate or higher number per day. In some embodiments of the invention, parameters are modified so that such a number can be achieved, and once the desired number is reached, stimulation is stopped for that day.

[0278] In some embodiments of the invention, this choice of daily beat dose is particularly suitable for patients with atrial fibrillation. In other embodiments, it is applied to patients without atrial fibrillation.

[0279] In some embodiments of the invention, the number of beats increases in response to the detection that the application of cardiac contractile modulation stimulation is reducing the number of atrial arrhythmic beats. In some cases, such a determination may indicate that the cardiac contractile modulation stimulation has insufficient antiarrhythmic effect, and that the application of cardiac contractile modulation stimulation is reduced and / or altered, for example, so that it is primarily used for other effects, such as an increase in cardiac output.

[0280] In another example, if an atrial (or other) sensor detects an increase in electrical activity in the atrium, it is assumed to be an atrial arrhythmia, and the delivery of cardiac contractile modulatory stimuli affecting the atria and / or AV nodes and / or ventricular conduction forming the AV nodes is increased and / or the timing and / or other parameters are altered to better manage the atrial arrhythmia.

[0281] In another example, during an atrial arrhythmia episode, if the ventricular heart rate increases but the actual demand does not increase (e.g., based on accelerometers or other activity sensors), the cardiac contractile modulation stimulation applied to the atria is increased and / or modified.

[0282] Exemplary stimulation from the atrium

[0283] Figure 6 This is a schematic diagram of the heart 100, showing the spatial extent 602 of a non-excitatory field from the right atrium according to some embodiments of the present invention.

[0284] Note the graphic distortion, but it is understandable. Stimulus signal parameters can be set so that significant portions of the interventricular septum, as well as key parts of the right atrium, left atrium, and AV node, are affected by cardiac systolic modulation stimulation. It is worth noting that this effect may reduce atrial arrhythmias in one or both atria. Optionally, pulse parameters can be selected so that the cardiac systolic modulation stimulation reaches the junction of the pulmonary vein and left atrium, which may reduce certain types of atrial arrhythmias.

[0285] As a potential benefit, it is worth noting that applying cardiac contractile modulation stimulation signals in a manner asynchronous with atrial pacing and / or at the time leading to the onset of an arrhythmia may be less dangerous because such additional atrial beating may not affect the ventricles (e.g., for the reasons described herein), or at most serve to induce a “natural” atrial arrhythmia that is not immediately life-threatening on its own. In some embodiments of the invention, the electrode 606 of lead 604 is used to detect a signal indicative of ventricular timing so that stimulation in the atria is timed as a short delay (e.g., 1-70 milliseconds) following ventricular excitation.

[0286] Figure 7This is a schematic diagram of the heart, showing the spatial extent 702 of a non-excitatory field of an electrode 707 from a lead 704 in the left atrium according to some embodiments of the present invention.

[0287] In the illustrated example, lead 704 is provided across the septum, dashed line 708 indicates a hidden portion of the lead, and note the drawing distortion. In the illustrated example, lead 704 passes through the interatrial septum (e.g., foramen ovale) and has a curved (optionally pre-shaped) section 710 (e.g., for assisting in anchoring and / or placing the tip). Optionally, as shown, tip 706 is positioned downwards to be closer to the ventricle. In some embodiments, the placement of tip 706 is selected so that the stimulation field “reaches” the pulmonary vein inlet 702 with cardiac contractility modulation. In some embodiments of the invention, electrode position and / or signal intensity and / or timing are selected to minimize or avoid potential effects in the ventricle, rather than contractility enhancement (if any). A potential advantage of placing the electrode in the atrium is that such an electrode can be used to apply a defibrillation intensity signal, although the amplitude limits its reach to the relevant atrium. Optionally, the timing of the signal is selected so that it drops during the absolute refractory period of the relevant ventricle (e.g., the ventricle that can be directly stimulated by the field).

[0288] It is worth noting that when stimulating from the atrium, stronger amplitudes and / or different durations may be required to ensure that the applied cardiac contractile modulating stimulation field reaches the desired non-atrial tissue.

[0289] In some embodiments of the invention, one lead is placed in the atrium and the other in the ventricle. Both are used to apply cardiac contractile modulation stimulation, or the cardiac contractile modulation stimulation is applied between the two leads.

[0290] In some embodiments of the invention, the amplitude of the cardiac contractility modulation stimulation signal is selected based on the cardiac cycle. For example, if the cardiac contractility modulation stimulation signal is applied to the atrium outside the absolute refractory period of the ventricle, the amplitude may be reduced (or the electrode location may be selected), so that the ventricle does not reach a dangerous level of electrical activity. Higher amplitudes (e.g., voltages) can be used when stimulating the ventricle during the ventricular refractory period and / or at the correct time, even if it “covers” both the atrium and the ventricle. For example, as described above, inducing arrhythmias in the atrium of a patient with arrhythmias may not be a problem, and / or less life-threatening than if the ventricle were so stimulated.

[0291] In some embodiments of the invention, both cardiac contractility modulation stimulation and CRT are applied to the same patient. While this dual application may share electrodes (e.g., left ventricular electrodes and / or right ventricular electrodes), in some embodiments of the invention, an atrial electrode is used to apply C2M (optionally with parameters that provide meaningful stimulation to the ventricles).

[0292] In some embodiments of the invention, cardiac systolic modulation stimulation is used to treat and / or prevent atrial arrhythmias. Optionally or additionally, cardiac systolic modulation stimulation is used as an adjunct or alternative treatment for heart failure ventricles. The last one may be applicable to hearts without atrial arrhythmias.

[0293] In some embodiments of the invention, sensors in the atria (or other parts of the heart and / or other parts of the body) are used to estimate the level of atrial arrhythmias, such as the presence of acute episodes of atrial arrhythmias and / or the prevalence of atrial arrhythmias. The treatment can be modified accordingly, for example, atrial electrodes (or electrodes closer to the atria) are activated and / or ventricular electrodes are activated in response to acute and / or chronic increases in atrial arrhythmias, with higher amplitude.

[0294] Some results from dogs

[0295] In one experiment, two healthy dogs received cardiac contractile modulation stimulation therapy and it was found that cardiac contractile modulation stimulation applied to the ventricular septum may reduce atrial arrhythmias and / or susceptibility to atrial arrhythmias.

[0296] More specifically, both dogs were subjected to rapid atrial pacing to induce atrial fibrillation (by mimicking atrial arrhythmias). This induction was readily achieved. Even after the rapid pacing was stopped, the dogs remained in atrial fibrillation for, for example, at least 10 minutes. Notably, in a typical heart, recurrent and persistent episodes of atrial fibrillation tend to increase the heart's tendency to spontaneously occur atrial fibrillation events and / or initiate atrial fibrillation, even if such fibrillation is induced.

[0297] When a cardiac systolic modulation stimulus (within the ventricle) is applied, atrial fibrillation terminates within one minute or less. This process of inducing atrial fibrillation and stopping it using cardiac systolic modulation stimulus is repeated several times.

[0298] Once cardiac systolic modulation stimulation was applied for several days (approximately one week, 5 hours daily), rapid pacing failed to induce atrial fibrillation. Multiple delayed attempts to induce atrial fibrillation, ranging from 1 minute to 3 hours (exact figures unavailable), were made after the end of cardiac systolic modulation stimulation. These attempts failed in both animals and after multiple attempts. Manual injection of a dose of proarrhythmic drugs to increase atrial sensitivity to arrhythmic triggers also failed to induce atrial fibrillation via rapid pacing.

[0299] Generally, we have found that rapid atrial pacing can induce atrial fibrillation before initiating cardiac systolic modulation stimulation (CPMS) therapy. However, CPMS activation quickly leads to NSR (normal sinus rhythm) reversal. Hours or weeks after animals receive CPMS, they cannot be induced even under the same conditions (anesthesia and rapid pacing) or with the administration of proarrhythmic drugs.

[0300] In some embodiments of the invention, cardiac systolic modulation stimulation therapy is used to help reduce the occurrence of atrial arrhythmias, for example, by applying it for 20 minutes, 40 minutes, 1 hour, 2 hours, or an intermediate or longer period. On an acute basis (e.g., if an atrial arrhythmia is detected), cardiac systolic modulation stimulation can be applied for a period of time such as 1 second, 10 seconds, 1 minute, 10 minutes, 20 minutes, or an intermediate or longer period, with the option of using some type of antiarrhythmic pacing.

[0301] It is worth noting that higher power levels and / or more sensing electrodes can be used for acute treatment, as patients may be willing to endure temporary discomfort if treatment is urgently needed. It should also be noted that while power consumption may increase with increasing signal amplitude, this may be less of a concern for acute treatment (e.g., applying a percentage of pulsations less than 20%, 10%, 5%, or moderate per day).

[0302] Optionally, the cardiac contractility modulation stimulus is applied to the interventricular septum. Optionally or additionally, the cardiac contractility modulation stimulus is applied to the atrium.

[0303] In some embodiments of the invention, cardiac contractile modulation stimulation is applied before and / or after the onset of an atrial arrhythmia episode.

[0304] In some embodiments of the invention, certain physiological parameters are used to determine the application of cardiac contractile modulation stimulation, such as increasing heart rate or exercise and / or based on the duration of antiarrhythmic drug administration. Applying cardiac contractile modulation stimulation may reduce the risk of atrial arrhythmias triggered by these or other proarrhythmic conditions.

[0305] In some embodiments of the invention, cardiac contractile modulation stimulation is applied as a preventative treatment according to a schedule, for example, between 1 and 20 minutes per hour.

[0306] This treatment can be scheduled throughout the 24-hour period, for example, to prevent atrial fibrillation from occurring during "off" hours.

[0307] In some embodiments of the invention, cardiac contractile modulation stimulation is applied after treatment of an atrial arrhythmia episode (e.g., by cardioversion), for example, between 1 and 120 minutes, or for example, between 5 and 60 minutes, potentially maintaining a non-arrhythmic state, especially in the face of a proarrhythmic state caused by the treated atrial arrhythmia episode and / or its treatment.

[0308] In some embodiments of the invention, cardiac contractile modulation stimulation is applied over a similar timeframe to prevent atrial fibrillation, for example, to prevent atrial arrhythmias, after defibrillation. More generally, in some embodiments of the invention, when detecting or estimating an increased level of atrial arrhythmias, the device 200 is used to provide cardiac contractile modulation stimulation to suppress such arrhythmias.

[0309] When cardiac systolic modulation stimulation is applied after treatment, the application of cardiac systolic modulation stimulation can be selectively delayed, for example, by 1 to 300 seconds, 30 to 200 seconds, or a delay of the middle or greater.

[0310] "Apply cardiac systolic modulation stimulation for XX minutes" means that the controller logic is set to apply a cardiac systolic modulation stimulation signal for each beat over a period of time (or possibly according to another schedule, such as every other beat). However, note that some beats will not be processed, for example, due to irregular ventricular excitation.

[0311] In some embodiments of the invention, a heart rate limit (above which no cardiac contractile regulation stimulation is applied) is increased.

[0312] Exemplary selection and treatment of atrial fibrillation patients

[0313] Figure 8 This is a flowchart of a method for patient selection and treatment of patients with atrial arrhythmia according to some embodiments of the present invention. Note that in some embodiments, the described actions may be performed in parallel and / or in other order.

[0314] In 802, patients with a cardiac condition and potential benefit from treatment are identified, for example, as described herein. For example, patients with heart failure of New York Heart Association class II (or higher) may be identified, and those with atrial fibrillation may be selected. For example, such patients may be selected to have an ejection fraction (EF) between 20% and 50%, for example, between 25% and 40% or 45%. Optionally or additionally, such patients may have chronic angina (e.g., angina pectoris). Optionally or additionally, such patients may be able to undergo 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 lung reserve, for example, expected to allow an increase in oxygenated blood flow of 5%–20%, 20%–40%, 40%–60%, 60%–100%, 100%–200%, and / or a moderate or greater percentage (permitted by cardiac output) relative to the patient's rest. In some embodiments of the present invention, the patient’s peak oxygen uptake is between 8 and 20 ml O2 / min / Kg.

[0315] In some embodiments of the invention, patients are selected based on the amount of treatable heartbeats. For example, when patient safety is taken into consideration, cardiac contractility modulation stimulation can be used to treat at least 20%, 40%, 50%, 80%, or a moderate percentage of the heart.

[0316] In step 804, the patient's atrial arrhythmia status can optionally be determined; for example, the patient may be identified as having paroxysmal atrial fibrillation. Note that in some embodiments, patients without atrial fibrillation but at risk of developing it (e.g., having sleep apnea) are selected. In some embodiments of the invention, the patient spends between 0% and 10% of their time in atrial arrhythmias (e.g., more than one month on average), between 10% and 30% of their time in atrial arrhythmias, between 30% and 50% of their time in atrial arrhythmias, or more than 50% of their time in atrial arrhythmias, possibly between 90% and 100% of their time in atrial arrhythmias. An increase in percentage may indicate an increase in the severity of the atrial arrhythmia. In some embodiments of the invention, the estimated risk of a patient having a 5%, 10%, 20%, 30%, 50%, 70%, or intermediate or higher risk of developing an atrial arrhythmia (e.g., using clinical and / or diagnostic methods known in the art) or progressing to chronic atrial fibrillation in the following year is included.

[0317] At 806, the patient's heart failure status can optionally be determined. Optionally, the HF status is defined based on a lower-than-expected cardiac output. Note that in some embodiments, patients without significant heart failure (e.g., New York Heart Association Stage I and / or below) are treated. In other embodiments, patients with acceptable resting behavior (e.g., New York Heart Association Stage II or II) are treated. In some embodiments of the invention, New York Heart Association Stage IV patients are treated.

[0318] In 808, lung reserve status may be optionally determined. In some cases, cardiac systolic stimulation therapy is independent of respiratory status and / or the availability of respiratory reserve.

[0319] In 810, for example, patient suitability for treatment is determined based on anticipated improvement, the presence of a treatable disease, and / or anticipated preventative effects and / or anticipated cardiac response (e.g., anticipated number of treatment beats). Particularly noteworthy is the selection of patients because they have atrial fibrillation (or other atrial arrhythmias) or despite the presence of such arrhythmias.

[0320] In 812, the initial stimulation settings can be optionally determined, such as the desired lead location, the tissue affected by cardiac contractile modulation stimulation (and thus the signal amplitude and / or timing), and / or the applied logic.

[0321] In some embodiments of the invention, a combination of timing and amplitude is used to determine which tissue will be within the signal range from the lead, and for how long. Planning may involve setting a desired range of such values ​​and running a simulation or other solver to determine the signal application parameters that meet the requirements.

[0322] In 814, one or more leads are implanted in and / or near the heart, such as the right atrium and / or right ventricle. Optionally, existing leads (e.g., pacemaker and / or defibrillator leads) may be reused or used in parallel for the application of cardiac systolic modulation stimulation.

[0323] In some embodiments of the invention, lead locations are selected (e.g., non-interval) to reduce the charging of nerves or nerve plexuses, such as those inside or outside the heart, and / or to reduce stimulation of other chest tissues.

[0324] In some embodiments of the invention, the electrodes are external leads or other non-implantable leads, such as electrodes on a catheter, for short-term treatment, such as cardioversion. Optionally, the electrical current is applied via a needle that penetrates the skin and other outer layers of the body.

[0325] In step 816, the electrode to be stimulated can be selected optionally.

[0326] In 818, the effect of initial signal parameters can be optionally monitored.

[0327] In 820, parameters and / or logic can be selectively programmed and / or reprogrammed (e.g., in response to such monitoring), for example, using an external controller.

[0328] Note that this method, as described herein, may include a treatment planning phase (e.g., up to 812, 88, 820) followed by a treatment phase (e.g., 814, 816), one of which may optionally be omitted. Exemplary selection and / or treatment for non-atrial fibrillation patients.

[0329] Figure 9 This is a flowchart illustrating methods for patient selection and treatment planning, and optionally, the execution of treatments, for patients with cardiac output and additional cardiac dysfunction, according to some embodiments of the present invention. In some embodiments of the invention, both dysfunctions are treated using the same cardiac contractility modulation stimulation signal.

[0330] At 902, consider patients with heart failure and / or atrial arrhythmias, as well as additional existing or potential cardiac dysfunction.

[0331] In 904, for example, as referenced Figure 8 The condition is determined to be heart failure and / or atrial arrhythmia.

[0332] In 906, identify additional (one or more) functional impairments. Exemplary functional impairments include: HOCM, implants such as valves (e.g., mitral, aortic, tricuspid), clips (e.g., mitral or tricuspid), diseased and / or weakened tissue, such as where functional impairment may be present (e.g., diseased cardiac tissue) or is potential (e.g., clips not yet implanted).

[0333] At 910, the initial settings for cardiac contractility modulation stimulation treatment are determined. In some embodiments of the invention, such settings are selected to strike a balance between maximizing the therapeutic effect of one functional disorder and maximizing the therapeutic effect of another. For example, a lead position may be selected that provides less cardiac output enhancement but simultaneously provides a satisfactory level of atrial fibrillation prevention / treatment and / or avoids stimulation of diseased tissue and / or reduces mechanical problems of the heart.

[0334] In 912, one or more leads can be selectively implanted into the heart.

[0335] At 914, treatment begins, optionally after the implantation.

[0336] In 916, the effectiveness of this type of treatment was monitored.

[0337] In 918, the stimulation parameters can be optionally reset.

[0338] Exemplary operation of implants

[0339] Figure 10 This is an operation flowchart of a cardiac treatment device (e.g., device 200) according to some embodiments of the present invention.

[0340] In 1002, an atrial event (e.g., the onset of excitation or the presence of an arrhythmia) may be optionally detected.

[0341] In 1004, a ventricular event (e.g., the onset of excitation or the presence of an arrhythmia) may be optionally detected.

[0342] These detected events may optionally be used as inputs to one or both decisions to apply treatment and / or to decide whether to apply treatment. In some embodiments of the invention, the order is the reverse of that shown herein – a decision regarding the potential treatment is performed first, followed by the detection of one or more events (if any).

[0343] In 1006, alternatively, protocols in use (e.g., selected or calculated from a set) may be considered, such as “apply cardiac contractile modulation stimulation for 7 hours” or “apply cardiac contractile modulation stimulation in response to atrial fibrillation” or “apply cardiac contractile modulation stimulation to alter cardiac excitation so that HOCM is less likely to obstruct aortic outlet”, each of which is an exemplary possible application protocol.

[0344] In 1008, a specific desired effect may be considered, such as a reduction in atrial arrhythmias. This may occur, for example, if an atrial arrhythmia is detected in 1002, or if an urgent need to increase cardiac output is detected.

[0345] In 1010, a general effect may optionally be considered, for example, providing a general dose of cardiac contractile regulation stimulation to reverse fetal genetic programs.

[0346] In 1012, trade-offs between various effects are considered, such as choosing the applied parameters for treating atrial fibrillation at the cost of a smaller improvement in cardiac output.

[0347] At 1014, signal parameters are selected to achieve this trade-off. It is worth noting that in some cases, these parameters are selected before or after the trade-off. In some embodiments of the invention, these parameters are selected based on parameters that are expected to be applicable to the heart at the current or near-beating state.

[0348] In 1016, optionally in response to passing a safety test, a signal is applied to the heart.

[0349] In 1018, the effects of the applied signal are monitored, and the goals and / or protocols used for future applications can be modified. For example, if the signal is insufficient to stop atrial fibrillation, the signal can be increased (e.g., up to a threshold parameter value).

[0350] General

[0351] It is anticipated that many related non-excitatory cardiac treatments will be developed during the patent terminology of this application; the term non-excitatory is intended to encompass all such new technologies of priori.

[0352] As used in this article, the term "about" refers to a range of 10%.

[0353] The terms “comprises”, “comprising”, “includes”, “including”, “has”, “having” and their conjugates mean “including but not limited to”.

[0354] The term "consisting of" means "including and limited to".

[0355] The term "consisting essentially of" means that the composition, method, or structure may include additional components, steps, and / or portions, provided that such additional components, steps, and / or portions do not substantially alter the fundamental and novel characteristics of the claimed composition, method, or structure.

[0356] As used herein, the singular forms “a,” “an,” and “the” include plural references unless the context clearly indicates otherwise. For example, the terms “a compound” or “at least one compound” can include a variety of compounds, including mixtures thereof.

[0357] Throughout this application, embodiments of the invention may be presented in a scope format. It should be understood that the scope format is for convenience and brevity only and should not be construed as an inflexible limitation of the scope of the invention. Therefore, the scope description should be considered as having specifically disclosed all possible sub-scopes and individual numerical values ​​within those scopes. For example, a description of the scope "from 1 to 6" should be considered as having explicitly disclosed sub-scopes such as "from 1 to 3," "from 1 to 4," "from 1 to 5," "from 2 to 4," "from 2 to 6," and "from 3 to 6," as well as individual numbers within those scopes, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the scope.

[0358] Whenever a range of numbers is indicated herein (e.g., “10-15”, “10 to 15”, or any pair of numbers linked by these other such ranges), it is intended to include any number (fraction or integer) within the indicated range limit, including the range limit, unless the context explicitly states otherwise. The terms “range” / “ranging” / “ranges” between the first and second indicated numbers, and “range” / “ranging” / “ranges” from the first indicated number to, “up to”, “until”, “through” (or another such range indication term) the second indicated number, are used interchangeably herein and are intended to include the first and second indicated numbers and all decimals and integers between them.

[0359] Unless otherwise stated, the figures used herein and any ranges of figures based thereon are approximations within the reasonable range of measurement precision and rounding error as understood by those skilled in the art.

[0360] As used herein, the term "method" refers to the manner, means, technique, and process used to accomplish a given task, including, but not limited to, those manner, means, techniques, and processes known to or readily developed from known manner, means, techniques, and procedures by practitioners in the fields of chemistry, pharmacology, biology, biochemistry, and medicine.

[0361] As used herein, the term “treating” includes eliminating, substantially inhibiting, slowing or reversing the progression of a condition, substantially improving the clinical or aesthetic symptoms of the condition, or substantially preventing the occurrence of the clinical or aesthetic symptoms of the condition.

[0362] It should be understood that certain features of the invention described in the context of a single embodiment for clarity may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the invention described in the context of a single embodiment may also be provided individually or in any suitable sub-combination or suitably in any other described embodiment of the invention. Certain features described in the context of various embodiments should not be considered essential features of those embodiments unless the embodiments would not function without those elements.

[0363] Although the invention has been described in conjunction with specific embodiments thereof, it will be apparent to those skilled in the art that many alternatives, modifications, and variations will be readily apparent. Therefore, it is intended to cover all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0364] 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, or patent application were specifically and individually indicated to be incorporated herein by reference. Furthermore, any reference or designation of any reference in this application should not be construed as an admission that such reference is available as prior art to this invention. The use of section headings should not be construed as an inherent limitation. Additionally, any priority documents of this application are incorporated herein by reference in their entirety.

Claims

1. A cardiac treatment device, characterized in that, include: The stimulation circuit is configured to generate a cardiac contractility modulation stimulation (C2MS) non-excitatory electrical signal, which is configured to be applied to the ventricular tissue during a ventricular refractory period. Atrial arrhythmia detection circuit; as well as The determination circuit, when the atrial arrhythmia detection circuit detects an atrial arrhythmia, controls the stimulation circuit to transmit the signal during a ventricular refractory period.

2. The apparatus according to claim 1, characterized in that: The determination circuit is configured to modify at least one parameter of the signal in response to the detection of the atrial arrhythmia.

3. The apparatus according to claim 2, characterized in that: The modification includes increasing the spatial extent of the tissue stimulated by the signal.

4. The apparatus according to claim 1, characterized in that: The determination circuit is configured to prevent the transmission when a ventricular arrhythmia is detected.

5. The apparatus according to claim 1, characterized in that: The determination circuit is configured to allow the transmission when a supraventricular arrhythmia is detected.

6. The apparatus according to claim 1, characterized in that: The device includes a memory having an indication of a dose of the signal to be applied and a duration of application, and wherein the determination circuit is configured to modify an actual duration of signal application based on an actual delivery of the signal.

7. The apparatus according to claim 1, characterized in that: The device includes a recorder configured to record the effect of the applied force on the detected atrial arrhythmia.

8. The apparatus according to any one of claims 1-7, characterized in that: The device is configured to also apply the signal during a non-responsive period in an atrium.

9. The apparatus according to any one of claims 1-7, characterized in that: The device does not have an atrial lead.

10. The apparatus according to any one of claims 1-7, characterized in that: The device includes a pacing circuit, wherein, in the event of increased cardiac demand, the determination circuit is programmable to apply a non-excitatory signal instead of applying an increase in pacing.

11. The apparatus according to claim 10, characterized in that: The determination circuit is programmable to apply the non-excitatory signal in response to a cardiac parameter sensed by the device.

12. The apparatus according to any one of claims 1-7, characterized in that: The determination circuit defines a control window of several beats in which no signal is applied after an arrhythmia is detected, wherein the window is one or zero beats.

13. The apparatus according to any one of claims 1-7, characterized in that: The atrial arrhythmia detection circuit is configured to detect atrial arrhythmias from signals measured from one or more ventricular leads.

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