Increasing peak vo2 in hf patients using cardiac contractility modulation stimulation

Abstract

Methods and associated devices for enhancing peak VO2 in patients are disclosed.SOLUTION: A method of enhancing peak VO2, comprising: selecting a subject having an impaired peak VO2 and estimated to have a likelihood of improving peak VO2; and applying cardiac contractility modulation stimulation to the subject. The method includes detecting a ventricular contraction using one or more leads placed in a ventricle of the patient and applying a cardiac contractility modulating stimulus to the ventricle of the patient after a delay from a time of the detection.SELECTED DRAWING: Figure 1B

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of priority under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 924,782, filed October 23, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] This application is related to U.S. Provisional Patent Application No. 62 / 924,776, filed on the same day, entitled "Cardiac Contractility Modulation for Patients with Atrial Arrhythmia."

[0003] This application is a continuation of the following PCT applications filed on the same day by the same applicant, Impulse Dynamics NV: Attorney Docket No. 85068, entitled "Cardiac Contractility Modulation for Patients with Atrial Arrhythmia," applicant Impulse Dynamics NV; Attorney Docket No. 85069, entitled "Method for Planning and Delivering Cardiac Electrical Stimulation," applicant Impulse Dynamics NV; This application is part of a concurrent application under attorney docket number 85070 entitled "Regulation of Cardiac Contractility in Respiration Relation."

[0004] The contents of the above applications are incorporated by reference as if fully set forth herein.

[0005] The present invention, in some embodiments thereof, relates to increasing peak VO2 in a patient using cardiac contractility control stimulation. [Background technology]

[0006] Cardiac contractility modulation therapy is delivered by an implantable device that applies a non-excitatory electrical signal (NES) that is coordinated with and synchronized to electrical activity in the cardiac cycle. Other than a pacemaker that delivers an electrical signal intended to cause contractions of the heart, cardiac contractility modulation therapy applies an NES that is coordinated with and synchronized to electrical activity in the cardiac cycle.

[0007] In cardiac contractility modulation therapy, electrical stimulation is applied to the myocardium during the absolute refractory period. Because electrical stimulation does not induce new myocardial contractions during this phase of the cardiac cycle, this type of stimulation is known as non-excitatory stimulation (NES).

[0008] Additional background art includes U.S. Patent No. 6,480,737, entitled "Area Delivery Safety System Using Detection of Atypical ECG"; U.S. Patent No. 9,713,723, entitled "Signal Delivery Through the Right Ventricular Septum"; No. 4,554,922, which apparently suggests that electrical signals applied during the relative refractory period prolong the refractory period and make tissue less prone to arrhythmias; (1)Lyon AR, Samara MA and Feldman DS.Cardiac contractility modulation therapy in advanced systolic heart failure.Nat.Rev.Cardiol.2013;10:584-98 (2)Tschope C,Kherad B,Klein O,Lipp A,Blaschke F,Gutterman D,Burkhoff D,Hamdani N,Spillmann F and Van Linthout S.Cardiac contractility modulation:mechanisms of action in heart failure with reduced ejection fraction and beyond.Eur.J.Heart Fail.2019;21:14-22. (3)Borggrefe MM, Lawo T, Butter C, Schmidinger H, Lunati M, Pieske B, Misier AR, Curnis A, Bocker D, Remppis A, Kautzner J, Stuhlinger M, Leclerq C, Taborsky M, Frigerio M, Parides M, Burkhoff D, and Hindricks G. Randomized, double blind study of non-excitatory, cardiac contractility modulation electrical impulses for symptomatic heart failure. Eur. Heart J. 2008;29:1019-1028 (4)Neelagaru SB, Sanchez JE, Lau SK, Greenberg SM, Raval NY, Worley S, Kalman J, Merliss AD, Krueger S, Wood M, Wish M, Burkhoff D, and Nademanee K. Nonexcitatory, cardiac contractility modulation electrical impulses: Feasibility study for advanced heart failure in patients with normal QRS duration. Heart Rhythm. 2006;3:1140-1147. (5) Kadish A, Nademanee K, Volosin K, Krueger S, Neelagaru S, Raval N, Obel O, Weiner S, Wish M, Carson P, Ellenbogen K, Bourge R, Parides M, Chiacchierini RP, Goldsmith R, Goldstein S, Mika Y, Burkhoff D, and Abraham WT. A randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. Am. Heart J. 2011;161:329-337, e1-2. (6) Abraham WT, Nademanee K, Volosin K, Krueger S, Neelagaru S, Raval N, Obel O, Weiner S, Wish M, Carson P, Ellenbogen K, Bourge R, Parides M, Chiacchierini RP, Goldsmith R, Goldstein S, Mika Y, Burkhoff D, and Kadish A. Subgroup analysis of a randomized controlled trial evaluating the safety and efficacy of cardiac contractility modulation in advanced heart failure. J Card Fail. 2011;17:710-717. (7)Abraham WT, Kuck KH, Goldsmith RL, Lindenfeld J, Reddy VY, Carson PE, Mann DL, Saville B, Parise H, Chan R, Wiegn P, Hastings JL, Kaplan AJ, Edelmann F, Luthje L, Kahwash R, Tomassoni GF, Gutterman DD, Stagg A, Burkhoff D, and Hasenfuss G. A Randomized Controlled Trial to Evaluate the Safety and Efficacy of Cardiac Contractility Modulation. JACC. Heart Fail. 2018;6:874 - 883. (8)Yu CM, Chan JY, Zhang Q, Yip GW, Lam YY, Chan A, Burkhoff D, Lee PW, and Fung JW. Impact of cardiac contractility modulation on left ventricular global and regional function and remodeling. JACC. Cardiovasc. Imaging. 2009;2:1341 - 1349. (9)Kuschyk J, Roeger S, Schneider R, Streitner F, Stach K, Rudic B, Weiss C, Schimpf R, Papavasilliu T, Rousso B, Burkhoff D, and Borggrefe M. Efficacy and survival in patients with cardiac contractility modulation: long - term single center experience in 81 patients. Int. J. Cardiol. 2015;183:76 - 81. (10) Muller D, Remppis A, Schauerte P, Schmidt-Schweda S, Burkhoff D, Rousso B, Gutterman D, Senges J, Hindricks G, and Kuck KH. Clinical effects of long-term cardiac contractility modulation (CCM) in subjects with heart failure caused by left ventricular systolic dysfunction. Clin. Res. Cardiol. 2017;106:893-904. (11) Anker SD, Borggrefe M, Neuser H, Ohlow MA, Roger S, Goette A, Remppis BA, Kuck KH, Najarian KB, Gutterman DD, Rousso B, Burkhoff D, and Hasenfuss G. Cardiac contractility modulation improves long-term survival and hospitalizations in heart failure with reduced ejection fraction. Eur. J. Heart Fail. 2019. (12) Liu M, Fang F, Luo XX, Ben Haim S, Burkhoff D, Chan JY, Chan CP, Cheung L, Rousso B, Gutterman D, and Yu CM. Improvement of long-term survival by cardiac contractility modulation in heart failure patients: A case-control study. Int. J. Cardiol. 2016;206:122-126. (13)Wang Y,Hou W,Zhou C,Yin Y,Lu S,Liu G,Duan C,Cao M,Li M,Toft ES and Zhang HJ.Meta-analysis of the incidence of lead dislodgement with conventional and leadless pacemaker systems.Pacing Clin.Electrophysiol.2018;41:1365-1371. (14) Ibrahim JG and Chen MH. Power prior distributions for regression models. Statist Sci. 2000;15:46-60. (15) Schuirmann DJ.A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability.J.Pharmacokinet.Biopharm.1987;15:657-80.

[0009] The disclosures of all references cited above and throughout this specification, as well as all references cited within those references, are hereby incorporated by reference. Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention, in some embodiments thereof, relates to increasing peak VO2 in a patient using cardiac contractility control stimulation. [Means for solving the problem]

[0011] Some aspects of the invention include: selecting a patient suitable for cardiac contractility stimulation to increase their peak VO2; Using cardiac contractility stimulation in a patient to increase their peak VO2; Using cardiac contractility control with only two leads; A potential benefit of reducing the number of leads, specifically the atrial lead, is known to be fewer intravenous leads; using input sensing only from the cardiac ventricles; determining when to apply cardiac contractility control stimulation using input sensing from only one or two leads.

[0012] According to some aspects of embodiments of the present disclosure, there is provided a method for planning cardiac contractility control therapy for a patient to enhance peak VO2, the method including selecting a patient who is estimated to have impaired peak VO2 and have the potential to improve peak VO2, and planning cardiac contractility control therapy for the patient.

[0013] According to some embodiments of the present disclosure, selecting includes selecting a patient who already has an implant suitable for providing cardiac contractility modulation therapy.

[0014] According to some embodiments of the present disclosure, selecting includes selecting a patient who is not known to have another medical condition that may prevent them from increasing peak VO2.

[0015] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient estimated to have pulmonary reserve.

[0016] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient with a peak VO2 value below 25 mlO2 / min / kg.

[0017] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient with a peak VO2 value below 20 mlO2 / min / kg.

[0018] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient with a peak VO2 value greater than 5 mlO2 / min / kg.

[0019] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient with a peak VO2 value greater than 9 mlO2 / min / kg.

[0020] According to some embodiments of the present disclosure, selecting the patient includes selecting the patient to be in a NYHA class selected from the group consisting of NYHA class II, NYHA class III, and NYHA class IVa.

[0021] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient with at least one pulmonary condition selected from the group consisting of a respiratory reserve (BR) greater than 30%, an oxygen uptake efficiency slope (OUES) less than 90%, a peak RER greater than 1.05, a VE / VCO2 ratio greater than 30, and O2 saturation that does not decline rapidly during exercise, e.g., declines by less than 10% over 20 minutes of exercise.

[0022] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient with an ejection fraction above 25% and below 50%.

[0023] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient with an ejection fraction above 35% and below 45%.

[0024] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient with heart failure.

[0025] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient with at least one condition selected from the group consisting of atrial fibrillation (AF), systolic heart failure (HF), diastolic HF, atrial tachycardia, angina pectoris, myocarditis, small vessel disease, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), and sleep apnea.

[0026] According to some embodiments of the present disclosure, planning includes planning a therapy that combines an additional cardiac therapy to provide cardiac contractility modulation therapy.

[0027] According to some embodiments of the present disclosure, selecting the patient includes selecting a patient who has impaired peak VO2 and is not known to have another medical condition that may limit increasing peak VO2, including selecting a patient who is not known to have a condition selected from the group consisting of limited pulmonary uptake of oxygen, pulmonary disease, limited blood flow, and peripheral vascular disease.

[0028] According to some embodiments of the present disclosure, the method further includes detecting an inappropriate beat if a difference between a ventricular contraction detected by the first ventricular lead and a ventricular contraction detected by the second ventricular lead exceeds 30 milliseconds, and not planning to apply cardiac contractility modulation stimulation.

[0029] According to an aspect of some embodiments of the present invention, there is provided a method for increasing peak VO2, comprising selecting a patient who has impaired peak VO2 and is estimated to have the potential to improve peak VO2, and applying cardiac contractility control stimulation to the patient's heart.

[0030] According to some embodiments of the present invention, selecting includes selecting a patient who is not known to have another medical condition that may prevent increasing peak VO2.

[0031] According to some embodiments of the invention, selecting comprises selecting a patient estimated to have pulmonary reserve.

[0032] According to some embodiments of the invention, selecting the patient comprises selecting a patient with a peak VO2 value below 25 mLO2 / min / kg. According to some embodiments of the invention, selecting the patient comprises selecting a patient with a peak VO2 value below 20 mLO2 / min / kg.

[0033] According to some embodiments of the invention, selecting the patient comprises selecting a patient with a peak VO2 value greater than 5 mLO2 / min / kg. According to some embodiments of the invention, selecting the patient comprises selecting a patient with a peak VO2 value greater than 9 mLO2 / min / kg.

[0034] According to some embodiments of the invention, selecting the patient comprises selecting the patient to be in a NYHA class selected from the group consisting of NYHA class II, NYHA class III, and NYHA class IVa.

[0035] According to some embodiments of the invention, selecting the patient includes selecting a patient with at least one pulmonary condition selected from the group consisting of a respiratory reserve (BR) greater than 30%, an oxygen uptake efficiency slope (OUES) less than 90%, a peak RER greater than 1.05, a VE / VCO2 ratio greater than 30, and O2 saturation that does not decline rapidly during exercise, e.g., a decline of less than 10% over 20 minutes of exercise.

[0036] According to some embodiments of the invention, selecting the patient comprises selecting a patient with an ejection fraction greater than 25% and less than 50%. According to some embodiments of the invention, selecting the patient comprises selecting a patient with an ejection fraction greater than 35% and less than 45%.

[0037] According to some embodiments of the invention, selecting the patient includes selecting a patient with heart failure.

[0038] According to some embodiments of the invention, selecting the patient includes selecting a patient with at least one condition selected from the group consisting of atrial fibrillation (AF), systolic heart failure (HF), diastolic HF, atrial tachycardia, angina pectoris, myocarditis, small vessel disease, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), and sleep apnea.

[0039] According to some embodiments of the invention, selecting the patient includes selecting a patient who has impaired peak VO2 and is not known to have another medical condition that may limit increasing peak VO2, including selecting a patient who is not known to have a condition selected from the group consisting of limited pulmonary uptake of oxygen, lung disease, limited blood flow, and peripheral vascular disease.

[0040] According to some embodiments of the present invention, applying cardiac contractility control stimulation to the patient's heart includes using two leads to apply cardiac contractility control stimulation.

[0041] According to some embodiments of the present invention, applying cardiac contractility control stimulation to the patient's heart includes using three leads to apply cardiac contractility control stimulation.

[0042] According to some embodiments of the present invention, applying cardiac contractility modulation stimulation to the patient's heart includes using at least one lead including two electrodes.

[0043] According to some embodiments of the present invention, applying cardiac contractility modulation stimulation to the patient's heart includes using at least one lead including at least one bipolar electrode.

[0044] According to some embodiments of the present invention, applying cardiac contractility modulation stimulation to the patient's heart includes using one or more leads positioned at a location selected from the group consisting of the interventricular septum, the right ventricle, the left ventricle, a location in the right ventricle, and a location in the left ventricle.

[0045] According to some embodiments of the present invention, applying cardiac contractility modulation stimulation to the patient's heart includes using two leads positioned in the ventricular wall.

[0046] According to some embodiments of the present invention, the method further includes implanting a cardiac contractility regulation device and lead in the selected patient.

[0047] According to some embodiments of the present invention, the method further includes detecting an inappropriate beat and preventing application of cardiac contractility modulation if a difference between a ventricular contraction detected by the first ventricular lead and a ventricular contraction detected by the second ventricular lead exceeds 30 milliseconds.

[0048] According to some embodiments of the present invention, the application of cardiac contractility modulation is inhibited for one cardiac cycle.

[0049] According to an aspect of some embodiments of the present invention, there is provided a method of increasing peak VO2, comprising detecting ventricular contraction using one or more leads in a ventricle of a patient, and applying a cardiac contractility modulation stimulus to the ventricle of the patient after a delay from the time of detection, thereby increasing the patient's peak VO2.

[0050] According to some embodiments of the present invention, applying cardiac contractility modulation in the ventricle is performed during the ventricular refractory period and not the atrial refractory period.

[0051] According to some embodiments of the present invention, the method further comprises applying cardiac contractility modulation to the atrium.

[0052] According to some embodiments of the present invention, the detecting and applying are repeated over a period of 12 weeks, and an increase in the patient's peak VO2 is observed after 12 weeks.

[0053] According to aspects of some embodiments of the present invention, there is provided a method of increasing peak VO2, comprising detecting ventricular contractions using no more than two leads placed in a patient's ventricle and no leads placed in the patient's atrium, and applying a cardiac contractility control stimulus to the patient's heart after a delay from the time of detection, thereby increasing the patient's peak VO2.

[0054] According to some embodiments of the invention, the detecting includes detecting using only one lead placed in the patient's ventricle, and the applying cardiac contractility modulation stimulation to the patient's heart includes using the same one lead placed in the patient's ventricle.

[0055] According to aspects of some embodiments of the present invention, there is provided a method of increasing peak VO2, comprising detecting ventricular contractions using no more than two leads placed in a patient's ventricle and no sensing using leads placed in the patient's atrium, and applying cardiac contractility modulation stimulation to the patient's heart even during atrial fibrillation, thereby increasing the patient's peak VO2.

[0056] According to aspects of some embodiments of the present invention, there is provided a method of increasing peak VO2, comprising detecting ventricular contraction using one or more leads in a patient's ventricle, and applying a cardiac contractility modulation stimulus to the patient's ventricle after a delay from the time of detection, thereby improving the patient's NYHA class by at least one class compared to the patient's baseline.

[0057] According to aspects of some embodiments of the present invention, there is provided a method of increasing peak VO2, comprising detecting ventricular contraction using one or more leads in a patient's ventricle, and applying a cardiac contractility modulation stimulus to the patient's ventricle after a delay from the time of detection, thereby improving the patient's NYHA class by at least 0.5 classes compared to the patient's baseline.

[0058] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of embodiments of this invention, exemplary methods and / or materials are described below. In case of conflict, the present specification, including definitions, will control. Additionally, the materials, methods, and examples are illustrative only and are not necessarily intended to be limiting.

[0059] As will be appreciated by those skilled in the art, some embodiments of the present invention may be embodied as a system, method, or computer program. Accordingly, some embodiments of the present invention may take the form of an entirely hardware embodiment, an entirely software embodiment (including firmware, resident software, microcode, etc.), or an embodiment combining software and hardware aspects, all of which may be generally referred to herein as a "circuit," "module," or "system." Furthermore, some embodiments of the present invention may take the form of a computer program embodied in one or more computer-readable medium(s) having computer-readable program code embodied thereon. Implementation of the methods and / or systems of some embodiments of the present invention may involve performing and / or completing selected tasks manually, automatically, or a combination thereof. Furthermore, according to the instrumentation and apparatus of some embodiments of the methods and / or systems of the present invention, some selected tasks may be implemented by hardware, software, or firmware, and / or a combination thereof, e.g., using an operating system.

[0060] For example, hardware for performing selected tasks according to some embodiments of the present invention may be implemented as a chip or circuit. As software, selected tasks according to some embodiments of the present invention may be implemented as a plurality of software instructions executed by a computer using a suitable operating system. In exemplary embodiments of the present invention, one or more tasks according to some exemplary embodiments of the methods and / or systems as described herein are performed by a data processor, such as a computer platform that executes a plurality of instructions. Optionally, the data processor includes volatile memory for filtering instructions and / or data, and / or non-volatile storage, such as a magnetic hard disk and / or removable media for filtering instructions and / or data. Optionally, a network connection is also provided. Optionally, a display and / or a user input device, such as a keyboard or mouse, are also provided.

[0061] Combinations of one or more computer-readable medium(s) may be utilized in some embodiments of the present invention. The computer-readable medium may be a computer-readable signal medium or a computer-readable storage medium. The computer-readable storage medium may be, for example, but not limited to, an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system, apparatus, or device, or any suitable combination of the foregoing. More specific examples (a non-exhaustive list) of computer-readable storage media include the following: an electrical connection having one or more cables, a portable floppy disk, a hard disk, a random access memory (RAM), a read-only memory (ROM), an erasable programmable read-only memory (EPROM or flash memory), optical fiber, a portable compact disc read-only memory (CD-ROM), an optical storage device, a magnetic storage device, or any suitable combination of the foregoing. In the context of this document, a computer-readable storage medium may be any tangible medium that contains or can store a program for use by or in connection with an instruction execution system, apparatus, or device.

[0062] A computer-readable signal medium may include, for example, a propagated data signal with computer-readable program code embodied therein, in baseband or as part of a carrier wave. Such a propagated signal may take any of a variety of forms, including, but not limited to, electromagnetic, optical, or any suitable combination thereof. A computer-readable signal medium may also be a computer-readable medium that is not a computer-readable storage medium and that can carry, propagate, or transport a program for use by or in connection with an instruction execution system, apparatus, or device.

[0063] The program code embodied in the computer readable medium and / or data used thereby may be transmitted using any suitable medium, including but not limited to wireless, wired, fiber optic cable, RF, etc., or any suitable combination of the foregoing.

[0064] Computer program code for carrying out operations for some embodiments of the present invention may be written in any combination of one or more programming languages, including, for example, object-oriented programming languages ​​such as Java, Smalltalk, C++, etc., and conventional procedural programming languages ​​such as the "C" programming language or similar programming languages. The program code may execute entirely on the user's computer, partially on the user's computer, as a stand-alone software package, partially on the user's computer and partially on a remote computer, or entirely on a remote computer or server. In the latter scenario, the remote computer may be connected to the user's computer via any type of network, including a local area network (LAN) or a wide area network (WAN), or the connection may be to an external computer (e.g., via the Internet using an Internet Service Provider).

[0065] Some embodiments of the present invention may be described below with reference to flowchart illustrations and / or block diagrams of methods, apparatus (systems), and computer program products according to embodiments of the present invention. It will be understood that each block of the flowchart illustrations and / or block diagrams, and combinations of blocks in the flowchart illustrations and / or block diagrams, can be implemented by computer program instructions. The computer program instructions may be provided to a general-purpose computer, a processor of a special-purpose computer, or a programmable data processing device that makes a machine, such that the instructions, executing via the computer's processor or other programmable data processing device, create means for performing the function(s) / acts indicated in the block(s) of the flowchart and / or block diagrams.

[0066] These computer program instructions may be stored on a computer-readable medium that can direct a computer, other programmable data processing apparatus, or other device to function in a particular manner, such that the instructions stored on the computer-readable medium create an article of manufacture that includes instructions that implement the functions / acts indicated in the flowchart and / or block diagram blocks.

[0067] The computer program instructions may be loaded into a computer, other programmable data processing apparatus, or other device to produce a series of operational steps that are executed on the computer, other programmable data processing apparatus, or other device to create a computer-implemented process such that the instructions executing on the computer or other programmable apparatus provide a process for performing the function(s) / acts indicated in the block(s) of the flowcharts and / or block diagrams.

[0068] Some of the methods described herein are generally designed for computational use only and may not be feasible or practical for purely manual performance by a human expert. For example, a human expert wishing to manually perform a similar task, such as providing an electrical signal to a heart, may be expected to use an entirely different method, e.g., one that uses the expert's knowledge and / or the pattern recognition capabilities of the human brain, which is far more efficient than manually experiencing the steps of the methods described herein.

[0069] Several embodiments of the present invention are described herein, by way of example only, with reference to the accompanying drawings. With specific reference now to the detailed drawings, it is emphasized that the matter shown is by way of example and for purposes of illustrative discussion of embodiments of the present invention. In this regard, the description taken in conjunction with the drawings will make apparent to those skilled in the art how embodiments of the invention may be practiced. [Brief explanation of the drawings]

[0070] [Figure 1A] 1 shows a graph of peak VO2 over time comparing the control group from the FIX-HF-5C study with the cardiac contractility control treatment group from the FIX-HF-5C2 study according to an example embodiment of the present invention. [Figure 1B] 1 is a graph showing the treatment effect between groups over time (difference between cardiac contractility modulation treatment group and control group) according to an example embodiment of the present invention. [Figure 2] A) NYHA functional class distribution at week 24 compared to baseline in the control group. B) NYHA functional class distribution at week 24 compared to baseline in the 2-Lead Optimizer group. [Figure 3A] 1 is an image of a cardiac contractility regulation device according to an example embodiment of the present invention. [Figure 3B] 1 is an illustration of a simplified block diagram of a cardiac therapy device according to an example embodiment of the present invention. [Figure 3C]1 is a simplified line drawing of an ECG signal and a cardiac contractility modulation stimulation signal according to an example embodiment of the present invention. [Figure 4] 1 is a simplified line drawing of a heart showing the location of various tissues and electrodes / leads according to an example embodiment of the present invention. [Figure 5A] 1 is a simplified flowchart illustration of a method for increasing peak VO2 according to an example embodiment of the present invention. [Figure 5B] 1 is a simplified flowchart illustration of a method for increasing peak VO2 according to an example embodiment of the present invention. [Figure 6] 1 is a simplified flowchart illustration of a method for planning cardiac contractility modulation therapy for a patient to enhance peak VO2 according to an example embodiment. DETAILED DESCRIPTION OF THE INVENTION

[0071] The present invention, in some embodiments thereof, relates to the use of cardiac contractility modulation stimulation to increase peak VO2 in a patient.

[0072] Cardiac contractility modulation is a therapy aimed at treating symptomatic heart failure patients who can benefit from improved cardiac output. The use of this therapy increases the strength of ventricular contractions, thereby enhancing the heart's pumping power by modulating (regulating) myocardial contractility.

[0073] Cardiac contractility modulation therapy is delivered by a pacemaker-like device that applies a non-excitatory electrical signal (NES) that is coordinated with and synchronized with the electrical activity in the cardiac cycle. Unlike a pacemaker that delivers an electrical signal intended to produce a contraction of the heart, cardiac contractility modulation therapy applies an NES that is coordinated with and synchronized with the electrical activity in the cardiac cycle.

[0074] In cardiac contractility modulation therapy, electrical stimulation is applied to the myocardium during the absolute refractory period. Because the electrical signal does not induce new myocardial contractions during this phase of the cardiac cycle, this type of stimulation is known as non-excitatory stimulation.

[0075] It is known that in some embodiments, cardiac contractility modulation signals may be excitatory to tissues other than the tissue to which they are applied. Various mechanisms by which cardiac contractility modulation signals may operate are described, for example, in “Cardiac contractility modulation: mechanisms of action in heart failure with reduced ejection fraction and beyond” by C. Tschope et al., European Journal of Heart Failure (2018), doi:10.1002 / ejhf.1349, and may help guide the selection of signal application parameters to take advantage of and / or follow one or more of these mechanisms.

[0076] For purposes of better understanding certain embodiments of the present invention, as illustrated in Figures 1A, 1B, 2A, 2B, 3B, 4-5B, and 6 of the drawings, reference will first be made to the structure and operation of a cardiac contractility regulation device as illustrated in Figure 3A.

[0077] Reference is now made to FIG. 3A, which is an image of a cardiac contractility regulation device according to an example embodiment of the present invention.

[0078] FIG. 3A illustrates a cardiac contractility control device 320 that can be used to provide cardiac contractility control therapy in a patient to enhance peak VO2.

[0079] Before describing at least one embodiment of the invention in detail, it is to be understood that the invention is not necessarily limited in its application to the details of construction and the arrangement of components and / or methods set forth in the following description and / or illustrated in the drawings, as the invention is capable of other embodiments or of being practiced or carried out in various ways.

[0080] Summary of the implementation An aspect of some embodiments of the present invention relates to selecting patients for whom a cardiac contractility modulation device may be used to increase their peak VO2; in some embodiments, the selection is based on the patient's pulmonary reserve.

[0081] Aspects of some embodiments of the present invention relate to treating a patient using cardiac contractility modulation therapy to increase the patient's peak VO2.

[0082] Aspects of some embodiments of the present invention relate to treating patients using contractile modulation therapy without an atrial lead and / or without atrial sensing and / or that ignores atrial status; in some embodiments, using only two ventricular leads; in some embodiments, using only one ventricular lead, optionally using morphology to assess whether the patient has a ventricular arrhythmia. In some embodiments, applying contractile modulation therapy without input from an atrial lead potentially ignores atrial fibrillation (AF) and potentially provides contractile modulation stimulation even during AF. In such embodiments, the dose of contractile modulation (number of contractile modulation stimulations per time unit) is potentially increased compared to sensing AF, and no contractile modulation stimulation is provided when AF is detected.

[0083] Overview An aspect of some embodiments of the present invention relates to selecting patients for whom cardiac contractility modulation therapy to enhance peak VO2 is planned.

[0084] In some embodiments, if the patient has an implant that is capable of providing cardiac contractility modulation therapy in addition to whatever other therapies the implant is capable of providing, the plan to provide cardiac contractility modulation therapy is based on the patient's cardiac condition and / or the patient's pulmonary condition.

[0085] In some embodiments, the patient's pulmonary condition is evaluated for suitability for providing cardiac contractility control to enhance peak VO2. In some embodiments, the patient's pulmonary condition is evaluated for the presence of pulmonary limitation as described further below. If the patient's pulmonary condition is such that the patient would benefit from improved peak VO2, it is planned to provide cardiac contractility control therapy in conjunction with additional cardiac therapy(ies) or by itself.

[0086] In some embodiments, the patient's cardiac condition is assessed to determine whether a cardiac therapy should be provided in addition to the cardiac contractility control. If the patient's cardiac condition indicates that the patient could benefit from an improvement in peak VO2, then a cardiac contractility control therapy is planned to be provided. If the patient's cardiac condition indicates that an additional cardiac therapy is desirable, then a cardiac contractility control therapy is optionally planned to be provided along with the additional cardiac therapy(ies) via electrical stimulation and / or drug therapy.

[0087] In some embodiments, a treatment plan is selected for the patient that may include providing cardiac contractility modulation therapy alone; providing cardiac contractility modulation therapy in conjunction with treatment of the patient's cardiac condition; or not providing cardiac contractility modulation therapy.

[0088] In some embodiments, potential patients are identified, tests are performed to assess and / or quantify one or more of the patient's pulmonary and cardiac conditions, and a suitable or even most suitable cardiac contractility modulation therapy is optionally selected for the patient.

[0089] An aspect of some embodiments of the present invention relates to a patient planning process. In some embodiments of the present invention, patients with impaired peak VO2 or at risk for impaired peak VO2 are presented, who may have heart failure. Such patients are optionally treated using cardiac contractility modulation therapy, for example, by implanting a therapeutic device and / or reprogramming an already implanted device. Treating patients using electrical stimulation may cause side effects and require trade-offs between different outcomes, for example, pain levels.

[0090] In some embodiments of the invention, an initial treatment is set, and parameters of the treatment are altered according to the effectiveness of the treatment and / or the implanted device is reprogrammed, it being understood that such reprogramming may be required even if the initial treatment plan appears optimal, for example, due to changes in the patient's physiological condition.

[0091] In some embodiments of the invention, the caregiver takes into account multiple considerations (e.g., as described herein), including, for example, the level of pain, the desired effect of increasing peak VO2, the desired heart failure-related effect, the potential effect of electrode and lead positioning, and / or the type of existing cardiac arrhythmia (e.g., ventricular) of the patient.

[0092] In some embodiments of the invention, a computer or table is used to determine the initial treatment. For example, the computer may contain rules or tables that dictate parameters and their expected effects, and the caregiver may select or be provided with a treatment plan that meets various requirements. Optionally, or in addition, the caregiver may input such a proposed treatment plan and have such a computer evaluate it.

[0093] In some embodiments of the invention, a computer is programmed with a dataset that collates one or more treatment effects of one or more treatment regimens by one or more parameters for patients with one or more characteristics. In some embodiments of the invention, machine learning methods are used to analyze such datasets to generate a parametric model (or other model) that can be queried to assess the expected range of treatment effects for the patient, or that can be used to automatically or semi-automatically search for suggested treatments.

[0094] An aspect of some embodiments of the present invention relates to selecting patients for the application of cardiac contractility modulation therapy to enhance peak VO2.

[0095] Cardiac contractility modulation therapy potentially increases the flow of oxygenated blood in a patient by, for example, between 5% and 20%, 20% and 40%, 40% and 60%, 60% and 100%, 100% and 200% and / or intermediate or even greater percentages compared to resting state.

[0096] Contractility control therapy potentially improves peak VO2 in the patient compared to the patient's baseline peak VO2 during contractility control therapy.

[0097] Contractility control therapy potentially improves peak VO2 in a patient compared to the patient's baseline peak VO2 even after contractility control therapy is stopped.

[0098] In some embodiments, the selected patients include patients with CHF.

[0099] In some embodiments, patients are selected based on their NYHA functional class. In some embodiments, patients are selected from NYHA classes II, III, and IVa. Such patients may potentially benefit from cardiac contractility control therapy and may be improved by 1 functional class, a full NYHA functional class, or at least a partial class, e.g., half a class, compared to the patient's baseline before cardiac contractility control therapy.

[0100] In some embodiments of the present invention, patients are selected for treatment based on the condition that peak VO2 is limited by cardiac considerations.

[0101] In some embodiments, the selected patients include patients with atrial fibrillation (AF), as well as those with persistent AF, where the cardiac contractility control therapy is delivered by a lead in the ventricle of the heart, and the patient's atrial rhythm does not affect the delivery of the cardiac contractility control therapy.

[0102] In some embodiments, cardiac contractility control therapy is optionally provided during the ventricular refractory period and not the atrial refractory period, potentially allowing for a longer delay after R-wave detection compared to cardiac contractility control therapy limited to the atrial refractory period.

[0103] In some embodiments, cardiac contractility modulation therapy is optionally provided to the atria at any time, and such stimulation does not potentially affect the HR of the heart due to the condition of atrial fibrillation.

[0104] In some embodiments, a strong cardiac contractility modulation stimulus is optionally provided that can activate the ventricles during the ventricular refractory period.

[0105] In some embodiments, low amplitude stimulation that does not activate the ventricles is optionally provided at any time.

[0106] In some embodiments, the patients selected include those in New York Heart Association (NYHA) functional class II / III / IVa who are participating in the trials described below.

[0107] In some embodiments, the selected patients include patients who are not known to have additional non-cardiac limitations for regulating cardiac contractility to enhance peak VO2.

[0108] Such additional restrictions include: Restrictions in the pulmonary intake of oxygen, such as those caused by lung disease; Restrictions in blood flow, such as those caused by restricted blood vessels; Peripheral blood flow restriction, such as caused by peripheral vascular damage may be mentioned.

[0109] In some embodiments, patients selected for cardiac contractility modulation therapy to enhance peak VO2 are patients who do not have pulmonary limitation or do not have pulmonary limitation above a certain limit.

[0110] It is known that increasing peak VO2 may require the patient to have some pulmonary reserve. Optionally, patients are selected if their respiratory reserve (e.g., potential increase in lung effectiveness) is at least 10%, at least 20%, at least 30%, at least 50%, or intermediate or greater values. A respiratory reserve (BR) below 30% is often considered low and indicates pulmonary disease that may limit improvement in peak VO2. BR may be defined as the difference between maximal voluntary ventilation (MVV) and the maximum ventilation measured during an exercise test.

[0111] In some embodiments of the invention, a patient is considered to potentially have useful pulmonary reserve based on the patient's oxygen uptake efficiency slope (OUES), for example, which is below 95%, 90%, 89%, 85%, 70% or an intermediate value.

[0112] In some embodiments of the invention, a patient is considered to potentially have useful pulmonary reserve based on the patient's peak RER being above, for example, 1, 1.05, 1.1, 1.15, or an intermediate value.

[0113] In some embodiments of the present invention, patients are considered to potentially have useful pulmonary reserve based on their AT being low rather than normal or crossing.

[0114] In some embodiments of the invention, a patient is considered to potentially have useful pulmonary reserve based on the patient's VE / VCO2 ratio being above, for example, 25, 30, 35, or an intermediate value.

[0115] In some embodiments of the invention, a patient is considered to potentially have useful pulmonary reserve based on the patient's O2 saturation not declining and / or not declining rapidly during exercise, e.g., declining by less than 20%, 10%, 5% or an intermediate value over a 20 minute period of exercise.

[0116] In some embodiments, patients selected for cardiac contractility modulation therapy to enhance peak VO2 include those receiving: atrial fibrillation (AF); systolic heart failure (HF); diastolic HF; atrial tachycardia; angina pectoris; myocarditis; small vessel disease; pulmonary hypertension; chronic obstructive pulmonary disease (COPD); sleep apnea; For example, peak VO2 measured at less than 20 mlO2 / min / kg, or even 25 mlO2 / min / kg - patients who may potentially benefit from increasing peak VO2; For example, a peak VO2 measured above 9 mlO2 / min / kg or even 5 mlO2 / min / kg Patients with one or more of the following are included:

[0117] In some embodiments, high risk patients are not selected for treatment with cardiac contractility modulation therapy.

[0118] In some embodiments, high-risk patients are also selected for treatment with cardiac contractility modulation therapy.

[0119] In some embodiments of the present invention, it is assumed that patients with higher peak VO2 have greater pulmonary reserve.

[0120] An aspect of some embodiments of the present invention relates to selecting a lead configuration for use in applying cardiac contractility modulation therapy to enhance peak VO2.

[0121] How many leads In some embodiments, the number of leads for use in cardiac contractility modulation therapy is selected.

[0122] In some embodiments, if the patient does not have a pre-existing implanted cardiac contractility regulation device and lead, a cardiac contractility regulation device with two leads is selected for implantation. Potential benefits of reducing the number of leads, and specifically reducing atrial leads, are known to have fewer leads in the venous system. Potential benefits of reducing the number of leads include reducing vessel blockage(s) and / or reducing supra-aortic syndrome.

[0123] In some embodiments, if the patient already has an implanted cardiac contractility regulation device and leads, the cardiac contractility regulation device is optionally programmed to sense the heart and / or apply cardiac contractility regulation therapy using only two leads.

[0124] In some embodiments, the cardiac contractility modulation device is optionally programmed to sense the heart and / or apply cardiac contractility modulation stimulation using more than just two leads.

[0125] In some embodiments, the cardiac contractility modulation device is optionally programmed to sense the heart on a lead different from that used to apply the cardiac contractility modulation stimulation.

[0126] In some embodiments, one or more of the leads are optionally used both for sensing and for applying cardiac contractility modulation stimulation.

[0127] In some embodiments, one or more of the leads includes one electrode or contact.

[0128] In some embodiments, one or more of the leads includes a bipolar lead with two electrodes.

[0129] In some embodiments, two leads are selected and used to apply cardiac contractility modulation therapy, each one of the two leads being associated with two electrodes.

[0130] In some embodiments, four leads are selected and used to apply cardiac contractility modulation therapy.

[0131] Where to sense In some embodiments, only one or two leads are used to sense the heart and determine when to apply cardiac contractility modulation therapy.

[0132] In some embodiments, a third, additional lead is used to sense electrical signals in the heart and detect the appropriate time to apply cardiac contractility modulation therapy. In some embodiments, the third sensing lead is optionally placed in the atrium, optionally in the right atrium.

[0133] In some embodiments, two leads are selected and used to apply cardiac contractility modulation therapy, and a third additional lead is used for sensing.

[0134] Where to apply cardiac contractility modulation stimuli An aspect of some embodiments of the present invention relates to selecting a location or locations for lead placement for use in applying cardiac contractility modulation therapy to enhance peak VO2.

[0135] In some embodiments, only two leads are selected and used to apply cardiac contractility modulation stimulation, hi some embodiments, each lead acts as one pole of bipolar stimulation.

[0136] In some embodiments, when two leads are used for cardiac contractility modulation stimulation, the two leads are optionally placed in the following positions: Both leads in the interventricular septum; Both leads in the right ventricle and, in some embodiments, one or both leads to the interventricular septum; Both leads in the left ventricle and, in some embodiments, one or both leads to the interventricular septum; one lead in the left ventricle and one lead in the right ventricle, and in some embodiments one or both leads to the interventricular septum; one lead in the atrium and one lead in the ventricle; At least one lead placed between the ventricle and the atrium; and U.S. Patent No. 9,713,723, entitled "Signal Delivery Through the Right Ventricular Septum," describes administering cardiac contractility modulation therapy via two leads placed against the ventricular septum. In some embodiments, methods taught in the above-referenced patents are used to administer cardiac contractility modulation therapy via two leads placed against the ventricular septum.

[0137] In some embodiments, the lead for applying cardiac contractility modulation stimulation is placed in the ventricle and is placed toward the apex of the heart rather than toward the atrium, for example, more than midway from the atrium along the ventricular wall toward the apex.

[0138] In some embodiments, if two leads are used, one of the two leads may be used for sensing.

[0139] In some embodiments, three leads are selected and used to apply cardiac contractility regulation therapy. In some embodiments, if the patient does not have a pre-existing cardiac contractility regulation device and leads implanted, a cardiac contractility regulation device with three leads is selected for implantation.

[0140] In some embodiments, when a sensing lead is used in addition to the two leads, the leads are optionally placed in the following locations: By way of non-limiting example, as shown in FIG. 4, two activation leads in the interventricular septum and a sensing lead in one of the left and right atria (not shown in FIG. 4).

[0141] An aspect of some embodiments of the present invention relates to selecting the type of cardiac contractility control device to implant for use in applying cardiac contractility control therapy to enhance peak VO2.

[0142] Clearly, the use of a two-lead cardiac contractility control device is sufficient to implement cardiac contractility control therapy to enhance peak VO2. U.S. Patent No. 6,480,737, entitled "Regional Delivery Safety System Using Atypical ECG Detection," describes how cardiac contractility control can be implemented without atrial sensing leads. In some embodiments, the methods taught in the above-referenced patents are used to implement cardiac contractility control therapy without atrial sensing.

[0143] In some embodiments, one or more of the leads used to apply cardiac contractility modulation stimulation are optionally used for sensing.

[0144] In some embodiments, if the patient does not have a pre-existing implanted cardiac contractility control device, a two-lead cardiac contractility control device is selected for implantation to implement cardiac contractility control therapy to enhance peak VO2. The potential benefit of reducing the number of leads, and specifically reducing atrial leads, is known to have fewer leads in the vein.

[0145] In some embodiments, the sensing lead is placed in the ventricle and toward the apex of the heart rather than toward the atrium, for example, along the ventricular wall or interventricular septum toward the apex, more than midway from the atrium, optionally sensing ventricular rather than atrial conditions.

[0146] Application of cardiac contractility modulation stimulation signals In some embodiments of the present invention, the cardiac contractility modulation stimulation signal may be applied during the absolute refractory period in the ventricle when it is not during the refractory (absolute refractory) period in the atrium.

[0147] In some embodiments of the invention, the amplitude of the signal applied to treat an ongoing AA episode may be greater than in chronic applications (e.g., between 10% and 500%, e.g., between 10% and 60%, between 60% and 150%, between 150% and 300%, between 300% and 500%, or greater or intermediate percentages). This may be due, for example, to pain or other side effects that are less significant to the patient, provided the patient is aware that the increase in treatment is temporary and / or is intended to treat an acute medical condition.

[0148] An aspect of some embodiments of the present invention relates to shortening the inhibitory period after a suspected arrhythmia when applying cardiac contractility modulation. In one example, a suspected ventricular arrhythmia beat results in an inhibitory window of only one beat, or optionally no beats. Potentially, this allows subsequent cardiac contractility modulation to operate on tissue that is still recovering from the abnormal heartbeat. Presumably, this reduces the arrhythmogenic tendency of the abnormal heartbeat and / or otherwise improves the function and / or potential healing of tissue in heart failure or other dysfunction. In some embodiments of the present invention, the length of the inhibitory window depends on the number of abnormal heartbeats (and / or the duration of the ventricular arrhythmia episode). In some embodiments of the present invention, there is no inhibitory window for atrial abnormal heartbeats, even if there is a window for ventricular abnormal heartbeats. In some embodiments of the present invention, a cardiac contractility modulation signal is applied even when the atria are excitable.

[0149] In some embodiments of the invention, the inhibit window is shortened and / or cardiac contractility modulation is applied during the atrial excitability time even in hearts free of atrial arrhythmias and / or even when there is no active atrial arrhythmia.

[0150] In some embodiments of the invention, a relatively low threshold for heart rate is used, for example, between about 90 or about 100 to about 110 beats per minute (BPM), which may prevent wasting energy at higher heart rates (as they have more beats in the simultaneous window and an exemplary treatment is 7 hours per day) and direct more applied energy to lower heart rates at the body's resting state.

[0151] In other embodiments, even higher heart rate thresholds may be used, for example, 120, 130, 140 heart rates or intermediate heart rates.

[0152] It is known that the heart rate may be measured approximately and / or not at a threshold, and some kind of fuzzy decision-making or hypothesis may be used to determine inhibition. For example, a signal may be inhibited with a probability that depends on the heart rate. In another example, once the heart rate drops, the threshold may be higher or lower than the threshold for stopping therapy when the heart rate is high.

[0153] In some embodiments of the invention, there are different inhibiting windows for different heart rates, for example, an arrhythmia-free inhibiting window is applied between about 80 and 110, and / or a one beat long inhibiting window is applied between 110 and 130, and a two beat long inhibiting window is applied between 120 and 160.

[0154] Exemplary Cardiac Therapy Device Reference is now made to FIG. 3B, which is an illustration of a simplified block diagram of a cardiac therapy device according to an exemplary embodiment of the present invention.

[0155] While existing equipment such as the Optimizer4 sold by Impulse Dynamics may be used, other equipment designs may be used as well.

[0156] FIG. 3B shows a cardiac therapy device including one or more leads 316 (optionally two leads) that can optionally be coupled to device 300 at one or more CAN connectors (not shown), as shown.

[0157] For example, a pulse generator 304 including a power circuit, for example, one or more storage capacitors, is optionally used to generate the signal.

[0158] In some embodiments of the present invention, ventricular detection 306 is optionally provided and is used to detect atypical ventricular activation that may be contraindicated for signal application.

[0159] In some embodiments of the present invention, an atrial detector 208 is optionally provided and used to detect atypical atrial activation, which may be used as an input into decision making by device 300 .

[0160] The sensor input 314 may receive data from one or more sensors, such as electrical sensors or other sensors, such as flow sensors, pressure sensors, and / or acceleration sensors. The data from the sensors is optionally further processed (e.g., by the controller 302 and / or the detectors 306, 308) and optionally used as input to a decision-making process in the device 300.

[0161] A controller 302 is optionally provided, implementing one or more logic circuits that determine, for example, the timing and / or other parameters of the signals and / or whether or not a signal should be applied.

[0162] Memory 318 is optionally provided to store, for example, logic, past effects, treatment plans, adverse events, and / or pulse parameters.

[0163] A data logger 310 is optionally provided to store device 300 and / or patient activity. Such logging and / or programming uses a communications module 321 (e.g., of a type known in the art) to send data and / or receive data, e.g., programming, e.g., pulse parameters, from device 300 to, e.g., a programmer (not shown).

[0164] In some embodiments of the present invention, the timing of cardiac contractility modulation is selected according to the expected effect of a cardiac drug on the refractory period, for example, to ensure that stimulation occurs throughout the refractory period. A signal applied near the end of the refractory period may have the effect of preventing subsequent activation, which is known to have some indications that may have anti-arrhythmic effects. Timing such activation may depend, for example, on the drug dosage and / or expected effect. Optionally, such effects are programmed into the controller 302 memory 318.

[0165] Reference is now made to FIG. 3C, which is a simplified line drawing of an ECG signal and a cardiac contractility modulation stimulation signal according to an example embodiment of the present invention.

[0166] Figure 3C shows a typical ECG signal 320 with a T wave 334 at its top. Below the ECG signal, Figure 3C shows a time series 321 of events related to cardiac contractility regulation, and below time series 321, Figure 3C shows an enlarged portion of time series 321 showing a time series 323 of a cardiac contractility regulation stimulation signal.

[0167] A timeline 321 of events related to cardiac contractility modulation shows a first event 319 of ventricular contraction detected by a first lead, a second event 322 of ventricular contraction detected by a second lead, and a third event of cardiac contractility modulation stimulation 325, ending with a fourth event 324 of the end of cardiac contractility modulation stimulation 325.

[0168] The time series 323 of cardiac contractility control stimulation signals shows only a portion of the time series 321 of events related to cardiac contractility control that is expanded compared to the time series 321 of events related to cardiac contractility control.

[0169] Referring to the time series 323 of the cardiac contractility control stimulation signal, the time series 323 begins when the cardiac contractility control device detects a ventricular contraction 322 and includes a pulse delay 326 followed by a series of one or more cardiac contractility control stimulation pulses having a particular pulse amplitude 328 and pulse width 330, followed by an equilibrium phase 332.

[0170] In some embodiments, the equilibrium phase begins before the T wave 334.

[0171] In some embodiments, the equilibrium phase begins after the onset of the T wave 334.

[0172] Some example values ​​for cardiac contractility modulation stimulation parameters include: - Pulse delay: >20 ms following detection of ventricular contraction - Pulse amplitude: over 10 / 20 / 50 / 100V and energy up to 0.01 / 0.1 / 0.5 / 1J - Pulse width: Use a pulse longer than 20 ms. - Pulse shape: biphasic alternating pulse shape, usually with more than 1 cycle. Figure 3 shows a non-limiting example of 2 cycles. - If a tachycardia limit <110 BPM (significantly less than 145 bpm) is detected, cardiac contractility control stimulation is not optionally performed. - One-cycle inhibition when inappropriate beats are detected: When an inappropriate beat is detected, e.g., when one or two sensing leads do not detect a ventricular contraction after a specified time following the previous ventricular contraction, cardiac contractility control stimulation is not applied for a period lasting, e.g., one cardiac cycle.

[0173] In some embodiments, the shape of the cardiac contractility modulation stimulation pulse is not necessarily square wave; by way of non-limiting example, the pulse shape may be sinusoidal or triangular.

[0174] In some embodiments, the cardiac contractility modulation stimulus is applied outside of the atrial refractory period.

[0175] Some non-limiting example values ​​for cardiac contractility modulation stimulation include: Pulse amplitude 7.5V; Two biphasic pulses, each approximately 5.14 ms wide; duration of the equilibration phase (where all involved electrodes are shorted together to discharge the electrode / tissue / interface capacitance) of approximately 40 ms; Pulse delay of LS to cardiac contractility regulation (pulse delay 326) of approximately 30 ms to 34 ms Examples include:

[0176] In some embodiments, if sensation is present until sensation is absent, the pulse amplitude is reduced, optionally down to a minimum of 4.5V.

[0177] In some embodiments, sensing ventricular contractions is performed via two leads.

[0178] A delay in contraction detected between the two leads greater than 30 ms is defined as an inappropriate beat.

[0179] In some embodiments, for each inappropriate beat that is detected, no cardiac contractility modulation stimulation is provided during the current and subsequent ventricular contractions.

[0180] In some embodiments, following detection of an inappropriate beat, detection of a ventricular contraction continues using two leads, e.g., once two appropriate beats are detected, where an appropriate beat is defined as a delay of less than 30 ms between the two leads, cardiac contractility control stimulation is again applied for a second cardiac contraction.

[0181] In some embodiments, for example, in the tests described in the "Test Description" section below, all sensing occurs in the ventricle.

[0182] In some embodiments of the invention, the absolute refractory period of the atria is assumed to be approximately 0.15 seconds, followed by a relative refractory period of approximately 0.03 seconds. In some embodiments of the invention, the absolute refractory period of the ventricles is assumed to be between 0.25 and 0.3 seconds, with an additional relative refractory period of 0.05 seconds. It is known that these times can vary between hearts and under various conditions, such as, for example, medication intake, anatomical excitation level, heart rate, recent arrhythmias, and / or exercise. In some embodiments of the invention, the cardiac contractility control stimulator is pre-programmed with parameters that take such refractory periods into account. Optionally, different numbers (e.g., stored in memory 218) are used for different conditions (e.g., different heart rates).

[0183] Reference is now made to FIG. 4, which is an illustration of a simplified line drawing of a heart showing the location of various tissues and electrodes / leads according to an example embodiment of the present invention.

[0184] FIG. 4 shows a heart 402 and parts of the heart: left atrium 403, right atrium 406, left ventricle 404, right ventricle 405, and interventricular septum 407, also called interventricular septum 407.

[0185] First, referring to portions of the heart, the following are shown: left ventricle 402 with LV free wall 404, interventricular septum 406, also called interventricular septum 406, aortic valve 408, mitral valve 410, left atrium 412, aorta 414, interatrial septum 416, pulmonary artery 418, right atrium 420, AV node 422 at the bottom of interatrial septum 416, right ventricle 124 with RV free wall 426, tricuspid valve 428, and pulmonary vein valve 430.

[0186] Also shown is a first stimulation lead 432 contacting the ventricular septum 406 with an electrode, and a second stimulation lead 434 contacting the ventricular septum 406 with an electrode at a second location thereon. In some embodiments, a single lead including two spatially separated stimulation electrodes may be used. In some embodiments, a lead may include one or more sensing electrodes.

[0187] While contact electrodes are mentioned, other types of electrodes may be used as well, for example, screw electrodes, suture electrodes, and floating electrodes.

[0188] In some embodiments of the invention, stimulation is bipolar, with one or more electrodes (e.g., a pair) each being a bipolar electrode, e.g., in the form of a tip surface and a ring electrode surface and / or operating themselves as a bipolar pair (e.g., one on each lead). Optionally, or in addition, a remote electrode operates (e.g., the device can operate) as a second electrode, e.g., for unipolar stimulation.

[0189] Leads 432 and / or 434 may be dual-use, for example, providing pacing, cardioversion and / or defibrillation signals in addition to non-excitatory signals such as cardiac contractility control signals.

[0190] In some embodiments, leads 432 and / or 434 may be used for sensing electrical activity, optionally using the same electrodes used for stimulation. In some embodiments, only one lead and / or only one electrode may be used for therapy. For example, a single ventricular or atrial lead may be used. Optionally, or in addition, in addition to or instead of leads within the chambers, leads are used outside the chambers, e.g., in the coronary sinus or other blood vessels outside the heart (e.g., on / attached to its outer surface and / or on the left side of the heart, e.g., left ventricle 402 and / or left atrium 412).

[0191] Note that Figure 4 is schematic and flattened. For example, in a real heart, the left atrium 412 and the right atrium 420 are both bounded by the interatrial septum 416.

[0192] Reference is now made to FIG. 5A, which is a simplified flowchart illustration of a method for increasing peak VO2.

[0193] The method of FIG. 5A includes: Selecting (502) a patient who has impaired peak VO2 and is not known to have another medical condition that may limit the ability to increase peak VO2; and applying (504) a cardiac contractility control stimulus to the patient's heart.

[0194] Reference is now made to FIG. 5B, which is a simplified flowchart illustration of a method for increasing peak VO2.

[0195] The method of FIG. 5B includes: Selecting (512) a patient who has impaired peak VO2 and is not known to have another medical condition that may limit the ability to increase peak VO2; Implantation of a two-lead cardiac contractility control device in selected patients (514) and applying (516) a cardiac contractility modulation stimulus to the patient's heart.

[0196] In some embodiments, patients selected for cardiac contractility modulation therapy to enhance peak VO2 include: atrial fibrillation (AF); systolic heart failure (HF); diastolic HF; atrial tachycardia; angina pectoris; myocarditis; small vessel disease; pulmonary hypertension; Chronic obstructive pulmonary disease (COPD) and Patients with one or more of the following sleep apnea disorders are included:

[0197] In some embodiments, patients selected for cardiac contractility modulation therapy to enhance peak VO2 include patients with: For example, peak VO2 measured at less than 20 mlO2 / min / kg or even 25 mlO2 / min / kg—patients who may potentially benefit from increasing peak VO2; For example, peak VO2 measured above 9 mlO2 / min / kg or even 5 mlO2 / min / kg—may not treat high-risk patients; Having a peak VO2 between 9 and 25 mlO2 / min / kg is selected for treatment.

[0198] For example, in the study described in the "Description of the Study" section below, patients with a peak VO2 between 9 and 25 mlO2 / min / kg were selected for treatment.

[0199] In some embodiments, patients selected for cardiac contractility modulation therapy to enhance peak VO2 include -Ventilatory reserve of 20% or more (up to 50%). Ventilatory reserve (BR) is usually determined during a pulmonary exercise stress test. It is the difference between the maximal voluntary ventilation (MVV) and the maximum ventilation measured during an exercise test. Some experts do not consider direct MVV measurement reliable because it is highly effort-dependent and very difficult to link to an acceptance criterion. However, FEV1 is well-defined as to when and how acceptable it is. Therefore, it is a fairly well-defined criterion that can be used to predict MVV. The formula for MVV is derived from FEV1, 40 * FEV1 or some 35 * Use FEV1. Calculation: BR(L / min)=MVV-Max VE BR(%)=(MVV-VE / MVV)×100 Example: If MVV = 82 L / min and VE at peak exercise is 65 L / min, then BR = 82 - 65 = 17, BR% = (82 - 65 / 82) x 100 = 21% FEV1 is a measure of a person's vital capacity to complete the first second of a forced expiration; -Oxygen Uptake Efficiency Slope (OUES) <89% - Peak RER > 1.1. Respiratory Exchange Ratio (RER) indirectly indicates the oxidative capacity of muscles to obtain energy; and Constant peak VO2 saturation for HF patients Patients with one or more of the following may also be included.

[0200] The study described in the "Description of Study" section used the following cardiac contractility control signal: a train of two bipolar pulses with a duration of 5.14 ms (milliseconds) per pulse phase, a voltage of 4.5 V to 7.5 V, and a delay of 30 to 35 ms after local excitation at the applied site (using bipolar leads), followed by a 40 ms charge balance phase. It is known that local excitation often occurs immediately after the onset of ventricular activation. In the balance pulse, the active electrodes are all short-circuited together. The voltage is reduced until there is likely a lack of sensation.

[0201] This signal can be modified, and in some embodiments of the invention, the equilibration phase can be omitted or can be of varying lengths, e.g., between 1 and 200 ms, e.g., between 10 and 50 ms, e.g., between 20 and 41 ms, or intermediate lengths.

[0202] The top voltage can be increased from 7.5V to, for example, 8V, 9V, 10V, 12V, 20V, 40V, 100V or intermediate or smaller values. It is noted that as an acute effect, sensation may not be considered a challenge.

[0203] The delay can be even shorter, for example, between 1 ms and 30 ms, between 5 and 20 ms, between 10 and 25 ms, or intermediate delays. The delay can be even longer, for example, between 35 and 50 ms, between 50 and 70 ms, or intermediate, smaller, or larger delays. It is known that even longer delays may be tolerable in AA patients, as they cause arrhythmias in the atria (due to cardiac contractility modulation applied outside the absolute refractory period of the atria), but may not be an issue in patients with atrial fibrillation. It is known that this may allow patients with long AV delays to be treated beneficially (e.g., by ignoring atrial effects).

[0204] The number of phases may also be varied, e.g., as few as 1, 2, or 3, or as many as 5, 10, 20, 50, or an intermediate or even greater number. The length of the phases may also be varied, e.g., between 1 and 100 ms, e.g., 2, 3, 5, 6, 6.6, 10, 15, 25, 50 ms, or an intermediate length. Also, not all of the phases need to be the same length and / or voltage. In addition, while square pulses are optionally used, other pulse shapes, e.g., curved, bent, triangular, and / or symmetrical and / or asymmetrical shapes, may be provided. In some embodiments, there is an inter-phase delay, e.g., 1, 2, 4, 5, 6, 10, 20 ms, or an intermediate or shorter or longer delay.

[0205] The energy delivered to the pulse may be, for example, 0.01, 0.1, 0.5, 1 J, 5 J, 10 J or intermediate or even smaller or larger energy levels.

[0206] The duration during which pulses are applied to the heart in one beat can be, for example, 5 ms, 10 ms, 20 ms, 30 ms, 40 ms, or an intermediate or even longer duration.

[0207] In some embodiments of the invention, any of the above numbers are varied, for example, by 5%, 10%, 20% or intermediate values.

[0208] The delay may be a calculated delay (if the patient is paced) or an approximation, and if two leads are used as bipolar electrodes, it is known to optionally use the minimum or average activation time to calculate the delay.

[0209] In some embodiments of the present invention, cardiac contractility regulation therapy is applied for, for example, 1, 2, 3, 4, 5, 6, 7, 8, 10, 15, 24 hours a day or an intermediate period, for example, 1, 2, 3, 4, 5, 8, 12, 24 weeks or an intermediate period or more weeks. During the treatment period, each heartbeat is optionally treated or intended to be treated. In other schemes, therapy may be administered per day, for example, according to a heart rate target as described herein.

[0210] It is known that a cardiac contractility control signal may not be applied to a heartbeat for reasons other than medication. For example, a heartbeat may be deemed unsafe in the sense that application of a cardiac contractility control signal during that beat could cause arrhythmia. Optionally, or in addition, the heart may be allowed to "recover" from the abnormal heartbeat for one or more "prohibited" beats.

[0211] In some embodiments, the elimination of the atrial lead was achieved via modifying the algorithm used to determine whether to apply a cardiac contractility modulation signal during a given beat to exclude atrioventricular timing criteria, and in some embodiments, also using enhanced criteria to evaluate the timing and sequence between the two ventricular leads.

[0212] In some embodiments of the invention (e.g., in the tests described below), the following algorithm is used to determine whether to apply a cardiac contractility modulation signal during a given beat:

[0213] A first optional section of the algorithm is to avoid stimulation with cardiac contractility control where the heart rate is too high, e.g., above a cutoff threshold, e.g., 90, 100, 110, 120, 130, 140, 145, 160, or any intermediate value. Optionally, this may prevent applying cardiac contractility control during VT or incipit CT and / or other arrhythmias, which may be detected as high heart rates.

[0214] A second optional section of the algorithm is to avoid stimulation if the delay between the two ventricular leads exceeds a certain threshold, e.g., 30 ms, although other numbers, e.g., 10 ms, 20 ms, 40 ms, 50 ms, and / or intermediate or even larger thresholds may be used. This delay may indicate multiple foci and / or irregular propagation directions in the ventricles.

[0215] The concrete algorithm of the example is - Sensing ventricular contractions in both ventricular leads - Determine if your heart rate is below 110 bpm - A detected systolic delay between the two leads greater than 30 ms is defined as an inappropriate beat. -For each detected inappropriate beat, not providing cardiac contractility modulation stimulation during the current and subsequent ventricular contractions (in some embodiments, cardiac contractility modulation may be provided on the next beat, but in other embodiments, the delay may be more than one beat). - Detection of inappropriate beats followed by consecutive detection of ventricular contractions in two leads. Once two appropriate beats (less than 3 ms delay) are detected, a cardiac contractility control stimulus is delivered to that cardiac contraction with a preset delay.

[0216] In some embodiments of the invention, irregular beats are detected based on AV delay and / or based on the morphology of the electrogram signal detected at one or more of the electrodes. Other methods of detecting potentially unsafe beats (e.g., beats in which the ventricle may be stimulated outside of its absolute refractory period) may be used as well.

[0217] Reference is now made to FIG. 6, which is an illustration of a simplified flow chart of a method for planning cardiac contractility modulation therapy for a patient to enhance peak VO2, according to one example embodiment.

[0218] The method shown in Figure 6 includes selecting (602) a patient who has impaired peak VO2 and is estimated to have the potential to improve peak VO2; and planning (604) a cardiac contractility control therapy for the patient.

[0219] In some embodiments, selecting includes selecting a patient who already has an implant suitable for providing cardiac contractility modulation therapy.

[0220] In some embodiments, selecting includes selecting a patient who is not known to have another medical condition that may prevent increasing peak VO2.

[0221] In some embodiments, selecting comprises selecting a patient estimated to have pulmonary reserve.

[0222] In some embodiments, the patient's pulmonary condition is assessed for suitability for providing cardiac contractility control to enhance peak VO2, as described below. In some embodiments, the patient's pulmonary condition is assessed for the presence of pulmonary limitation, as described further below. If the patient's pulmonary condition is such that the patient would benefit from improved peak VO2, it is planned to provide cardiac contractility control therapy in conjunction with additional cardiac therapy(ies) or by itself.

[0223] In some embodiments, the patient's cardiac condition is evaluated to determine whether a cardiac therapy should be provided in addition to cardiac contractility control. If the patient's pulmonary condition indicates that the patient would benefit from an improvement in peak VO2, a cardiac contractility control therapy is planned to be provided. If the patient's cardiac condition indicates that an additional cardiac therapy is desirable, a cardiac contractility control therapy is optionally planned to be provided along with the additional cardiac therapy(ies).

[0224] In some embodiments, a treatment plan is selected for the patient that may include providing cardiac contractility modulation therapy alone, providing cardiac contractility modulation therapy in conjunction with a treatment for the patient's cardiac condition, or not providing cardiac contractility modulation therapy.

[0225] Test Description Reference is now made to the following test descriptions which together with the above descriptions illustrate some embodiments of the present invention in a non-limiting manner.

[0226] The following example describes the safety, performance, and efficacy of cardiac contractility modulation delivered by a two-lead Optimizer Smart System, termed the "FIX-HF-5C2 Study."

[0227] Introduction: One of the objectives of this study was to examine the performance, safety, and clinical effectiveness of a two-lead system compared with a three-lead system.

[0228] Methods: Patients were eligible for participation if they had NYHA III / IVa symptoms despite appropriate medical therapy, had a LVEF of 25-45%, and were not eligible for CRT. All subjects who received the Optimizer2 lead implant were confirmed at weeks 12 and 24. Device matching provided multiple cardiac contractility control signals that were effectively delivered. The primary endpoint was the estimated difference in change in peak VO2 from baseline to week 24 between FIX-HF-5C2 (two-lead device) subjects compared with control subjects from the previous FIX-HF-5C study. The primary safety endpoint was assessment of the rate of device-related adverse events between FIX-HF-5C2 (two-lead device) subjects compared with FIX-HF-5C (three-lead device) subjects.

[0229] Results: Sixty subjects were included, 88% male, 66 ± 9 years old, with a LVEF of 34 ± 6%, 68% with ischemic cardiomyopathy, and 15% with atrial fibrillation. Cardiac contractility control delivery did not differ between the two-lead and three-lead systems (19,892 ± 3472 vs. 19,583 ± 4998 beats / day). The change in peak VO2 from baseline to week 24 was greater in the two-lead device group compared with the control group, 1.72 ml / kg / min (95% Bayesian confidence interval [BCI]: 1.02, 2.42). Adverse events did not differ between groups, except for a reduction in Optimizer-related adverse events in the two-lead group compared with the three-lead group (8% vs. 0%, p = 0.03).

[0230] Some conclusions: Two-lead systems effectively deliver a comparable amount of cardiac contractility control pulses to three-lead systems (including in patients with atrial fibrillation), are equally safe, and improve peak VO2 and NYHA functional class. Device-related adverse events are fewer with two-lead systems.

[0231] Cardiac contractility modulation is an electrical device-based therapy developed for the treatment of chronic heart failure. Cardiac contractility modulation signals are non-excitatory electrical signals applied during the absolute refractory period of the heart that normally favorably influence the biology of the failing myocardium.

[0232] Cardiac contractility modulation has been studied in several randomized trials, including a double-blind, double-crossover trial in Europe (FIX-HF-4 trial), a blinded, randomized pilot trial in the United States, a prospective randomized trial in the United States including 428 subjects (FIX-HF-5 trial), and a second prospective randomized trial in the United States and the EU including 160 subjects (FIX-HF-5C trial). Collectively, the results of these previous randomized trials demonstrated that cardiac contractility modulation improves functional class, quality of life, and exercise tolerance, particularly in patients with a left ventricular ejection fraction (LVEF) between 25% and 45%, NYHA III symptoms despite guideline-directed medical therapy (and an ICD, if indicated), normal QRS duration (i.e., not a candidate for CRT), and sinus rhythm. Based on these findings, the Optimizer System received approval by the U.S. Food and Drug Administration for use in this patient population. Additional information from the registration trial suggests that LVEF improved by approximately 5 percentage points, clinical benefits were sustained through two years of follow-up, and cardiac contractility control therapy was associated with a reduced rate of hospitalizations for heart failure compared to the number of hospitalizations observed in the year before implantation of the Optimizer System.

[0233] All of the aforementioned studies were performed with the Optimizer device, which employs three leads placed in the heart: one in the right atrium and two in the right ventricular septum. While the RV septal lead is used for both sensing and delivery of the contractile control signal, the atrial lead is used only to sense the timing of atrial depolarizations. This information was used as input to an algorithm that ensured proper timing of contractile control signal delivery during the absolute refractory period of the myocardium, including contractile control delivery or inhibition of premature ventricular contractions. This requirement imposed technical limitations on the use of contractile control in patients with atrial fibrillation or atrial flutter. Although the contractile control signals delivered by the two-lead and three-lead Optimizer systems were identical, the upper atrial rate above which contractile control delivery was inhibited could be set as high as 179 bpm with the three-lead system, compared with 110 bpm with the two-lead system. Additionally, as with cardiac rhythm devices in general, device-related adverse events are primarily lead-related (e.g., see ), so reducing the number of leads may reduce adverse events.

[0234] A novel cardiac contractility control delivery algorithm has been developed that eliminates the need for an atrial sensing lead, leading to the development of the two-lead Optimizer device. The FIX-HF-5C2 trial was a prospective, multicenter, single-arm study designed to examine the performance, safety, and clinical effectiveness of this two-lead Optimizer Smart System.

[0235] method Sixty subjects were enrolled from seven medical centers in the United States and one medical center in Germany. Subjects were evaluated at baseline and again at 12 and 24 weeks after implantation. Inclusion and exclusion criteria are summarized in Table 1. Key criteria included: adult subjects with an LVEF of ≥ 25% and ≤ 45% by echocardiography (assessed by a central laboratory); NYHA III or ambulatory IV symptoms that were stable for 30 days prior to enrollment despite 90 days of guideline-directed heart failure medical treatment, and no indication for cardiac resynchronization therapy (CRT). Patients were excluded if they had been hospitalized for heart failure requiring intravenous loop diuretics, inotropes, or hemofiltration within 30 days; if they had received any form of inotropic therapy within 30 days prior to enrollment; if their peak VO2 on cardiopulmonary stress testing (CPX) was <9 or >20 mlO2 / min / kg (assessed by a central laboratory); if they had a potentially treatable cause of heart failure (e.g., valvular heart disease or congenital heart disease); if their exercise tolerance was limited by a condition other than heart failure; or if they were scheduled for or had recently undergone CABG, PCI, or MI. Notably, patients with atrial fibrillation may be enrolled, compared with all previous trials in the United States. [Table 1]

[0236] The timeline of events is summarized in Table 2. Following eligibility assessment, subjects underwent implantation of a 2-lead Optimizer Smart System. After device programming, subjects were generally discharged from the hospital the same day as implantation or the next day. Approximately 2 weeks later, subjects returned for routine wound checks and device checks (when parameters of the cardiac contractility control signal were checked and optimized). Study follow-up visits for clinical evaluation occurred at 12 and 24 weeks (± 2 weeks) after device implantation. In addition to interim safety assessments, on-site clinicians assessed NYHA and repeated CPX testing at these visits. [Table 2] * Results of a 12-lead EKG and echocardiogram (from a study-eligible 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. ** If so, visits should continue every 6 months until a PMA application is issued by FDA for device verification and reporting of Optimizer device-related SAEs.

[0237] Test endpoints The primary efficacy endpoint was assessment of improvement from baseline in exercise capacity at 24 weeks, as measured by peak VO2 obtained during cardiopulmonary exercise testing (CPX). CPX data were evaluated by an independent core laboratory. Changes in peak VO2 from baseline to 24-week follow-up in subjects implanted with the 2-lead system were compared to changes observed in control subjects in the previous FIX-HF-5C trial (using Bayesian statistics as detailed below).

[0238] Performance of the 2-Lead Optimizer System was based on an assessment of the average daily amount of cardiac contractility control signals delivered between the 2-week visit (device check and parameter optimization) through the end of the 24-week study period. The device contains, among other things, an internal counter that keeps track of the total number of cardiac contractility control signals delivered, and this information is readily available for device interrogation using the system's programmer. Performance was specifically assessed through a comparison between the number of cardiac contractility control signals delivered by the 2-lead device and the number of signals delivered in subjects implanted with a 3-lead system over 24 weeks in the previous FIX-HF-5C study. Additional efficacy endpoints included New York Heart Association functional class and NT-ProBNT assessment.

[0239] The primary safety endpoint was the proportion of subjects experiencing device-related or procedure-related complications throughout the 24-week follow-up period. Complications were adjudicated by an independent Event Adjudication Committee (EAC). The EAC reviewed, adjudicated, classified, and authorized all reported SAEs that occurred over the 24-week course of the study. Classification included whether the event was related to the device or implantation procedure and whether such an event constituted a "complication" as defined by the EAC authorization. The committee also adjudicated the cardiac and heart failure associations of deaths and hospitalizations.

[0240] All-cause mortality and a composite of cardiovascular mortality and hospitalization for heart failure constituted additional safety endpoints.

[0241] Cardiopulmonary Stress Test Procedure As in the previous FIX-HF-5C study, rigorous quality criteria and procedures were used during the conduct of the CPX study to optimize test quality and ensure maximum effort was achieved by each subject. All studies were supervised by the same core laboratory employed in the previous FIX-HF-5 and FIX-HF-5C studies. Specific quality criteria included: (1) In-house training in standardized procedures for conducting CPX testing; (2) validation study in normal subjects and revalidation every 6 months; (3) Providing subjects with instructions on how to prepare for the CPX exam; and (4) Prompt feedback from the core laboratory on the quality of each test and requests for retesting of inappropriate tests was included.

[0242] (1) the subject had an irregular or oscillatory breathing pattern; (2) the data were nonphysiological; (3) the test instrument identified the problem; and (4) The test was lower than the maximum value. In this case, the test is deemed inappropriate and is terminated by the subject / supervising physician / technologist before the subject reaches voluntary exhaustion.

[0243] Reasons for early termination included symptoms other than heart failure (e.g., angina, heart rhythm irregularities, or leg, foot, or back pain), or the subject was technically required to perform the test.

[0244] Metabolic data were collected for 2 minutes prior to the start of exercise to confirm RER and VO2, and subjects' ventilation was normal, physiological, and stable at rest before the test began. Metabolic data were then collected during the test and after its completion during an additional 2-minute recovery period. Peak VO2 and peak respiratory exchange ratio (RER) were determined by a core laboratory from the average gas exchange data for 20 seconds from the start of exercise to the end of exercise. If an RER of 1.05 or greater was achieved, the test was considered a maximal effort.

[0245] Statistics The objectives of this study were to determine whether the 2-Lead Optimizer Smart System performs similarly to the recently US-FDA-approved 3-Lead Optimizer System in terms of the amount of cardiac contractility modulation delivered, whether the device is equally safe in terms of device-related and procedure-related complications (primary safety endpoint), and whether the device provides similar clinical benefit in terms of improved exercise tolerance (primary efficacy endpoint) and improved functional class (secondary efficacy endpoint). The current study is a single-arm, treatment-only study. Therefore, the results of this study were compared with data from previous FIX-HF-5C control and treated patients treated with the 3-Lead Optimizer System.

[0246] Baseline demographic data were summarized using descriptive statistics. Demographic data from the previous FIX-HF-5C study were also summarized here and compared with those of patients enrolled in this study. Continuous data were compared using two-sample t-tests, and categorical data were compared using Fisher's exact test.

[0247] Effectiveness: Peak VO2 Similar to the design of the primary efficacy analysis of FIX-HF-5C (and the US-FDA collaborative study), the design of the primary efficacy analysis of FIX-HF-5C2 used a Bayesian repeated measures model to estimate group differences in change in mean peak VO2 from baseline to week 24 in FIX-HF-5C2 2-Lead Optimizer subjects compared with FIX-HF-5C control subjects, with a 30% information borrow (70% underweighting) from the corresponding treatment group difference observed in the FIX-HF-5 subgroup data. The 30% borrowing was based on the Ibrahim & Chen power prior methodology.

[0248] Efficacy: NYHA Changes from baseline in at least one NYHA category were assessed and compared between groups via Fisher's exact test. Shift tables for NYHA class in the FIX-HF-5C2 study were analyzed using the extended McNemar's test for paired data and for comparisons between groups via the Cochran-Mantel-Haenszel test for more than two groups.

[0249] Equipment performance Device performance was assessed via evaluation of the total number of contractile control pulses delivered throughout the 24-week study follow-up period. A device was considered to perform as intended if the number of delivered contractile control pulses was equivalent to the total number of contractile control pulses delivered by the 3-lead system during the 24-week period of the FIX-HF-5C study. Bioequivalence was demonstrated by the difference in the predicted mean total contractile control delivery between FIX-HF-5C2 and FIX-HF-5C, with a two-sided 100 (1-2α)% confidence interval. μ5C2-μ5C The lower and upper limits of bioequivalence were θ L and θ U θ L <0<θ U and θ L =-0.125 μ5C2 and θ U =0.125 μ5C According to Schuirmann, bioequivalence is defined as the difference μ5C2-μ5CA two-sided 100(1-2α)% confidence interval for the interval (θ L ,θ U Based on the estimated mean values ​​of the FIX-HF-5C study, the lower and upper limits of bioequivalence are -125 times the estimated mean value and +125 times the estimated mean value (i.e., 19583 * The cardiac contractility pulses / day was calculated as (-2448, 2448) from the estimated daily rate of cardiac contractility delivered (19,583) observed in the 5C study as 0.125 = ±2448.

[0250] safety The primary safety analysis assessed the rate of procedure-related or device-related complications throughout the 24-week follow-up period. Exact binomial 95% confidence intervals were generated for the complication-free population. These rates were compared to those observed in the FIX-HF-5C trial via Fisher's exact test.

[0251] All-cause mortality, cardiovascular mortality, and a composite of hospitalization due to heart failure were assessed using Kaplan-Meier analysis. Results were compared with those of the FIX-HF-5C control group using the log-rank test.

[0252] Sample size justification Sixty subjects were enrolled in the FIX-HF-5C2 trial. Simulations were used to quantify the power and type I error of the primary efficacy analysis under various assumptions and magnitudes of treatment effect, with data prospectively simulated for both the FIX-HF-5C control and FIX-HF-5C device patients. For example, assuming the variance of change in peak VO2 in the FIX-HF-5C2 and FIX-HF-5C populations was equivalent to the estimated variance in the FIX-HF-5 trial, the study had approximately 80% power to detect a mean difference in peak VO2 of 0.65 mL / kg / min. The type I error was estimated to be approximately 0.10 or less, which was deemed acceptable by regulatory authorities for the FIX-HF-5C2 trial.

[0253] result Subject disposition is summarized in Table 3. A total of 153 subjects were screened at eight centers. Of these, 60 were eligible, enrolled, and implanted with the 2-lead Optimizer System. One subject discontinued the study prior to week 24 due to incarceration. There were no deaths during the 24-week study period, and all 59 remaining subjects completed the final follow-up visit, including assessment of cardiac contractility control delivery and NYHA functional class. Of these, 55 subjects (91.7%) completed the 24-week CPX study. The reasons for four subjects not completing the study were intercurrent knee replacement surgery, knee injury, lung tumor, and pulmonary embolism (one each). In addition, four 24-week CPX studies in which patients refused requests for repeat testing were deemed inappropriate by the core laboratory, resulting in 52 studies being included in the primary endpoint analysis. However, to ensure the robustness of the findings, additional analyses including these inappropriate studies were conducted. [Table 3] 1 Visits before 24 weeks 2 Only subjects with valid peak VO2 as determined by a core laboratory at the indicated visit were included

[0254] Baseline characteristics The baseline characteristics of the FIX-HF-5C2 subjects, along with the baseline characteristics of the FIX-HF-5C trial groups, are presented in Table 4; as detailed above, the results of the previous FIX-HF-5C trial will be used as the basis for evaluation of the performance of the 2-lead Optimizer System (compared to the FIX-HF-5C Optimizer group) and clinical efficacy (compared to the FIX-HF-5C control group). First, consistent with the goal of implementing the 2-lead system, 15% of the FIX-HF-5C2 subjects had persistent atrial fibrillation. Additionally, FIX-HF-5C2 subjects tended to be older than FIX-HF-5C control subjects (66.3 ± 8.9 vs. 62.8 ± 11.4 years), had a lower prevalence of diabetes (30% vs. 48.8%), and had smaller LV end-diastolic diameters (57.7 ± 6.8 vs. 60.2 ± 7.0); however, LVEF did not differ between groups (34.1 ± 6.1 vs. 32.5 ± 5.2%). Baseline peak VO2 was similar between the two groups, but FIX-HF-5C2 subjects exercised longer than FIX-HF-5C control subjects (11.6 ± 2.9 vs. 10.6 ± 3.1 min). All other baseline characteristics were similar between groups. NT-proBNP (not recorded in the previous FIX-HF-5C study) was only minimally elevated at baseline (median (IQR) 511 (219,867) pg / ml) and did not change significantly over the 24-week study period (median (IQR) 524 (245,1182) pg / ml). [Table 4-1] [Table 4-2] 1 Comparisons were made with the FIX-HF-5C2 Optimizer group via Fisher's exact test for dichotomous variables and via two-sample t-test for continuous variables.

[0255] Subjects in FIX-HF-5C2 received guideline-recommended medications similar to those in FIX-HF-5C (Supplementary Table 1), except for the heavy use of concomitant angiotensin receptor / neprilysin inhibitors (ARNi) and antiarrhythmics (primarily amiodarone); the increased ARNi use was attributed to the later start date of the study, while the use of antiarrhythmics was attributed to the higher prevalence of atrial fibrillation. [Table 5] 1 Comparison was made with the Optimizer group of FIX-HF-5C2 using Fisher's exact test.

[0256] According to the study protocol, medication was to remain stable unless mandated by study considerations. The number of medication adjustments between baseline and 24 weeks is detailed in Supplementary Table 2. For each drug class, the number of dose increases was balanced by the number of dose decreases; for this analysis, any increase or decrease in dose was counted. There were two cases of switching an angiotensin receptor blocker to sacubitril / valsartan and one case of the reverse switch. [Table 6] Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ABR, angiotensin receptor blocker; ARNi, combined angiotensin receptor / neprilysin inhibitor.

[0257] Equipment performance The mean daily number of contractility control pulses delivered during the 24-week study period is summarized in Table 5. The devices were programmed to deliver contractility control therapy for 5 hours per day, evenly distributed over each 24-hour period. Assuming a mean heart rate of 72 bpm (from Table 4), the expected daily number of beats eligible for delivery of a contractility control signal is 21,600. As summarized in Table 5, the mean daily number of beats was just under 20,000 (95% of expected), which was not significantly different between the FIX-HF-5C (3-lead system) and FIX-HF-5C2 (2-lead system) studies. Based on statistical testing according to the rules detailed in the methods, the 95% confidence interval for the difference between the two groups was the interval θ L ,θ U Because the variances fall entirely within the range (i.e., -2448, +2448), the total delivery of cardiac contractility control at 24 weeks is comparable between the 2-lead (FIX-HF-5C2 study) and 3-lead (FIX-HF-5C study) Optimizer systems. Also importantly, as detailed in Table 5, the amount of cardiac contractility control signal delivered did not differ significantly between subjects with and without persistent atrial fibrillation. [Table 7] * Differences between all patients in FIX-HF-5C2 and patients treated with cardiac contractility control in FIX-HF-5C.

[0258] Peak VO2 Baseline peak VO2 was similar between FIX-HF-5C2 2-Lead Optimizer and FIX-HF-5C control patients at baseline (Figure 1A). As detailed above, follow-up results for the primary analysis were available for 52 of these subjects. Peak VO2 progressively increased over time in the 2-Lead Optimizer group (0.80 ml / kg / min from baseline to 24 weeks) but declined in the FIX-HF-5C control group (0.93 ml / kg / min from baseline to 24 weeks). Bayesian analysis of the difference between the groups (Figure 1B), the primary endpoint, showed a mean of 1.08 (95% Bayesian confidence interval [BCI]: 0.38, 1.78) ml / kg / min at 12 weeks, which increased to 1.72 (95% BCI: 1.02, 2.42) ml / kg / min by 24 weeks, both of which were highly statistically significant (Bayesian posterior probability of significance equals 1.00). Thus, exercise capacity improved in response to cardiac contractility control therapy delivered by the 2-Lead Optimizer System compared with FIX-HF-5C control patients.

[0259] Reference is now made to FIG. 1A, which shows a graph of peak VO2 over time comparing the control group from the FIX-HF-5C and the cardiac contractility control treatment group from the FIX-HF-5C2 study according to one example embodiment of the present invention.

[0260] FIG. 1A shows a graph 101 with an X-axis of time in weeks and a Y-axis showing peak VO2 in units of ml / kg / min.

[0261] Graph 101 shows a first line 106 showing peak VO2 over time from the control group from the FIX-HF-5C study, and a second line 105 showing peak VO2 over time from the cardiac contractility control treatment group from the FIX-HF-5C2 study.

[0262] Bars above and below the data points on the graphs represent statistical estimates of the error in the data values ​​based on the individual data and population size of the experiment.

[0263] Reference is now made to FIG. 1B, which shows a graph of between-group treatment effect (difference between cardiac contractility modulation treatment group and control group) over time according to an example embodiment of the present invention.

[0264] FIG. 1B shows a graph 111 with an X-axis of time in weeks and a Y-axis showing the difference (Δ) in peak VO2 between groups in units of ml / kg / min.

[0265] Graph 11 shows a line 115 that indicates the difference between groups over time, where the difference is positive if the peak VO2 of the cardiac contractility control group is greater than the peak VO2 of the control group.

[0266] Sensitivity analyses were performed for the primary analysis, including a Bayesian analysis with adjustment for covariates for heart failure etiology and baseline ejection fraction. In all cases, the posterior probability of superiority of the 2-lead Optimizer System compared with FIX-HF-5C control patients was 1.00, exceeding the threshold of 0.975 required to demonstrate superiority. In addition, the confirmatory non-Bayesian (frequentist) estimate without 30% borrowing from the FIX-HF-5 data was equivalent (2.21 mL / kg / min) with a p-value <0.001, indicating that borrowing was not necessary to achieve statistical significance for the primary efficacy endpoint. Finally, when including the four inappropriate CPX trials, the frequentist estimate of benefit was 2.09 mL / kg / min (p <0.001).

[0267] Additional analysis showed that respiratory exchange ratios (RER, a measure of subjective effort) were similar between 2-Lead Optimizer and FIX-HF-5C control subjects at both baseline (1.15 ± 0.06 vs. 1.14 ± 0.07, p = 0.50) and 24 weeks (1.16 ± 0.04 vs. 1.16 ± 0.07, p = 0.96). Finally, exercise duration increased from baseline to 24 weeks by 1.31 ± 2.08 minutes in subjects treated with cardiac contractility control with the 2-Lead Optimizer System compared with 0.60 ± 2.31 minutes in FIX-HF-5C control subjects.

[0268] NYHA NYHA improved by at least 1 functional class at 24 weeks in 83.1% of subjects treated with the 2-lead Optimizer system compared with only 42.7% in the FIX-HF-5C control group (p<0.001). Comparison of NYHA distribution between the 2-lead Optimizer and FIX-HF-5C control groups is summarized in Figure 2A and Figure 2B, respectively.

[0269] Reference is now made to Figures 2A and 2B, which are graphs of New York Heart Association (NYHA) functional class distribution at 24 weeks relative to baseline in the control and 2-Lead Optimizer groups.

[0270] FIG. 2A shows a graph 201 with an X-axis 202 showing NYHA functional class and a Y-axis 203 showing the proportion of patients in the control group.

[0271] FIG. 2A shows the NYHA functional class of the control group at baseline 205 and at 24 weeks 206.

[0272] FIG. 2B shows a graph 211 with an X-axis 212 of NYHA functional class and a Y-axis 213 showing the proportion of patients in the 2-lead Optimizer group.

[0273] Figure 2B shows the NYHA functional class of the 2-lead Optimizer group at baseline 215 and at 24 weeks 216.

[0274] As illustrated, there was a greater shift to lower NYHA side in the 2-lead Optimizer group than in the FIX-HF-5C control group (p<0.001).

[0275] Analysis of primary safety endpoints The primary safety endpoint was the composite proportion of subjects in the 2-lead Optimizer group who experienced Optimizer device-related or procedure-related complications throughout the 24-week follow-up period, as determined by EAC. Only one complication was observed: a hematoma at the Optimizer implant site, which required the patient to be hospitalized overnight for observation. The hematoma resolved without treatment, and there were no further complications in this case. Thus, the complication rate was 1.7% (1 / 60, CI 0.0%, 8.9%). This compares with the 10.3% complication rate seen in 3-lead Optimizer subjects in the FIX-HF-5C trial (p=0.07, CI 4.2%, 20.1%).

[0276] Secondary safety endpoints As mentioned above, there were no deaths among the two-lead Optimizer subjects during the 24-week study period, in contrast to four deaths among the FIX-HF-5C control subjects during the same follow-up period. Serious adverse events were tabulated by treatment group and compared using Fisher's exact test (Table 6). Except for a small number of Optimizer device-related events with the two-lead system, there were no significant differences between the two-lead Optimizer (FIX-HF-5C2) subjects and the FIX-HF-5C control or three-lead Optimizer (FIX-HF-5C) subjects (p=0.03). It is noteworthy that the majority of Optimizer device-related events in previous studies of the FIX-HF-5C three-lead system were due to lead migration and lead fracture; no device-related complications were reported with the two-lead device. Importantly, there were no incidences of ventricular premature contractions or ventricular tachycardia in the FIX-HF-5C2 study. [Table 8] 1 Comparison of FIX-HF-5C2 with the Optimizer group via Fisher's exact test 2 Number and percentage of subjects. Subjects were counted only once within each category.

[0277] Consideration The results demonstrate that compared with a three-lead system, the two-lead Optimizer Smart System device delivers an equivalent amount of contractility control therapy and likely reduces device-related events related to one less lead. Compared with the results of the previous FIX-HF-5C trial, improvements in peak VO2 and NYHA appear to be equivalent (or greater) than with the two-lead system. In addition, device performance did not differ between patients with normal sinus rhythm or atrial fibrillation. Thus, this trial represents a significant advancement for patients eligible for contractility control therapy and potentially expands the patient eligibility pool to include patients with persistent atrial fibrillation.

[0278] The previous Optimizer system required the atrial lead to sense p-waves timed relative to depolarizations in the two RV septal leads, part of an algorithm that ensured delivery of cardiac contractility control signals during the absolute refractory period of the myocardium. Removal of the atrial lead was achieved through a modification of the algorithm, removing the atrioventricular timing criteria while simultaneously strengthening the criteria used to assess timing and sequence between the two RV leads. Building on previous extensive benchtop and preclinical testing of the algorithm, these results demonstrating no ventricular premature beats or ventricular tachycardia events with FIX-HF-5C2 provide important additional safety information.

[0279] The Bayesian model-based mean change in peak VO2 from baseline to week 24 in the FIX-HF-5C2 study increased by 0.80 (95% BCI: 0.18, 1.40) ml / kg / min, while the model-based mean change in peak VO2 from baseline to week 24 in the FIX-HF-5C control group decreased by 0.93 (95% BCI: -1.46, -0.39). The corresponding treatment effect (i.e., the Bayesian primary model-based mean difference in change in peak VO2 at week 24 between the FIX-HF-5C2 treatment group and the FIX-HF-5C control group) was 1.72 (95% BCI: 1.02, 2.42) ml / kg / min. This was supported by a frequentist analysis (i.e., no borrowing), which showed a cardiac contractility-modulating treatment effect of 2.21 ml / kg / min. This effect is near the upper limit of the Bayesian model-based mean treatment effect of 0.84 ml / kg / min (95% BCI: 0.12, 1.52) identified in the previous FIX-HF-5C trial. The larger mean treatment effect identified in this study is due to the fact that peak VO2 in patients in the FIX-HF-5C2 group significantly increased above baseline at 24 weeks, whereas cardiac contractility control in patients in the FIX-HF-5C group remained largely unchanged from baseline. It is possible to speculate as to why the treatment groups performed differently in the FIX-HF-5C and FIX-HF-5C2 trials. Because both trials were open-label and the same core laboratory oversight was applied to both studies, a placebo effect is unlikely. One difference between the trials is that in FIX-HF-5C, patients underwent two CPX tests at each time point in addition to a 6-minute walk test, whereas in FIX-HF-5C2, only one CPX test was performed at each time point and there was no 6-minute walk test. This methodological difference may affect patient performance with serial testing; the results of FIX-HF-5C2 may reflect greater familiarity with repeated testing, whereas the more frequent exercise testing used in the FIX-HF-5C trial may blunt this effect. Nevertheless, the less frequent CPX testing schedule used in the FIX-HF-5C2 trial is more reflective of how patients are serially assessed in clinical practice and in front-line clinical trials.

[0280] limit A potential limitation of this study is that it was a nonrandomized, open-label trial using a historical control group from the previous FIX-HF-5C trial. The two trials were reasonably contemporaneous, completed less than 2 years after each other. The only significant difference in background medication was the slightly higher use of valsartan / sacubitril (4% vs. 15%) in the current trial, due to its introduction into clinical practice toward the completion of enrollment in the FIX-HF-5C trial. With regard to open labeling, this aspect is similar to the previous FIX-HF-5C trial, and we view it as unlikely to affect comparisons made between the two trials.

[0281] Some conclusions The 2-Lead Optimizer Smart System potentially reduces the overall lead device size from 3 to 2 leads, enabling cardiac contractility control signal delivery in patients with atrial arrhythmias. Compared with 3-lead systems, 2-lead systems deliver comparable amounts of cardiac contractility control pulses, are equally safe, and improve peak VO2 and NYHA functional class. There are fewer lead-related device-related adverse events than with 3-lead systems. Therefore, the availability of 2-lead systems represents a significant advance in the development of cardiac contractility control therapy for patients with heart failure.

[0282] It is anticipated that numerous related cardiac contractility regulation devices will be developed between the filing of this application and the life of the maturing patent, and the scope of the term cardiac contractility regulation device is intended to include such new and pioneering technology.

[0283] The terms "comprising," "including," "having," and their cognates mean "including, but not limited to."

[0284] The term "consisting of" is intended to mean "including and limited to."

[0285] The term "consisting essentially of" means that a composition, method, or structure may include additional components, steps, and / or moieties, but only if the additional components, steps, and / or moieties do not materially alter the basic and novel characteristics of the claimed composition, method, or structure.

[0286] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, the term "a unit" or "at least one unit" may include multiple units, including mixtures thereof.

[0287] The words "example" and "exemplary" are used herein to mean "serving as an example, instance, or illustration." Any embodiment described as "example" or "exemplary" is not necessarily to be construed as preferred or advantageous over other embodiments and / or excludes the incorporation of features from other embodiments.

[0288] The word "optionally" is used herein to mean "provided in some embodiments and not provided in other embodiments." Any particular embodiment of the present invention may include multiple "optional" features unless such features are inconsistent.

[0289] Throughout this application, various embodiments of the present invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be construed as including all specifically disclosed possible subranges, as well as individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be construed as including specifically disclosed subranges, such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numerical values ​​within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of fractional ranges.

[0290] Whenever a numerical range is given herein (e.g., "10-15," "10 to 15," or any pair of numbers connected by another such range designator), it is intended to include any number (fractional or integer) within the indicated range limits, inclusive of the range limits, unless the content clearly dictates otherwise. The phrases "range / ranging / ranges between" a first number and a second number, and "range / ranging / ranges" from a first number to a second number "to," "up to," "up to," or "between" (or another such range term) indicate that the numbers are used interchangeably herein and are intended to include the first and second numbers and all decimal and integer values ​​therebetween.

[0291] Unless otherwise indicated, numbers used herein and any numerical ranges based thereon are approximations within the accuracy and reasonable measurement and rounding errors as understood by one of ordinary skill in the art.

[0292] As used herein, the term "method" refers to ways, means, techniques and procedures for accomplishing a given task, including, but not limited to, ways, means, techniques and procedures known to or readily developed from known ways, means, techniques and procedures by the practitioner of the chemical, pharmacological, biological, biochemical and medical arts.

[0293] As used herein, the term "treating" includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating the clinical or cosmetic symptoms of a condition, or substantially preventing the appearance of clinical or cosmetic symptoms of a condition.

[0294] It is to be appreciated that certain features of the invention that are described for clarity in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, various features of the invention that are described for brevity in the context of a single embodiment may also be provided separately or in any suitable subcombination, or as preferred, in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be construed as essential features of those embodiments, unless the embodiment is inoperable without those elements.

[0295] While the present invention has been described in conjunction with specific embodiments thereof, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the appended claims.

[0296] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference in their entirety to the same extent as if each individual publication, patent, and patent application was specifically and individually indicated to be incorporated herein by reference. In addition, citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. To the extent section headings are used, they should not be construed as necessarily limiting. Additionally, the priority document(s) of this application are incorporated herein by reference in their entirety.

Claims

1. 1. A method of planning a treatment plan for a cardiac contractility control device to increase peak VO2 in a patient with reduced peak VO2, comprising: calculating, by a computer, a selection of one or more treatment plans for a patient that takes into account one or more patient parameters, the one or more patient parameters including a level of pulmonary reserve; using a data set that matches one or more therapeutic effects of the one or more treatment plans with one or more characteristics of the cardiac contractility control device and the one or more patient parameters, at least one of the one or more therapeutic effects including an increase in peak VO2 in response to a cardiac contractility control stimulus, the patient having reduced peak VO2 and having pulmonary reserve suitable for achieving an increase in peak VO2 in response to a cardiac contractility control stimulus; receiving the one or more treatment plans by the cardiac contractility regulation device.

2. 10. The method of claim 1, wherein the one or more characteristics of the cardiac contractility regulation device include sensing ventricular contractions using two leads positioned to be placed in the right ventricle.

3. 3. The method of claim 1 or 2, wherein calculating the selection of the one or more treatment regimens comprises the computer calculating the initial therapy based on the one or more parameters of the patient and a rule or table indicating an expected effect using the initial therapy.

4. 4. The method of any one of claims 1 to 3, wherein the dataset is analyzed using machine learning methods to generate a parametric model that can be queried to assess the expected range of treatment effect for a patient or used to automatically or semi-automatically search for suggested treatments.

5. The method of claim 2 , wherein the one or more characteristics of the cardiac contractility modulation device further include a lead selected for use in applying the cardiac contractility modulation stimulation.

6. The method of claim 2 , wherein one or both of the leads in the right ventricle are positioned to rest against the interventricular septum.

7. 7. The method of claim 1, further comprising: the computer calculating to cause the device to prevent application of cardiac contractility control stimulation if the device detects an inappropriate beat when a difference between a ventricular contraction detected by a first ventricular lead and a ventricular contraction detected by a second ventricular lead exceeds 30 milliseconds.

8. 8. The method of claim 1, further comprising the computer calculating the device to apply cardiac contractility modulation to a lead implanted in a ventricle and during a ventricular refractory period but not during an atrial refractory period.

9. The method of any one of claims 1 to 8, further comprising the computer calculating that the device applies cardiac contractility modulation to the atria.

10. 10. The method of claim 1, further comprising the computer calculating such that the device detects ventricular contractions using only one lead placed in the patient's ventricle and determines to apply cardiac contractility modulation stimulation to the patient's heart using the same single lead placed in the patient's ventricle.

11. 11. The method of any one of claims 1 to 10, further comprising the computer calculating the device to provide cardiac contractility control stimulation even during atrial fibrillation (AF).

12. 12. The method of any one of claims 1-11, wherein the one or more parameters of the patient further comprise at least one of: peak VO2 level, pain level, desired effect of increasing peak VO2, desired heart failure-related effect, potential effect of electrode and lead positioning, type of existing cardiac arrhythmia of the patient, and NYHA class of the patient.

13. 13. The method of claim 12, wherein the cardiac arrhythmia is a ventricular arrhythmia.

14. 13. The method of claim 12, wherein the patient's NYHA class is selected from the group consisting of NYHA class II, NYHA class III, and NYHA class IVa.

15. The one or more parameters of the patient are: Respiratory reserve (BR) greater than 30%; oxygen uptake efficiency slope (OUES) below 90%; Peak RER greater than 1.05; VE / VCO greater than 30 ２ ratio; and O decreases by less than 10% over the 20-minute exercise period ２ 15. The method of any one of claims 1 to 14, further comprising at least one pulmonary condition selected from the group consisting of: saturation.

16. The one or more parameters of the patient are: The method of any one of claims 1 to 15, further comprising patients with an ejection fraction greater than 25% and less than 50%.

17. The one or more parameters of the patient are: atrial fibrillation (AF); systolic heart failure (HF); diastolic HF; atrial tachycardia; angina pectoris; Myocarditis; small vessel disease; pulmonary hypertension; Chronic obstructive pulmonary disease (COPD); and 17. The method of any one of claims 1 to 16, further comprising at least one condition selected from the group consisting of: sleep apnea.

18. The reduced peak VO2 was 25 mlO ２ 18. The method of any one of claims 1 to 17, comprising a peak VO2 value of less than 1 / min / kg.

19. The patient with the reduced peak VO2 is ２ 19. The method of claim 18, wherein the patient has a peak VO2 value of greater than 1 / min / kg.

20. The patient is not known to have another medical condition that may limit the patient's ability to increase peak VO2, and the other medical condition that may limit the patient's ability to increase peak VO2 is: Limited pulmonary intake of oxygen, pulmonary disease, Restriction of blood flow, and 19. The method of any one of claims 1 to 18, wherein the disease is selected from the group consisting of: peripheral vascular disease.

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