WO2017040218A1

WO2017040218A1 - Restoring autonomic balance

Info

Publication number: WO2017040218A1
Application number: PCT/US2016/048766
Authority: WO
Inventors: David Olson; Aaron KNUTTILA; Tolga Tas; David Lerner
Original assignee: Sunshine Heart Company Pty Ltd.
Priority date: 2015-08-28
Filing date: 2016-08-25
Publication date: 2017-03-09

Abstract

An example electrical stimulation system for use in combination with a non-pulsatile or low-pulsatile ventricular assist device and for restoration of autonomic balance by stimulating at least one nerve. The system includes a stimulation source including a controller configured to control delivery of electrical stimulation at a stimulation rate modeled to simulate a baroreceptor discharge related to an intrinsic heart rate, a lead operably coupled to the stimulation source, and at least one electrode operably coupled to the lead, wherein the at least one electrode is positionable in contact with or adjacent to the at least one nerve.

Description

RESTORING AUTONOMIC BALANCE

CLAIM OF PRIORITY

This application claims the benefit of priority of U.S. Provisional Patent Application Serial Number 62/211,270, titled "Simulated Arterial Pulsatility Devices, Systems, and Methods for Restoration of Autonomic Balance in Heart Failure" to David Olson et al., and filed on August 28, 2015, which is herein incorporated by reference in its entirety.

TECHNICAL FIELD

This disclosure relates generally to heart failure treatment, and more specifically to techniques for restoring autonomic balance in heart failure patients.

BACKGROUND

Left ventricular assist devices (LVADs) are increasingly being used to treat heart failure patients whose own hearts have become incapable of meeting the patients' metabolic needs. The current generation of LVADs are continuous flow, non-pulsatile pumps that are used for both bridge to transplant and destination therapy.

In a healthy heart under normal pulsatile blood pressure conditions, the carotid sinus and aortic arch baroreceptor discharge rate increases with increasing pressure, notably during the systolic pressure increase, as shown in FIGS. 1 A and IB, which are from FIG. 9-2 of "Textbook in Medical Physiology And Pathophysiology Essentials and Clinical Problems," 2nd edition, by Poul- Erik Paulev and Gustavo Zubieta-Calleja. This creates a parasympathetic response that in turn inhibits sympathetic nerve outflow and contributes to maintaining autonomic balance.

A number of pathological and other conditions may lead to the loss of the body's ability to appreciate the magnitude and pulsatility of blood pressure or flow. For example, accidental trauma from unilateral or bilateral carotid endarectomy or acute cardiogenic shock may lead to baroreflex failure. In addition, even for an intact baroreflex, continuous flow LVADs result in the loss of arterial pulsatility. Regardless of root cause, these phenomena may lead to a number of deleterious physiological effects.

When a non-pulsatile LVAD is used to treat heart failure, the reduction or even total loss of pulsatility can lead to lower rates of baroreceptor afferent discharge due to the reduced deformation of the baroreceptors. That is, since the baroreceptors adapt to the mean arterial pressure, if a static arterial pressure occurs as a result of the continuous flow ventricular assist device, the baroreceptors can reset to that pressure and the discharge rate can decrease and remain low. This in turn can lead to less inhibition of sympathetic nerve activity (SNA) and thus a further worsening of heart failure. There is a need in the art for improved systems, methods, and devices for addressing the lower rates of baroreceptor afferent discharge and thereby improving the heart failure condition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 A and IB are graphs depicting a relationship between blood pressure and impulse frequency.

FIG. 2A is a conceptual diagram illustrating an example stimulation system that may be used to implement various aspects of this disclosure.

FIG. 2B is a schematic illustration of an example system of an electrode cuff around a nerve for electrical activation, in accordance with various aspects of this disclosure.

FIG. 3 is a functional block diagram illustrating components of an example implantable stimulation source that may be used to implement various aspects of this disclosure.

FIG. 4 is a conceptual diagram illustrating an example stimulation system that may be used to implement various aspects of this disclosure.

FIG. 5 is another conceptual diagram illustrating an example stimulation system that may be used to implement various aspects of this disclosure. FIG. 6A is another conceptual diagram illustrating an example stimulation system that may be used to implement various aspects of this disclosure.

FIG. 6B is a conceptual diagram illustrating another example stimulation system that may be used to implement various aspects of this disclosure.

FIG. 7A is a conceptual diagram illustrating another example stimulation system that may be used to implement various aspects of this disclosure.

FIG. 7B is a conceptual diagram illustrating an example electrode cuff that may be used to implement various aspects of this disclosure.

FIG. 8 is a conceptual diagram depicting an example system that can implement various aspects of this disclosure.

OVERVIEW

In some examples, this disclosure is directed to an electrical stimulation system for use in combination with a non-pulsatile or low-pulsatile ventricular assist device and for restoration of autonomic balance by stimulating at least one nerve. The system comprises a stimulation source including a controller configured to control delivery of electrical stimulation at a stimulation rate modeled to simulate a baroreceptor discharge related to an intrinsic heart rate, a lead operably coupled to the stimulation source, and at least one electrode operably coupled to the lead, wherein the at least one electrode is positionable in contact with or adjacent to the at least one nerve.

In some examples, this disclosure is directed to an electrical stimulation system for restoration of autonomic balance by stimulating at least an aortic depressor nerve. The system comprises a stimulation source including a controller configured to control delivery of electrical stimulation at a stimulation rate modeled to simulate a baroreceptor discharge related to an intrinsic heart rate, a lead operably coupled to the stimulation source, and at least one electrode operably coupled to the lead, wherein the at least one electrode is positionable in contact with or adjacent to the aortic depressor nerve. DETAILED DESCRIPTION

This disclosure is generally directed to using various simulated arterial pulsatility devices, systems, and methods to restore autonomic balance in heart failure patients fitted with ventricular assist devices (VADs), e.g., left ventricular assist devices (LVAD), or in patients with baroreflex failure that are not fitted with a VAD. Substituting electrically or mechanically induced neuron depolarization in place of normal baroreceptor output can be the foundation of the therapeutic methods, systems, and devices, as described in detailed below. More specifically, using various aspects of this disclosure, direct mechanical stimulation of the baroreceptors or electrical stimulation of the nerves that innervate the baroreceptors with a stimulation rate modeled to simulate a natural or intrinsic heart rate can cause nerve traffic that is similar to what would be created by actual systolic arterial blood pressure pulses if they were present. The direct stimulation can replace the missing baroreceptor discharges that are lacking due to the weak or missing systolic arterial blood pressure pulses, which can be caused by the use of continuous flow VADs, for example, or baroreflex failure. By inducing afferent baroreceptor neural traffic, the input to the parasympathetic nervous system can be maintained and the autonomic balance can be preserved or shifted toward a more balanced state with the resulting beneficial impact on the heart failure condition. In this manner, the techniques of this disclosure can, in some example implementations, be used to overcome the aforementioned shortcomings in patients using continuous flow, nonpulsatile VADs, or in patients with baroreflex failure.

As will be shown in the various embodiments herein, the stimulation source can either be independent of, or synchronized to, the patient's natural heart rhythm. As will also be discussed herein with respect to various implementations, the stimulation source can be either an implanted or external (extracorporeal).

According to certain embodiments, the nerves that innervate the baroreceptors can be stimulated directly via electrical stimulation. For example, the nerves that innervate the baroreceptors of the right and/or left carotid sinus, aortic arch including the aortic depressor nerve, or some combination can be electrically stimulated. As will be explained below, in certain implementations, the target nerve to innervate the carotid sinus baroreceptors can be the sinus nerve or other nerves or branches cranial to the carotid sinus baroreceptors. In other embodiments in which the aortic arch is to be innervated, the target nerve can include the aortic depressor nerve. Alternatively, any known nerve that innervates the desired baroreceptors can be stimulated according to various embodiments herein.

One specific example of a system targeting the sinus nerve with electrical stimulation is set forth in FIGS. 2 A and 2B, which depict an electrical stimulation system 10 that can include an implanted stimulation source 12, a lead 14, and one or more electrodes 16. In an example stimulation source 12 is depicted in FIG. 3. In this specific example, the system 10 can include an electrode 16 positioned in the patient to be coupled to the sinus nerve 30, as shown in FIG. 2B. According to one embodiment, the electrode 16 (and any other electrode in any system disclosed or contemplated herein) can include an electrode cuff 16. In one example, the electrode cuff 16 can include a bipolar electrode cuff 16 having two electrodes. In another example, the electrode cuff 16 can include a tripolar electrode cuff 16 having three electrodes.

Alternatively, the cuff 16 can have four or more electrodes. In a further alternative, the electrode 16 can be a single electrode 16. In yet further alternative implementations, the electrode 16 can be one, two, three, or more electrodes. In addition to a cuff configuration, in alternative implementations, the electrode 16 can also have other configurations, such as a helical electrode, a patch electrode, a straight electrode, or any other known configuration. It is understood that the lead 14 has an equivalent number of conductors (not shown) depending on the number of electrodes 16. It is further understood that any of these electrode implementations can be incorporated into any system embodiment disclosed or contemplated herein.

In some examples, electrical stimulation system 10 can target one or both of the carotid sinus nerve and the aortic depressor nerve.

According to the various embodiments herein having an implanted stimulation source, the implanted stimulation source 12 is a controlled voltage or current source capable of providing a pulse train output or some other known source of electrical signals that produces a neurostimulation signal. The stimulation source 12 can have a power source, e.g., power source 208 of FIG. 3, and a controller, e.g., controller 200 of FIG. 3. For example, in one embodiment, the controller is a processor that can be used to control the rate and strength of the signal transmitted by the source 12. For example, the processor can be programmed with the neurostimulation parameters, including waveform, amplitude, rate, and any other known parameters for neurostimulation. In accordance with some implementations, the parameters may be adjusted as necessary to achieve the desired therapy effects, such as by reprogramming the controller. The controller can, in some exemplary embodiments, be programmed and/or reprogrammed via wireless means. Alternatively, the controller can be programmed or reprogrammed via any known means.

In certain embodiments, the stimulation source 12 can have a communication component (not shown) with a transceiver (not shown) that is configured to communicate with an external programmer and/or other known external devices that may be use to communicate with the stimulation source 12.

Further, in accordance with some implementations, the stimulation source 12 is powered by a primary battery or a rechargeable battery that can be recharged wirelessly. Alternatively, the stimulation source 12 can be powered by any known energy source.

In this example, as in all the embodiments having implanted stimulation sources, the lead 14 is operably coupled to the stimulation source 12 and the one or more electrodes 16, such that a neurostimulation signal generated by the stimulation source 12 can be transmitted via the lead 14 to the electrodes 16. As shown in FIG. 2B, the electrode 16, according to one embodiment, is coupled to or otherwise in contact with a nerve, such as, for example, the sinus nerve 30. In other embodiments having two or more electrodes, each of the electrodes is coupled to or otherwise in contact with the nerve. In the specific example depicted in FIG. 2B and as discussed above, the electrode 16 is a cuff electrode 16 that is positioned around the sinus nerve 30. As can be seen in the figure, the sinus nerve 30 is positioned between the internal carotid artery 32 and the external carotid artery 34 and extends to the carotid sinus baroreceptors 36, as discussed above. FIG. 3 is a conceptual diagram illustrating an example stimulation system that may be used to implement various aspects of this disclosure. In the example shown in FIG. 3, the stimulation system 12 can include a controller 200, a memory 202, a stimulation generator 204, a telemetry circuitry 206, and a power source 208. A memory 202 can include any volatile or non- volatile media, such as a random access memory (RAM), read only memory (ROM), non-volatile RAM (NVRAM), electrically erasable programmable ROM (EEPROM), flash memory, and the like. The memory 202 can store computer- readable instructions that, when executed by the controller 200, can cause the stimulation source 12 to perform various functions described in this disclosure. The memory 202 can store, for example, stimulation electrode combinations, therapy programs, and operating instructions.

The stimulation generator 204, under the control of the controller 200, can generate stimulation signals for delivery to the patient via an electrode or selected combinations of electrodes.

The power source 208 can deliver operating power to the various components of the stimulation system 12. The power source 208 can include a rechargeable or non-rechargeable battery and a power generation circuit to produce the operating power.

The telemetry circuit 206 can support wireless communication between the stimulation system 12 and an external programmer (not depicted). The telemetry circuit 206 can accomplish communication by various techniques including, but not limited to, proximal inductive interaction, ultrasonic, and radiofrequency (RF) communication techniques. The controller 200 can receive, via the telemetry circuit 206, values for various stimulation parameters such as amplitude and electrode combinations.

FIG. 4 depicts another embodiment of a system 50 targeting the sinus nerve with electrical stimulation. In this implementation, the electrical stimulation system 50 has not only an implanted stimulation source 52, a lead 54, and one or more electrodes 56, but also a sensing lead 58 (also referred to as a "sense" or "detection" lead). It is understood that the other components (the stimulation source 52, lead 54, and electrode 56) can operate in the same fashion or a similar fashion as the corresponding components in the system 10 described above, except as set forth herein. In some examples, electrical stimulation system 50 can target one or both of the carotid sinus nerve and the aortic depressor nerve.

The sensing lead 58 is disposed or positioned such that it is adjacent to or in contact with the patient' s heart (not shown). Alternatively, the sensing lead 58 can be positioned anywhere in or on the patient's body such that the lead 58 can sense electrical heart activity. The sensing lead 58 can be positioned to detect heart signals according to any configuration or method of any known sensing lead. Alternatively, any system embodiment disclosed or contemplated herein can have one or more sensing electrodes without a sensing lead. For example, any system embodiment can have one or more sensing electrodes positioned in the stimulation source 52 (such as in the header (not shown) of the stimulation source 52). In a further alternative, the sensing electrodes can be positioned in any known location that can allow for sensing as disclosed herein. In yet another alternative, any system embodiment disclosed herein can have a combination of one or more sensing electrodes at the stimulation site and one or more electrodes positioned in the stimulation source 52.

Returning to the embodiment of FIG. 4, the sensing lead 58 allows for synchronization of the system 50 with the heart. More specifically, the sensing lead 58 detects one or more signals of the heart and transmits that information to the controller (not shown) in the stimulation source 52, which is configured to synchronize the transmission of electrical signals to the electrode 56 to be in desired synchronization with the patient's heart. In one implementation, the sensing lead 58 is an electrocardiogram (ECG) sense lead, an intracardiac electrogram (EGM) sense lead, an epicardial sense lead, an endocardial sense lead, or a subcutaneous sense lead. Alternatively, instead of a sensing lead, the system 50 can detect the heart activity via a known heart sounds detector or a blood pressure detection apparatus. In a further alternative implementation, the system 50 can detect the respiration rate and perform some calculation (such as, for example, multiplying the respiration rate by some factor) and thereby approximate the heart rate. While respiration rate is asynchronous to the intrinsic heart rate, the respiration rate is still associated with the patient' s physiology and would vary based on metabolic demand. It is understood that any of these heart signal detection components can be incorporated into any of the embodiments disclosed or contemplated herein.

Alternatively, in those electrical stimulation embodiments that do not provide for synchronization with the patient's heart, the stimulation rate can be asynchronous to the patient' s intrinsic heart rate. In such embodiments, the stimulation rate is determined through programmed parameters that are programmed into the controller of the stimulation source.

FIG. 5 depicts another embodiment of a system 70 targeting the sinus nerve with electrical stimulation. In this implementation, the electrical stimulation system 70 has a lead 72 and an electrode 74, along with an external stimulation source (not shown). That is, the lead 72 has sufficient length to extend through an incision or port 76 in the patient's skin and out of the patient's body to the external stimulation source (not shown). It is understood that other stimulation embodiments disclosed herein can also be coupled to an external stimulation source. In some examples, electrical stimulation system 70 can target one or both of the carotid sinus nerve and the aortic depressor nerve.

FIGS. 6 A and 6B depict another embodiment of an electrical stimulation system 90 that has an implanted stimulation source 92, a lead 94, and at least one electrode 96. In this specific example, the electrode 96 is positioned in the patient to be coupled to or otherwise in contact with the aortic nerve 98, as shown in FIG. 6B. In this specific example, the electrode 96 is a cuff electrode 96 that is positioned around the aortic nerve 98. As can be seen in FIG. 6B, the aortic nerve 98 extends to the aortic arch baroreceptors 100. In some examples, electrical stimulation system 90 can target one or both of the carotid sinus nerve and the aortic depressor nerve.

As seen in FIG. 6A, in some example configurations, the electrical stimulation system 90 can include one or more of leads 120, 122, 124, and 126 having one or more respective electrode(s) 128, 130, 132, and 134. These leads and electrodes can be configured to provide electrical stimulation to one or more of a left carotid sinus nerve, left aortic depressor nerve, right carotid sinus nerve, and right aortic depressor nerve.

According to other implementations, the baroreceptors are stimulated directly via mechanical stimulation. For example, the baroreceptors of one or more of the right and/or left carotid sinus, aortic arch including the aortic depressor nerve, or some combination can be mechanically stimulated.

One specific example of a system targeting the aortic arch with mechanical stimulation is set forth in FIGS. 7 A and 7B, which depict a mechanical baroreceptor cuff 110 that can be positioned around the aortic arch 112, as shown in FIG 7 A. The cuff 110 is configured to mechanically manipulate the blood vessel walls around the ascending aorta 114 and aortic arch 112. In this specific example, the cuff 110 is an electro -magnetically actuated cuff 110. As shown in FIG. 7B, the cuff 110 has electromagnetic coils 116 that create force either clockwise or counter-clockwise with respect to the circumference of the aorta 114. The coils 116 are configured to be activated such that alternating sections attract, thereby causing the remaining sections to be stretched. This stretching of the cuff 110 locally activates baroreceptors in that area. Further, the cuff 1 10 is also configured to allow for subsequently activating different coils, thereby resulting in stimulation of the entire circumference. Alternatively, as will be discussed in further detail below, the cuff 110 can be any mechanical cuff 1 10 for physically manipulating the blood vessel walls. Alternatively, the cuff 110 can be any known mechanical cuff, such as a cuff made of electro-active polymers.

It is understood that the electromagnetic cuff 110 of FIGS. 7 A and 7B is coupled to a power source (not shown) and a controller (not shown). Similarly, it is understood that any cuff embodiment disclosed or contemplated herein would be coupled to a power source and controller. Like the controller discussed above with respect to the electrical stimulation embodiments, in certain embodiments, the controller is a processor that can be used to control the rate and strength of the signal transmitted by the power source to the cuff 110. For example, the processor can be programmed with the stimulation parameters, including waveform, amplitude, rate, and any other known parameters for stimulation. In accordance with some implementations, the parameters may be adjusted as necessary to achieve the desired therapy effects, such as by reprogramming the controller. The controller can, in some exemplary embodiments, be programmed and/or reprogrammed via wireless means. Alternatively, the controller can be programmed or reprogrammed via any known means.

In certain embodiments, the power source (not shown) can have a communication component (not shown) with a transceiver (not shown) that is configured to communicate with an external programmer and/or other known external devices that may be use to communicate with the power source.

It is further understood that the electromagnetic cuff 1 10 of FIGS. 7 A and 7B can, in certain alternative embodiments, be coupled to a sensing lead (not shown). Similarly, it is understood that any mechanical cuff embodiment disclosed or contemplated herein could be coupled to a sensing lead. The sensing lead or sensing electrode can be substantially similar to the various sensing embodiments disclosed or contemplated above with respect to FIG. 4 and the related discussion.

The various simulated arterial pulsatility techniques described above can restore autonomic balance in a heart failure patient fitted with a ventricular assist device (VAD), e.g., left ventricular assist device (LVAD). As described below with respect to FIG. 8, in some example implementations, the various simulated arterial pulsatility techniques can be combined with information received from the LVAD, one or more external sensors, and/or one or more implantable sensors. This additional information can help ensure that the imparted pulsatility conforms with the pulsatility that would have existed prior to implantation of the LVAD, for example.

FIG. 8 is a conceptual diagram depicting an example system that can implement various aspects of this disclosure. In particular, FIG. 8 depicts a system 300 that can include a ventricular assist device 302, e.g., LVAD, a simulated arterial pulsatility system 304 that can induce neuron depolarization in place of normal baroreceptor output using the various electrical and/or mechanical stimulation techniques described above. Various example simulated arterial pulsatility systems 304 were described above, including systems 10, 50, 70, and 90.

The system 300 can include one or more implantable sensors 306, e.g., one or more implantable physiological sensors. Non-limiting examples of implantable sensors include an ultrasound sensor, a bio-impedance sensor, a pressure transducer, an optical sensor, a strain gauge sensor (for measurement of vessel circumference), and an acoustic sensor (to sense blood flow or heart valve action), which can be used to approximate the phase of the cardiac cycle.

The system can include one or more external sensors 308. As described in more detail below, the external sensor(s) can include a pulse oximeter, plethysmograph, a Doppler flow meter, a surface electrocardiogram (ECG), and/or other non-invasive device to optimize pulse triggering, modulation frequency, or other parameter to optimize the imparted pulsatility.

In the example system 300 in FIG. 8, one or more of the VAD 302, the external sensor(s) 306, and the implantable sensor(s) 306 can communicate with the simulated arterial pulsatility system 304. In a non-limiting example, the VAD 302, the external sensor(s) 308, and the implantable sensor(s) 306 can communicate with the simulated arterial pulsatility system 304 using wireless links 310A-310C. In other examples, a wired communication link can be used.

As indicated above, additional information received from one or more of the VAD 302, the external sensor(s) 308, and the implantable sensor(s) 306 can help ensure that the pulsatility imparted by the simulated arterial pulsatility system 304 conforms with the pulsatility that would have existed prior to implantation of the VAD, for example. In some example implementations, the neurostimulation parameters generated by the simulated arterial pulsatility system 304 can be set and allowed to run open loop. Using this approach, the simulated arterial pulsatility system 304 can initially set a neurostimulation pattern to modulate at a typical physiological heart rate, e.g., 60 beats per minute (1 hertz (Hz)).

In another example implementation, the implantable sensor(s) 306, for example, can derive an electrophysiological signal initiated by the sinoatrial (S A) node, atrioventricular (AV) node or other natural or artificial pacemaker and can transmit a signal to the simulated arterial pulsatility system 304 that can include information representing the electrophysiological signal. The controller 200 of the simulated arterial pulsatility system 304 can use this information to control the stimulation generator 204 to synchronize or trigger neurostimulation pulses with the body's intrinsic heart rate or artificially generated pacing rate. In some examples, the controller 200 may include an analog-to-digital converter (ADC). The ADC can receive a signal from the SA node and/or other automaticity foci, a pacing device, and/or a VAD. For example, S A node information can be received via an ECG or EGM and VAD information can provide a pump status, including pump rate. The ADC can digitized the signal and the controller 200 can apply an algorithm, e.g., Fast Fourier transform (FFT), parametric spectral analysis, etc., to access the frequency content of the signal. Using the frequency content information, the controller 200 can determine the stimulation parameters, including a rate and a duty cycle, for example. This can enable triggering neurostimulation pulses, pulse trains, etc. from the intracardiac electrograms of the cardiovascular electrical conduction system, VAD, and/or from an artificial pacemaker.

In another approach, the implantable sensor(s) 306, for example, can derive the patient' s heart rate and incorporate this rate into the neurostimulation duty cycle generated and delivered by the simulated arterial pulsatility system 304. Using these techniques and other similar approaches, the pulse pattern, amplitude, duty cycle, frequency, and pulse width, as well as other typical neuromodulation parameters, can be modulated or adapted based on the measured electrophysiology signals from the body's cardiovascular electrical conducting system. This latter embodiment can have the benefit of imparting pulsatility at the individual patient's "natural" frequency, which can ensure that the imparted pulsatility conformed with the pulsatility that would have been extent prior to implantation of the LVAD. It can also allow the addition of a time or phase delay with respect to selected EGM anatomical landmarks such as the R-wave.

In another embodiment in the example of baroreflex failure due to illness or trauma, many of the benefits described above with respect to imparting pulsatility at the individual patient's intrinsic heart rate can also be accomplished by using implantable sensor(s) 306 such as pressure, optical, velocity, and/or flow related sensors to measure one or more aspects of intra- arterial blood flow. For example, one or more of an implantable ultrasound sensor, pressure transducer, optical sensor, bio-impedance sensor, strain gauge sensor for measurement of vessel circumference, and acoustic sensor (to sense blood flow or heart valve action) may be used to approximate the phase of the cardiac cycle. Feedback from the processed signals from one or more of these sensors can be used by the simulated arterial pulsatility system 304 to synchronize, time, or otherwise inform the neuro stimulation pattern and signal strength in much the same way as the approaches described above.

In some existing VAD devices, the VAD 302 can measure the electrophysiology signal. In some example implementations, the VAD 302 can transmit a signal to the simulated arterial pulsatility system 304 that can include information representing the electrophysiology signal. The LVAD can transmit the signal wirelessly using wireless link 310B (or using a wired connection). As described above, the controller 200 of the simulated arterial pulsatility system 304 can use this information to control the stimulation generator 204 to synchronize or trigger neurostimulation pulses with the body' s natural pacemaker. This can enable triggering neurostimulation pulses, pulse trains, etc. from the R-wave of the signals from the electrical conducting system of the cardiovascular system.

In other example configurations, the LVAD can transmit additional or alternative LVAD-derived parameters to the simulated arterial pulsatility system 304, which the controller 200 can use to generate various pulse generation patterns or signal strength to optimize pulsatility or other performance measures. As an example, the controller 200 can use the LVAD flow rate to generate the neuromodulation pulse generation signal strength and/or pattern.

In some example configurations, an external (e.g., non-invasive) device 308 can be used to adjust or calibrate one or more neurostimulation parameters at an initial set up instance. As an example, information one or more of a pulse oximeter, plethysmograph, Doppler flow meter, surface ECG, and other noninvasive device can be used to optimize pulse triggering, modulation frequency, or other parameter to optimize the imparted pulsatility.

In one or more of the foregoing techniques, the simulated arterial pulsatility system 304 can analyze the derived physiological or LVAD-derived signal to derive information for use by the controller 200 and the stimulation generator 204. As an example, the controller 200 can utilize pattern recognition techniques to identify relevant electrophysiological features from the ECG or EGM signals. The controller 200 can use the R wave time position, for example, to affect or trigger the timing of pulses generated by stimulation generator 204. In another example implementation, the controller 200 can analyze an ECG signal, e.g., using parametric or non-parametric spectral analysis techniques, to identify a dominant frequency associated with the intrinsic heart rate. This dominant frequency can indicate the patient's heart rate. The controller 200 can use this "heart rate" to modify a modulation frequency of the stimulation generator 204 to simulate the patient's natural heart rate. While multiple embodiments are disclosed, still other embodiments of the present invention will become apparent to those skilled in the art from the following detailed description, which shows and describes illustrative embodiments of the invention. As will be realized, the invention is capable of modifications in various obvious aspects, all without departing from the spirit and scope of the present invention. Accordingly, the drawings and detailed description are to be regarded as illustrative in nature and not restrictive.

As mentioned above, various conditions may lead to the loss of the body's ability to appreciate the magnitude and pulsatility of blood pressure or flow. For example, accidental trauma from unilateral or bilateral carotid endarectomy or acute cardiogenic shock may lead to baroreflex failure. The baroreflex failure may be a partial failure, however. In such a case, various aspects of this disclosure can gradually, e.g., as the baroreflex failure proceeds, increase the "intensity" or degree of augmentation of pulsatility, even in patients that do not have a ventricular assist device. As such, the techniques described in this disclosure are not limited to use in combination with a VAD, e.g., LVAD. Rather, the techniques described can replace the missing baroreceptor discharges that are lacking due to the weak or missing systolic arterial blood pressure pulses, which can be caused by baroreflex failure.

In some example implementations, to detect the progression of failure in order to gradually increase the intensity of pulsatility, the stimulation system, e.g., stimulation system 10, can monitor a blood pressure signal and ping spectral analysis to show the progressive attenuation of the intrinsic heart rate component of the blood pressure signal and use this feedback to modulate the stimulation signal. Although the present invention has been described with reference to preferred embodiments, persons skilled in the art will recognize that changes may be made in form and detail without departing from the spirit and scope of the invention.

Various Notes and Examples

Example 1 includes subject matter (such as a device, system, circuit, apparatus, or machine, method, means) for use in combination with a nonpulsatile or low-pulsatile ventricular assist device and for restoration of autonomic balance by stimulating at least one nerve, the subject matter comprising: a stimulation source including a controller configured to control delivery of electrical stimulation at a stimulation rate modeled to simulate a baroreceptor discharge related to an intrinsic heart rate; a lead operably coupled to the stimulation source; and at least one electrode operably coupled to the lead, wherein the at least one electrode is positionable in contact with or adjacent to the at least one nerve.

In Example 2, the subject matter of Example 1 can optionally include, wherein delivery of electrical stimulation via the at least one electrode causes stimulation of the at least one nerve, thereby modulating a discharge simulating a baroreceptor discharge rate associated with the at least one nerve.

In Example 3, the subject matter of one or more of Examples 1 and 2 can optionally include, wherein the stimulation source is configured to communicate with the ventricular assist device.

In Example 4, the subject matter of Example 3 can optionally include, wherein the stimulation source is configured to receive a signal including information representing an electrophysiology signal from the ventricular assist device, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

In Example 5, the subject matter of Example 4 can optionally include, wherein the controller is configured to use the received signal to synchronize or trigger delivery of electrical stimulation. In Example 6, the subject matter of one or more of Examples 3-5 can optionally include, wherein the stimulation source is configured to receive a signal including information representing a flow rate from the ventricular assist device, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

In Example 7, the subject matter of one or more of Examples 1 -6 can optionally include, wherein the stimulation source is in communication with at least one implantable sensor, wherein the at least one implantable sensor is configured to derive an electrophysiology signal from a sinoatrial node, wherein the stimulation source is configured to receive a signal including information representing the electrophysiology signal from the at least one implantable sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

In Example 8, the subject matter of one or more of Examples 1 -7 can optionally include, wherein the stimulation source is in communication with at least one implantable sensor, wherein the at least one implantable sensor is configured to derive a physiological parameter, wherein the stimulation source is configured to receive a signal including information representing the physiological parameter from the at least one implantable sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

In Example 9, the subject matter of Example 8 can optionally include, wherein the at least one implantable sensor is selected from the group consisting of: an ultrasound sensor, a pressure transducer, an optical sensor, a strain gauge sensor, and an acoustic sensor.

In Example 10, the subject matter of one or more of Examples 1 -9 can optionally include, wherein the stimulation source is in communication with at least one external sensor, wherein the at least one external sensor is configured to derive a physiological parameter, wherein the stimulation source is configured to receive a signal including information representing the physiological parameter from the at least one external sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal. In Example 11 , the subject matter of Example 10 can optionally include, wherein the at least one external sensor is selected from the group consisting of: a pulse oximeter, a plethysmograph, a Doppler flow meter, and a surface electrocardiogram (ECG).

In Example 12, the subject matter of one or more of Examples 1-1 1 can optionally include, wherein the at least one electrode comprises a cuff electrode.

In Example 13, the subject matter of one or more of Examples 1 -12 can optionally include, wherein the stimulation source is configured to receive a signal including information representing a physiological parameter from at least one of the following: an implantable sensor, an external sensor, and the ventricular assist device.

In Example 14, the subject matter of one or more of Examples 1 -13 can optionally include, wherein the at least one nerve is at least one of a carotid sinus nerve and an aortic depressor nerve.

Example 15 includes subject matter (such as a device, system, circuit, apparatus, or machine, method, means) for restoration of autonomic balance by stimulating at least an aortic depressor nerve, the subject matter comprising: a stimulation source including a controller configured to control delivery of electrical stimulation at a stimulation rate modeled to simulate a baroreceptor discharge related to an intrinsic heart rate; a lead operably coupled to the stimulation source; and at least one electrode operably coupled to the lead, wherein the at least one electrode is positionable in contact with or adjacent to the aortic depressor nerve.

In Example 16, the subject matter of Example 15 can optionally include, wherein delivery of electrical stimulation via the at least one electrode causes stimulation of the aortic depressor nerve, thereby modulating a discharge simulating a baroreceptor discharge rate associated with the aortic depressor nerve. In Example 17, the subject matter of one or more of Examples 15-16 can optionally include, wherein the stimulation source is in communication with at least one implantable sensor, wherein the at least one implantable sensor is configured to derive an electrophysiology signal from a sinoatrial node, wherein the stimulation source is configured to receive a signal including information representing the electrophysiology signal from the at least one implantable sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

In Example 18, the subject matter of one or more of Examples 15-17 can optionally include, wherein the stimulation source is in communication with at least one implantable sensor, wherein the at least one implantable sensor is configured to derive a physiological parameter, wherein the stimulation source is configured to receive a signal including information representing the physiological parameter from the at least one implantable sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

In Example 19, the subject matter of Example 18 can optionally include, wherein the at least one implantable sensor is selected from the group consisting of: an ultrasound sensor, bio-impedance sensor, a pressure transducer, an optical sensor, a strain gauge sensor, and an acoustic sensor.

In Example 20, the subject matter of one or more of Examples 15-19 can optionally include, wherein the stimulation source is in communication with at least one external sensor, wherein the at least one external sensor is configured to derive a physiological parameter, wherein the stimulation source is configured to receive a signal including information representing the physiological parameter from the at least one external sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

In Example 21 , the subject matter of Example 20 can optionally include, wherein the at least one external sensor is selected from the group consisting of: a pulse oximeter, a plethysmograph, a Doppler flow meter, and a surface electrocardiogram (ECG). In Example 22, the subject matter of one or more of Examples 15-21 can optionally include, wherein the at least one electrode comprises a cuff electrode.

In Example 23, the subject matter of one or more of Examples 15-22 can optionally include, wherein the at least one electrode is a first electrode and the lead is a first lead, the system further comprising: a second electrode operably coupled to a second lead, wherein the second electrode is positionable in contact with or adjacent to a carotid sinus nerve.

Each of these non-limiting examples can stand on its own, or can be combined in various permutations or combinations with one or more of the other examples.

The above detailed description includes references to the accompanying drawings, which form a part of the detailed description. The drawings show, by way of illustration, specific embodiments in which the invention can be practiced. These embodiments are also referred to herein as "examples." Such examples can include elements in addition to those shown or described.

However, the present inventors also contemplate examples in which only those elements shown or described are provided. Moreover, the present inventors also contemplate examples using any combination or permutation of those elements shown or described (or one or more aspects thereof), either with respect to a particular example (or one or more aspects thereof), or with respect to other examples (or one or more aspects thereof) shown or described herein.

Method examples described herein can be machine or computer- implemented at least in part. Some examples can include a computer-readable medium or machine-readable medium encoded with instructions operable to configure an electronic device to perform methods as described in the above examples. An implementation of such methods can include code, such as microcode, assembly language code, a higher-level language code, or the like. Such code can include computer readable instructions for performing various methods. The code may form portions of computer program products. Further, in an example, the code can be tangibly stored on one or more volatile, non- transitory, or non- volatile tangible computer-readable media, such as during execution or at other times. Examples of these tangible computer-readable media can include, but are not limited to, hard disks, removable magnetic disks, removable optical disks (e.g., compact disks and digital video disks), magnetic cassettes, memory cards or sticks, random access memories (RAMs), read only memories (ROMs), and the like.

The above description is intended to be illustrative, and not restrictive. For example, the above-described examples (or one or more aspects thereof) may be used in combination with each other. Other embodiments can be used, such as by one of ordinary skill in the art upon reviewing the above description. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims. Also, in the above Detailed Description, various features may be grouped together to streamline the disclosure. This should not be interpreted as intending that an unclaimed disclosed feature is essential to any claim. Rather, inventive subject matter may lie in less than all features of a particular disclosed embodiment. Thus, the following claims are hereby incorporated into the Detailed Description as examples or embodiments, with each claim standing on its own as a separate embodiment, and it is contemplated that such embodiments can be combined with each other in various combinations or permutations. The scope of the invention should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

Claims

CLAIMS What is claimed is:

1. An electrical stimulation system for use in combination with a nonpulsatile or low-pulsatile ventricular assist device and for restoration of autonomic balance by stimulating at least one nerve, the system comprising: a stimulation source including a controller configured to control delivery of electrical stimulation at a stimulation rate modeled to simulate a baroreceptor discharge related to an intrinsic heart rate;

a lead operably coupled to the stimulation source; and

at least one electrode operably coupled to the lead, wherein the at least one electrode is positionable in contact with or adjacent to the at least one nerve.

2. The system of claim 1 , wherein delivery of electrical stimulation via the at least one electrode causes stimulation of the at least one nerve, thereby modulating a discharge simulating a baroreceptor discharge rate associated with the at least one nerve.

3. The system of any one of claims 1 and 2, wherein the stimulation source is configured to communicate with the ventricular assist device.

4. The system of claim 3, wherein the stimulation source is configured to receive a signal including information representing an electrophysiology signal from the ventricular assist device, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

5. The system of claim 4, wherein the controller is configured to use the received signal to synchronize or trigger delivery of electrical stimulation.

6. The system of any one of claims 3-5, wherein the stimulation source is configured to receive a signal including information representing a flow rate from the ventricular assist device, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

7. The system of any one of claims 1-6, wherein the stimulation source is in communication with at least one implantable sensor, wherein the at least one implantable sensor is configured to derive an electrophysiology signal from a sinoatrial node, wherein the stimulation source is configured to receive a signal including information representing the electrophysiology signal from the at least one implantable sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

8. The system of any one of claims 1-7, wherein the stimulation source is in communication with at least one implantable sensor, wherein the at least one implantable sensor is configured to derive a physiological parameter, wherein the stimulation source is configured to receive a signal including information representing the physiological parameter from the at least one implantable sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

9. The system of claim 8, wherein the at least one implantable sensor is selected from the group consisting of: an ultrasound sensor, a pressure transducer, an optical sensor, a strain gauge sensor, and an acoustic sensor.

10. The system of any one of claims 1-9, wherein the stimulation source is in communication with at least one external sensor, wherein the at least one external sensor is configured to derive a physiological parameter, wherein the stimulation source is configured to receive a signal including information representing the physiological parameter from the at least one external sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

11. The system of claim 10, wherein the at least one external sensor is selected from the group consisting of: a pulse oximeter, a plethysmograph, a Doppler flow meter, and a surface electrocardiogram (ECG).

12. The system of any one of claims 1-11, wherein the at least one electrode comprises a cuff electrode.

13. The system of any one of claims 1-12, wherein the stimulation source is configured to receive a signal including information representing a physiological parameter from at least one of the following: an implantable sensor, an external sensor, and the ventricular assist device.

14. The system of any one of claims 1 -13, wherein the at least one nerve is at least one of a carotid sinus nerve and an aortic depressor nerve.

15. An electrical stimulation system for restoration of autonomic balance by stimulating at least an aortic depressor nerve, the system comprising:

a stimulation source including a controller configured to control delivery of electrical stimulation at a stimulation rate modeled to simulate a baroreceptor discharge related to an intrinsic heart rate;

a lead operably coupled to the stimulation source; and

at least one electrode operably coupled to the lead, wherein the at least one electrode is positionable in contact with or adjacent to the aortic depressor nerve.

16. The system of claim 15, wherein delivery of electrical stimulation via the at least one electrode causes stimulation of the at least one nerve, thereby modulating a discharge simulating a baroreceptor discharge rate associated with the aortic depressor nerve.

17. The system of any one of claims 15-16, wherein the stimulation source is in communication with at least one implantable sensor, wherein the at least one implantable sensor is configured to derive an electrophysiology signal from a sinoatrial node, wherein the stimulation source is configured to receive a signal including information representing the electrophysiology signal from the at least one implantable sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

18. The system of any one of claims 15-17, wherein the stimulation source is in communication with at least one implantable sensor, wherein the at least one implantable sensor is configured to derive a physiological parameter, wherein the stimulation source is configured to receive a signal including information representing the physiological parameter from the at least one implantable sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

19. The system of claim 18, wherein the at least one implantable sensor is selected from the group consisting of: an ultrasound sensor, bio-impedance sensor, a pressure transducer, an optical sensor, a strain gauge sensor, and an acoustic sensor.

20. The system of any one of claims 15-19, wherein the stimulation source is in communication with at least one external sensor, wherein the at least one external sensor is configured to derive a physiological parameter, wherein the stimulation source is configured to receive a signal including information representing the physiological parameter from the at least one external sensor, and wherein the controller is further configured to control delivery of electrical stimulation using the received signal.

21. The system of claim 20, wherein the at least one external sensor is selected from the group consisting of: a pulse oximeter, a plethysmograph, a Doppler flow meter, and a surface electrocardiogram (ECG).

22. The system of any one of claims 15-21, wherein the at least one electrode comprises a cuff electrode.

23. The system of any one of claims 15-22, wherein the at least one electrode is a first electrode and the lead is a first lead, the system further comprising: a second electrode operably coupled to a second lead, wherein the second electrode is positionable in contact with or adjacent to a carotid sinus nerve.