阅读说明：本技术 心脏再同步治疗的非侵入式评估 (Non-invasive assessment of cardiac resynchronization therapy ) 是由 R·W·斯塔德勒 B·施特格曼 R·科内卢森 S·高希 Y·K·周 J·M·吉尔伯格 T 于 2016-01-29 设计创作，主要内容包括：本文涉及心脏再同步治疗的非侵入式评估。本文中描述了用于非侵入式地判定患者是否可受益于心脏再同步治疗的系统、方法和界面。一种示例性方法涉及向心脏组织递送超声波能量。响应于向所述心脏组织递送超声波能量,利用处理单元从分布在患者躯干上的多个电极中的每个电极接收躯干表面电势信号。针对所述多个电极的至少一个子集,利用所述处理单元基于从所述电极感测到的所述信号来计算躯干表面激活时间。由所述处理单元经由显示器向用户呈现所述躯干表面激活时间的不同步程度的指示。(This document relates to non-invasive assessment of cardiac resynchronization therapy. Systems, methods, and interfaces for non-invasively determining whether a patient may benefit from cardiac resynchronization therapy are described herein. One exemplary method involves delivering ultrasonic energy to cardiac tissue. In response to delivering ultrasonic energy to the cardiac tissue, a torso-surface potential signal is received with a processing unit from each of a plurality of electrodes distributed on a torso of a patient. Calculating, with the processing unit, torso-surface activation times based on the signals sensed from the electrodes for at least a subset of the plurality of electrodes. Presenting, by the processing unit, to a user via a display, an indication of a degree of dyssynchrony of the torso-surface activation times.)

1. A system, the system comprising:

means (120) for delivering ultrasound energy to cardiac tissue;

means (140) for receiving, with a processing unit, a torso-surface potential signal from each of a plurality of electrodes distributed on a torso of a patient in response to delivering ultrasonic energy to the cardiac tissue;

processing means (140) for calculating, with the processing unit, torso-surface activation times based on the signals sensed from the electrodes for at least a subset of the plurality of electrodes; and

means (132) for presenting, by the processing unit, to a user via a display, an indication of a degree of dyssynchrony of the torso-surface activation times.

2. The system of claim 1, wherein the ultrasonic energy is High Intensity Focused Ultrasound (HIFU).

3. The system of claim 2, wherein the HIFU is delivered by a transducer.

4. The system of any one of claims 1-3, wherein receiving the torso-surface potential signal and calculating the torso-surface activation time comprises: receiving a first torso-surface potential signal and calculating a first torso-surface activation time for a first time during intrinsic conduction of the heart of the patient, and receiving a second torso-surface potential signal and calculating a second torso-surface activation time for a second time during CRT pacing of the heart, and

wherein presenting the indication of the degree of dyssynchrony comprises: presenting an indication of a change in dyssynchrony of the CRT pacing from the intrinsic conduction to the heart.

5. The system of any of claims 1-4, wherein the ultrasonic energy is delivered at a Sound Pressure Level (SPL) of up to 3 megapascals (MPa) for pacing cardiac tissue.

6. The system of any of claims 1-5, wherein the ultrasonic energy is delivered to at least one localized area on a left ventricular wall.

7. The system of any of claims 1-6, wherein the ultrasonic energy is delivered for non-invasive cardiac resynchronization therapy involving ultrasonic stimulation of at least one right ventricular site and at least one left ventricular site with delivery of stimulation timed relative to a P-wave on the surface ECG.

8. The system of claim 7, wherein the ultrasound pacing is delivered at various timings relative to expected intrinsic ventricular depolarizations.

9. The system of claim 8, wherein the delivery of ultrasound pacing may be timed at a time interval after the start of the surface ECG P-waves such that the time interval may be 80ms shorter than an intrinsic P-R interval, 60ms shorter than the intrinsic P-R interval, 50ms shorter than the intrinsic P-R interval, 40ms shorter than the intrinsic P-R interval, 30ms shorter than the intrinsic P-R interval, 20ms shorter than the intrinsic P-R interval, 10ms shorter than the intrinsic P-R interval.

Technical Field

The present disclosure relates to electrophysiology, and more particularly to assessing electrical activation patterns of the heart.

Background

The heart beat is controlled by the sinoatrial node, a group of conducting cells in the right atrium located near the entrance to the superior vena cava. The depolarization signal generated by the sinoatrial node activates the atrioventricular node. The atrioventricular node temporarily delays the propagation of the depolarization signal, allowing it to flow out of the atrium before it is delivered to the ventricles of the heart. The coordinated contraction of the two ventricles drives blood flow through the torso of the patient. In some cases, depolarization signaling from the atrioventricular node to the left and right ventricles may be interrupted or slowed. This may lead to dyssynchrony of left and right ventricular contractions, and ultimately to heart failure or death.

Cardiac Resynchronization Therapy (CRT) may correct electrical dyssynchrony symptoms by providing pacing therapy to one or both ventricles or atria (e.g., by providing pacing to stimulate early activation of the left or right ventricle). By pacing the contraction of the ventricles, the ventricles can be controlled such that they contract synchronously. Patients undergoing CRT have experienced improved ejection fraction, increased exercise capacity and improved health. Even though patients may benefit from CRT, some patients are reluctant to incur the cost of implanting an ICD unless there is significant certainty that CRT will promote his or her health. Accordingly, it is desirable to develop a non-invasive method or system to determine whether CRT is beneficial to a patient before the patient experiences the expense of implanting a medical device.

Disclosure of Invention

In general, the present disclosure relates to techniques for non-invasively determining whether a patient may benefit from Cardiac Resynchronization Therapy (CRT). The non-invasive method includes using at least one surface ECG electrode to determine whether there is baseline electrical heterogeneity of the patient's heart. When the heart is in its natural rhythm, the baseline electrical heterogeneity of the heart is defined as asynchronous electrical activation of the ventricles at the time of depolarization. If electrical heterogeneity of the heart is present, High Intensity Focused Ultrasound (HIFU) is applied to a localized region of cardiac tissue to trigger or cause depolarization of the cardiac tissue, and a change in the electrical heterogeneity from baseline to non-invasively triggered depolarization or pacing is evaluated to determine whether CRT is effective. The ultrasound transducer is placed on the outside of the patient's body, on the skin, over the cardiac tissue (e.g., tip, etc.). The delivery of HIFU may be timed relative to a fiducial point on the patient's baseline ECG signal, e.g., at a predetermined interval from the start of a surface P-wave. Additionally or alternatively, HIFU may be focused to activate different regions of cardiac tissue and evaluate the effectiveness of therapy for different stimulation sites to create a pre-procedure "roadmap" for implantation to the optimal patient-specific stimulation site. The effectiveness of CRT can be fully determined without incurring surgical expense.

One embodiment relates to non-invasively determining whether multi-site pacing would be beneficial to a patient in terms of producing changes in electrical activation of the heart that are beneficial in response to cardiac resynchronization therapy. The first ultrasound pacing, delivered to the first tissue site, and the second ultrasound pacing will be delivered to the second tissue site simultaneously or sequentially at predetermined time intervals. Both the first ultrasound pacing and the second ultrasound pacing are delivered within the same cardiac cycle. The electrical response from the multi-site pacing is then compared to the electrical response generated from the single pacing in order to determine which pacing method reduces or eliminates the heterogeneity.

The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages will be apparent from the description and drawings, and from the claims.

Drawings

FIG. 1 is a diagram of an exemplary system including an electrode device, an imaging device, a display device, and a computing device.

FIG. 2 is an exemplary graphical user interface depicting mechanical motion information of a portion of a patient's heart.

Fig. 3A is a schematic diagram of an exemplary external electrode device for measuring torso-surface potentials.

Fig. 3B is a schematic diagram of another exemplary external electrode device for measuring torso-surface potentials.

FIG. 4 is a flowchart depicting the steps involved in determining whether a patient is a candidate for cardiac resynchronization therapy.

FIG. 5 is a flow chart of an exemplary timing algorithm for ultrasound pacing when the patient is not experiencing atrial fibrillation.

FIG. 6 is a flow diagram of yet another exemplary timing algorithm for ultrasound pacing when the patient is not experiencing atrial fibrillation.

FIG. 7 is a flow diagram of yet another exemplary timing algorithm for ultrasound pacing when the patient is not experiencing atrial fibrillation.

Fig. 8 is a series of stimulated isochronal plots for torso-surface activation times of QRS narrowed after normal broadened QRS intrinsic rhythm and CRT pacing.

Fig. 9 is a diagram of an exemplary system including an exemplary Implantable Medical Device (IMD).

Fig. 10A is a diagram of the exemplary IMD of fig. 15.

Fig. 10B is a diagrammatic view of an enlarged view of the distal end of an electrical lead disposed in the left ventricle of fig. 10A.

Fig. 11A is a block diagram of an exemplary IMD (e.g., the IMD of fig. 9-10).

Fig. 11B is another block diagram of exemplary IMD (e.g., implantable pulse generator) circuitry and associated leads employed by the systems and devices of fig. 9-10 to provide three sensing channels and corresponding pacing channels.

Fig. 12 depicts a mixture of an intrinsic burst and a monomorphic pacing burst in response to delivering ultrasound pacing.

Fig. 13 depicts another mixture of intrinsic and monomorphic pacing complexes in response to delivering ultrasound pacing.

Fig. 14 depicts another mixture of intrinsic and monomorphic pacing complexes in response to delivering ultrasound pacing.

Fig. 15 depicts an image of a canine heart with a marker on the left side of the heart.

Fig. 16 depicts a single intrinsic beat immediately following a consistent pace at a basal septum (basal septum) pacing location using a frequency of 200KHz and a pulse width of 1 ms.

Fig. 17A depicts an intensity duration curve showing cardiac capture occurring at various ultrasound amplitudes and pulse widths for 200Khz with a transducer probe diameter of 5 cm.

Fig. 17B depicts an intensity duration plot showing cardiac capture at various ultrasound amplitudes and pulse widths for 420kHz with a transducer probe diameter of 3 cm.

Fig. 17C depicts an intensity duration curve showing cardiac capture occurring at various ultrasound amplitudes and pulse widths for 220kHz with a transducer probe diameter of 3 cm.

Fig. 18A depicts one intrinsic beat after capture occurring at the tip in response to ultrasound pacing being delivered.

Fig. 18B depicts one intrinsic beat after capture that occurs in response to ultrasound pacing being delivered.

Fig. 18C depicts one intrinsic beat after capture at a region believed to be the basal septum in response to ultrasound pacing being delivered.

Fig. 19A depicts one intrinsic beat following capture occurring at a region believed to be the Right Ventricular Outflow Tract (RVOT) in response to ultrasound pacing being delivered.

Fig. 19B depicts one intrinsic beat following capture occurring at a region considered to be the RVA/midseptum in response to ultrasound pacing being delivered.

Fig. 19C depicts an intrinsic beat following capture occurring at a region considered to be the RVOT in response to ultrasound pacing being delivered.

Detailed Description

In the following detailed description of illustrative embodiments, reference is made to the accompanying drawings that form a part hereof, and in which is shown by way of illustration specific embodiments that may be practiced. It is to be understood that other embodiments may be utilized and structural changes may be made without departing from (e.g., still falling within) the scope of the present disclosure presented herein.

The effectiveness of therapy (e.g., CRT) can be performed without the need to implant a medical device within the patient. Thus, the present disclosure may provide some assurance to a particular patient that is indeed a candidate for CRT. Additionally, the present disclosure may be used to remove patients who may not find CRT useful. Since the present disclosure is able to determine the effectiveness of CRT without the need for an implanted device, cost savings will be realized by paying for services and the responsible parties of the device (such as patients, hospitals, insurance companies, governments, etc.).

Exemplary systems, devices and methods will be described with reference to fig. 1-11. It will be apparent to those skilled in the art that elements or processes of one embodiment may be used in combination with elements or processes of other embodiments, and that the possible embodiments of such methods, apparatus and systems using combinations of features set forth herein are not limited to the specific embodiments shown in the figures and/or described herein. Further, it should be appreciated that the embodiments described herein may include many elements that are not necessarily shown to scale. Still further, it will be appreciated that while certain timings, one or more shapes and/or sizes or types of elements may be more advantageous than others, the timings of the processes herein, as well as the sizes and shapes of the various elements, may be modified while remaining within the scope of the present disclosure.

From a unipolar Electrocardiogram (ECG) recording, the electrical activation time near a reference location (e.g., which may be a location selected for the left ventricular lead during implantation) may be detected or estimated. Such electrical activation time may be measured and displayed or communicated to the implanter by a system that acquires an ECG signal and generates a measure of electrical activation (e.g., q-LV) time. Examples of ECG template acquisition and ECG signal analysis methods are generally disclosed in U.S. patent No. 6,393,316 (Gillberg et al), U.S. patent No. 7,062,315 (Koyrakh et al), and U.S. patent No. 7,996,070 (van Dam et al).

As described herein, in at least one or more embodiments, the motor mapping used to select lead placement sites for cardiac resynchronization therapy may use an algorithm that utilizes q-LV data (e.g., electrical activation time) in conjunction with mechanical motion map timing to optimally select a site for the LV leads.

As described herein, various exemplary systems, methods, and interfaces may be configured for using an electrode apparatus (including external electrodes, imaging devices, display devices, and computing devices) to non-invasively assist a user (e.g., a physician) in selecting one or more locations (e.g., implant site regions) for one or more implantable electrodes proximate to a heart of a patient and/or navigating one or more implantable electrodes to the selected location(s). An exemplary system 100 including an electrode device 110, an imaging device 120, a display device 130, and a computing device 140 is depicted in fig. 1.

The electrode arrangement 110 as shown includes a plurality of electrodes incorporated or included in a band wrapped around the chest or torso of the patient 14. Electrode device 110 is operatively coupled to computing device 140 (e.g., by one or more wired electrical connections, wirelessly, etc.) so as to provide electrical signals from each of these electrodes to computing device 140 for analysis. An exemplary electrode arrangement 110 will be described in more detail with reference to fig. 3A-3B.

The imaging device 120 may be any type of imaging device configured to image, or provide an image of, at least a portion of a patient in a non-invasive manner. For example, the imaging device 120 may provide an image of at least a portion of the patient without the use of any components or parts that may be located within the patient, other than a non-invasive tool such as a contrast solution. It will be appreciated that the example systems, methods, and interfaces described herein may non-invasively assist a user (e.g., a physician) in determining whether a treatment, such as CRT, may be effective for a particular patient. In addition, the system facilitates selecting a location for an implantable electrode proximate to a heart of a patient, and after the example systems, methods, and interfaces have provided non-invasive assistance, the example systems, methods, and interfaces may then provide assistance with implanting or navigating the implantable electrode into the patient (e.g., proximate to the heart of the patient).

For example, after the exemplary systems, methods, and interfaces have provided non-invasive assistance, these exemplary systems, methods, and interfaces may then provide image-guided navigation that may be used to navigate a lead including electrodes, leadless electrodes, wireless electrodes, catheters, and the like, within the body of a patient. Further, although the example systems, methods, and interfaces are described herein with reference to a patient's heart, it should be understood that the example systems, methods, and interfaces may be applicable to any other portion of the patient's body.

The imaging device 120 may be configured to capture or acquire x-ray images (e.g., two-dimensional x-ray images, three-dimensional x-ray images, etc.) of the patient 14. Imaging device 120 may be operatively coupled to computing apparatus 140 (e.g., via one or more wired electrical connections, wirelessly, etc.) such that images captured by imaging device 120 may be transmitted to computing apparatus 140. Further, the computing device 140 may be configured to control the imaging device 120, for example, to configure the imaging device 120 for capturing images, to change one or more settings of the imaging device 120, and/or the like.

It will be appreciated that while the imaging device 120 as shown in fig. 1 may be configured to capture x-ray images, any other alternative imaging modality may also be used by the exemplary systems, methods, and interfaces described herein. For example, the imaging device 120 may be configured to capture an image, or image data, using: isocentric fluoroscopy, biplane fluoroscopy, ultrasound, Computed Tomography (CT), multi-slice computed tomography (MSCT), Magnetic Resonance Imaging (MRI), high frequency ultrasound (HIFU), Optical Coherence Tomography (OCT), intravascular ultrasound (IVUS), two-dimensional (2D) ultrasound, three-dimensional (3D) ultrasound, four-dimensional (4D) ultrasound, intra-operative CT, intra-operative MRI, and the like. Further, it should be understood that the imaging device 120 may be configured to capture multiple successive images (e.g., consecutively) to provide video frame data. In other words, moving image data may be provided by using a plurality of images acquired over time by the imaging device 120. In addition, these images may also be acquired and displayed in two, three, or four dimensions. In a more advanced form, four-dimensional surface rendering of the heart or other region of the body may also be achieved by combining cardiac data or other soft tissue data from an atlas map or from pre-operative image data captured by MRI, CT or echocardiography modalities. Image datasets from mixed modes, such as Positron Emission Tomography (PET) combined with CT or Single Photon Emission Computed Tomography (SPECT) combined with CT, may also provide functional image data superimposed on the tissue data for reaching target locations within the heart or other region of interest.

The display device 130 and the computing device 140 may be configured to display and analyze data (e.g., like the alternative electrical activation data, image data, mechanical motion data, etc.) collected or acquired using the electrode device 110 and the imaging device 120 to non-invasively assist the user in selecting the location of the implanted electrode. In at least one embodiment, the computing device 140 may be a server, a personal computer, or a tablet computer. Computing device 140 may be configured to receive input from input device 142 and transmit output to display device 130. Further, the computing device 140 may include a data storage device that may allow access to processing programs or routines and/or one or more other types of data, e.g., for driving a graphical user interface configured to non-invasively assist a user in selecting a location of an implantable electrode, etc.

The computing device 140 may be operatively coupled to the input device 142 and the display device 130, for example, to transmit data to or from each of the input device 142 and the display device 130. For example, the computing device 140 may be electrically coupled to each of the input device 142 and the display device 130, e.g., using analog electrical connections, digital electrical connections, wireless connections, bus-based connections, network-based connections, internet-based connections, etc. As further described herein, a user may provide input to input device 142 to manipulate or modify one or more graphical depictions displayed on display device 130 to view and/or select one or more target or candidate locations of a portion of a patient's heart as further described herein.

Although the input device 142 as depicted is a keyboard, it should be understood that the input device 142 may include any device capable of providing input to the computing device 140 in order to perform the functions, methods, and/or logic described herein. For example, the input device 142 may include a mouse, a trackball, a touch screen (e.g., a capacitive touch screen, a resistive touch screen, a multi-touch screen, etc.), and the like. Likewise, display device 130 may include any device capable of displaying information to a user, such as a graphical user interface 132 including an anatomical graphical depiction of a patient's heart, an image of the patient's heart, a graphical depiction of the location of one or more electrodes, a graphical depiction of one or more target or candidate locations, an alphanumeric representation of one or more values, a graphical depiction or real image of implanted electrodes and/or leads, and so forth. For example, the display device 130 may include a liquid crystal display, an organic light emitting diode panel, a touch panel, a cathode ray tube display, and the like.

The graphical user interface 132 displayed by the display device 130 may include or display one or more regions for displaying graphical depictions, displaying images, allowing selection of one or more regions or areas of such graphical depictions and images, and the like. As used herein, a "zone" of the graphical user interface 132 may be defined as a portion of the graphical user interface 132 within which information may be displayed or functions may be performed. The regions may exist within other regions, which may be displayed separately or simultaneously. For example, smaller regions may be positioned within a larger region, the regions may be positioned side-by-side, and so on. Additionally, as used herein, a "region" of the graphical user interface 132 may be defined as a portion of the graphical user interface 132 that is positioned to have a smaller area than the area within which it is positioned.

The processing programs or routines stored and/or executed by the computing device 140 may include programs or routines for: computational mathematics, matrix mathematics, decomposition algorithms, compression algorithms (e.g., data compression algorithms), calibration algorithms, image construction algorithms, signal processing algorithms (e.g., fourier transforms, fast fourier transforms, etc.), normalization algorithms, comparison algorithms, carrier mathematics, or any other processing required to implement one or more of the exemplary methods and/or processes described herein. Data stored and/or used by computing device 140 may include, for example: image data from imaging device 120, electrical signal data from electrode device 110, graphics (e.g., graphical elements, icons, buttons, windows, dialogs, pull-down menus, graphical regions, 3D graphics, etc.), graphical user interfaces, results from one or more processing programs or routines employed in accordance with the disclosure herein, or any other data that may be necessary to perform the one or more processes or methods described herein.

In one or more embodiments, the exemplary systems, methods, and interfaces can be implemented using one or more computer programs executing on a programmable computer, such as a computer, including, for example, processing power, data storage (e.g., volatile or non-volatile memory and/or storage elements), input devices, and output devices. Program code and/or logic described herein may be applied to input data to perform the functions described herein and generate desired output information. The output information may be applied as input to one or more other devices and/or methods as described herein or to be applied in a known manner.

The one or more programs for implementing the systems, methods, and/or interfaces described herein may be provided using any programmable language, such as a high level procedural and/or object oriented programming language suitable for communication with a computer system. Any such program may be stored, for example, on any suitable device (e.g., storage medium) readable by a general-purpose or special-purpose program running on a computer system (e.g., including a processing device) for configuring and operating the computer system when the program is read by the suitable device to perform the procedures described herein. In other words, in at least one embodiment, the exemplary systems, methods, and/or interfaces may be implemented using a computer-readable storage medium configured with a computer program, where the storage medium so configured causes a computer to operate in a specific and predefined manner to perform the functions described herein. Further, in at least one embodiment, the example systems, methods, and/or interfaces may be described as being implemented by logic (e.g., object code) encoded in one or more non-transitory media including code for execution and when executed by a processor may be operable to perform operations such as the methods, processes, and/or functions described herein.

The computing device 140 may be, for example, any fixed or mobile computer system (e.g., controller, microcontroller, personal computer, minicomputer, tablet computer, and the like). The precise configuration of computing device 130 is not limiting and virtually any device capable of providing suitable computing and control capabilities (e.g., graphics processing, etc.) may be used. As described herein, a digital file may be any medium (e.g., volatile or non-volatile memory, CD-ROM, punch card, recordable tape, etc.) that contains digital bits (e.g., encoded in binary, ternary, etc.) that may be readable and/or writable by the computing device 140 described herein. Also, as described herein, a file in a user-readable format can be any representation of data (e.g., ASCII text, binary numbers, hexadecimal numbers, decimal numbers, diagrams, etc.) presentable on any medium (e.g., paper, display, etc.) readable and/or understandable by a user.

In the above views, it will be readily apparent that the functionality as described in one or more embodiments in accordance with the present disclosure may be implemented in any manner as will be known to those of skill in the art. As such, the computer language, computer system, or any other software/hardware to be used to implement the processes described herein should not be limited to the scope of the systems, processes, or programs described herein (e.g., the functionality provided by such systems, processes, or programs).

As used herein, mechanical motion data may be defined as data relating to mechanical motion of one or more regions of the patient's heart, such as portions of the wall of the patient's heart. It may be desirable for the target location for implantable electrode placement in the patient's heart to also have a late mechanical motion timing (e.g., motion that is more late than other portions of the patient's heart, motion that is more late than a selected threshold or time, etc.). The mechanical motion data may be measured and determined using the exemplary imaging device 120 and computing device 140. For example, a plurality of frames of image data may be captured using the imaging device 120 and analyzed by a computing device to determine mechanical motion information or data for one or more regions of the patient's heart.

The local 3D motion of the heart wall can be decomposed into two components: the first component expresses a change in distance between adjacent points and is referred to as strain (e.g., contraction, when the distance is small or expanding, when the distance increases, etc.), and the second, non-strain component may not relate to a change in distance between adjacent points but may relate to translation and/or rotation. The strain may be anisotropic. In particular, the circumferential strain when a cross-section (segment) perpendicular to the long axis of the heart chamber changes length can be distinguished from the longitudinal strain when a line substantially parallel to the long axis changes length. The exemplary imaging device 120 described herein may be configured to provide image data to provide a graphical depiction of the contraction and expansion as a change in size of the vessel tree (or in other words, as a change in distance between points) while visualizing rotation and translation in parallel without changing the distance.

The imaging device 120, which may be a computer X-ray machine, may be guided at the heart of the patient and may be activated in order to produce a time sequence of X-ray images of the heart region at the field of view. To expose blood vessels (such as, for example, coronary blood vessels) at a region of the heart under a field of view, X-ray images may preferably be obtained under an angiographic procedure by injecting a contrast agent into the patient. In the case where the vessel to be examined is a coronary vein, angiography may be performed after inserting a balloon into the vein (e.g., coronary sinus) and inflating it to prevent blood flow from dispersing the contrast agent prior to acquiring the image.

For example, a time series of two-dimensional X-ray projection images may be captured by the imaging device of fig. 1 and may be stored by the computing device 140. The two-dimensional image may be an angiogram acquired after the patient has been injected with a contrast agent. The time series may include "snapshots" (e.g., cine-angio runs) of the coronary vessels at the same projection angle during at least a portion of the patient's cardiac cycle. Further, the projection direction may be selected to be substantially orthogonal to the surface of the heart at the region of interest or to its main velocity component.

The vessel of interest may be tracked through a time series of images to identify the movement of the vessel through at least a portion of the cardiac cycle. Tracking of the vessel through the time series of images may be performed by calculating local area transformations from one frame to the next or by tracking selected control points in the detected vessel. While according to some embodiments, tracking the vessel may be performed by a hybrid combination of the two methods.

Examples of systems and/or imaging devices configured to capture and determine mechanical motion information may be described in the following applications: U.S. patent application publication No. 2005/0008210 issued on 13.1.2005 to evaron (Evron), et al, U.S. patent application publication No. 2006/0074285 issued on 6.4.2006 to saka (Zarkh), et al, U.S. patent application publication No. 2011/0112398 issued on 12.2011.5.12 to saka, U.S. patent application publication No. 2013/0116739 issued on 9.5.2013 to Brada (Brada), et al, U.S. patent No. 6,980,675 issued on 27.12.2005 to evaron, et al, U.S. patent No. 7,286,866 issued on 23.10.20.2007 to oherland (oklund), U.S. patent No. 7,308,297 issued on 11.12.2011.11 to ridy (Reddy), et al, U.S. patent No. 7,308,299 issued on 11.12.2011.11.11.s.3.s.3568 to brarell (berrell), U.s patent No. 7,321,677 issued on 2008 to 2008.3.3.s, U.S. patent No. 7,454,248 issued on 11/18 th of bruiser et al, U.S. patent No. 7,499,743 issued on 3/3 th of 2009 of gas (Vass) et al, U.S. patent No. 7,565,190 issued on 21 th of 2009 of 7/21 th of enckrlander et al, U.S. patent No. 7,587,074 issued on 8 th of 2009 of saka et al, U.S. patent No. 7,599,730 issued on 6 th of 2009 of 10/6 th of Hunter (Hunter) et al, U.S. patent No. 7,613,500 issued on 3 th of 2009 of 11/3 th of gas et al, U.S. patent No. 7,742,629 issued on 22 th of 2010 of 6/29 th of Hunter et al, U.S. patent No. 7,747,047 issued on 6/29 th of 2010 of afulong et al, U.S. patent No. 2010 of 7,778,685 issued on 17 th of 2010 of 8/17 th of gas et al, U.S. patent No. 7,778,686 issued on 12 th of 2010 of 10/10 th of oxkrlander et al, U.S. patent No. 5 issued on 2011 et al, U.S. patent No. 2011.S. 5 of 2011.S. published on 10/10 th of 2011 et al, and U.S. published by 2011 of 2011 et al, U.S. patent No. 8,060,185 issued on 15/11/2011 to hunter et al, and U.S. patent No. 8,401,616 issued on 19/3/2013 to frard (Verard) et al, each of which is incorporated herein by reference in its entirety.

Mechanical motion data or information may be provided to the user to assist the user in selecting a position for the implanted electrode. An exemplary graphical user interface 132 depicting mechanical motion information of a portion of a patient's heart is shown in fig. 2. The graphical user interface 132 is configured for depicting at least a portion of a vascular anatomy 200 of a heart of a patient and mechanical motion information relative to the vascular anatomy 200. As shown, the vascular anatomy 200 is a coronary sinus positioned proximate to a left ventricle of a patient. The vessel anatomy 200 further includes a plurality of branches 202, such as the coronary sinus. Each branch and multiple locations within each branch may provide candidate site regions or locations for an implantable electrode. The implantable electrode may be implanted in a location having the latest time of mechanical movement. As used herein, the mechanical motion time may be the time between the onset of contraction and a common fiducial point, such as, for example, the onset of a QRS depolarization complex for that particular cardiac cycle on an external ECG lead.

As shown, the mechanical motion time may be represented by color/grayscale scaling or encoding, and the vessel anatomy 200 may be based on the size 210. As shown, the dimension 210 extends from a dark gray/color corresponding to approximately 40 milliseconds (ms) to a light white/color corresponding to approximately 240 ms. In this way, the user may view the graphical user interface 132 to see or determine the mechanical motion times of different regions of the heart (e.g., different regions of the vascular anatomy). Additionally, the graphical user interface 132 may alphanumerically depict mechanical motion times 206 for one or more regions 204 identified on the vascular anatomy 200. Using the graphical user interface 132, the user may select a target or candidate location 208 for implantation that may have the most late or near-late mechanical movement time. As shown, the target location 208 may have a mechanical movement time of 240 ms.

It may be desirable for the target or candidate site region or location for implantable electrode placement to also have a delayed electrical activation time in addition to the delayed mechanical movement time. In addition to or alternatively, the electrical activation time may be used in place of the mechanical activation time.

Electrical activation data for one or more regions of a patient's heart may be determined using an electrode arrangement 110 as shown in FIG. 1 and FIGS. 3A-3B. The example electrode arrangement 110 may be configured to measure body surface potentials of the patient 14, and more particularly torso surface potentials of the patient 14. As shown in fig. 3A, an exemplary electrode arrangement 110 may include a set of electrodes 112 or an electrode array, a strap 113, and an interface/amplifier circuit 116. The electrode 112 may be attached or coupled to a strap 113 and the strap 113 may be configured to wrap around the torso of the patient 14 such that the electrode 112 encircles the patient's heart. As further shown, the electrodes 112 may be positioned around the circumference of the patient 14, including the posterior, lateral, posterolateral, and anterior locations of the torso of the patient 14.

Further, the electrodes 112 may be electrically connected to an interface/amplifier circuit 116 via a wired connection 118. The interface/amplifier circuitry 116 may be configured to amplify the signals from the electrodes 112 and provide these signals to the computing device 140. Other exemplary systems may use wireless connections to transmit these signals sensed by the electrodes 112 to the interface/amplifier circuitry 116 and, in turn, to the computing device 140, e.g., as a data channel.

Although in the example of fig. 3A, electrode arrangement 110 includes straps 113, in other examples, any of a variety of mechanisms may be employed, such as tape or adhesive to aid in the spacing and placement of electrodes 112. In some examples, strap 113 may include an elastic band, a strip of tape, or a cloth. In other examples, the electrodes 112 may be positioned separately on the torso of the patient 14. Further, in other examples, the electrodes 112 (e.g., arranged in an array) may be part of a patch, vest, or other device positioned therein, and/or to secure the electrodes 112 to the torso of the patient 14.

The electrodes 112 may be configured to encircle the heart of the patient 14 and record or monitor the electrical signals associated with depolarization and repolarization of the heart after the signals have propagated through the torso of the patient 14. Each of the electrodes 112 may be used in a monopolar configuration in order to sense torso-surface potentials reflecting cardiac signals. Interface/amplifier circuitry 116 may also be coupled to a return electrode or inertial electrode (not shown) that may be used in conjunction with each electrode 112 for unipolar sensing. In some examples, there may be about 12 to about 50 electrodes 112 spatially distributed around the torso of the patient. Other configurations may have more or fewer electrodes 112.

The computing device 140 may record and analyze torso-surface potential signals sensed by the electrodes 112 and amplified/conditioned by the interface/amplifier circuitry 116. The computing device 140 may be configured to analyze these signals from the electrodes 112 to provide, for example, alternative electrical activation data (such as alternative electrical activation times) representative of actual or local electrical activation times of one or more regions of the patient's heart, as will be further described herein. The measurement of the activation time may be performed by choosing an appropriate fiducial point (e.g., a peak, a minimum slope, a maximum slope, a zero crossing, an out-of-bounds, etc. of the near-field or far-field EGM) and measuring the time between the onset of depolarization of the heart (e.g., the onset of a QRS complex) and the fiducial point (e.g., within the electrical activity). The activation time between the start of the QRS complex (or peak Q wave) and the fiducial point may be referred to as the Q-LV time.

Additionally, the computing device 140 may be configured to provide a graphical user interface depicting alternative electrical activation times obtained using the electrode arrangement 110. The example systems, methods, and/or interfaces may non-invasively use the electrical information collected with the electrode apparatus 110 in order to identify, select, and/or determine whether one or more regions of the patient's heart may be optimal or desirable for implantable electrode placement.

Fig. 3B illustrates another example electrode arrangement 110 that includes a plurality of electrodes 112 configured to encircle the heart of the patient 14 and record or monitor the electrical signals associated with depolarization and repolarization of the heart after the signals have propagated through the torso of the patient 14. The electrode arrangement 110 may include a vest 114 to which a plurality of electrodes 112 may be attached or to which the electrodes 112 may be coupled. In at least one embodiment, the plurality of electrodes 112 or the electrode array may be used to collect electrical information, such as, for example, alternative electrical activation times. Similar to electrode arrangement 110 of fig. 3A, electrode arrangement 110 of fig. 3B may include an interface/amplifier circuit 116 electrically coupled to each of electrodes 112 by a wired connection 118 and configured to transmit signals from electrodes 112 to computing device 140. As illustrated, the electrodes 112 may be distributed over the torso of the patient 14, including, for example, the front, side, and back surfaces of the torso of the patient 14.

The vest 114 may be formed from a braid to which the electrodes 112 are attached. The vest 114 may be configured to maintain the position and spacing of the electrodes 112 on the torso of the patient 14. Further, the vest 114 may be marked to assist in determining the location of the electrodes 112 on the torso surface of the patient 14. In some examples, there may be about 25 to about 256 electrodes 112 distributed around the torso of the patient 14, although other configurations may have more or fewer electrodes 112.

As described herein, electrode arrangement 110 may be configured to measure electrical information (e.g., electrical signals) representative of different regions of a patient's heart. More specifically, the activation times of different regions of the patient's heart may be roughly estimated from surface Electrocardiogram (ECG) activation times measured using surface electrodes adjacent to surface areas corresponding to the different regions of the patient's heart.

Fig. 4 is a method 1200 for determining whether a patient is a candidate for CRT. At block 1202, the electrode apparatus 110 is placed over the torso of a patient. At block 1204, data is collected from unipolar signals acquired from the electrode arrangement 110 during intrinsic conduction, as described in U.S. patent application serial No. 13/462,480, "ASSESSING INTRA-cartialactivity patents", filed 5, month 2, 2012 and assigned to the assignee of the present invention, the disclosure of which is incorporated herein by reference in its entirety. At block 1206, a portion of the signal is stored into a memory. At block 1208, a determination is made as to whether electrical dyssynchrony is preset. If electrical dyssynchrony does not exist, the patient is not a candidate for CRT and the procedure terminates at block 1210. The mechanical dyssynchrony may be established according to CardioGuide-type imaging or according to ultrasound strain imaging. Ultrasound strain imaging (via speckle tracking) may be used as a means for determining asynchrony (thus combining ultrasound imaging with HIFU for a full ultrasound system). One or more embodiments relate to determining out-of-sync (i.e., spread or standard deviation of strain in different locations) rather than focusing on a single location with the latest activation. If electrical dyssynchrony exists, ultrasound energy (e.g., High Intensity Focused Ultrasound (HIFU)) is delivered to the localized tissue region at block 1212. For example, HIFU at Sound Pressure Levels (SPL) of up to 3 megapascals (MPa) may be used to stimulate cardiac tissue. At block 1214, a signal from the electrical device 110 is monitored. At block 1216, data collected from the unipolar signals acquired during the delivery of the ultrasonic energy is stored in memory. At block 1218, a determination is made as to whether the ultrasound pacing in the local tissue corrects or minimizes the electrical dyssynchrony. If the ultrasound pacing does correct the electrical dyssynchrony, control of the logic is transferred to block 1226, which optionally optimizes the pacing control settings (A-V delay, V-V delay, pacing output, etc.) and/or pacing position. By contrast, if the ultrasound pacing is not correcting for electrical dyssynchrony, control of the logic is transferred to block 1220, where a determination is made as to whether another location from which pacing energy is delivered may be more appropriate. If all stimulation regions have been evaluated, control of the logic is transferred to block 1210 and the evaluation is stopped. The patient is not a candidate for CRT. If all stimulation regions have not been evaluated, control of the logic is transferred to block 1224, causing another tissue location for stimulation to be evaluated by processing blocks 1212-1220. Once a determination is made that the ultrasound pacing correction or electrical dyssynchrony is minimized, the patient is determined to be a candidate for CRT at block 1228.

Fig. 5 is a flow chart of an exemplary timing algorithm for delivering ultrasound energy when a patient is not experiencing atrial fibrillation. At block 1302, from a small group of beats (e.g., 5 beats), sensing of the P-wave occurs and a QRS complex from the surface ECG begins. The goal is to determine the minimum electrical dyssynchrony that is possible according to a given pacing site. This requires fusing the paced depolarization with intrinsic ventricular depolarization. Thus, it is important to time the ultrasound pacing with respect to the intrinsic depolarization of the ventricles. Thus, ultrasound pacing and dyssynchrony measurements are performed over a range of timings relative to expected or expected intrinsic ventricular depolarizations. At block 1304, an average PR interval (referred to as a "desired PR interval") is determined from a small group of beats. The PR interval is the time required for an electrical pulse to leave the SA node and pass through the atrium, AV node, bundle support, and purkinje mesh. The PR interval includes a P-wave followed by a short flat line. At block 1306, the next P-wave is sensed by the electrical device 110. The ultrasound pacing is timed to be slightly less than the desired PR interval. At block 1312, the time for delivering ultrasound pacing is adjusted. For example, the time for delivering ultrasound pacing is less than the desired PR interval. At block 1314, ultrasound pacing is delivered to the tissue. At block 1316, the electrical response of the tissue to the ultrasound pacing is measured and stored in memory. At block 1318, a determination is made as to whether all responses to each pacing beat have been collected and stored. The total number of paced beats is represented by N, while X is used for a count that is initialized to zero before method 1300 has begun. If not, control of the logic transfers to block 1320 to increment the beat count so that X is X + 1. Additionally, the PR interval is adjusted. For example, ultrasound pacing is emitted over a range of PR intervals evaluated over perhaps 6 beats, with, for example, desired PR-60ms, desired PR-50, desired PR-40, desired PR-30, desired PR-20, desired PR-10. The dyssynchrony is measured and stored each time according to an electrical device 110 (e.g., an ECG strip, vest, etc.). The minimum measured electrical dyssynchrony for the 6 beats is then compared to the stored minimum electrical dyssynchrony for the 6 intrinsic beats. The difference between the minimum electrical dyssynchrony of the 6 paced beats and the minimum electrical dyssynchrony of the 6 intrinsic beats is proportional to the expected CRT benefit. At block 1324, the difference in minimum electrical dyssynchrony between the paced beat and the intrinsic beat is displayed on a Graphical User Interface (GUI) of the computer. The GUI will display a quantity or color visualization that indicates that CRT is beneficial or not beneficial to the patient. In either case, more effective therapy can be delivered since each CRT candidate is more positively identified. In addition, healthcare costs are reduced by removing patients that may not be candidates for CRT.

Fig. 6 is a flow diagram of another exemplary timing algorithm for delivering ultrasound energy when a patient is not experiencing atrial fibrillation. The method 1500 begins at block 1502 where it is determined whether an expected RR interval and regularity of RR intervals from a group of beats (e.g., 5 beats) are present. The desired RR interval may be an average RR interval of the total number of beats. After the last RR interval, delivery of the ultrasound pacing is timed according to the desired RR interval minus an offset (e.g., 60ms) at block 1504. The offset may depend on the measured regularity and be considered as if the patient is in AF if the regularity is too high, as described below. At block 1506, ultrasound pacing is delivered. At block 1508, the electrical response obtained via the electrical device 110 is measured and stored in memory. At block 1510, a determination is made as to whether the pre-specified total number of pacing beats, N, has been evaluated. If not, the beat count X is incremented by 1 and the process of blocks 1502 to 1508 are repeated with a range of offset values (60ms, 50ms, 40ms, 30ms, 20ms, 10ms) and each time measuring out of sync from the ECG strip. Again, the minimum electrical dyssynchrony associated with the 6 pacing beats is chosen for comparison with the minimum electrical dyssynchrony associated with the 6 intrinsic beats. The minimum electrical asynchrony difference between the paced beat and the intrinsic beat is proportional to the expected CRT benefit.

With respect to the methods depicted in fig. 5-6, if an R-wave is sensed before delivering ultrasound pacing, the pacing is disabled and the measurement sequence is restarted.

FIG. 7 depicts a timing algorithm method 1400 when a patient is in atrial fibrillation or when the patient's heart rhythm is extremely irregular. At block 1402, a signal from the electrical device 110 is monitored in response to the intrinsic beat. After which it is an AF response algorithm for a period of time (e.g., 30 seconds). For example, at block 1404, RR intervals (e.g., averaging 10 beats) are averaged. The initial RR interval is also referred to as the "desired RR interval". At block 1406, if the next QRS is sensed before the expected RR interval expires, the expected RR interval is shortened by, for example, 30ms at block 1410. If the next QRS is longer than the desired RR interval, the desired RR interval is lengthened, for example, by 30ms at block 1408. At block 1412, blocks 1406 through 1410 are repeated for a pre-specified period of time, e.g., 30 seconds. At block 1412, at the end of the time period, ultrasound pacing is triggered at block 1414 at the desired RR interval minus an offset (like 50 ms). Beat-to-beat updates continue for the desired RR interval, and ultrasound pacing is delivered at the desired RR interval (minus a 50ms offset) every, e.g., 10 th beat. The process is repeated where a pre-specified number of paces (e.g., 10 paces) have been delivered, thereby measuring the dyssynchrony of each paced beat. At block 1416, a minimum of 10 pacing beats is chosen for comparison to a minimum obtained from the 10 intrinsic beats. The difference is proportional to the expected CRT benefit.

The present disclosure demonstrates that HIFU and surface electrodes can be used to non-invasively determine whether a patient would benefit from CRT prior to implantation of a cardiac rhythm device. In addition, the present disclosure enables determination of an optimal site for placement of one or more ventricular pacing leads. Moreover, programming of the optimal device parameters is achieved. For example, electrodes on a multipolar right ventricular lead or left ventricular lead are selected. In addition, HIFU is used to select the optimal timing (e.g., A-V delay, V-V delay) of the pacing pulses delivered to the electrodes. Optimally, however, the pacing control parameters may be optimized by using an ECG strip.

Fig. 8 depicts a series of stimulated isochronal plots for torso-surface activation times of QRS that generally broaden the QRS intrinsic rhythm and narrow after CRT pacing. Application of CRT is shown to narrow the QRS, thereby improving the cardiac condition of the patient from the widened QRS.

Fig. 9 is a conceptual diagram illustrating an exemplary therapy system 10 subsequently implanted in a patient for delivering pacing therapy to the patient 14 after determining whether CRT is beneficial to the patient. The patient 14 may, but need not, be a human. The therapy system 10 may include an implantable medical device 16(IMD) that may be coupled to leads 18, 20, 22. IMD 16 may be, for example, an implantable pacemaker, cardioverter, and/or defibrillator that provides electrical signals to heart 12 of patient 14 via electrodes coupled to one or more of leads 18, 20, 22 (e.g., electrodes that may be implanted in accordance with the description herein, such as using non-invasive selection of an implantation site area).

Leads 18, 20, 22 extend into heart 12 of patient 14 in order to sense electrical activity of heart 12 and/or deliver electrical stimulation to heart 12. In the example shown in fig. 9, Right Ventricular (RV) lead 18 extends through one or more veins (not shown), the superior vena cava (not shown), and right atrium 26 and into right ventricle 28. Left Ventricular (LV) coronary sinus lead 20 extends through one or more veins, the vena cava, right atrium 26, and into coronary sinus 30 to a region adjacent to the free wall of left ventricle 32 of heart 12. Right Atrial (RA) lead 22 extends through one or more veins and the vena cava, and into right atrium 26 of heart 12.

IMD 16 may sense electrical signals attendant to the depolarization and repolarization of heart 12, among other things, via electrodes coupled to at least one of leads 18, 20, 22. IMD 16 may be configured to determine or positively locate an active electrode on leads 18, 20, 22 using the exemplary methods and processes described herein. In some examples, IMD 16 provides pacing therapy (e.g., pacing pulses) to heart 12 based on electrical signals sensed within heart 12. IMD 16 is operable to adjust one or more parameters associated with pacing therapy, such as, for example, AV delay and other various timings, pulse widths, amplitudes, voltages, burst lengths, and the like. Further, IMD 16 may be operable to deliver pacing therapy using various electrode configurations, which may be unipolar, bipolar, quadrupolar, or other multipolar. For example, a multipolar lead may include several electrodes that may be used to deliver pacing therapy. Thus, the multipolar lead system may provide or administer multiple electrical vectors to pacing. The pacing vector may include at least one cathode, which may be at least one electrode positioned on at least one lead; and at least one anode, which may be at least one electrode positioned on at least one lead (e.g., the same lead or a different lead) and/or on a housing or CAN of the IMD. While the improvement in cardiac function due to pacing therapy may depend primarily on the cathode, electrical parameters such as impedance, pacing threshold voltage, current drain, longevity may be more dependent on the pacing vector, which includes both the cathode and the anode. IMD 16 may also provide defibrillation therapy and/or cardioversion therapy via electrodes located on at least one of leads 18, 20, 22. Further, IMD 16 may detect cardiac arrhythmias of heart 12, such as fibrillation of ventricles 28, 32, and deliver defibrillation therapy in the form of electrical pulses to heart 12. In some examples, IMD 16 may be programmed to deliver a progression of therapy, e.g., pulses with elevated energy levels, until fibrillation of heart 12 ceases.

Fig. 10A and 10B are conceptual diagrams illustrating IMD 16 and leads 18, 20, 22 of the therapy system 10 of fig. 9 in greater detail. Leads 18, 20, 22 may be electrically coupled to a therapy delivery module (e.g., to deliver pacing therapy), a sensing module (e.g., to sense one or more signals from one or more electrodes), and/or any other module of IMD 16 via connector block 34. In some examples, the proximal ends of leads 18, 20, 22 may include electrical contacts that are electrically coupled to corresponding electrical contacts within connector block 34 of IMD 16. Further, in some examples, the leads 18, 20, 22 may be mechanically coupled to the connector block 34 by way of set screws, connecting pins, or another suitable mechanical coupling mechanism.

Each of the leads 18, 20, 22 includes an elongated, insulated lead body that may carry a plurality of conductors (e.g., concentrically coiled conductors, straight conductors, etc.) separated from one another by a separator (e.g., a tubular insulating sheath). In the illustrated example, the bipolar electrodes 40, 42 are positioned adjacent the distal end of the lead 18. Further, bipolar electrodes 44, 45, 46, 47 are located near the distal end of lead 20, and bipolar electrodes 48, 50 are located at the distal end of lead 22.

Electrodes 40, 44, 45, 46, 47, 48 may take the form of ring electrodes, and electrodes 42, 50 may take the form of extendable helix tip electrodes mounted retractably within insulative electrode heads 52, 54, 56, respectively. Each electrode 40, 42, 44, 45, 46, 47, 48, 50 may be electrically coupled to a corresponding conductor (e.g., helical and/or straight) within the lead body of its associated lead 18, 20, 22, and thereby coupled to a corresponding electrical contact at the proximal end of the lead 18, 20, 22.

Additionally, electrodes 44, 45, 46, and 47 may have a thickness of about 5.3mm²To about 5.8mm²The electrode surface area of (a). Electrodes 44, 45, 46, and 47 may also be referred to as LV1, LV2, LV3, and LV4, respectively. LV electrodes on lead 20 (i.e., left ventricular electrode 1(LV1)44, left ventricular electrode 2(LV2)45, left ventricular electrode 3(LV3)46, left ventricle 4(LV4)47, etc.) may be spaced at variable distances. For example, electrode 44 may be spaced from electrode 45 by, for example, about 21 millimeters (mm), electrodes 45 and 46 may be spaced from each other by, for example, a distance of about 1.3mm to about 1.5mm, and electrodes 46 and 47 may be spaced from each other by, for example, a distance of 20mm to about 21 mm.

Electrodes 40, 42, 44, 45, 46, 47, 48, 50 may further be used to sense electrical signals (e.g., morphological waveforms within an Electrogram (EGM)) that occur with the depolarization and repolarization of heart 12. The sensed electrical signals may be used to determine which of the electrodes 40, 42, 44, 45, 46, 47, 48, 50 are most effective in improving cardiac function. Electrical signals are conducted to IMD 16 via respective leads 18, 20, 22. In some examples, IMD 16 may also deliver pacing pulses via electrodes 40, 42, 44, 45, 46, 47, 48, 50 in order to cause depolarization of cardiac tissue of patient's heart 12. In some examples, as illustrated in fig. 10A, IMD 16 includes one or more housing electrodes (e.g., housing electrode 58) that may be integrally formed with an outer surface of a housing 60 (e.g., a hermetic housing) of IMD 16 or otherwise coupled to housing 60. Any of electrodes 40, 42, 44, 45, 46, 47, 48 and 50 may be used for unipolar sensing or pacing in combination with housing electrode 58. In other words, any of electrodes 40, 42, 44, 45, 46, 47, 48, 50, 58 may be used in combination to form a sensing vehicle, e.g., a sensing vehicle that may be used to assess and/or analyze the effectiveness of pacing therapy. It is generally understood by those skilled in the art that other electrodes may also be selected to define or be used for pacing and sensing carriers. Further, any of the electrodes 40, 42, 44, 45, 46, 47, 48, 50, 58 that are not used to deliver pacing therapy may be used to sense electrical activity during the pacing therapy.

As described in further detail with reference to fig. 10A, the housing 60 may enclose a therapy delivery module that may include a stimulation generator for generating cardiac pacing pulses and defibrillation or cardioversion shocks, and a sensing module for monitoring the patient's heart rate. The leads 18, 20, 22 may also include elongated electrodes 62, 64, 66, respectively, which may take the form of coils. IMD 16 may deliver defibrillation shocks to heart 12 via any combination of elongated electrodes 62, 64, 66 and housing electrode 58. Electrodes 58, 62, 64, 66 may also be used to deliver cardioversion pulses to heart 12. Further, the electrodes 62, 64, 66 may be made of any suitable electrically conductive material, such as, but not limited to, platinum alloys, and/or other materials known to be useful in implantable defibrillation electrodes. Since electrodes 62, 64, 66 are not generally configured to deliver pacing therapy, any of electrodes 62, 64, 66 may be used to sense electrical activity (e.g., for determining electrode effectiveness, for analyzing pacing therapy effectiveness, etc.) and may be used in conjunction with any of electrodes 40, 42, 44, 45, 46, 47, 48, 50, 58. In at least one embodiment, RV elongate electrode 62 may be used to sense electrical activity of the patient's heart during pacing therapy delivery (e.g., in conjunction with housing electrode 58 forming an RV elongate coil, or a defibrillation electrode-to-housing electrode vector).

The configuration of the exemplary therapy system 10 shown in fig. 9-11 is merely an example. In other examples, the therapy system may include epicardial leads and/or patch electrodes instead of or in addition to the transvenous leads 18, 20, 22 illustrated in fig. 9. Further, in one or more embodiments, IMD 16 need not be implanted within patient 14. For example, IMD 16 may deliver various cardiac therapies to heart 12 via percutaneous leads that extend through the skin of patient 14 to various locations within or outside heart 12. In one or more embodiments, system 10 may utilize wireless pacing (e.g., using energy transmission to the intracardiac pacing component(s) via ultrasound, inductive coupling, RF, etc.) and sense cardiac activity using electrodes on the can/housing and/or subcutaneous leads.

In other examples of a therapy system that provides electrical stimulation therapy to heart 12, such a therapy system may include any suitable number of leads coupled to IMD 16, and each of the leads may extend to any location within or near heart 12. For example, other examples of a treatment system may include three transvenous leads positioned as illustrated in fig. 9-11. Still further, other therapy systems may include a single lead extending from IMD 16 into right atrium 26 or right ventricle 28, or two leads extending into right atrium 26 and right ventricle 28, respectively.

Fig. 11A is a functional block diagram of one exemplary configuration of IMD 16. As shown, IMD 16 may include a control module 81, a therapy delivery module 84 (which may include a stimulation generator, for example), a sensing module 86, and a power source 90.

Control module 81 may include a processor 80, memory 82, and telemetry module 88. Memory 82 may include computer-readable instructions that, when executed by processor 80, for example, cause IMD 16 and/or control module 81 to perform various functions attributed to IMD 16 and/or control module 81 described herein. Further, memory 82 may include any volatile, non-volatile, magnetic, optical, and/or electrical media, such as Random Access Memory (RAM), read-only memory (ROM), non-volatile RAM (NVRAM), Electrically Erasable Programmable ROM (EEPROM), flash memory, and/or any other digital media. An exemplary CAPTURE MANAGEMENT module may be the Left Ventricular CAPTURE MANAGEMENT (LVCM) module described in U.S. patent No. 7,684,863 entitled LV THRESHOLD MEASUREMENT AND CAPTURE MANAGEMENT, issued on 23/3/2010 AND entitled "LV THRESHOLD MEASUREMENT AND CAPTURE MANAGEMENT," which is hereby incorporated by reference in its entirety.

The processor 80 of the control module 81 may comprise any one or more of a microprocessor, controller, Digital Signal Processor (DSP), Application Specific Integrated Circuit (ASIC), Field Programmable Gate Array (FPGA), and/or equivalent discrete or integrated logic circuitry. In some examples, processor 80 may include components such as any combination of one or more microprocessors, one or more controllers, one or more DSPs, one or more ASICs, and/or one or more FPGAs, as well as other discrete or integrated logic circuitry. The functions attributed to processor 80 herein may be embodied as software, firmware, hardware, or any combination thereof.

The control module 81 may be used to determine the effectiveness of the electrodes 40, 42, 44, 45, 46, 47, 48, 50, 58, 62, 64, 66 using the example methods and/or processes described herein according to a selected one or more programs, which may be stored in the memory 82. Further, control module 81 may control therapy delivery module 84 to deliver therapy (e.g., electrical stimulation therapy, such as pacing) to heart 12 according to the selected one or more therapy programs, which may be stored in memory 82. More specifically, control module 81 (e.g., processor 80) may control various parameters of the electrical stimulation delivered by therapy delivery module 84, such as AV delay, amplitude of pacing pulses, pulse width, frequency, or polarity of electrodes, etc., which may be specified by one or more selected therapy protocols (e.g., AV delay adjustment protocol, pacing therapy protocol, pacing recovery protocol, capture management protocol, etc.). As shown, therapy delivery module 84 is selectively coupled to electrodes 40, 42, 44, 45, 46, 47, 48, 50, 58, 62, 64, 66, e.g., via conductors of respective leads 18, 20, 22, or in the case of housing electrode 58, via electrical conductors disposed within housing 60 of IMD 16. Therapy delivery module 84 may be configured to generate and deliver electrical stimulation therapy, such as pacing therapy, to heart 12 using one or more of electrodes 40, 42, 44, 45, 46, 47, 48, 50, 58, 62, 64, 66.

For example, therapy delivery module 84 may deliver pacing stimuli (e.g., pacing pulses) via ring electrodes 40, 44, 45, 46, 47, 48 coupled to leads 18, 20, and 22, respectively, and/or helical tip electrodes 42 and 50 of leads 18 and 22. Further, for example, therapy delivery module 84 may deliver a defibrillation shock to heart 12 via at least two of electrodes 58, 62, 64, 66. In some examples, therapy delivery module 84 may be configured to deliver defibrillation stimulation in the form of pacing, cardioversion, or electrical pulses. In other examples, therapy delivery module 84 may be configured to deliver one or more of these stimulation types in other signal forms, such as sinusoidal waves, square waves, and/or other substantially continuous time signals.

IMD 16 may further include a switch module 85, and control module 81 (e.g., processor 80) may use switch module 85 to select which available electrodes are used to deliver therapy (such as pacing pulses for pacing therapy), or which are used for sensing, e.g., via a data/address bus. Switch module 85 may include a switch array, switch matrix, multiplexer, or any other type of switching device suitable to selectively couple sensing module 86 and/or therapy delivery module 84 to one or more selected electrodes. More specifically, the therapy delivery module 84 may include a plurality of pacing output circuits. Each of these multiple pacing output circuits may be selectively coupled to one or more of electrodes 40, 42, 44, 45, 46, 47, 48, 50, 58, 62, 64, 66 (e.g., a pair of electrodes for delivering therapy to the pacing carrier), for example, using switching module 85. In other words, each electrode may be selectively coupled to one of the pacing output circuits of the therapy delivery module using switching module 85.

Sensing module 86 is coupled (e.g., electrically coupled) to sensing devices, which may include electrodes 40, 42, 44, 45, 46, 47, 48, 50, 58, 62, 64, 66 in additional sensing devices to monitor electrical activity of heart 12, e.g., Electrocardiogram (ECG)/Electrogram (EGM) signals, etc. The ECG/EGM signal may be used to measure or monitor activation time (e.g., ventricular activation time, etc.), Heart Rate (HR), Heart Rate Variability (HRV), heart rate oscillation (HRT), deceleration/acceleration capability, deceleration sequence incidence, T-wave alternation (TWA), P-wave to P-wave interval (also referred to as P-P interval or a-a interval), R-wave to R-wave interval (also referred to as R-R interval or V-V interval), P-wave to QRS complex interval (also referred to as P-R interval, a-V interval, or P-Q interval), QRS complex morphology, ST segment (i.e., segment connecting QRS complex and T-wave), T-wave changes, QT, electrical vector, and the like.

Switching module 85 may also be used with sensing module 86 to select which of the available electrodes are used or enabled, for example, to sense electrical activity of the patient's heart (e.g., one or more electrical vectors of the patient's heart using any combination of electrodes 40, 42, 44, 45, 46, 47, 48, 50, 58, 62, 64, 66). Likewise, switch module 85 may also be used with sensing module 86 to select which of the available electrodes are not used (e.g., disabled) to sense, for example, electrical activity of the patient's heart (e.g., one or more electrical carriers of the patient's heart using any combination of electrodes 40, 42, 44, 45, 46, 47, 48, 50, 58, 62, 64, 66), and so on. In some examples, control module 81 may select electrodes that act as sense electrodes via a switching module within sensing module 86, e.g., by providing signals via a data/address bus.

In some examples, sensing module 86 includes a channel including an amplifier having a relatively wider passband than an R-wave or P-wave amplifier. The signal from the selected sensing electrode may be provided to a multiplexer and then converted by an analog-to-digital converter to a multi-bit digital signal for storage in memory 82, for example, as an Electrogram (EGM). In some examples, such EGMs may be stored in memory 82 under the control of direct memory access circuitry.

In some examples, control module 81 may function as an interrupt driven device and may be responsive to interrupts by the pacemaker timing and control module, where the interrupts may correspond to the occurrence of sensed P-waves and R-waves and the generation of cardiac pacing pulses. Any required mathematical calculations may be made by processor 80 and any updates to the values or intervals controlled by the pacemaker timing and control module may occur after such interrupts. Portions of memory 82 may be configured for a plurality of recirculating buffers capable of retaining one or more series of measured intervals that may be analyzed by, for example, processor 80 in response to an occurrence of a pacing or sensing interruption in order to determine whether patient heart 12 is currently exhibiting atrial or ventricular tachyarrhythmia.

Telemetry module 88 of control module 81 may include any suitable hardware, firmware, software, or any combination thereof for communicating with another device, such as a programmer. For example, telemetry module 88 may receive downlink telemetry from and transmit uplink telemetry to a programmer by way of an antenna (which may be an internal and/or external antenna) under the control of processor 80. Processor 80 may provide data and control signals to be transmitted up to the programmer, for example, via an address/data bus to telemetry circuitry within telemetry module 88. In some examples, telemetry module 88 may provide the received data to processor 80 via a multiplexer.

The various components of IMD 16 are further coupled to a power source 90, which may include a rechargeable or non-rechargeable battery. A non-rechargeable battery may be selected to last for years, while a rechargeable battery may be inductively charged from an external device, for example, daily or weekly.

Fig. 11B is another embodiment of a functional block diagram of IMD 16. Fig. 11B depicts bipolar RA lead 22, bipolar RV lead 18, and bipolar LV CS lead 20, without LA CS pace/sense electrodes, coupled with Implantable Pulse Generator (IPG) circuitry 31 having a programmable mode and parameters to pace a biventricular DDD/R type known in the art. In turn, the sensor signal processing circuit 91 is indirectly coupled to the timing circuit 83 and to the microcomputer circuit 33 via a data and control bus. The IPG circuit 31 is shown in a functional block diagram generally divided into a microcomputer circuit 33 and a pacing circuit 21. Pacing circuit 21 includes a digital controller/timer circuit 83, an output amplifier circuit 51, a sense amplifier circuit 55, an RF telemetry transceiver 41, an activity sensor circuit 35, and a number of other circuits and components described below.

Crystal oscillator circuit 89 provides the basic timing clock for pacing circuit 21, while battery 29 provides power. A power-on-reset circuit 87 is responsive to initial connection of the circuit to the battery for defining an initial operating condition and similarly resets the operational state of the device in response to detection of a low battery charge. Reference mode circuit 37 generates a stable voltage reference and current for analog circuits within pacing circuit 21, while analog-to-digital converter ADC and multiplexer circuit 39 digitizes the analog signals and voltages to provide real-time telemetry regarding whether the cardiac signals of sense amplifier 55 are transmitted upward via RF transmitter and receiver circuit 41. The voltage reference and bias circuit 37, ADC and multiplexer 39, power-on-reset circuit 87 and crystal oscillator circuit 89 may correspond to those currently used in any other currently commercially available implantable cardiac pacemaker.

If the IPG is programmed to a rate response mode, the signal output by one or more physiological sensors is used as a Rate Control Parameter (RCP) to derive physiological escape intervals. For example, escape intervals are adjusted in proportion to the activity level of the patient as presented in Patient Activity Sensor (PAS) circuit 35 in the depicted, exemplary IPG circuit 31. A patient activity sensor 27 is coupled to the IPG housing and may take the form of a piezoelectric crystal transducer as is well known in the art, and its output signal is processed and used as the RCP. The sensor 27 generates electrical signals in response to sensed physical activity, which are processed by the activity circuit 35 and provided to the digital controller/timer circuit 83. The activity circuit 35 and the associated sensor 27 may correspond to the circuits disclosed in the following documents: U.S. patent No. 5,052,388 issued on 1/10/1991 AND entitled "METHOD AND APPARATUS FOR IMPLEMENTING ACTIVITY SENSING IN A PULSE GENERATOR FOR implanting activity sensing in a PULSE GENERATOR" AND U.S. patent No. 4,428,378 issued on 31/1/1984 AND entitled "RATE ADAPTIVE PACER (rate adaptive pacemaker"), each of which is incorporated herein by reference in its entirety. Likewise, the example systems, devices, and methods described herein may be practiced in conjunction with alternative types of sensors, such as oxygenation sensors, pressure sensors, pH sensors, and respiration sensors to provide rate-responsive pacing capabilities. Alternatively, the QT time may be used as a rate indicating parameter, in which case no additional sensor is required. Similarly, the exemplary embodiments described herein may also be practiced in non-frequency-responsive pacemakers.

Data transmission to and from the external programmer is accomplished through the telemetry antenna 57 and associated RF transceiver 41 for both demodulation of received downlink telemetry and for transmission of uplink telemetry. The ability to transmit telemetry upward will typically include the ability to transmit stored digital information such as operating modes and parameters, EGM histograms, and other events, along with atrial and/or ventricular electrical activity and real-time EGMs that mark channel pulses (indicating the occurrence of sensed and paced depolarizations in the atria and ventricles), as is well known in the pacing art.

The microcomputer 33 contains a microprocessor 80 and associated system clock and RAM and ROM chips 82A and 82B, respectively, on the processor. Further, the microcomputer circuit 33 includes a separate RAM/ROM chip 82C for providing additional memory capacity. The microprocessor 80 is typically operated in a reduced power consumption mode and is interrupt driven. Microprocessor 80 wakes up in response to a defined interrupt event, which may include, among other things, the a, RV, and LV trigger signals generated by the timer in digital timer/controller circuit 83, and the a, RV, and LV event signals generated by sense amplifier circuit 55. The particular values of the intervals and delays timed down by the digital controller/timer circuit 83 are controlled by the microcomputer circuit 33 through the data and control bus according to the programmed parameter values and operating mode. Additionally, if applicable, if the timer interrupt is programmed to operate as a frequency-responsive pacemaker, the timer interrupt may be provided, for example, every cycle or every two seconds, to allow the microprocessor to analyze the activity sensor data and update the basal A-A, V-A or V-V escape intervals. Microprocessor 80 may also be used to define variable, operational AV delay intervals and the energy delivered to each ventricle.

In one embodiment, microprocessor 80 is a custom microprocessor adapted to fetch and execute instructions stored in RAM/ROM unit 82 in a conventional manner. However, it is contemplated that other embodiments may be suitable for practicing the present invention. For example, an off-the-shelf commercially available microprocessor or microcontroller, or custom dedicated hard-wired logic or state machine type circuitry may perform the functions of microprocessor 80.

Digital controller/timer circuit 83 operates under the general control of microcomputer 33 to control the timing functions and other functions within pacing circuit 320 and includes a set of timing circuits and associated logic circuits, some of which are depicted as being relevant to the present invention. The depicted timing circuit includes a URI/LRI timer 83A, V-V delay timer 83B, an intrinsic interval timer 83C for timing past V-event-to-V event intervals or V-event-to-A event intervals or V-V conduction intervals, an escape interval timer 83D for timing A-A, V-A and/or V-V pacing escape intervals, an AV delay interval timer 83E for timing a previous A-event or A-triggered A-LVp delay (or A-RVp delay), a post-ventricular timer 83F for timing a post-ventricular time period, and a date/time clock 83G.

The AV delay interval timer 83E is loaded with the appropriate delay interval for one ventricular chamber (e.g., a-RVp delay or a-LVp delay determined using known methods) to start from the previous a pace or a event timeout. The interval timer 83E triggers the delivery of pacing stimulation and may be based on one or more previous cardiac cycles (or from a data set empirically derived for a given patient).

The post-event timer 83F times down the post-ventricular time period following an RV event or LV event or RV trigger or LV trigger and the post-atrial time period following an a event or a trigger. The duration of the time period after the event may also be selected as a programmable parameter stored in the microcomputer 33. The post-ventricular time period includes PVARP, post-atrial ventricular blanking period (PAVBP), Ventricular Blanking Period (VBP), post-ventricular atrial blanking period (PVARP), and Ventricular Refractory Period (VRP), although other periods may be suitably defined, at least in part, according to the operating circuitry employed in the pacing engine. The post-atrial time period includes an Atrial Refractory Period (ARP), during which the a events are ignored for the purpose of resetting any AV delay, and an Atrial Blanking Period (ABP), during which atrial sensing is disabled. It should be noted that the start of the post-atrial time period and AV delay may begin substantially simultaneously with the start or end of each a event or a trigger, or in the case of an a trigger, may begin at the end of a pacing after the a trigger. Similarly, the post-ventricular time period and the start of the V-A escape interval may begin substantially simultaneously with the start or end of a V event or V trigger, or in the case of a V trigger, at the end of V pacing after the V trigger. Microprocessor 80 also optionally calculates AV delay, a post-ventricular time period, and a post-atrial time period as a function of sensor-based escape intervals established in response to one or more RCPs and/or with intrinsic atrial rate.

The output amplifier circuit 51 contains a RA pacing pulse generator (LA pacing pulse generator if LA pacing is provided), a RV pacing pulse generator, and a LV pacing pulse generator, or any of those corresponding to those currently used in any commercially available cardiac pacemaker that provides atrial and ventricular pacing. To trigger generation of a paced RV or paced LV pulse, digital controller/timer circuit 83 generates a trigger RV signal upon a delay timeout of a-RVp (in the case of RV priming) or a trigger LV upon an a-LVp delay timeout (in the case of LV priming) by AV delay interval timer 83E (or V-V delay timer 83B). Similarly, at the end of a V-A escape interval timed by escape interval timer 83D, digital controller/timer circuit 83 generates an RA trigger signal that triggers the output of a pacing RA pulse (or a LA trigger signal that triggers the output of a LA pacing pulse, if provided).

The output amplifier circuit 51 includes switching circuitry for coupling selected pairs of pacing electrodes from the lead conductors and the IND _ CAN electrode 20 to the RA pacing pulse generator (and LA pacing pulse generator if provided), the RV pacing pulse generator, and the LV pacing pulse generator. Selection of pacing/sensing electrode pairs and control circuit 53 selects lead conductors and associated pacing electrode pairs to be coupled to atrial and ventricular output amplifiers within output amplifier circuit 51 for accomplishing RA, LA, RV and LV pacing.

Sense amplifier circuitry 55 includes circuitry corresponding to any of those currently employed in current cardiac pacemakers for atrial and ventricular pacing and sensing. High impedance P-wave and R-wave sense amplifiers may be used to amplify the pressure differential signals generated by the passage of cardiac depolarization wavefronts across the sensing electrode pair. High impedance sense amplifiers use high gain to amplify low amplitude signals and rely on pass band filters, time domain filtering, and amplitude threshold comparisons to distinguish P-waves or R-waves from background electrical noise. Digital controller/timer circuit 83 controls the sensitivity settings of the atrial and ventricular sense amplifiers 55.

The sense amplifier is typically decoupled from the sense electrodes during the blanking period before, during, and after the delivery of pacing pulses to any pacing electrodes of the pacing system to avoid saturation of the sense amplifier. Sense amplifier circuitry 55 includes blanking circuitry for decoupling selected pairs of lead conductors and IND-CAN electrode 20 from the inputs of the RA sense amplifier (and LA sense amplifier, if provided), RV sense amplifier, and LV sense amplifier during ABP, PVABP, and VBP. Sense amplifier circuitry 55 also includes switching circuitry for coupling selected sense electrode lead conductors and IND-CAN electrode 20 to the RA sense amplifier (and LA sense amplifier if provided), RV sense amplifier and LV sense amplifier. Again, the sense electrode selection and control circuit 53 may select conductors and associated pairs of sense electrodes to be coupled with the atrial and ventricular sense amplifiers within the output amplifier circuit 51 and sense amplifier circuit 55 for accomplishing RA, LA, RV and LV sensing along the desired uni-polar and bi-polar sense carriers.

The right atrial depolarization or P-wave in the RA-sense signal sensed by the RA sense amplifier produces an RA-event signal that is transmitted to the digital controller/timer circuit 83. Similarly, left atrial depolarization or P-wave in the LA sense signal sensed by the LA sense amplifier (if provided) produces an LA-event signal that is communicated to the digital controller/timer circuit 83. Ventricular depolarization or R-wave in the RV sense signal sensed by the ventricular sense amplifier results in an RV event signal that is communicated to the digital controller/timer circuit 83. Similarly, ventricular depolarization or R-wave in the LV-sense signal sensed by the ventricular sense amplifier produces an LV-event signal that is transmitted to the digital controller/timer circuit 83. RV event signals, LV event signals, RA event signals, and LA sense signals may be responsive or refractory, and may be inadvertently triggered by electrical noise signals or abnormally conducted depolarization waves, rather than true R-waves or P-waves.

The techniques described in this disclosure, including the techniques attributed to IMD 16, computing device 140, and/or various component parts, may be implemented at least in part in hardware, software, firmware, or any combination thereof. For example, various aspects of the techniques may be implemented in one or more processors, including one or more microprocessors, DSPs, ASICs, FPGAs, or any other equivalent integrated or discrete logic circuitry, as well as any combinations of such components, embodied in a programmer (such as a physician or patient programmer, stimulator, image processing device, or other device). The terms "module," "processor," or "processing circuitry" may generally refer to any of the preceding logic circuitry (alone or in combination with other logic circuitry), or any other equivalent circuitry.

Such hardware, software, and/or firmware may be implemented within the same device or within separate devices to support the various operations and functions described in this disclosure. Furthermore, any of the described units, modules or components may be implemented together or separately as separate but cooperating logic devices. Depiction of different features as modules or units is intended to highlight different functional aspects and does not necessarily imply that what modules or units must be realized by separate hardware or software components. Rather, functionality associated with one or more modules or units may be performed by separate hardware or software components, or integrated within common or separate hardware or software components.

When implemented in software, the functions granted to the systems, devices, and techniques described in this disclosure may be embodied as instructions on a computer-readable medium (such as RAM, ROM, NVRAM, EEPROM, flash memory, magnetic data storage media, optical data storage media, etc.). The instructions may be executable by one or more processors to support one or more aspects of the functionality described in this disclosure.

As indicated above, to facilitate evaluating whether a patient is a candidate for CRT based on the monitored output, the one or more indications (e.g., indicators or graphical indications) of cardiac electrical dyssynchrony may be determined based on torso-surface activation times during both intrinsic conduction of the heart and during CRT. A difference between the indication during intrinsic conduction and CRT may indicate that CRT will provide a benefit to the patient, e.g., the patient is a candidate for CRT. Also, during non-invasive assessment, implantation, or follow-up to determine whether the patient is a CRT candidate, one or more indications of cardiac electrical dyssynchrony for each of the plurality of lead locations may be determined based on torso-surface activation times resulting from delivery of CRT at the location, or with electrode configurations or parameter values. In this way, differences between indications of cardiac electrical dyssynchrony associated with respective locations, electrode configurations, or parameter values may be compared to determine a preferred location, configuration, or value.

One set of experiments confirmed that: triggered non-invasive pacing may be accomplished with ultrasound applied to the skin. When combined with a system for assessing electrical heterogeneity, such ultrasound pacing may be used to determine whether a patient would benefit from CRT. Performing non-invasive assessments helps reduce the cost of the healthcare system. Fig. 12 to 14 are associated with the first experiment, while fig. 15 to 19 are associated with the second experiment.

In a first dog experiment performed with a closed chest, a 200kHz transducer was placed on the skin above the tip. Fig. 15 is a 2D ultrasound image depicting the tip of the heart (near the top of the image) when the ventricular septum is generally in the middle of the image (with the LV to the left and RV to the right). The same acoustic window was used for both experiments. Depth marks (in cm) are depicted on the left side. Various transducers with various frequencies and/or various probe diameters are employed to test the delivery of ultrasound pacing through the skin to cardiac tissue. The piston transducer was used for the first experiment; however, those skilled in the art will appreciate that various other transducers may be used. For example, a phased array of transducers, which is many small transducers, may also be used.

The timing of the delivery of pacing is not based on the atrium (i.e., the detection of P-wave signals or pulses). A delay is added when the atrium is activated or fired. The delay may be swept over a range of values, like 50ms to 200ms, in order to achieve different degrees of fusion between the left ventricular pacing and the intrinsic activation of the ventricles. After the delay expires, ultrasound pacing is delivered to the cardiac tissue (e.g., the ventricle). After delivering ultrasound pacing, a determination is made as to whether capture of cardiac tissue has occurred. Stimulation that causes the ventricles to respond (e.g., ultrasound pacing) is often referred to as capturing cardiac tissue.

A contrast agent (e.g., Lumason or microbubbles) is injected intravenously in response to the ultrasound waves to enhance mechanical stimulation of the heart. In this experiment, the contrast agent was injected 4 minutes 33 seconds before time reference zero (not shown). The transducer generates a pressure of 700KPa and a pulse width of 50ms at a frequency of 200 kHz. The transducer was triggered 20ms after sensing P-waves (via Medtronic 5076 lead located in the Right Atrium (RA)). Fig. 12-14 show that intermittent pacing is achieved, depending on the small movements of the transducer and the motion due to respiration. Fig. 12 depicts a cardiac response to delivering ultrasound pacing (i.e., HIFU pacing). The X-axis is time in seconds and the Y-axis is in millivolts for each of the three ECG vectors (designated I, II and III) on the dog's skin. The pacing burst is monomorphic, indicating that activation of a consistent location is occurring in response to HIFU pacing.

Fig. 13 depicts a cardiac response to delivering ultrasound pacing, such as HIFU pacing. Leads are applied to the skin to determine where pacing is occurring (i.e., which portion of the heart is beginning to pace). The X-axis is time in seconds, while the Y-axis is in millivolts for each vector in the 9 lead ECG (designated I, II, III, V1-V6) on the dog's skin. Fig. 14 is an enlarged portion of fig. 13.

Fig. 16, 17A-17C, 18A-18C, and 19A-19C relate to a second experiment that confirms results from the first experiment. Three different ultrasound frequencies and two different probe diameters were used. Fig. 16 shows that consistent pacing was achieved at the base diaphragm pacing site using a frequency of 200KHz and a pulse width of 1 ms. In the second experiment, contrast agent delivery was continued instead of delivering a single patch of contrast agent as was done in the first experiment. The ECG results shown in fig. 16 are considered to represent the basal septal pacing position. The ECG vectors (I-III and V1-V6) come from electrodes placed directly on the skin of the dog. The intrinsic rhythm is shown to have occurred between approximately 3.5 seconds and 4 seconds. The ultrasound pacing is delivered 20ms after the P-wave is detected or sensed. As shown in the graph, consistent pacing occurs at the base septum location.

Fig. 17A-17C show capture occurring at different frequencies (200kHz, 420kHz, and 220kHz) and probe diameters (e.g., 3cm, 5 cm). Fig. 17A-17C depict pulse widths (ms) along the X-axis and pressures (KPa) along the Y-axis. For the data represented in FIG. 17A, a 200KHz and 5cm transducer was employed. For example, with a transducer using a 200KHz frequency and 5cm diameter, capture typically occurs at block 1500; capture rarely occurs at block 1502; and capture does not occur at block 1504 of fig. 17A. Effective capture typically occurs at ultrasonic pressures above 400 kPa. Capture does not occur at or below 300 KPa.

Referring to FIG. 17B, a 420KHz transducer with a 3cm diameter is employed. Capture occurs at block 1500; capture rarely occurs at block 1502; and capture does not occur at block 1504 of fig. 17B. Effective capture typically occurs at 500kPa or greater when the pulse width is between 0.1ms and 50 ms. Capture does not occur at or below 300 KPa.

Referring to FIG. 17C, a 220KHz and 3cm transducer is employed. Capture occurs at block 1500; capture rarely occurs at block 1502; and capture does not occur at block 1504 of fig. 17C. Effective capture typically occurs between 0.5ms and 10ms along the X-axis at pressures of 600KPa or above. Capture does not occur at or below 400 KPa.

Fig. 18A to 18C and fig. 19A to 19C confirm that: various regions of the heart are effectively responsive to the delivery of HIFU pacing. The data generated in fig. 18A relies on the transducer using a 200KHz frequency. Ultrasound was delivered to the cardiac tip at an amplitude of 500KPa, 10ms pulse width. The data generated in fig. 18B relies on the transducer using a 220KHz frequency. Ultrasound was delivered to the cardiac tip at an amplitude of 700KPa, 5ms pulse width. The data generated in figure 18C relies on a transducer at a frequency of 220KHz, with an amplitude of 600KPa and a pulse width of 1.0ms for a region considered to be the base diaphragm.

The data generated for the graphs of fig. 19A-19C all use transducers with a frequency of 420 KHz. The data presented in figure 19A relates to ultrasound delivery at 600KPa amplitude and 0.10ms pulse width, which is delivered to a region believed to be the Right Ventricular Outflow Tract (RVOT). The data presented in figure 19B relates to ultrasound delivery at 700KPa amplitude and 0.50ms pulse width, which is delivered to the RVA/septa. The data presented in figure 19C relates to ultrasound delivery at 700KPa amplitude and 1ms pulse width, which is delivered to a region considered RVOT.

Throughout the present disclosure, a determination can be made efficiently and non-invasively as to whether a patient can benefit from CRT therapy. It is believed that the methods herein will reduce overall healthcare costs.

The following paragraphs, enumerated consecutively from 1 to 21, provide different aspects of the invention. In one embodiment, in the first paragraph (1), the present invention provides a method comprising:

delivering ultrasonic energy to cardiac tissue;

receiving, with a processing unit, a torso-surface potential signal from each of a plurality of electrodes distributed on a torso of a patient in response to delivering ultrasonic energy to the cardiac tissue;

calculating, with the processing unit, torso-surface activation times based on the signals sensed from the electrodes for at least a subset of the plurality of electrodes; and

presenting, by the processing unit, to a user via a display, an indication of a degree of dyssynchrony of the torso-surface activation times.

Embodiment 2 is a method according to paragraph 1, wherein the ultrasonic energy is High Intensity Focused Ultrasound (HIFU).

Embodiment 3 is a method according to any of paragraphs 1 or 2,

wherein receiving the torso-surface potential signals and calculating the torso-surface activation times comprises: receiving a first torso-surface potential signal and calculating a first torso-surface activation time for a first time during intrinsic conduction of the heart of the patient, and receiving a second torso-surface potential signal and calculating a second torso-surface activation time for a second time during CRT pacing of the heart, and

wherein presenting the indication of the degree of dyssynchrony comprises: presenting an indication of dyssynchrony changes from the CRT pacing that is inherently conducted to the heart.

Embodiment 4 is a method according to any of paragraphs 1-3, wherein the ultrasonic energy is delivered at a Sound Pressure Level (SPL) of up to 3 megapascals (MPa) for pacing cardiac tissue.

Embodiment 5 is a method according to any of paragraphs 1 to 4, wherein the ultrasonic energy is delivered to at least one localized area on a left ventricular wall.

Embodiment 6 is a method according to any of paragraphs 1-5, wherein the ultrasonic energy is delivered for non-invasive cardiac resynchronization therapy involving ultrasonic stimulation of at least one right ventricular site and at least one left ventricular site with delivery of stimulation timed relative to a P-wave on the surface ECG.

Embodiment 7 is a method according to any of paragraphs 1 to 6, wherein the ultrasonic energy is delivered to at least one localized area on a left ventricular wall.

Embodiment 8 is a method according to any of paragraphs 1-7, wherein the ultrasound pacing is delivered at various timings relative to expected intrinsic ventricular depolarizations.

Embodiment 9 is a method according to any of paragraphs 1 to 8, wherein the delivery of the ultrasound pacing may be timed at a time interval after the start of the surface ECG P-waves such that the time interval may be 80ms shorter than an intrinsic P-R interval, 60ms shorter than the intrinsic P-R interval, 50ms shorter than the intrinsic P-R interval, 40ms shorter than the intrinsic P-R interval, 30ms shorter than the intrinsic P-R interval, 20ms shorter than the intrinsic P-R interval, 10ms shorter than the intrinsic P-R interval.

Embodiment 10 is a system, comprising:

means for delivering ultrasound energy to cardiac tissue;

means for receiving, with a processing unit, a torso-surface potential signal from each of a plurality of electrodes distributed on a torso of a patient in response to delivering ultrasonic energy to the cardiac tissue;

means for calculating, with the processing unit, torso-surface activation times based on the signals sensed from the electrodes for at least a subset of the plurality of electrodes; and

means for presenting, by the processing unit, to a user via a display, an indication of a degree of dyssynchrony of the torso-surface activation times.

Embodiment 11 is a system according to paragraph 10 wherein the ultrasonic energy is High Intensity Focused Ultrasound (HIFU).

Embodiment 12 is a system according to any of paragraphs 10 or 11, wherein the HIFU is delivered by a transducer.

Embodiment 13 is a system according to any of paragraphs 10 to 12, wherein receiving the torso-surface potential signals and calculating the torso-surface activation times comprises: receiving a first torso-surface potential signal and calculating a first torso-surface activation time for a first time during intrinsic conduction of the heart of the patient, and receiving a second torso-surface potential signal and calculating a second torso-surface activation time for a second time during CRT pacing of the heart, and

wherein presenting the indication of the degree of dyssynchrony comprises: presenting an indication of dyssynchrony changes from the CRT pacing that is inherently conducted to the heart.

Embodiment 14 is a system according to any of paragraphs 10-11, wherein the ultrasonic energy is delivered at a Sound Pressure Level (SPL) of up to 3 megapascals (MPa) for pacing cardiac tissue.

Embodiment 15 is a system according to any of paragraphs 10-14, wherein the ultrasonic energy is delivered to at least one localized area on a left ventricular wall.

Embodiment 16 is a system according to any of paragraphs 10-15, wherein the ultrasonic energy is delivered for non-invasive cardiac resynchronization therapy involving ultrasonic stimulation of at least one right ventricular site and at least one left ventricular site with delivery of stimulation timed relative to a P-wave on the surface ECG.

Embodiment 17 is a system according to any of paragraphs 10 to 16, wherein the ultrasonic energy is used to evaluate electrical stimulation affecting cardiac resynchronization therapy.

Embodiment 18 is a system according to any of paragraphs 10-17, wherein the ultrasound pacing is delivered at various timings relative to expected intrinsic ventricular depolarizations.

Embodiment 19 is a system according to any of paragraphs 10-18, wherein the delivery of the ultrasound pacing may be timed at a time interval after the start of the surface ECG P-waves such that the time interval may be 80ms shorter than an intrinsic P-R interval, 60ms shorter than the intrinsic P-R interval, 50ms shorter than the intrinsic P-R interval, 40ms shorter than the intrinsic P-R interval, 30ms shorter than the intrinsic P-R interval, 20ms shorter than the intrinsic P-R interval, 10ms shorter than the intrinsic P-R interval.

Embodiment 20 is a method comprising:

delivering ultrasonic energy to cardiac tissue;

receiving, with a processing unit, a torso-surface potential signal from each of a plurality of electrodes distributed on a torso of a patient in response to delivering ultrasonic energy to the cardiac tissue;

calculating, with the processing unit, torso-surface activation times based on the signals sensed from the electrodes for at least a subset of the plurality of electrodes; and

presenting, by the processing unit to a user via a display, an indication of a degree of dyssynchrony of the torso-surface activation times, wherein the ultrasonic energy is High Intensity Focused Ultrasound (HIFU),

wherein receiving the torso-surface potential signals and calculating the torso-surface activation times comprises: receiving a first torso-surface potential signal and calculating a first torso-surface activation time for a first time during intrinsic conduction of the heart of the patient, and receiving a second torso-surface potential signal and calculating a second torso-surface activation time for a second time during CRT pacing of the heart, and

wherein presenting the indication of the degree of dyssynchrony comprises: presenting an indication of dyssynchrony changes from the CRT pacing that is inherently conducted to the heart.

Embodiment 21 is a method comprising:

delivering ultrasonic energy to cardiac tissue;

receiving, with a processing unit, a torso-surface potential signal from each of a plurality of electrodes distributed on a torso of a patient in response to delivering ultrasonic energy to the cardiac tissue;

calculating, with the processing unit, torso-surface activation times based on the signals sensed from the electrodes for at least a subset of the plurality of electrodes; and

presenting, by the processing unit to a user via a display, an indication of a degree of dyssynchrony of the torso-surface activation times,

wherein receiving the torso-surface potential signals and calculating the torso-surface activation times comprises: receiving a first torso-surface potential signal and calculating a first torso-surface activation time for a first time during intrinsic conduction of the heart of the patient, and receiving a second torso-surface potential signal and calculating a second torso-surface activation time for a second time during CRT pacing of the heart, and

wherein presenting the indication of the degree of dyssynchrony comprises: presenting an indication of dyssynchrony changes from the CRT pacing that is inherently conducted to the heart.

Embodiment 22 is a system or method according to any of the preceding paragraphs and relates to ultrasound strain imaging (via speckle tracking) as a means for determining dyssynchrony. In this embodiment, ultrasound imaging is combined with HIFU for a full ultrasound system. According to this embodiment, the area of late mechanical activation determines the optimal location for placement of the lead.

Embodiment 23 is a system or method according to any of the preceding paragraphs and relates to determining out-of-sync (i.e., spread or standard deviation of strain in different locations) rather than focusing on a single location with the latest activation.

The present disclosure has been provided with reference to illustrative embodiments and is not intended to be construed in a limiting sense. As previously mentioned, those skilled in the art will recognize that other various illustrative applications may use the techniques as described herein to take advantage of the beneficial features of the apparatus and methods described herein. Various modifications of the illustrative embodiments, as well as additional embodiments of the disclosure, will be apparent upon reference to this description.