The system that controls blood pressure

Abstract

To provide a system for transmitting blood pressure reduction electrical stimulation to the heart of a patient capable of determining a desirable AV delay.SOLUTION: The atrium is paced and the ventricle is paced with a given (arbitrary) delay to obtain a desired blood pressure change. Then, the atrium is sensed, the ventricle is paced, the blood pressure change is observed, and the resulting blood pressure change is compared with the paced-atrium-paced-ventricle desired blood pressure change. In the case where the blood pressure changes are not substantially equal, the timing of the sensed-atrium-paced-ventricle stimulation is adjusted on the basis of the comparison. The new modified resulting blood pressure change is observed, and the modified blood pressure change is compared with the paced-atrium-paced-ventricle desired blood pressure change. Adjustment and observation may be repeated until the timing of the sensed-atrium-paced-ventricle stimulation achieves the same blood pressure change as the desired blood pressure change of the paced-atrium-paced-ventricle stimulation.SELECTED DRAWING: Figure 9

Description

[Technical field]

[0001] The present invention relates to the field of treating hypertension by controlling cardiac function, including filling and contraction. Certain embodiments of the invention involve the application of localized electrical stimulation to the heart. [Background technology]

[0002] It is known that fluctuations in blood pressure usually occur due to, for example, increased activity (which usually raises blood pressure) or significant blood loss (which tends to cause a reduction in blood pressure). However, blood pressure is usually maintained within a limited range, for example due to the body's baroreflex, whereby elevated or lowered blood pressure affects the function of the heart and the characteristics of the cardiovascular system through a feedback loop. Such feedback control is realized by the nervous system and the endocrine system (e.g. natriuretic peptides). In people with hypertension, the baroreflex is functional but blood pressure remains elevated.

[0003] High blood pressure (e.g., blood pressure above 140 / 90 mmHg) is a serious health problem that affects many people. For example, approximately 74.5 million people aged 20 years or older living in the United States have high blood pressure. High blood pressure can lead to life-threatening conditions such as stroke, heart attack, and / or congestive heart failure. Approximately 44.1% of people with hypertension and receiving up-to-date treatment have their hypertension satisfactorily controlled. Correspondingly, 55.9% of the same people have it poorly controlled. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] US Patent Application Publication No. 2012 / 0215272 [Patent Document 2] US Patent Application Publication No. 2011 / 0172731 [Patent Document 3] U.S. P.O. Application Serial No. 13 / 688,978 [Patent Document 4] US Patent Application Publication No. 2012 / 0041502 Summary of the Invention [Problem to be solved by the invention]

[0005] Traditionally, treatment for high blood pressure has involved medication and lifestyle changes. Treatment of hypertension is not effective for all patients. Additionally, side effects may prevent certain patients from taking the medication. Thus, there remains a need for additional techniques to lower blood pressure. [Means for solving the problem]

[0006] The present invention discloses a method and system for reducing blood pressure.

[0007] The present invention applies focused electrical stimulation to the heart, including at least two different stimulation patterns, each configured to reduce blood pressure to a different extent. The cardiac stimulation may alternate between stimulation patterns based on the patient's needs, for example, alternating a certain degree of blood pressure reduction during a portion of a 24-hour cycle (e.g., daytime or a portion thereof) with another, different degree of blood pressure reduction during another portion of the 24-hour period (e.g., nighttime or a portion thereof). As another example, the cardiac stimulation may alternate between a first stimulation pattern that provides a first degree of blood pressure reduction during periods of vigorous activity by the patient and a second stimulation pattern that provides a second, different degree of blood pressure reduction during periods of light activity by the patient.

[0008] In some embodiments, instead of or in addition to treating hypertension pharmacologically, hypertension is treated mechanically. In some embodiments, an electrical stimulator, such as a pacemaker or other type of device having a pulse generator, may be used to stimulate the patient's heart to reduce blood pressure. If the heart is stimulated in a consistent manner to reduce blood pressure, the cardiovascular system may eventually adapt to the stimulation and return to a higher blood pressure. Thus, in some embodiments, the adaptation response of the cardiovascular system is reduced or The stimulation patterns may be configured such that the baroreflex can be modulated so that it is reduced or even prevented.

[0009] Some embodiments may take advantage of the slow baroreflex response that occurs after therapy is discontinued or reduced. Under such circumstances, it may take a long time for blood pressure levels to return to pre-treatment values, and therapy may be discontinued or reduced for an extended period of time. Then, therapy may be resumed at the therapeutic level that was applied before therapy was discontinued or reduced for an extended period of time, before blood pressure levels reach pre-treatment values.

[0010] In some embodiments, an electrical stimulator may be used to stimulate the patient's heart to cause at least some of the atrial contractions to occur with the atrioventricular valves closed, which may allow less blood to enter the corresponding ventricle than if the atrioventricular valves were open during the atrial contraction, which would provide a rapid drop in blood pressure.

[0011] In some embodiments, the patient's heart may be stimulated using an electrical stimulator such that the atrial pressure caused by atrial contraction of the atrium overlaps in time with the passive pressure increase in the atrium, thereby providing a combined atrial pressure in the atrium caused by atrial contraction and the passive pressure increase that is higher than the atrial pressure in the atrium in the absence of stimulation. This may cause increased atrial expansion, thereby lowering blood pressure through hormonal and / or neuronal pathways. This reduction in blood pressure may take some time to manifest, depending on the hormonal and / or neuronal pathways.

[0012] The atrial pressure caused by the atrial contraction may reach a peak atrial pressure caused by the atrial contraction. The passive pressure rise of the atrium may reach a peak passive pressure rise of the atrium. Alternatively, or in addition, the overlap in time of the atrial pressure caused by the atrial contraction of the atrium and the passive pressure rise of the atrium may include an overlap in time of the peak atrial pressure and the peak passive pressure rise caused by the atrial contraction. In some embodiments, the overlap of the peak atrial pressure and the peak passive pressure rise may result in a composite atrial pressure (of the atrial pressure and the passive pressure rise caused by the atrial contraction) that is higher than the atrial pressure of the atrium in the absence of stimulation.

[0013] In some embodiments, the electrical stimulator may be used to stimulate the patient's heart to cause at least some atrial contraction within a single cardiac cycle while the atrioventricular valves remain closed, and / or such that the intra-atrial pressure produced by the atrial contraction of the atrium overlaps in time with a passive increase in intra-atrial pressure in the atrium, whereby the combination of the intra-atrial pressure produced by the atrial contraction and the passive increase in intra-atrial pressure provides an intra-atrial pressure in the atrium that is higher than the intra-atrial pressure in the atrium in the absence of stimulation.

[0014] In some embodiments, prosthetic valves may be used in the treatment of hypertension. There are several medical conditions in which several atrioventricular (AV) valves are dysfunctional. In some cases, the valve may be replaced by the implantation of an artificial (prosthetic) valve. These artificial valves may be configured to passively open and close in response to the internal pressure difference between the atrium and ventricle, similar to the natural valves. Passive artificial valves are typically classified into three types based on their mechanical structure: caged ball valves, tilting disc valves, and bileaflet valves. Alternatively, Thus, in some embodiments, an active prosthetic valve may be used that is configured to actively open and close.

[0015] In one aspect of the invention, an embodiment of a system for reducing blood pressure in a patient having a pre-treatment blood pressure is provided. The system may include at least one stimulation electrode for stimulating at least one chamber of a heart of the patient with a stimulation pulse. The system may include a stimulation electrode for transmitting a stimulation pulse to at least one chamber of a heart. The stimulation pattern may include at least one controller configured to apply a turn. may include a first stimulation setting and a second stimulation setting different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting is an atrial kick. and / or configured to control intra-atrial pressure, atrial dilation, or both.

[0016] In one aspect of the invention, an embodiment of a system for reducing blood pressure is provided. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart. The system may include at least one controller configured to administer a stimulation pattern comprising a plurality of stimulation pulses. At least one of the plurality of stimulation pulses may be At least one stimulation pulse may have a first stimulation setting configured to reduce an atrial kick in at least one ventricle, and at least one stimulation pulse of the plurality of stimulation pulses may have a second stimulation setting configured to reduce a baroreflex response to the reduction in the atrial kick so as to limit an increase in blood pressure value occurring during the stimulation pulse to a predetermined value or range of values. Good too.

[0017] In another aspect of the invention, an embodiment of a device is provided for reducing blood pressure in a patient having a pre-treatment blood pressure and a pre-treatment ventricle filling volume. The device includes a stimulation circuit configured to deliver stimulation pulses to at least one of an atrium and a ventricle. The device may include a processor circuit coupled to the stimulation circuit and preferably also to the sensing circuit.

[0018] In some embodiments, the device processor circuitry may be configured to operate in an operational mode in which the device controls an AV delay, as used herein, the AV delay being the time between ventricular excitation and / or contraction and atrial excitation and / or contraction. In addition, as used herein, an AV delay in a system or method may be understood to mean a delay that occurs within a single beat between a contraction or a contraction of the ventricle. detection of the onset of atrial activation, timing of the expected onset of atrial activation, and delivery of at least one excitatory stimulus to the atrium. may also be understood to mean the time delay between one of the transmissions of

[0019] The AV delay may be established by delivering at least one stimulation pulse to both at least one atrium and at least one ventricle. Such a degree may be achieved, for example, by using at least one sensing electrode for sensing natural activity in the heart (e.g., the right atrium in the absence of stimulation). In addition, the degree of stimulation pulse transmission may be adjusted and set accordingly.

[0020] Preferably, ventricular activation is timed to commence prior to delivery of one or more stimulation pulses to the atrium. When regulated, delivery of a stimulating pulse to the heart is controlled by one or more excitatory pulses delivered to the atria. It is timed to be delivered to the atrium earlier than the expected next natural onset of excitation.

[0021] In some embodiments, at least one stimulation pulse is delivered to one or more cardiac chambers rather than to the atrium. In such cases, an AV delay may be established by transmitting a pulse to one or more of the atria. Natural activity of the ventricle may be sensed, and ventricular activation and / or contraction timing may be sensed. The pulse may be set to precede its natural expected timing based on the degree of atrial activity detected.

[0022] In some embodiments, the processor circuitry determines atrial activation in the at least one atrium. Approximately 0 milliseconds (ms) to approximately 50 ms before the start of ventricular filling, ventricular activation begins. The processor circuit may be configured to operate in a mode of operation to stimulate the ventricle such that the volume of the atrial filling is reduced from a pre-treatment ventricular filling volume and the patient's blood pressure is reduced from a pre-treatment blood pressure. In such an embodiment, atrial activation may be sensed to determine the onset of atrial activation. For example, the processor circuit may be configured to operate in a mode of operation to deliver one or more excitatory pulses to the ventricle about 0 ms to about 50 ms before the next atrial activation is expected to occur. The time interval between the onset of atrial activation and the moment the atrial activation is sensed may be known or estimated and may be used to calculate the timing of the onset of atrial activation. For example, it may be known or estimated that atrial activation is sensed 5 ms after the onset of atrial activation and the onset of atrial activation may be determined. If the ventricle is to be stimulated 20 ms before the next expected sense of atrial activation, then the ventricle will be stimulated 25 ms before the next expected sense of atrial activation.

[0023] In another embodiment, the processor circuitry is adapted to stimulate the atrium and stimulate the at least one ventricle. Approximately 0 to 50 ms after the onset of ventricular excitation, atrial excitation begins, thereby ventricular filling. The processor circuit may be configured to operate in a mode of operation in which the filling volume is reduced from a pre-treatment ventricular filling volume and the patient's blood pressure is reduced from a pre-treatment blood pressure. The device may be configured to operate in a mode of operation in which one or more excitatory pulses are delivered to the atrium about 0 ms to about 50 ms after the one or more excitatory pulses are delivered to the patient's ventricle. In such embodiments, pacing may be timed without relying on sensing atrial activation. Preferably, in such embodiments, pacing is timed to a period of time that is independent of atrial activation to ensure that one or more excitatory pulses are delivered to the atrium before natural activation occurs. is detected. Preferably, atrial activation is set to commence about 0 ms to about 50 ms after the onset of ventricular activation when the intrinsic atrial activation rate is less than the intrinsic ventricular activation rate.

[0024] In some embodiments, the timing of mechanical contractions relative to electrical excitation of the chambers for a patient can be determined by, for example, sensing changes in atrial and ventricular pressure, wall motion using ultrasound (e.g., echocardiography or echocardiography), implantation and / or imaging using known techniques in the art. Alternatively, it may be determined using external sensors, such as by sensing changes in impedance or the opening and closing of a heart valve, including, for example, a pressure sensor, an impedance, an ultrasound sensor, and / or one or more sound sensors and / or one or more blood flow sensors.

[0025] The timing of one or more excitatory pulses to produce a desired pattern of contractions The timing of mechanical contractions relative to electrical excitation of the chamber for the patient to be delivered to the heart at may be taken into account and the processor circuitry configured accordingly. This may be done in a closed loop mode using one or more implanted sensors and / or may be done from time to time (e.g., at the time of implantation and / or testing of the device), for example, using an interface with an external measurement device.

[0026] The mode of operation is to stimulate the ventricle to contract before the start of at least one atrium contraction. The method may include initiating

[0027] The operating mode is to stimulate the ventricles and cause the ventricles to contract before the end of at least one atrial contraction. and initiating contraction of the at least one atrium, thereby opening the AV valve during at least a portion of the contraction of the at least one atrium. may include causing the

[0028] The mode of operation may include stimulating the ventricle to cause it to begin contracting less than 100 ms after the start of contraction of at least one atrium.

[0029] Optionally, care is taken to ensure that atrial contraction begins before ventricular contraction reaches peak intracardiac pressure, even though atrial contraction is usually faster than ventricular contraction, which means that ventricular contraction begins before atrial contraction begins. Thus, one of the following settings may be selected:

[0030] a. The mode of operation may include stimulating the ventricle to begin contracting at some point during atrial contraction but before the atrium reaches its peak internal pressure due to atrial contraction.

[0031] b. The mode of operation may include stimulating the ventricle to begin contracting at some point during atrial contraction but after the atrium has reached its peak internal pressure due to atrial contraction.

[0032] c. The mode of operation includes stimulating the ventricle in a manner that causes contraction to commence in both the atrium and ventricle at essentially the same time (e.g., within 5 ms of each other). Good too.

[0033] d. The operating mode may include stimulating the ventricle to begin contracting at a time such that peak atrial contraction occurs when the ventricle is near or at full dilation, thereby causing increased atrial wall dilation as further detailed below with respect to the ventricular isovolumic and rapid ejection phases.

[0034] The operating mode is to stimulate the ventricle to contract a small amount of the ventricle prior to the onset of at least one atrium contraction. and at least partially contracting the AV valve during the initiation of contraction of at least one atrium. may include causing the

[0035] Preferably, the processor circuitry is adapted to detect when one or more excitatory pulses are delivered to a ventricle of the patient. The atrium may be configured to operate in a mode of operation in which one or more excitatory pulses are delivered to the atrium between about 0 ms and about 50 ms from the

[0036] In another aspect, an embodiment of a method for reducing blood pressure in a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume is provided, the method including delivering stimulation pulses from a stimulation circuit to at least one of an atrium and a ventricle and inhibiting atrial activation in at least one atrium. The ventricles are stimulated so that ventricular excitation begins approximately 0 ms to approximately 50 ms before the start of the heartbeat. and operating a processor circuit coupled to the stimulation circuit to operate in an operating mode that reduces ventricular filling volume from a pre-treatment ventricular filling volume and reduces the patient's blood pressure from a pre-treatment blood pressure.

[0037] In such embodiments, atrial activation may be sensed to determine the onset of atrial activation. For example, the method may include delivering one or more excitatory pulses to the ventricle about 0 ms to about 50 ms before next atrial activation is expected to occur. The time interval between the onset of atrial activation and the moment that atrial activation is sensed may be known and may be used to determine the timing of the onset of atrial activation. For example, atrial activation may be sensed 5 ms after the onset of atrial activation. If it is known or estimated that the ventricle will be stimulated 20 ms before the onset of atrial activation, then the ventricle will be stimulated 25 ms before the next expected sense of atrial activation. become.

[0038] In another embodiment, the method includes stimulating the atrium and stimulating the ventricular Atrial excitation is initiated between approximately 0 ms and approximately 50 ms after the onset of excitation, thereby correcting the ventricular filling volume. and operating a processor circuit coupled to the stimulation circuit to operate in an operating mode that reduces a pre-treatment ventricular filling volume and reduces a blood pressure of the patient from a pre-treatment blood pressure. For example, the method may include delivering one or more excitatory pulses to the atrium between about 0 ms and about 50 ms after the one or more excitatory pulses are delivered to the patient's ventricle. In such embodiments, pacing may be timed without relying on sensing atrial activation. Preferably, such embodiments provide one or more triggers before natural activation occurs. Atrial activation is sensed to ensure that the above excitatory pulse is delivered to the atrium. Preferably, atrial activation is configured to commence between about 0 ms and about 50 ms after onset of ventricular activation when the intrinsic atrial activation rate is lower than the intrinsic ventricular activation rate.

[0039] In some embodiments, the timing of the mechanical contractions relative to the electrical excitation of the chamber for the patient may be assessed using, for example, ultrasound (e.g., echocardiography or echocardiography) or other known means. The timing of the mechanical contractions relative to the electrical excitation of the chamber for the patient may be considered and the timing at which one or more excitatory pulses are delivered to the heart may be selected to generate a desired pattern of contractions.

[0040] The operating mode is to stimulate the ventricles to contract before at least one atrium begins to contract. This may include contracting.

[0041] The operating mode is to stimulate the ventricles to contract before at least one atrium begins to contract. contracting the at least one atrium, thereby closing the AV valve during at least a portion of the contraction of the at least one atrium. The present invention may include enabling the user to

[0042] The operating mode is to stimulate the ventricles to contract before at least one atrium has finished contracting. contracting such that the AV valve is closed during the onset of at least one atrial contraction. The method may include:

[0043] Preferably, the method includes delivering one or more excitatory pulses to the atrium between about 0 ms and about 50 ms after the one or more excitatory pulses are delivered to the patient's ventricle. .

[0044] In another aspect, an embodiment of a device is provided for reducing blood pressure in a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume. The device comprises: a stimulation circuit configured to deliver a stimulation pulse to the cardiac chamber. The device may include a processor circuit coupled to the stimulation circuit, the processor circuit being configured to generate approximately 40% atrial contraction and approximately 100% ventricular contraction when an atrioventricular valve associated with the atrium is closed. atrial contraction to induce contraction of at least one of the cardiac chambers, thereby reducing ventricular filling volume from a pre-treatment ventricular filling volume and reducing the patient's blood pressure from a pre-treatment blood pressure; The device may be configured to operate in a mode of operation that stimulates the atria to initiate contraction about 60 ms or less prior to AV valve closure. This may be accomplished, for example, by causing the atria to begin contracting about 60 ms or less prior to AV valve closure. Preferably, this timing may be set periodically (e.g., at the time of implantation) based on data from an external sensor and / or as a closed loop using one or more implanted sensors.

[0045] In another aspect, an embodiment of a device for reducing blood pressure in a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume is provided. The device includes a stimulation device for providing stimulation to at least one cardiac chamber. The device may include a stimulation circuit configured to deliver pulses. The device may include a processor circuit coupled to the stimulation circuit. The processor circuit may be configured to cause about 50% to about 95% of the atrial contraction during a ventricular systole, thereby reducing ventricular filling. and configured to operate in an operational mode that paces at least one heart chamber such that the volume of the cardiac chamber is reduced from a pre-treatment ventricular filling volume and the patient's blood pressure is reduced from a pre-treatment blood pressure. This may be, for example, to cause the atrium to contract about 50 ms to 5 ms before the start of ventricular contraction. This can be achieved by initiating a ventricular contraction. Preferably, the timing of the start of ventricular contraction may be set according to the timing of AV valve closure. Preferably, this timing may be set periodically (e.g., at the time of implantation) based on data from an external sensor and / or as a closed loop using one or more implanted sensors.

[0046] In another aspect, an embodiment provides a method performed with an implantable myocardial stimulator associated with a patient's heart to treat a blood pressure disorder in a patient having a pre-treatment blood pressure. The method may include stimulating the heart to contract an atrium while an associated heart valve remains closed, such that the contraction expands the ventricle, and the expansion of the ventricle reduces the patient's blood pressure below the pre-treatment blood pressure. This may be accomplished, for example, by contracting the atrium at a time when the internal pressure of the ventricle is at its highest, such that the active force of the atrial contraction increases the intraatrial pressure and atrial expansion beyond the highest passive internal pressure and expansion caused by the contraction of the associated ventricle. In such a case, the timing of the maximum contraction of the atrium should coincide with the end of an isovolumic period, or The timing must be during the rapid ejection phase of the ventricle. Optionally, this timing can be based on data from an external sensor and / or using one or more implanted sensors. The metric may be set periodically (eg, at implantation time) as a closed loop.

[0047] In another aspect, one embodiment provides a system for reducing blood pressure in a patient by controlling intra-atrial pressure and atrial expansion, the system including a stimulation circuit configured to deliver stimulation pulses to at least one heart chamber of the patient's heart, and a pulse generator configured to perform the delivery of stimulation pulses of one or more stimulation patterns to the at least one heart chamber. and at least one controller configured to: At least one of them is that the atrial pressure caused by the atrial contraction overlaps with the passive atrial pressure increase in time. By matching, the heart may be stimulated such that the intra-atrial pressure in the atrium caused by the stimulation is higher than the intra-atrial pressure in the atrium in the absence of stimulation, due to a combination of the intra-atrial pressure caused by atrial contraction and the passive pressure increase, and the patient's blood pressure is lowered.

[0048] The intra-atrial pressure in the atria resulting from the stimulation may cause increased atrial dilation in the atria lowering blood pressure through hormonal and / or neural pathways.

[0049] The atrial pressure caused by the atrial contraction may reach a peak atrial pressure caused by the atrial contraction. The passive pressure rise of the atrium may reach a peak passive pressure rise of the atrium. Alternatively, or in addition, the overlap in time of the atrial pressure caused by the atrial contraction of the atrium and the passive pressure rise of the atrium may include an overlap in time of both the peak atrial pressure and the peak passive pressure rise caused by the atrial contraction. In some embodiments, the overlap of the peak atrial pressure and the peak passive pressure rise may result in a composite atrial pressure (of the atrial pressure and the passive pressure rise caused by the atrial contraction) that is higher than the atrial pressure of the atrium in the absence of stimulation.

[0050] At least one of the stimulation pulses may include stimulating an atrium of the heart. At least one of the stimulation pulses may include stimulating a ventricle of the heart. At least one of the stimulation pulses may further be delivered to the atrium at a substantially equal rate, if desired. and pacing the ventricles, or at a rate faster than the rate at which the ventricles are paced. This may include pacing the atrium.

[0051] At least one of the stimulation pulses may include stimulating the atrium so that it contracts twice during a single cardiac cycle, for example, by stimulating the atrium twice during a single cardiac cycle or by stimulating the atrium once during a single cardiac cycle.

[0052] Optionally, at least one of the stimulation pulses may include stimulating the atrium so that the atrium contracts only once during a single cardiac cycle.

[0053] At least one of the stimulation pulses stimulates the heart to reduce or prevent atrial stimulation. The method may further include inciting the

[0054] The one or more stimulation patterns stimulate the heart to reduce or prevent atrial stimulation. At least one of the stimulation patterns may further include a plurality of heartbeats. wherein at least some of the stimulation pulses stimulate the heart such that intra-atrial pressure in the atrium caused by atrial contraction overlaps in time with a passive increase in internal pressure of the atrium such that the intra-atrial pressure in the atrium caused by the stimulation is higher than the intra-atrial pressure in the atrium in the absence of stimulation due to a combination of the intra-atrial pressure caused by the atrial contraction and the passive increase in internal pressure, and at least some of the stimulation pulses are configured to reduce or prevent atrial stimulation.

[0055] A stimulation pulse may be provided such that both atrial stimulations are reduced or prevented in a single beat, and the intra-atrial pressure produced by atrial contraction of the atrium overlaps in time with the passive pressure rise in the atrium, such that the intra-atrial pressure in the atrium produced by the stimulation is higher than the intra-atrial pressure in the atrium in the absence of stimulation, due to the combination of the intra-atrial pressure produced by atrial contraction and the passive pressure rise.

[0056] At least one stimulation pattern is configured to stimulate the intra-atrial pressure in the atrium by atrial contraction. The atria have a first atrial contraction that begins when the atrioventricular valves are open and ends after the atrioventricular valves are closed, and a second atrial contraction that occurs due to a combination of the atrial pressure generated by the atrial contraction and the passive increase in pressure in the atria, which is higher than the intraatrial pressure in the atria in the absence of stimulation. The intraatrial pressure was set to induce a second atrial contraction that overlapped in time with the passive atrial pressure rise. The first atrial contraction may be sensed and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may include at least one stimulation pulse sensed and paced. The contractions may be paced.

[0057] Alternatively, at least one of the stimulation patterns may be configured such that the intra-atrial pressure in the atrium caused by the stimulation is The atria have a first atrial contraction that begins when the atrioventricular valves are open and ends before the atrioventricular valves are closed, in a single beat, so that the intraatrial pressure in the atria is higher than it would be in the absence of stimulation due to a combination of the intraatrial pressure caused by the atrial contraction and the passive increase in intraatrial pressure. The resulting intraatrial pressure induces a second atrial contraction that overlaps in time with the passive increase in atrial pressure. The stimulation pulse may include at least one stimulation pulse configured to sense a first atrial contraction and pace the second atrial contraction. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0058] The one or more stimulation patterns have different ratios of (1) a first stimulation pulse that stimulates the heart such that an intra-atrial pressure in the atrium caused by atrial contraction overlaps in time with a passive increase in the atrium pressure, so that the intra-atrial pressure in the atrium caused by the stimulation is higher than the intra-atrial pressure in the atrium in the absence of stimulation due to a combination of the intra-atrial pressure caused by atrial contraction and the passive increase in the atrium pressure, and (2) a second stimulation pulse that stimulates the heart such that atrial stimulation is reduced or prevented. Optionally, one or more of the stimulation patterns may be used in combination. The number of stimulation patterns may include at least one stimulation pulse configured to stimulate the heart to reduce or prevent atrial stimulation and to stimulate the heart such that intra-atrial pressure in the atrium caused by atrial contraction overlaps in time with a passive internal pressure increase in the atrium, such that the intra-atrial pressure in the atrium caused by the stimulation is higher than the intra-atrial pressure in the atrium in the absence of stimulation due to the combination of the intra-atrial pressure caused by atrial contraction and the passive internal pressure increase (both in a single cardiac cycle).

[0059] The one or more stimulation patterns include alternating between a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that the intra-atrial pressure of the atrium caused by atrial contraction overlaps in time with a passive internal pressure rise of the atrium, so that the intra-atrial pressure of the atrium caused by the stimulation is higher than the intra-atrial pressure of the atrium in the absence of stimulation due to a combination of the intra-atrial pressure caused by atrial contraction and the passive internal pressure rise, and (2) a second stimulation pulse that does not provide an intra-atrial pressure caused by atrial contraction of the atrium that overlaps in time with the passive internal pressure rise of the atrium. Good too.

[0060] The at least one stimulation pulse includes pacing at least one of an atrium of the heart and a ventricle of the heart such that the relative timing of activation corresponds to an atrioventricular delay of about 2 ms. It's okay to do that.

[0061] At least one stimulation pulse is delivered to at least one of the atria of the heart and the ventricle of the heart such that the relative timing of excitation corresponds to an atrioventricular delay of about 30 ms to about 0 ms, or even 10 ms to 0 ms. The method may include pacing at least one of the

[0062] In another aspect, an embodiment provides a method for lowering a patient's blood pressure by controlling atrial pressure and atrial expansion. The method may be performed using an implantable myocardial stimulator associated with the patient's heart. The method may include stimulating the heart to provide an atrial pressure caused by atrial contraction that overlaps in time with a passive increase in pressure in the atrium, such that the combination of the atrial pressure caused by the atrial contraction and the passive increase in pressure induces a higher atrial pressure in the atrium than would be the atrial pressure in the absence of stimulation, and the patient's blood pressure is lowered.

[0063] The intra-atrial pressure in the atria resulting from the stimulation may cause increased atrial dilation in the atria, lowering blood pressure through hormonal or neuronal pathways.

[0064] The atrial pressure caused by the atrial contraction may reach a maximum atrial pressure caused by the atrial contraction. The passive pressure rise of the atrium may reach a maximum passive pressure rise of the atrium. Alternatively or additionally, the overlap in time of the atrial pressure caused by the atrial contraction of the atrium and the passive pressure rise of the atrium may include overlap in time of both the maximum atrial pressure and the maximum passive pressure rise caused by the atrial contraction. In some embodiments, the overlap of the maximum atrial pressure and the maximum passive pressure rise may result in a composite atrial pressure (of the atrial pressure and the passive pressure rise caused by the atrial contraction) that is higher than the atrial pressure of the atrium in the absence of stimulation. Thus, the method may include stimulating the heart such that the maximum value of the atrial pressure caused by the atrial contraction of the atrium overlaps in time with the maximum passive pressure rise of the atrium.

[0065] The method may include stimulating an atrium of the heart. The method may additionally or alternatively include stimulating a ventricle of the heart. The method may further include pacing the atrium and ventricle at substantially equal rates, or pacing the atrium at a rate faster than the rate at which the ventricle is paced or contracts.

[0066] The method may, for example, stimulate the atrium twice during a single cardiac cycle, or stimulate the atrium twice during a single cardiac cycle. The method may further include stimulating the atrium once at the same time, thereby causing the atrium to contract twice during a single cardiac cycle.

[0067] Optionally, the method further comprises stimulating the atrium so that the atrium contracts only once during a single cardiac cycle. The present invention may include the steps of:

[0068] The method may further include stimulating the heart to reduce or prevent atrial stimulation. Stimulating the heart may include delivering a stimulation pattern to the heart over multiple beats, at least some of the stimulation pulses of the stimulation pattern being configured to stimulate the heart such that an atrial pressure caused by atrial contraction of the atrium overlaps in time with a passive pressure rise in the atrium such that the atrial pressure in the atrium caused by the stimulation is higher than the atrial pressure in the atrium in the absence of stimulation due to a combination of the atrial pressure and the passive pressure rise caused by the atrial contraction, and at least some of the stimulation pulses are configured to reduce or prevent atrial stimulation. The stimulation pulses may be provided such that both atrial stimulations are reduced or prevented in a single beat, and the atrial pressure caused by atrial contraction of the atrium overlaps in time with a passive pressure rise in the atrium such that the atrial pressure in the atrium caused by the stimulation is higher than the atrial pressure in the atrium in the absence of stimulation due to a combination of the atrial pressure and the passive pressure rise caused by the atrial contraction.

[0069] Stimulating the heart includes, in a single beat, a first atrial contraction that begins when the atrioventricular valves are open and ends after the atrioventricular valves are closed, such that the intraatrial pressure in the atrium caused by the stimulation is higher than the intraatrial pressure in the atrium in the absence of stimulation, due to a combination of the intraatrial pressure caused by the atrial contraction and passive pressure increase, and A passive atrial pressure increase was set up to induce a second atrial contraction that overlapped in time. The first atrial contraction may be sensed and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced. Atrial contractions may be paced.

[0070] Alternatively, stimulating the heart may include, in a single beat, having a first atrial contraction that begins when the atrioventricular valves are open and ends before the atrioventricular valves are closed, and having a first atrial contraction that is caused by an atrial contraction of the atrium, such that the atrial pressure in the atrium caused by the stimulation is higher than the atrial pressure in the atrium in the absence of stimulation, due to a combination of the atrial pressure caused by the atrial contraction and a passive increase in atrial pressure. The intraatrial pressure was set to induce a second atrial contraction that overlapped in time with the passive atrial pressure rise. The method may include delivering at least one stimulation pulse sensed by a first atrial contraction. The first atrial contraction may be sensed and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0071] This method comprises the steps of: (1) determining whether the intraatrial pressure caused by the atrial contraction is proportional to the time of the passive intraatrial pressure rise; a first stimulation pulse for stimulating the heart such that the atrial pressure in the atrium caused by the stimulation is higher than the atrial pressure in the atrium in the absence of stimulation due to a combination of the atrial pressure caused by atrial contraction and a passive atrial pressure increase, and (2) a second stimulation pulse for stimulating the heart such that atrial stimulation is reduced or prevented. Optionally, one or more stimulation patterns may be used. The stimulation circuit may include at least one stimulation pulse configured to stimulate the heart to reduce or prevent atrial stimulation and to stimulate the heart such that intra-atrial pressure in the atrium caused by atrial contraction overlaps in time with a passive pressure increase in the atrium such that the intra-atrial pressure in the atrium caused by the stimulation is higher than the intra-atrial pressure in the atrium in the absence of stimulation due to the combination of the intra-atrial pressure caused by atrial contraction and the passive pressure increase (both in a single cardiac cycle).

[0072] This method comprises the steps of: (1) determining whether the intraatrial pressure caused by the atrial contraction is proportional to the time of the passive intraatrial pressure rise; and (2) a second stimulation pulse that does not provide an intraatrial pressure generated by atrial contraction of the atrium that overlaps in time with the passive pressure rise of the atrium, so that the intraatrial pressure of the atrium generated by the stimulation is higher than the intraatrial pressure of the atrium in the absence of stimulation due to a combination of the intraatrial pressure generated by atrial contraction and the passive pressure rise of the atrium. The method may further include alternating between a plurality of stimulation patterns having different ratios.

[0073] The method comprises synchronizing the atria of the heart such that the relative timing of excitation corresponds to an atrioventricular delay of approximately 2 ms. and pacing at least one of the ventricles of the heart. stomach.

[0074] The method involves regulating the cardiac output so that the relative timing of excitation corresponds to an atrioventricular delay of about 30 ms to about 0 ms. and pacing at least one of the atrium of the heart and the ventricle of the heart. It's fine.

[0075] In another aspect, an embodiment provides a method for lowering blood pressure in a patient. The method may be performed using an implantable myocardial stimulator associated with the patient's heart. The method may include delivering stimulation pulses of one or more stimulation patterns to at least one cardiac chamber of the patient's heart. At least one of the stimulation pulses may have a first stimulation setting and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting. Of the first stimulation setting and the second stimulation setting, At least one of the may be configured to reduce or prevent tufted stimulation. Stimulation pulses having stimulation settings configured to reduce or prevent may be delivered as needed.

[0076] The delivery of the stimulation pulses on demand may include one or more of the following:

[0077] a. Configured to limit treatment to when needed, e.g., to reduce or prevent tuft irritation Limit delivery of selected stimulation settings to times when the patient's blood pressure is known or predicted to be abnormally high. This is achieved by monitoring real-time feedback of one or more blood pressure related parameters. This may involve using baseline measurements or basing the desired predictive pattern on past measurements of the same patient. For example, in some patients, BP may be elevated 24 hours a day. whereas some patients may have elevated BP for only part of a 24-hour period (eg, daytime or nighttime).

[0078] b. Do not treat when high BP is needed, e.g., if the elevated BP is due to a healthy and thus avoid delivery of stimulation settings configured to reduce or prevent tuft stimulation when such a condition may be desirable. For example, BP is known to increase during activity and fall again when activity decreases (e.g., during exercise or physical work, which is naturally associated with elevated BP).

[0079] Stimulation pulses having stimulation settings configured to reduce or prevent facilitatory stimulation may be provided for only a portion of a 24 hour period, which may be during or a portion of the night, or may be during or a portion of the day.

[0080] Stimulation pulses having stimulation settings configured to reduce or prevent atrial stimulation may be provided only when the heart rate is below a predetermined threshold, the predetermined threshold being an absolute value such as 90 bpm. The predetermined threshold may be set to a value related to the patient's average heart rate. For example, the predetermined threshold may be at least one of a heart rate 30 times above the average heart rate and a heart rate above the 80th percentile.

[0081] Stimulation pulses having stimulation settings configured to reduce or prevent atrial stimulation may be provided only when the patient is at rest or has an activity level below a predetermined threshold. The method includes detecting the patient's activity by sensing at least one of movement, posture, respiratory rate, and heart rate. The method may further include determining whether the person is at rest or has an activity level below a predetermined threshold.

[0082] If desired, a patient may be considered to be "at rest" or "at a low activity level" when the patient's activity is low. For example, a patient may be considered to be "at rest" or "at a low activity level" as long as the heart rate does not exceed a predetermined threshold or only low activity is detected (e.g., characterized by moderate and / or slow movement and / or slow postural changes and / or no significant increase in breathing, etc.). For example, sedentary activities such as reading or talking, or movements around the house or in the office, may be considered to be at a sufficiently low activity level to allow delivery of stimulation pulses having stimulation settings configured to reduce or prevent acicular stimulation.

[0083] One or more stimulation patterns are selected based on measured blood pressure parameters. The method may further comprise altering one or more stimulation patterns when a baroreflex is detected. It may further include.

[0084] In another aspect, one embodiment provides a system for reducing blood pressure in a patient, the system comprising: a stimulation circuit configured to deliver stimulation pulses of one or more stimulation patterns to at least one heart chamber of a patient's heart; and at least one controller configured to effectuate the delivery of the stimulation pulses of the one or more stimulation patterns to the at least one heart chamber. At least one of the stimulation pulses may have a first stimulation setting, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting may include a tufted stimulation setting. Stimulation pulses having stimulation settings configured to reduce or prevent facilitatory stimulation may be delivered as needed.

[0085] At least one controller reduces or prevents tufted stimulation for only a portion of a 24-hour period. The portion of a 24 hour period may be nighttime or a portion thereof, or may be daytime or a portion thereof.

[0086] At least one controller reduces atrial stimulation only when the heart rate is below a predetermined threshold. The predetermined threshold may be configured to deliver stimulation pulses having a stimulation setting configured to reduce or prevent the patient's average heart rate. The predetermined threshold may be an absolute value, such as 90 bpm. For example, the predetermined threshold may be at least one of a heart rate 30 beats above the average heart rate and a heart rate above the 80th percentile.

[0087] At least one controller may be configured to detect when the patient is at rest or at a low activity level. The system may be configured to deliver stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation only when the patient is at rest or in a low resting state by sensing at least one of movement, posture, respiratory rate, and heart rate. The device may be configured to determine whether the activity level is a level that is too high.

[0088] The at least one controller may be configured to select one or more stimulation patterns based on the measured blood pressure parameter. The device may be configured to change one or more stimulation patterns when a baroreflex is detected. good.

[0089] In another aspect, an embodiment may provide a method of adjusting a pulse setting of a system for controlling blood pressure, the method comprising: measuring an atrium and a ventricle of a patient's heart during at least one cardiac cycle; The method may include receiving associated intra-atrial pressure data. The intra-atrial pressure data may result from the system delivering a stimulation pulse having a first pulse setting to the heart. The method includes analyzing intraatrial pressure data and determining a first pulse setting that is adjusted according to the analysis. and providing a second pulse setting different from the first pulse setting. The analyzing step may include analyzing the intra-atrial pressure data to estimate an overlap in time between the intra-atrial pressure caused by the atrial contraction and a passive atrium pressure rise. The analyzing step may further include analyzing the intra-atrial pressure data to estimate an overlap in time between the peak atrial pressure caused by the atrial contraction and a peak passive atrium pressure rise. The analyzing step may include analyzing the intra-atrial pressure data to estimate an overlap in time between the first intra-atrial pressure (or peak atrial pressure) obtained in a cardiac cycle in which the stimulation pulse is delivered. The method may include comparing the intraatrial pressure in the atrium to a second intraatrial pressure in the atrium in the absence of stimulation. The analyzing may further include plotting the intra-atrial pressure data and / or mathematically analyzing the intra-atrial pressure data.

[0090] In another aspect, an embodiment may provide a system for lowering blood pressure, the system comprising: a first atrium that is adapted to receive information about an internal pressure variation in the atrium during at least one cardiac cycle of the heart; means for providing a stimulation pulse to at least one cardiac chamber; means for generating a stimulation pulse; and The means for generating stimulation pulses may be configured to generate stimulation pulses to control the timing of atrial contractions relative to the timing of ventricular contractions during a single cardiac cycle in accordance with information about pressure variations within the atrium.

[0091] The information about the internal pressure variations in the atrium may include information about the occurrence of an atrial contraction and / or information about the occurrence of a ventricular contraction. The means for generating stimulation pulses is configured to generate, for at least one cardiac cycle, at least one atrial stimulation pulse causing an atrial contraction and / or at least one ventricular stimulation pulse causing a ventricular contraction. The means for generating stimulation pulses may be configured to generate at least one atrial stimulation pulse based on information about the occurrence of an atrial contraction and / or information about the occurrence of a ventricular contraction in a timed relationship to the occurrence of an atrial contraction and / or the occurrence of a ventricular contraction. and / or generating at least one ventricular stimulation pulse based on information about the occurrence of a ventricular contraction and / or information about the occurrence of an atrial contraction in a timed relationship to the occurrence of a ventricular contraction and / or the occurrence of an atrial contraction. The information about the occurrence of atrial contractions may include information about the occurrence of P-wave patterns in the natural stimulation pattern of the cardiac cycle. All of this information includes information about the occurrence of the QRS complex in the natural stimulation pattern of the cardiac cycle. It's fine.

[0092] In another aspect, an embodiment may provide a system for lowering blood pressure, the system providing information about the timing of one or more cardiac activity events. means for generating a stimulation pulse, and means for applying the stimulation pulse to at least one cardiac chamber. The device may include means for applying a signal to the cardiac activity sensor. The information about the stimulation pulse may include at least one of an occurrence of an atrial contraction of the atrium, an occurrence of a ventricular contraction of the ventricle, an opening of an atrioventricular valve, a closing of an atrioventricular valve, electrical activity of the atrium, electrical activity of the ventricle, blood flow, an intraatrial pressure of the atrium, a change in intraatrial pressure of the atrium, and a heart rate. The stage may be configured to generate stimulation pulses to time atrial contractions relative to ventricular contractions based on the information.

[0093] The timing of atrial contraction relative to ventricular contraction corresponds to an AV delay ranging from approximately 30 ms to approximately 0 ms. The means for generating a stimulation pulse may be a pulse generated in a range of about 30 ms to about 0 ms before ventricular excitation occurs. The excitation stimulus is provided to the atrium within a certain time, and the excitation occurs within a range of about 30 ms to about 0 ms after the atrial excitation occurs. The stimulation pulse is configured to provide an excitatory stimulus to the ventricle and / or to provide an excitatory stimulus to the atrium and then provide an excitatory stimulus to the ventricle within a range of about 30 ms to about 0 ms. may be made.

[0094] Information about the timing of one or more cardiac activity events is collected during a single cardiac cycle. It contains information about the timing between two or more cardiac activity events. Good too.

[0095] The means for generating a stimulation pulse causes an atrial contraction for at least one cardiac cycle. The means for generating stimulation pulses may be configured to generate at least one atrial stimulation pulse and / or at least one ventricular stimulation pulse causing a ventricular contraction. The means for generating stimulation pulses may generate the at least one atrial stimulation pulse based on information about the occurrence of an atrial contraction and / or information about the occurrence of a ventricular contraction in a timed relationship to the occurrence of an atrial contraction and / or the occurrence of a ventricular contraction, and / or generate the at least one atrial stimulation pulse based on information about the occurrence of atrial contraction and / or information about the occurrence of a ventricular contraction in a timed relationship to the occurrence of atrial contraction and / or the occurrence of a ventricular contraction. The at least one ventricular stimulation pulse may be configured to be generated based on the information about the occurrence of a ventricular contraction and / or the information about the occurrence of an atrial contraction in a timed relationship to the occurrence of an atrial contraction. The information contained information about the occurrence of P-wave patterns in the natural stimulation pattern of the cardiac cycle. The information about the occurrence of ventricular contractions may include information about the occurrence of QRS complexes in the natural stimulation pattern of the cardiac cycle.

[0096] In another aspect, an embodiment provides another method for lowering a patient's blood pressure by controlling intra-atrial pressure and atrial expansion. The method may be performed using an implantable myocardial stimulation device associated with the patient's heart. The method includes one or more stimulation patterns. delivering a stimulation pulse of the first channel to at least one cardiac chamber, At least one of the stimulation pulses has a first stimulation setting and at least one of the stimulation pulses is and a second stimulation setting different from the first stimulation setting, and at least one of the first stimulation setting and the second stimulation setting is configured to suppress atrial pressure caused by atrial contraction of the atrium by a passive increase in intra-atrium pressure. and transmitting a stimulation to cause the atrium to contract such that the atrium and the atrium contract such that the stimulation overlap in time, and the overlap of the intra-atrial pressure caused by the atrial contraction and the passive pressure increase provides an intra-atrial pressure in the atrium that is higher than the intra-atrial pressure in the atrium in the absence of stimulation, thereby causing increased atrial expansion of the atrium that lowers blood pressure through a hormonal or neuronal pathway.

[0097] Optionally, at least one of the first stimulation setting and the second stimulation setting is atrial contraction. The method may be configured to have an atrial contraction such that a peak atrial pressure caused by the stimulation overlaps in time with a peak passive pressure increase in the atrium, and the method may include causing increased atrial expansion of the atrium, which provides an intra-atrial pressure in the atrium that is higher than an intra-atrial pressure in the atrium in the absence of stimulation, by the overlapping of the peak atrial pressure and the peak passive pressure increase caused by the atrial contraction, thereby lowering blood pressure through a hormonal or neuronal pathway.

[0098] In another aspect, one embodiment provides a system for lowering a patient's blood pressure by controlling intra-atrial pressure and atrial expansion. The system includes one or more stimulation patterns. a stimulation circuit configured to deliver a stimulation pulse of the first channel to at least one cardiac chamber. and at least one controller configured to execute delivery of stimulation pulses of one or more stimulation patterns to the at least one heart chamber. At least one of the stimulation pulses may have a first stimulation setting and at least one of the stimulation pulses may have a second stimulation setting that is different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting may be configured to contract the atria of the heart such that an intra-atrial pressure caused by atrial contraction of the atrium overlaps in time with a passive increase in intra-atrial pressure of the atrium such that a combination of the intra-atrial pressure caused by the atrial contraction and the passive increase in intra-atrial pressure of the atrium provides an intra-atrial pressure in the atrium that is higher than the intra-atrial pressure in the atrium in the absence of stimulation, thereby causing increased atrial expansion of the atrium that lowers blood pressure through hormonal or neuronal pathways. One may be configured to cause the atria of the heart to contract such that a peak atrial pressure produced by atrial contraction overlaps in time with a peak passive atrial pressure increase in the atria, thereby providing a higher atrial pressure in the atria than the atrial pressure in the atria in the absence of stimulation, causing increased atrial expansion of the atria which lowers blood pressure through hormonal or neuronal pathways.

[0099] In another aspect, an embodiment provides a method for treating a patient's blood pressure disorder by controlling atrial pressure and atrial expansion. The method may be performed using an implantable myocardial stimulator associated with the patient's heart having a pre-treatment blood pressure. The method may include stimulating the heart to contract an atrium while a heart valve associated with the atrium is closed such that contraction expands the atrium, and expanding the atrium preferably contracts when ventricular pressure is highest such that the active force of atrial contraction increases atrial pressure and expansion beyond the maximum passive pressure and expansion caused by ventricular contraction, thereby resulting in a reduction in the patient's blood pressure from the pre-treatment blood pressure.

[0100] In another aspect, an embodiment of a system for reducing blood pressure is provided. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart with a stimulation pattern comprising at least one stimulation pulse. The system may include at least one controller configured to receive input related to a patient's blood pressure and adjust the stimulation pattern based on the blood pressure. For example, the input may be Receive data sensed by one or more sensors (embedded or external) , and / or may include receiving user-supplied data. For example, during implantation and / or periodic checks, the user may request information regarding the measured blood pressure. Data may be provided.

[0101] Preferably, the system receives from the measurement sensor and / or the user interface: It includes an input port for receiving this input via wired and / or wireless communication. The input may comprise data related to blood pressure (BP), or changes in BP, which may be measured as systolic BP (SysBP), diastolic BP, mean arterial BP, and / or other relevant BP parameters. For example, at least one sensor may sense pressure or changes in pressure in one or more cardiac chambers and adjust the stimulation pattern based on the pressure or changes in pressure. In another embodiment, the sensor may sense pressure in more than one chamber and adjust stimulation based on the relationship of the pressure waveforms of the two chambers.

[0102] The controller controls a parameter of at least one first stimulation setting of the at least one stimulation pulse. The stimulation pattern may be adjusted by performing an adjustment process that includes adjusting

[0103] The first stimulation setting may be configured to reduce or prevent atrial kick in at least one ventricle.

[0104] The parameters may include adjustment of an AV delay. For example, a natural AV delay is a delay between the onset of atrial activation and the onset of cardiac activation, whether this occurs naturally (i.e., without delivery of a stimulus to the heart) or by timing the delivery of a stimulus to one or more of the atria and ventricles. The onset of ventricular excitation may be in the range of 120-200 ms. If desired, the AV delay can be adjusted. This means changing the normal AV delay (e.g., 120 ms) to a shorter AV delay (e.g., cardiac The time from the onset of atrial activation to the onset of ventricular activation is 0 to 70 ms, or ventricular activation occurs before atrial activation. In one embodiment, the AV delay is adjusted to -50ms. Stimulation settings having an AV delay between -40 ms and 70 ms, preferably between -40 ms and 60 ms, more preferably between -50 ms and 0 ms, or between 0 and 70 ms, preferably between >0 and 70 ms, are selected to reduce or prevent atrial stimulation. It is selected.

[0105] The stimulation pattern configured to reduce atrial stimulation is about 3 minutes after application of electricity to the heart. 2. Cause a drop in blood pressure by at least a predetermined amount within 1 second and for a duration of at least 1 minute The stimulation pattern may be configured to maintain the reduction in blood pressure for the interval. For example, the stimulation pattern may be selected and adjusted based on feedback related to one or more sensed BP parameters. and / or may be adjusted.

[0106] The time interval may be at least 5 minutes.

[0107] The predetermined amount of blood pressure reduction may be 8 mmHg or less.

[0108] The predetermined amount of blood pressure reduction may be at least 4% of the patient's pre-treatment blood pressure.

[0109] The patient's blood pressure may not exceed the predetermined average value by more than a predetermined amount during the time interval. The predetermined amount may be a difference of about 8 mmHg or less. In some embodiments, The patient's blood pressure may exceed the predetermined average value for some beats, but the patient's mean blood pressure may not exceed the predetermined average value.

[0110] The controller may be configured to apply a plurality of stimulation patterns and, during stimulation, receive corresponding input data for each stimulation pattern related to the patient's blood pressure. The controller may further comprise a controller configured to receive, for each of the plurality of stimulation patterns, at least one blood pressure variability pattern related to the input data. The controller may be configured to calculate a blood pressure variability parameter. The controller may be configured to adjust the stimulation pattern in response to the blood pressure variability parameter.

[0111] The controller may be configured to adjust the stimulation pattern to one having the best blood pressure variability parameters.

[0112] The best blood pressure variability parameter may be one that indicates the lowest degree of baroreflex or the lowest degree or degree of adaptation as detailed herein.

[0113] The best blood pressure variability parameter may be one that indicates the degree of baroreflex or adaptation within a predetermined range as detailed herein.

[0114] At least two of the plurality of stimulation patterns each include at least one stimulation pulse having a stimulation setting configured to reduce or prevent atrial stimulation in at least one ventricle and / or control intra-atrial pressure and / or expansion. The at least two stimulation patterns may differ from each other in the number of times or the length of time that the at least one stimulation pulse is delivered in succession.

[0115] The multiple stimulation patterns may differ by the number or length of time that the system is configured to successively elicit a predetermined AV delay.

[0116] At least two of the plurality of stimulation patterns may differ from the others by one or more stimulation settings included within each of the at least two stimulation patterns.

[0117] The plurality of stimulation patterns includes a first stimulation setting and a second stimulation setting that is administered after the first stimulation setting. The second stimulation setting may include at least one stimulation setting based on an algorithm that uses blood pressure variability parameters associated with input data of the first stimulation setting. The setting may be:

[0118] The system may include a blood pressure sensor for providing input data related to the patient's blood pressure.

[0119] The blood pressure sensor may be implantable.

[0120] The blood pressure sensor and controller may be configured to operate at least partially as a closed loop.

[0121] In another aspect, an embodiment of a system for reducing blood pressure is provided. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart with a stimulation pulse. The system may include a controller. The controller may be configured to provide a first stimulation pattern comprising at least one stimulation setting configured to reduce or prevent atrial kick in at least one ventricle during a first time interval and to receive first input data related to the patient's blood pressure during the first time interval. The controller may be configured to calculate at least one blood pressure variability parameter related to the first input data. The controller may be configured to provide a first stimulation pattern comprising at least one stimulation setting configured to reduce or prevent atrial kick in at least one ventricle during the first time interval. at least one of the second stimulation patterns having a second stimulation setting configured to prevent The controller may be configured to adjust the parameter. The second stimulation setting may be based on the at least one blood pressure variability parameter. The controller may be configured to deliver the second stimulation pattern for a second time interval.

[0122] In another aspect, an embodiment of a system for reducing blood pressure is provided. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart with a stimulation pulse. The system may include atrial kick stimulation in at least one ventricle. A stimulation pattern comprising at least one stimulation setting configured to reduce or prevent The stimulation pattern may include at least one controller configured to administer the stimulation pattern to the subject. and selected to cause an immediate reduction in blood pressure from the initial pressure value to a reduced pressure value and to maintain the patient's mean resting blood pressure at least 8 mmHg below the initial pressure. Good too.

[0123] The reduced blood pressure value may be maintained for a time interval of at least 1 minute.

[0124] In another aspect, an embodiment of a kit for reducing blood pressure is provided, the kit including at least one device for setting a stimulation pattern for reducing blood pressure. The device may include at least one stimulation electrode. The device may include an adjustable The device may include a controller for setting a stimulation pattern and a set of instructions for adjusting the stimulation pattern based on input related to the patient's blood pressure.

[0125] In another aspect, one embodiment provides a system for lowering blood pressure. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart. The system may include a stimulation electrode for reducing or preventing atrial stimulation in at least one ventricle. at least one controller configured to execute a stimulation pattern including at least one stimulation pulse having at least one stimulation setting configured to At least one stimulation setting should be selected such that maximum atrial expansion is equal to the unstimulated atrial expansion. The atrial expansion may be configured to be approximately equal to or less than the maximum atrial expansion of the same heart.

[0126] In any of the embodiments described herein, atrial expansion may be measured, calculated, and / or estimated as known in the art. Atrial contraction is known to affect intra-atrial pressure and atrial expansion. Atrial pressure and expansion depend on atrial volume, which depends on the amount of blood inside the atria and the active forces generated by muscular contraction. In a healthy heart, intra-atrial pressure increases when the atria contract. It decreases when atrial contraction stops, blood flows out of the atria, and the ventricles fill. When the ventricles then contract, the AV valves close and the atria begin to fill again, since there are no valves to prevent blood from flowing from the venous system into the atria. The internal pressure generated within the ventricles can be further determined by various mechanisms, one of which is The increased intraatrial pressure caused by the closed AV valves also increases atrial volume and associated atrial dilation, which is related to the bulging of the AV valves into the atrium. Contraction of the atria when the AV valves are closed increases intraatrial pressure and increases atrial dilation, because the closed valves prevent a reduction in volume. The increased atrial dilation stimulates baroreceptors (also known as stretch receptors) present in the atrial walls. These baroreceptors are involved in the hormonal and / or neuronal reduction of blood pressure.

[0127] Thus, in some embodiments, the measurement of atrial expansion may include measuring intra-atrial pressure. In some embodiments, the measurement of atrial expansion may include measuring or estimating the dimensions (e.g., diameter, size, or circumference) of the atrium. In some cases, if a single atrial contraction occurs per cardiac cycle, the amount of blood in the atrium is predicted to be greater than if the atrium contracts twice during a single cardiac cycle. Thus, the atrial expansion may include measuring the intra-atrial pressure. In some embodiments, the measurement of atrial expansion may include measuring or estimating the dimensions (e.g., diameter, size, or circumference) of the atrium. In some cases, if a single atrial contraction occurs per cardiac cycle, the amount of blood in the atrium is predicted to be greater than if the atrium contracts twice during a single cardiac cycle. If the contraction occurs once per cardiac cycle and the atrial contraction is completely opposed to the closed valve, Intraatrial pressure and / or atrial dilation is greater than if the atria contracted twice per cardiac cycle. However, if the atrium only contracts against a closed valve, there is no atrial stimulation, and in some embodiments a balance may be achieved (per cardiac cycle and / or per pacing pattern) between the values ​​set for intra-atrial pressure (and atrial expansion) and atrial stimulation.

[0128] At least one stimulation setting is designed to maximize the atrium contraction when the AV valves are open. The present invention may be configured as follows.

[0129] The at least one stimulation setting is configured to alter the mechanics of at least one atrial contraction such that the mechanics of the at least one atrial contraction differs from the mechanics of a preceding natural atrial contraction. The mechanics of atrial contraction may be assessed using known techniques including, for example, ultrasound (e.g., echocardiography or echocardiography).

[0130] The at least one stimulation setting may be configured to reduce the force of at least one atrial contraction, e.g., to reduce atrial spasm or atrial flutter. The force of atrial contraction may be reduced by temporarily generating atrial flutter. One example is delivering a burst of rapid stimulation pulses to the atrium for a short period of time. The force of atrial contraction may be measured using known means by sensing atrial pressure and / or its derivatives, such as wall motion or wall flow. Such sensing may be used as closed loop feedback and / or from time to time (e.g., at the time of implantation and / or testing).

[0131] At least one stimulation setting may be configured to prevent at least one atrial contraction, for example, by temporarily generating an atrial spasm or atrial flutter, one example being delivery of a burst of rapid stimulation pulses to the atrium for a short period of time.

[0132] In another aspect, an embodiment of a system for reducing blood pressure is provided. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart. The at least one controller may be configured to deliver a stimulation pattern of stimulation pulses to the patient's heart. The at least one controller may be configured to administer a ventilator to the patient based on a state of the AV valve. The device may be configured to receive relevant inputs, such as from implanted or external acoustic or blood flow sensors, via wired or wireless communication, and / or from a user. The at least one controller may be provided via the valve-like The device may be configured to adjust at least one stimulation pattern based on the state.

[0133] Inputs related to the state of the patient's AV valve may indicate the timing of AV valve closure.

[0134] Input related to the status of the patient's AV valves may be provided based on a heart sound sensor.

[0135] Input related to the state of the patient's AV valve may be provided based on a blood flow sensor.

[0136] The blood flow sensor may include an implanted sensor.

[0137] The blood flow sensor may include an ultrasonic sensor for sensing blood flow through the AV valve.

[0138] The blood flow sensor and controller may be configured to operate at least partially as a closed loop.

[0139] The stimulation pattern is configured to reduce or prevent atrial kick in at least one ventricle. The stimulation device may include at least one stimulation pulse.

[0140] The step of adjusting the at least one stimulation pattern may include adjusting an AV delay of the at least one stimulation pulse.

[0141] In another aspect, an embodiment of a system for reducing ventricular filling volume in a patient having a pre-treatment ventricular filling volume is provided. The system includes: The system may include at least one controller configured to administer delivery of one or more stimulation patterns of stimulation pulses to at least one cardiac chamber. At least one of the stimulation pulses may be a first stimulation pulse. and at least one of the stimulation pulses has a second stimulation setting different from the first stimulation setting. At least one of the first and second stimulation settings may be configured to reduce or prevent atrial kicks, thereby reducing ventricular filling volume from a pre-treatment ventricular filling volume.

[0142] The first stimulation setting and the second stimulation setting may be configured to reduce or prevent atrial kick.

[0143] The first stimulation setting may have an AV delay that is different from the AV delay of the second stimulation setting.

[0144] At least one of the one or more stimulation patterns may be repeated at least twice during a one hour period.

[0145] The at least one controller may be configured to apply the one or more stimulation patterns continuously for a time interval lasting 10 minutes or more. The first stimulation setting may be configured to apply the one or more stimulation patterns continuously for at least 50% of the time interval. configured to reduce or prevent atrial kicks in at least one ventricle during good.

[0146] The second stimulation setting may have a longer AV delay than the first stimulation setting.

[0147] The second stimulation setting has a longer AV delay than the first stimulation setting.

[0148] The one or more consecutive stimulation patterns may comprise at least one stimulation pulse having the first stimulation setting for at least about 85% of the time interval.

[0149] The time interval may be at least 30 minutes long. The time interval may be at least 1 hour long. It may be the length.

[0150] The time interval may be at least 24 hours long.

[0151] The one or more sequential stimulation patterns have a third stimulation setting different from the first stimulation setting and the second stimulation setting and are configured to reduce or prevent atrial kick in at least one ventricle. The stimulation pulse may include at least one stimulation pulse generated.

[0152] The one or more consecutive stimulation patterns have a third stimulation setting different from the first stimulation setting and the second stimulation setting, and the one or more consecutive stimulation patterns have an atrial kick in at least one ventricle for less than about 50% of the time interval. At least one stimulation pulse may be configured to reduce or prevent stomach.

[0153] The one or more successive stimulation patterns may comprise a third stimulation configured to reduce or not prevent atrial kick in at least one ventricle for about 20% or less of the time interval.

[0154] The one or more sequential stimulation patterns may comprise a sequence of 10 to 60 stimulation pulses having a first stimulation setting, the first stimulation setting comprising a sequence of 10 to 60 stimulation pulses for reducing or inhibiting an atrial kick in at least one ventricle and a sequence of 1 to 10 beats embedded within the 10 to 60 stimulation pulses. The sequence of 1 to 10 beats may have a longer AV delay than the first stimulation setting.

[0155] The sequence of 1 to 10 beats may include at least one stimulation pulse having a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle.

[0156] A sequence of 1 to 10 beats includes at least one stimulation pulse with the second stimulation setting. It may include.

[0157] The sequence of 1 to 10 beats may include a natural AV delay.

[0158] At least one beat of the sequence of 1 to 10 beats may occur without stimulation.

[0159] The first stimulation setting is set so that the increase in blood pressure occurring during the stimulation pulse is limited to a predetermined value. , the first stimulation setting may be configured to reduce an atrial kick in at least one ventricle, and the second stimulation setting may be configured to reduce a baroreflex response or adaptation to the reduced atrial kick.

[0160] The second stimulation setting is configured to allow the blood pressure to increase for approximately one to five beats. It may be possible.

[0161] The stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting.

[0162] The stimulation pattern may include a plurality of stimulation pulses having a second stimulation setting.

[0163] The stimulation pattern may have a second stimulation setting at between about 1% of the plurality of stimulation pulses and about 40% of the plurality of stimulation pulses.

[0164] The stimulation pattern corresponds to the ratio of time constants of the response to increases and decreases in blood pressure. The ratio of stimulation pulses having the first stimulation setting to stimulation pulses having the second stimulation setting. It's okay to be.

[0165] The first stimulation configuration may include a first AV delay and the second stimulation configuration may include a second AV delay. The first AV delay may be shorter than the second AV delay.

[0166] The stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting.

[0167] The stimulation pattern may include a plurality of stimulation pulses having a second stimulation setting.

[0168] The stimulation pattern may have a second stimulation setting at between about 1% of the plurality of stimulation pulses and about 40% of the plurality of stimulation pulses.

[0169] The stimulation pattern corresponds to the ratio of time constants of the response to increases and decreases in blood pressure. The ratio of stimulation pulses having the first stimulation setting to stimulation pulses having the second stimulation setting. It's okay to be.

[0170] The stimulation pattern may include a ratio of about 8 to about 13 stimulation pulses having the first stimulation setting to about 2 to about 5 stimulation pulses having the second stimulation setting.

[0171] One of the first stimulation setting and the second stimulation setting may be configured to elicit a hormonal response from the patient's body.

[0172] In another aspect, an embodiment of a system for reducing ventricular filling volume in a patient having a pre-treatment ventricular filling volume is provided. The system includes: a stimulation pulse provided to at least one cardiac chamber; The system may include at least one controller configured to administer delivery of one or more stimulation patterns of stimulation pulses to at least one cardiac chamber, wherein at least one of the stimulation pulses initiates ventricular activation about 0 ms to about 70 ms after onset of atrial activation, thereby increasing ventricular filling to a level lower than pre-treatment levels. For example, the processor circuit may include settings configured to reduce ventricular filling volume by detecting one or more excitation pulses between about 0 ms and about 70 ms after onset of ventricular activation occurs in at least one atrium or between about 0 ms and about 70 ms after one or more excitatory pulses are delivered to the atrium. It may be configured to operate in a mode of operation in which an excitatory pulse is delivered to the ventricle.

[0173] In some embodiments, the timing of sensed atrial activation may be determined by taking into account the delay between the actual onset of activation and its setting. For example, if the sensing delay is estimated to be 20-40 ms and the stimulation pulse is delivered 0-70 ms after the onset of atrial activation, In the case of the above, the system may be configured to deliver a pulse between 40 ms before the next anticipated sensed event and 30 ms after the next anticipated sensed event or 30 ms after the next sensed event. Similarly, the stimulation pulse may be delivered to the ventricle between 0 and 50 ms before the onset of atrial activation. If the same detection delay of 20-40 ms is assumed, the system will detect the next expected detection event 40 The pulse may be configured to be delivered between 100 ms and 90 ms before the next expected sensed event. The sensing delay may be due to one or more of the distance between the location of activation onset and the sensing electrode, the level of the electrical signal, the characteristics of the sensing circuitry, and a threshold set for the sensed event. The delay may be, for example, For example, the duration of signal propagation from the origin of excitation to the electrode location, the duration related to the frequency response of the sensing circuitry, and / or the time it takes for the signal propagation energy to reach a level detectable by the sensing circuitry. The delay may be significant, for example, in the range of between about 5 ms and about 100 ms. One approach to estimating the delay is to use a method in which both the atrium and ventricle are sensed. One approach is to use the time difference between the AV delay measured when the atrium is paced and the AV delay when the ventricle is sensed. Another approach may use a calculation of the amplifier response time based on set thresholds, signal strength and frequency content. Another approach may include modifying the delay used with atrial sensing until the effect on blood pressure is the same as that obtained by pacing both the atrium and ventricle with the desired AV delay.

[0174] In another aspect, an embodiment of a system for reducing ventricular filling volume in a patient having a pre-treatment ventricular filling volume is provided. The system includes: a stimulation pulse provided to at least one cardiac chamber; The at least one controller may include a stimulation circuit configured to deliver one or more stimulation pulses to the at least one cardiac chamber for a time interval lasting 10 minutes or more. At least one of the stimulation pulses may be configured to deliver a stimulation pattern of , may have a first stimulation setting configured to reduce or prevent atrial kicks in at least one ventricle for at least 5 minutes of the time interval, and at least one of the stimulation pulses has a second stimulation setting different from the first stimulation setting, thereby reducing the ventricular filling volume from a pre-therapy ventricular filling volume.

[0175] In another aspect, a method is provided for reducing ventricular filling in a patient having a pre-treatment ventricular filling volume, the method comprising: The method may include delivering one or more stimulation patterns of stimulation pulses to the stimulation device. At least one of the pulses is in at least one ventricle for at least 5 minutes of the time interval. and a first stimulation setting configured to reduce or prevent atrial kicks at At least one of the stimulation pulses has a second stimulation setting that is different from the first stimulation setting.

[0176] Other systems, methods, features and advantages of the invention will be or become apparent to one with skill in the art upon examination of the following figures and detailed description. All such additional systems, methods, features and advantages are intended to be included within this description and this summary, be within the scope of the invention, and be protected by the following claims. [Brief description of the drawings]

[0177] [Figure 1] 1 is a graph showing the systolic blood pressure of a hypertensive patient receiving a stimulation signal plotted against time. [Diagram 2] FIG. 2 is an enlarged view of a portion indicated by a dashed rectangle A in FIG. [Figure 3A] FIG. 3 is an enlarged view of the portion between points a and a′ in FIG. 2. [Figure 3B] FIG. 2 is an enlarged view of the portion indicated by the dashed rectangle A' in FIG. [Figure 4] FIG. 2 is an enlarged view of the portion indicated by the dashed rectangle B in FIG. [Figure 5A] FIG. 2 is an enlarged view of the portion indicated by the dashed rectangle C in FIG. [Figure 5B] FIG. 5B is an enlarged view of the portion between points c and c' in FIG. 5A. [Figure 6] 1 is a graph showing the systolic blood pressure of a hypertensive patient receiving a stimulation signal plotted against time. [Figure 7] 1 is a graph showing the systolic blood pressure of a hypertensive patient receiving a stimulation signal plotted against time. [Figure 8] 1 is a flow chart illustrating a method for setting and / or selecting a stimulation pattern. [Figure 9] FIG. 1 is a schematic diagram illustrating a system for reducing blood pressure. [Figure 10A] 1 is a time plot of the electrocardiogram, aortic pressure and left ventricular pressure of a healthy dog ​​heart. [Figure 10B] 1 is a time plot of the electrocardiogram, aortic pressure and left ventricular pressure of a healthy dog ​​heart. [Figure 11A] 1 is a time plot of the heart in a hypertensive dog showing right atrial pressure, the expanded diastolic portion of right ventricular pressure, right ventricular pressure and an electrocardiogram. [Figure 11B] 1 is a time plot of the heart in a hypertensive dog showing right atrial pressure, the expanded diastolic portion of right ventricular pressure, right ventricular pressure and an electrocardiogram. [Figure 12] 1 is a graph showing right atrial pressure, right ventricular pressure, enlarged diastolic portion, right ventricular pressure, left ventricular pressure, as well as aortic pressure and electrocardiogram on the same graph in a hypertensive dog heart. [Figure 13] 1 is a flow chart illustrating a method for lowering blood pressure. [Figure 14] 24 is a flow chart illustrating a device for lowering blood pressure performing one or more of the methods described herein, such as the methods of FIGS. 13 and 23. [Figure 15] FIG. 1 is a schematic diagram showing an artificial valve according to one embodiment of the present invention. [Figure 16] 1 is a graph showing the systolic blood pressure of a hypertensive patient receiving a stimulation signal plotted against time. [Figure 17] 1 is a graph showing ventricular volumes, intraventricular pressures, intraatrial pressures, and an electrocardiogram (ECG) plotted against time, highlighting the isovolumic and rapid ejection phases of a single cardiac cycle. [Figure 18] A set of graphs showing the electrocardiogram (ECG), right ventricular pressure (RV pressure), right atrial pressure (RA pressure), aortic pressure (Ao pressure), and left ventricular pressure (LV pressure) tracing a period when stimulation changes from sinus rhythm to atrial and ventricular pacing with a 2 ms AV delay, showing a significant increase in atrial pressure. [Figure 19]A set of graphs showing the electrocardiogram (ECG), right ventricular pressure (RV pressure), right atrial pressure (RA pressure), aortic pressure (A0 pressure), and left ventricular pressure (LV pressure) tracing a period when stimulation changes from sinus rhythm to atrial and ventricular pacing with an AV delay of 40 ms, showing no significant increase in atrial pressure. [Figure 20A] 1 is a graph of atrial pressure over a period of time illustrating the different degrees of overlap between atrial pressure and passive pressure rise in the atrium caused by atrial contraction at different intervals, and illustrating an example of no overlap between atrial pressure and passive pressure rise in the atrium caused by atrial contraction; [Figure 20B] 1 is a graph showing atrial pressure over a period of time, illustrating different degrees of overlap between atrial pressure and passive pressure rise in the atrium caused by atrial contraction at different intervals, showing an example where atrial pressure and passive pressure rise in the atrium caused by atrial contraction are combined with a 30 ms delay between their onset. [Figure 20C] 1 is a graph of atrial pressure over time illustrating the different degrees of overlap between atrial pressure and passive pressure rise caused by atrial contraction in the atrium at different intervals, comparing the different degrees of overlap with delays of 0 ms, 10 ms, 20 ms, 30 ms, 40 ms, 50 ms, and 60 ms. [Figure 21] 1 is a graph plotting a patient's mean blood pressure over a 24-hour period. [Figure 22] 1 is a graph plotting the average blood pressure of a patient over a 24-hour period without treatment and with treatment according to one embodiment. [Figure 23] 4 is a flow chart illustrating an exemplary method for controlling intra-atrial pressure and atrial expansion, according to one embodiment. [Figure 24] 1 is a graph showing the relationship between AV delay and reduction in systolic blood pressure for a particular patient. [Diagram 25] 1 is a graph showing systolic blood pressure over a 24-hour period for a particular outpatient. [Figure 26]FIG. 26 is a graph showing systolic blood pressure over a 24-hour period for another particular outpatient, different from the patient in FIG. 25. [Figure 27] 1 is a graph showing the effect of blood pressure lowering treatment in dogs disclosed herein, plotting the change in systolic blood pressure (mmHg) over time (days). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0178] The present invention may be better understood with reference to the following drawings and description. The components in the drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the invention. Moreover, in the drawings, like reference numbers indicate corresponding parts throughout the different views.

[0179] The human heart has two atria and two ventricles. In a normal cardiac cycle, cardiac contraction begins with an atrial contraction, which is followed by a ventricular contraction.

[0180] The mechanical process of cardiac contraction is controlled by electrical conduction in the heart. During each beat, a wave of depolarization is induced by cells in the sinoatrial node. The depolarization propagates in the atria to the atrioventricular (AV) node and then to the ventricles. In a healthy heart, the atrioventricular delay, i.e., the delay time between the onset of atrial and ventricular excitation, is usually between 120 milliseconds (ms) and 200 ms. The relative timing of atrial and ventricular contraction is influenced, among other things, by the relative timing of excitation of each chamber and by the time required by the chambers to generate a mechanical contraction as a result of electrical activation (which depends on size, speed of propagation, differences in myocyte properties, etc.).

[0181] Before contraction, the heart muscle relaxes, allowing blood to flow freely from the atria to the ventricles through the valves between them. This period can be divided into a rapid filling phase and a slow filling phase. In the rapid filling phase, blood from the venous system and the atria fills rapidly into the ventricles. The rapid filling phase lasts for approximately 110 ms and begins immediately after the relaxation of the ventricles, filling the atrial chambers. This is followed by a slow filling phase that continues until the onset of contraction. The duration of the slow filling phase is dependent on the heart rate. As the atria then contract, pressure increases within the atria, forcing blood to flow more rapidly into the ventricles. This contribution of atrial contraction to ventricular filling is known as the "atrial kick." The atrial kick is normally responsible for approximately 10% to 30% of ventricular filling.

[0182] 17 shows the changes in ventricular volume, intraventricular pressure, intraatrial pressure, and cardiac electrical activity over a period of a single cardiac cycle. As used herein, a cardiac cycle is the period between two relaxations of the ventricles. The duration of a cardiac cycle is inversely proportional to the heart rate, so that a slower heart rate increases the cardiac cycle duration, and an increase in heart rate decreases the cardiac cycle duration. At a typical human rate of 75 beats per minute, one cardiac cycle is approximately 0.8 seconds long.

[0183] Referring to FIG. 17, the cardiac cycle may be said to begin at the onset of atrial excitation when observing the P wave on the ECG. Then, about 50-70 ms thereafter, the atrium begins to contract for about 70-110 ms. As the atria contract, the pressure inside the atria rises and reaches a peak. The atria then begin to relax and the pressure drops, represented in Figure 17 by point 1701. Meanwhile, the electrical impulse propagates to the ventricles, which then initiate ventricular excitation with an AV delay of about 120-200 ms (AV delay can be about 250 ms or longer in some unhealthy individuals). This ventricular excitation appears on the ECG as a QRS complex. As the ventricles contract, pressure rises within the ventricles, and a corresponding The valve between the atrium and the ventricle (AV valve) is passively closed, thereby stopping the flow of blood from the atrium to the ventricle and preventing backflow.

[0184] During the next period of ventricular contraction, known as the isovolumic contraction period, or isovolumic phase, which lasts approximately 50 ms, the ventricular valves all close and the intraventricular pressure rises rapidly while the volume does not change significantly, as shown in FIG. 17 by the intraventricular pressure and volume lines within vertical lines 1703 and 1704 which demarcate the isovolumic phase.

[0185] As the intraventricular pressure increases further, the valve between the ventricle and the artery opens, and blood is ejected from the ventricle and away from the heart, as shown by line 1704 in FIG. 17. This ventricular systole is divided into a rapid ejection phase and a slow ejection phase. The rapid ejection phase lasts for about 90-110 ms, during which time the stroke volume is reduced by about 2. The rapid ejection period is represented in FIG. 17 as the period between lines 1704 and 1705. can be.

[0186] During the isovolumic phase and at the beginning of the rapid ejection phase, the contraction of the ventricles typically causes a passive increase in intraatrial pressure. This increase in intraatrial pressure is believed to be due to the mechanical effect of the contraction of the ventricles on the associated atria. For example, this increase in intraatrial pressure may be due to the atria being intimately connected to the much larger ventricles. Contraction of the large ventricular muscle affects the associated atria. The increase in intraatrial pressure may be due to the valves bulging backwards into the atria, which may be due to an increase in internal pressure in the ventricles. Passive filling of the atria continues throughout the cardiac cycle (including between points 1701 and 1702) due to the lack of valves between the atria and the vasculature. This continuous passive filling coupled with the increase in internal pressure due to the mechanical effect of ventricular contraction may contribute to the increase in intraatrial pressure.

[0187] Thus, the passive atrial pressure increase peaks sometime between the latter half of the isovolumic phase (i.e., about 25-35 ms after the onset of the isovolumic phase) and the beginning of the rapid ejection phase (e.g., within about the first 10 ms of the rapid ejection phase), as represented by point 1702 in Figure 17. The passive atrial pressure increase may be higher than the peak atrial pressure due to atrial contraction, as shown by the higher atrial pressure at point 1702 relative to the lower atrial pressure at point 1701 in Figure 17.

[0188] The rapid ejection phase is followed by a slow ejection phase lasting approximately 130-140 ms, after which all valves close again and the ventricle relaxes in an isovolumic relaxation state for approximately 60-80 ms, during which time the internal pressure of the ventricle drops, at which point the valves between the ventricle and the atrium reopen to allow blood to flow freely into the ventricle, after which a new cardiac cycle may commence.

[0189] Control of intra-atrial pressure and atrial dilation In the present disclosure, cardiac stimulation may be used to increase intra-atrial pressure and expansion, thereby lowering blood pressure (BP). The increase in intra-atrial pressure may be achieved by stimulating the heart such that the intra-atrial pressure in the atrium caused by atrial contraction overlaps in time with the passive increase in pressure in the atrium, such that the intra-atrial pressure in the atrium caused by the stimulation is higher than the intra-atrial pressure in the atrium in the absence of stimulation, due to the combination of the intra-atrial pressure caused by atrial contraction and the passive increase in pressure.

[0190] In embodiments, the peak intraatrial pressure may be reached by inducing maximum atrial contraction during the period of overlap with the maximum passive increase in intraatrial pressure. For example, cardiac stimulation may be used to reach the peak intraatrial pressure caused by atrial contraction between about 25-35 ms after the start of the isovolumic phase and about 10 ms after the end of the isovolumic phase. The increase in intraatrial pressure (due to the intraatrial pressure caused by atrial contraction overlapping with the passive increase in intraatrial pressure) increases atrial expansion, which is known to affect blood pressure through hormonal and / or neuronal pathways. For example, the increased atrial expansion may cause the secretion of atrial natriuretic hormone or atrial natriuretic peptide, which may lower blood pressure.

[0191] In embodiments, cardiac stimulation may be applied chronically or transiently to increase intra-atrial pressure and atrial expansion and cause secretion of atrial natriuretic hormone or atrial natriuretic peptide. Chronic application of cardiac stimulation is not necessary, as transient stimulation may be sufficient to increase intra-atrial pressure and atrial expansion, cause hormone secretion, and reduce blood pressure. The change in atrial expansion may be temporary as observed in the pressure plot, and the temporary expansion may be even more effective in causing the release of atrial natriuretic hormone or atrial natriuretic peptide and lowering blood pressure than long-term expansion. In embodiments, beneficially, the temporary increase in intra-atrial pressure may not result in a long-term increase in intra-atrial pressure.

[0192] In some embodiments, a peak atrial pressure produced by an atrial contraction is considered to have occurred during a period overlapping with a peak passive increase in atrial pressure if the peak atrial pressure completely or at least partially coincides with a peak passive increase in atrial pressure. For example, if a maximum atrial contraction is predicted to occur within about 20 ms before or after a predicted peak passive increase in atrial pressure, the peak atrial pressure produced by an atrial contraction is considered to have occurred during a period overlapping with a peak passive increase in atrial pressure.

[0193] In some embodiments, the maximum atrial pressure refers to the highest part of the contraction or passive pressure increase, which has a pressure value that is at least about 25% higher than the pressure value of the remaining atria. Optionally, when only one peak in pressure is observed from the atrial contraction and passive pressure increase, When two peaks are observed, the maximum atrial pressure generated by atrial contraction is the maximum atrial pressure. The peak atrial pressure caused by atrial contraction and the peak passive increase in atrial pressure are believed to occur during a period of overlap with the high passive increase, and are separated by no more than about 30 ms. Optionally, the time overlap can be detected mathematically by analyzing the measurements and / or visually, for example, by plotting the atrial pressure over a period of time or the change in atrial pressure over a period of time.

[0194] BP or changes in BP may be measured as systolic BP (SysBP), diastolic BP, mean arterial BP, BP of one or more chambers, and / or any other relevant BP parameters. In some embodiments, an electrical stimulator, such as a pacemaker or other type of device having a pulse generator, may be used to stimulate the patient's heart and lower blood pressure. Electrodes electrically connected to the electrical stimulator by a wired or wireless connection may be positioned adjacent to the heart chamber. The electrical stimulator may be activated to deliver pulses to the heart chamber via the electrodes.

[0195] In some embodiments, stimulating the heart so that the atrium reaches an increased (preferably maximum) intra-atrial pressure caused by atrial contraction in a period overlapping with a (preferably maximum) passive increase in intra-atrial pressure may result in lowering of blood pressure. For simplicity, in the following description, such stimulation may be referred to as "AC (atrial contraction) stimulation." AC stimulation is a method of providing at least one stimulation pulse to at least the atrium of the heart such that the atrium reaches the maximum intra-atrial pressure caused by atrial contraction in the period from the latter half of the isovolumic phase to about the first 10 ms of the rapid ejection phase. Such stimulation pulses may include delivering stimulation pulses to at least one of the chambers. In this document, this is referred to as the "AC stimulation pulse" or "AC pulse."

[0196] As used herein, a "stimulation pulse" refers to a single beat (a single beat is two ventricular pulses). The method may include a sequence of one or more excitatory electrical pulses (or stimulation pulses) delivered to one or more chambers of the heart within a time frame between relaxation of the atria (defined as the period during which only one contraction of the atria occurs while the ventricles relax twice). Optionally, such excitatory electrical pulses (or stimulation pulses) are further referred to as pacing pulses. For example, in some embodiments, the stimulation pulses are delivered to one or more of the ventricles. The method may include one or more electrical pulses delivered to one or more locations in the atrium, and / or one or more electrical pulses delivered to one or more locations in the atrium. In some embodiments, the stimulation pulses include a first electrical pulse delivered to the atrium and a corresponding second electrical pulse delivered to the ventricle. and a second electrical pulse delivered to the stimulator. The stimulation pulse may include a first electrical pulse delivered to an atrium, a second electrical pulse delivered to a corresponding ventricle, and a third electrical pulse delivered to the atrium after a refractory period associated with the first pulse has elapsed. The method may include a single pulse being delivered to multiple locations in the chamber.

[0197] In some embodiments, the AC pulse may be delivered at a timing to have the atrial pressure caused by atrial contraction of the atrium overlap in time with the passive pressure increase in the atrium, relative to the cardiac cycle, such that the atrial pressure in the atrium caused by the stimulation is higher than the atrial pressure in the atrium in the absence of stimulation due to a combination of the atrial pressure caused by the atrial contraction and the passive pressure increase. Preferably, the AC pulse may be delivered to cause the atrium to reach a peak atrial pressure caused by atrial contraction at a time that overlaps with a peak passive pressure increase in the atrium, relative to the cardiac cycle. Optionally, the timing of delivery of this AC pulse may be based on one or more sensed events, e.g. For example, the time may be set according to events associated with the cardiac cycle.

[0198] For example, atrial and / or ventricular activation may be sensed and an AC pulse may be delivered to the atria and / or ventricles accordingly. For example, a pacing pulse may be delivered approximately -20 to 30 ms from ventricular sensing or pacing and at least approximately 20 ms from the end of the atrial refractory period. The AC pulse may be delivered to the atrium at a timing that is predicted to occur within milliseconds. Optionally, heart rate and ventricular activation or contraction may be sensed and the timing of the next ventricular contraction or activation may be estimated, and the AC pulse may be delivered such that the atrial pressure caused by the atrial contraction in the subsequent beat overlaps in time with the passive atrial pressure increase. Optionally, the AC pulse may be delivered such that the atrial contraction in the subsequent beat reaches a peak atrial pressure caused by the atrial contraction at a time that overlaps in time with the peak atrial passive pressure increase. For example, the AC pulse may include a stimulus delivered to the atrium about 30-0 ms prior to predicted ventricular activation or about 50-120 ms prior to the predicted onset of ventricular contraction.

[0199] In some embodiments, the stimulation pulse is delivered to a first atrium that is sensed or paced. Activation, the electrical impulse transmitted to the corresponding ventricle, and the refractory period associated with the atrium being first activated The first cardiac pulse may include another electrical pulse delivered to the atrium after the first cardiac pulse is completed. Atrial excitation (e.g., transmission of a first excitatory pulse to the atrium) to another excitatory pulse to the atrium The period until the transmission may be about 150 to 250 ms.

[0200] In some embodiments, the AC pulse corresponds to a first electrical pulse delivered to the atrium. and a second electrical pulse delivered to the ventricle. The relative timing is controlled to cause the atrium to contract at some point during the period from the latter half of the isovolumic phase to the beginning of the rapid ejection phase of the heart in that beat. Because the time from delivery of the excitatory pulse to the onset of contraction is longer for the ventricle than for the atrium, the delay in delivery of the first and second pulses may have a negative value, such as about -20 to 0 ms.

[0201] This exact timing may vary for different patients and different conditions (e.g., different placement of one or more electrodes in the chamber). In some embodiments, the AC pulse settings can be adjusted, for example, at the time of implantation of the device and / or periodically, for example, during routine testing or during use (e.g., one or more The control unit 10 may adjust the speed (based on feedback from relevant sensors).

[0202] For example, AC pulses having different settings may be delivered to the patient and the intra-atrial pressure may be sensed until a desired intra-atrial pressure is sensed, which is produced by an atrial contraction of the atrium overlapping in time with a passive intra-atrial pressure increase in the atrium. In some embodiments, the desired intra-atrial pressure may be any intra-atrial pressure above the intra-atrial pressure that the atrium would reach without stimulation. Optionally, the desired intra-atrial pressure may be the highest of multiple intra-atrial pressures produced by multiple AC pulses having different settings. For example, the AC Pulse may be selected as the lowest internal pressure (or one of the highest internal pressures). The AV pulse settings may be different by having different AV delays between a sensed or paced atrial contraction and a paced or sensed ventricular contraction, so that one or more AV pulse settings may be selected for use over a period of time for a given patient.

[0203] For example, AC pulses having different settings may be delivered to the patient and atrial pressure may be sensed until a desired degree of overlap is observed between the peak peak atrial pressure caused by atrial contraction and the peak passive atrial pressure rise. For example, the AC pulses may be varied by having different AV delays between a sensed or paced atrial contraction and a paced or sensed ventricular contraction. As a result, one or more AC pulses may be delivered to the patient and atrial pressure may be sensed for a period of time for a given patient. One or more AV pulse settings may be selected.

[0204] Optionally, the AC pulses may be delivered as part of a pacing pattern in which the configuration of various pulses within the pattern varies, with one or more patterns being able to reduce or enhance atrial stimulation. The pulse selection is configured to prevent one or more overlapping of the internal pressures. Or, they may be selected for repeated use based on multiple parameters.

[0205] Stimulation settings refer to one or more parameters of one or more stimulation pulses delivered in a single cardiac cycle, such as power, the time interval between electrical pulses contained in a single stimulation pulse (e.g., AV delay or delay between two atrial pulses), the delivery period relative to the natural rhythm of the heart, the timing of the stimulation pulse or may be used for the length of a portion thereof, and between two or more chambers and / or within a single chamber. The AC stimulation setting, i.e., the "AC The "setting" may include the setting of one or more AC pulses.

[0206] In some embodiments, the sensing comprises detecting electrical activity of one or more chambers of the heart. The method includes detecting one or more of the following: In some embodiments, the sensing includes detecting cardiac activity using sounds of the cardiac cycle. For example, closure of the AV valve results in the first sound of a heartbeat. This closure also signifies the beginning of the isovolumic phase. Optionally, a pulse setting may be selected for a subsequent AC pulse based on the timing of the AV valve closure and the heart rate. For example, a stimulation pulse may be provided to the atrium about 80 to 10 milliseconds prior to the next predicted closure of the AV valve.

[0207] If desired, the refractory period of a cardiac chamber (e.g., atrium) may be estimated as known in the art. The AC pulse may include delivering a stimulation pulse to the atrium that induces an atrial contraction. For example, the stimulation pulse may be timed for delivery after the end of the refractory period, or the stimulation pulse may have electrical properties such that if delivered during the relevant refractory period, it induces a contraction despite its relatively rapid timing.

[0208] In some embodiments, the heartbeat is sensed, for example, based on electrical activity, sound, pressure, and / or any other means, as known in the art.

[0209] In some embodiments, the one or more AC pulses are part of a sequence of pulses. The pacing pattern may be provided as a single pacing pulse or as a pacing pattern encompassing multiple beats. The pacing pattern may include multiple pacing pulses having different settings. Optionally, the pulses may all be AC ​​pulses, but some may have different pulse settings than others. Optionally, only some of the pulses in a given pattern may be configured to cause the atrium to produce increased or highest intra-atrial pressure caused by atrial contraction during the period between the late isovolumic phase and the early rapid ejection phase.

[0210] One or more pulse settings (e.g., between events being detected and / or communicated) It is further noted that the timing) may be optimized and / or adjusted to suit a particular patient and / or differences in a patient's cardiac function.

[0211] For example, a patient's heart rate may vary for many reasons, including activity and time of day. Changes in heart rate may result in changes in the relative timing of cardiac events. Thus, one or more of the following parameters may be sensed or used to optimize and control pulse settings: and / or adjustments may be made.

[0212] For example, aortic pressure and / or sounds associated with the opening of one or both heart valves can be used to precisely target the timing of the start and / or end of the isovolumic phase and / or the start of the rapid ejection phase, which may be compared to the time at which a pulse is delivered and / or a cardiac event is sensed such that the timing of the desired contraction is more precisely and / or more repeatedly achieved.

[0213] In another example, the timing from delivery or sensing of an excitatory stimulus (to the atrium and / or ventricle) to the point at which peak pressure (due to contraction or passive internal pressure rise) is sensed in the atrium may be measured.

[0214] Other options include monitoring one or more of heart rate, patient activity, posture, and / or respiratory rate. It may be a matter of adjusting the AC pulse settings accordingly.

[0215] Indeed, any of the above combinations may be used to adjust and / or optimize, for example, one or more of the timing between atrial activation and peak atrial pressure generated by atrial contraction, ventricular activation, peak atrial passive pressure, and the timing of the isovolumic and / or rapid ejection phases. Optionally, the atrial pressure resulting from delivery of the stimulation pulse may be measured, and the adjustment may include selecting stimulation settings in accordance with the measured resulting pressure. These measurements may further be correlated with the patient's heart rate under various conditions. Patient specific measurements may be used to adjust or optimize pulse settings.

[0216] The optimization and / or adjustment as described above may be performed, for example, as a closed loop, possibly with a sensor associated with an implanted stimulation device. Alternatively, the optimization and / or adjustment may be performed as an open loop. The optimization and / or adjustment may be an ongoing process (especially if a sensor is implanted, for example, according to heart rate) and / or may be performed during implantation when the patient has the device, at times, and / or when needed. Finally, the optimization and / or adjustment may be automated and / or involve a physician.

[0217] Embodiments may implement different pacing techniques to achieve a desired overlap between AC stimulation and the passive increase in intra-atrial pressure caused by atrial contraction. In some embodiments, AC stimulation may include pacing the atrium at an atrial rate substantially equal to the intrinsic ventricular rate or at an atrial rate greater than the intrinsic ventricular rate. Additionally, different pacing techniques may be implemented to achieve a desired overlap between AC stimulation and the passive increase in intra-atrial pressure caused by atrial contraction. Alternatively, the desired AC stimulation may be achieved, resulting in two atrium contractions.

[0218] For one contraction of the atrium, a pacing technique that achieves the desired AC stimulation is, for example, as follows: It may include the following.

[0219] a. Atrial sensing (optionally including anticipating atrial activation) and ventricular pacing ng, b. May require atrial pacing prior to the time of expected ventricular sensing , ventricular sensing and atrial pacing, or c. Atrial pacing and ventricular pacing.

[0220] With respect to the two contractions of the atrium, pacing techniques that achieve the desired AC stimulation are, for example: It may include the following:

[0221] a. sense atrial activation first, sense the ventricle, and pace the atrium in the same cardiac cycle to produce a second contraction; b. sense the atrium, pace the ventricle, and pace the atrium in the same cardiac cycle to produce a second contraction; c. Pace the atrium, sense the ventricle, and pace the atrium again, or d. Pace the atrium, pace the ventricle, then pace the atrium again.

[0222] Other pacing techniques may be utilized to achieve the desired AC stimulation and overlap between the passive increase in intra-atrial pressure caused by atrial contraction, and thus, notwithstanding the specific benefits associated with the pacing techniques described herein, the present embodiments should be considered broadly applicable to any pacing technique that provides the desired AC stimulation and overlap.

[0223] Figures 18-19 show two different stimulation patterns delivered to the heart of anesthetized healthy dogs. 1 is a graph showing an electrocardiogram (ECG), right ventricular pressure (RV pressure), right atrial pressure (RA pressure), aortic pressure (Ao pressure), and left ventricular pressure (LV pressure) traced over a period of time. According to one embodiment, FIG. 18 shows an atrial pulse with a 2 ms AV delay from stimulation from sinus rhythm. The figure shows the change from the atrial contraction to the pacing of the ventricle, which results in the overlap of the atrial pressure due to the atrial contraction and the atrial pressure due to the passive atrial pressure increase. In this example, the pacing with an AV delay of 2 ms results in the overlap of the atrial pressure due to the atrial contraction and the atrial pressure due to the passive atrial pressure increase. 19 shows a 40 ms AV delay, which resulted in a smaller degree of overlap and no significant increase in atrial pressure. Optionally, the greater degree of overlap may be defined as a function of the proximity of the peak atrial pressure, i.e., the closer the peaks are to each other, the greater the degree of overlap, until the peaks completely overlap and a single peak atrial pressure is observed. Optionally, the degree of overlap is a function of the peak atrial pressure sensed, with higher pressure peaks being characterized by a greater degree of overlap.

[0224] In the experiments related to Figures 18-19, healthy dog ​​hearts were fitted with pacemakers configured with algorithms that allow pacing at specific AV delays. The pacemaker was connected to the heart via two pacing electrodes, one in the right atrial appendage and one in the right ventricular apex. Four solid-state pressure sensors were inserted into the right atrium, right ventricle, left ventricle, and aorta. In addition, a unipolar ECG lead was also connected to the animal. The sensor was connected to an amplifier and data acquisition system. The signal was sampled at a rate of 1 kHz and the results were recorded as shown in Figures 18 to 19. A graph was provided. As shown, the graph includes plots of, from bottom to top, ECG, RV pressure, RA pressure, Ao pressure, and LV pressure.

[0225] In each experiment, the heart was contracted using natural sinus rhythm for a few beats and then paced with specified AV delays in both the atrium and ventricle.

[0226] Referring to each of FIGS. 18-19, during a period of sinus rhythm 1802, two separate increases in intraatrial pressure are observed. The initial increase in atrial pressure 1804 is followed by atrial electrical activity (P wave 1806), The second increase in atrial pressure 1808 corresponds to an isovolumic contraction of the ventricle (a sudden increase in intraventricular pressure). This occurs during the rapid ejection phase (characterized by a rapid increase in atrial pressure) and continues briefly during the early rapid ejection phase (which begins when aortic pressure begins to rise). The effect of ventricular contraction on atrial pressure causes a second atrial pressure increase 1808, which is reached during isovolumic contraction, as shown in the RA pressure plots in Figures 18-19. The peak atrial pressure is slightly higher than the peak atrial pressure reached during atrial contraction.

[0227] As discussed above, embodiments may include provisions for maximizing intra-atrial pressure and therefore atrial expansion. More specifically, stimulation may be delivered to the atrium at a time relative to the cardiac cycle that overlaps with the maximum atrial passive pressure increase, causing the atrium to reach the maximum intra-atrial pressure produced by atrial contraction. FIG. 18 shows a ventricular pace 1810 followed 2 ms after an atrial pace. The atria and ventricles are paced with a 2 ms AV delay, as represented by the sequence 1812 followed by One example of the timing that may be used is shown in Figure 18. Figure 18 shows three examples of this pacing.

[0228] Referring to the right atrial pressure (RA) plot in Figure 18, three examples of this pacing are shown. In the right atrial pressure plot, significant increases in atrial pressure can be seen at points 1814, 1816, and 1818. These significant increases in atrial pressure are caused by simultaneous or nearly simultaneous increases in atrial pressure due to atrial contraction and ventricular contraction. That is, comparing the sinus rhythm portion 1802 of the right atrial pressure plot with the AV delayed pacing portion 1803 of the right atrial pressure plot, the first atrial pressure in the sinus rhythm portion 1802 is 1806. The increase 1804 and the second increase 1808 in atrial pressure are the increase 1804 in atrial pressure and the increase 1808 in atrial pressure. are essentially superimposed with the AV delay pacing portion 1803 such that they combine to result in higher intra-atrial pressure increases 1814, 1816, and 1818.

[0229] Optionally, the AC pulse may have a setting that includes a predefined AV delay between the sensed or paced atrial activation and the paced or sensed ventricular activation. The AV delay may be selected such that the atrial pressure and the passive atrial pressure increase caused by the atrial contraction essentially overlap as described above, and such that the atrial pressure of the atrium, which is a combination of the atrial pressure and the passive pressure increase caused by the atrial contraction, is higher than the atrial pressure of the atrium in the absence of stimulation (or stimulated differently). The AV delay may be selected such that the maximum atrial pressure and the maximum passive atrial pressure increase caused by the atrial contraction essentially overlap as described above. This setting may vary from patient to patient, and may even vary in time for a given patient. Nevertheless, in most cases, an AV delay of about 30 ms to about 0 ms is preferred. Depending on the patient (e.g., as illustrated by the example of a healthy dog ​​heart shown in FIG. 18), the AV delay between atrial and ventricular activation may be from about 30 ms to about 0 ms, or from about 20 ms to about 0 ms.

[0230] When sensing is used to detect cardiac events for which an AV delay is set, the following may optionally be taken into consideration: first, if electrical activation is sensed, then the actual It should be noted that there is a delay between the actual activation and its detection. This may be due to the location of the sensing electrodes and limitations of the sensing system. Thus, for example, the period from sensed atrial activation to delivery of a pacing pulse to the ventricle will be shorter than the desired AV delay. If sensing is based on a mechanical event (e.g., contraction or valve closure), the time between actual activation and the occurrence of the mechanical event must also be taken into account. Several examples of relative timing of the sensed event and delivery of the pacing pulse are disclosed herein. Additionally, settings may be adjusted at the time of implantation and / or periodically to accommodate the patient's specific timing, as described in detail in this application.

[0231] In contrast to the surprising beneficial results achieved by pacing with an AV delay that causes atrial contraction of the atrium to overlap in time with atrial passive pressure rise, thereby providing an intraatrial pressure in the atrium that is higher than the intraatrial pressure in the atrium in the absence of stimulation (as in the embodiment of FIG. 18) due to the combination of the intraatrial pressure caused by the atrial contraction and the passive pressure rise. Although the AV delay is shorter than that of normal (e.g., 140 ms in the dog heart), This does not result in a significant increase in intraatrial pressure. As shown in Figure 19, after the sinus rhythm portion 1802, the heart was paced with a 40 ms AV delay during an AV delay pacing portion 1803, as represented by an atrial pace 1910 followed 40 ms later by a ventricular pace 1912. Figure 19 shows two examples of this pacing. 19. Referring to the atrial pressure (RA) tracing portion a short time after pacing, the 40 ms AV delay did not result in a significant atrial pressure increase relative to the atrial pressure increases 1804 and 1808 in the sinus rhythm portion 1802, despite the 40 ms AV delay being shorter than the normal 140 ms AV delay. Instead, as shown in FIG. 19, the 40 ms AV delay resulted in two separate atrial pressure increases 1904 and 1908. and 1908, which were approximately equal to the previous intraatrial pressure increases 1804 and 1808.

[0232] Thus, a comparison of Figures 18 and 19 shows that a significantly increased intra-atrial pressure occurs when the contraction of the atrium and the later part of the isovolumic contraction of the ventricle or the early part of the rapid ejection phase occur simultaneously or nearly simultaneously, as in Figure 18. This significant increase in intra-atrial pressure may result in the release of desired stress-related hormones to lower blood pressure. Thus, embodiments pace the atria and ventricles with an AV delay of approximately 2 ms.

[0233] 20A-20C illustrate several theoretical examples for combining atrial pressure due to atrial contraction and passive atrial pressure rise. In these examples, different degrees of overlap are shown, and the atrial pressure due to atrial contraction and passive atrial pressure rise are summed, as described in detail below. First, the atrial pressure was traced during a natural cardiac cycle, for example as shown during sinus rhythm 1802 in FIGS. 18 and 19. From this tracing, the atrial pressure due to atrial contraction 1804 and passive atrial pressure rise 1804 was extracted. In FIG. 20A, the atrial pressure is traced during the onset of atrial contraction to the onset of passive atrial pressure rise. Assuming a 60 ms delay before onset, two internal pressure curves (corresponding to 1802 and 1804 in FIG. 18) As can be seen, the atrial contraction lasted for about 60 ms and the maximum intracardiac pressure reached almost 1.5 mmHg. In contrast, the passive increase in intracranial pressure continued for approximately 50 ms and reached a maximum intracranial pressure slightly higher than 2 mmHg. The atrial contraction lasted approximately 60 ms (approximately the assumed delay), so The internal pressure increase is observed as a separate part in this trace, with two distinct maxima. The maximum internal pressure observed is the maximum internal pressure of the passive internal pressure increase 1804.

[0234] FIG. 20B shows in more detail the theoretical relationship between the atrial pressure and the passive pressure rise in the atrium due to atrial contraction. In this trace, the onset of passive intracardiac pressure rise 1804 (dashed line) was assumed to occur 30 ms after the onset of atrial contraction 1802 (dotted line), as shown. The races were summed and the sum was traced as internal pressure trace 204 (solid line). As can be seen in the example, due to some overlap, the combined lines 204 are overlapping. Although the peak pressure observed in the non-matching passive pressure rise 1804 (dashed line) was somewhat higher, two peaks were still visible, each of which was associated with Corresponding to traces 1802 and 1804.

[0235] Timing the peak atrial pressure from atrial contraction to coincide with the peak passive pressure rise so that the peak occurs as a single event may result in the highest atrial pressure attainable, but embodiments may result in a significant beneficial increase in atrial pressure for a period of time following this single event. In other words, to stimulate the heart to achieve a higher atrial pressure in the atrium than would be the case in the absence of stimulation due to the combination of the atrial pressure and the passive pressure rise caused by the atrial contraction, the timing of stimulation need only result in a combination (e.g., sum) of the atrial pressure and the passive pressure rise caused by the atrial contraction being higher than the peak atrial pressure that would occur in the absence of stimulation. When the peak atrial pressure from atrial contraction occurs simultaneously with the peak passive pressure rise in the atrium, the combination (e.g., sum) of these pressures is likely to be higher than either pressure individually. However, providing a combined atrial pressure higher than both of the individual atrial pressures is not limited to a single event occurring simultaneously with a peak value, but also applies over a range of periods during which the atrial pressures overlap each other, as described in more detail below.

[0236] In FIG. 20C, the intracardiac pressure due to atrial contraction and the passive intracardiac pressure rise are shown with various theoretical FIG. 20B illustrates how the atrial and ventricular contractions are combined with a degree of overlap, thus illustrating how controlling the relative timing of the atrial and ventricular contractions may affect the composite intraatrial pressure. In this example, similar to FIG. 20B, the time delay from the onset of atrial contraction to the onset of passive intraatrial pressure rise is Thus, at each time point, the intra-atrial pressure due to atrial contraction is summed with the passive intra-atrial pressure increase at the same time point, thus providing a composite intra-atrial pressure. The composite (e.g., summed) intra-atrial pressure for various examples is traced in FIG. 20C.

[0237] Trace 201 in FIG. 20C is the same as the trace shown in FIG. 20A and shows the release of internal pressure due to atrial contraction. On the other hand, in trace 207, the atrial contraction causes a 60 ms delay in the passive intracardiac pressure rise. The atrial pressure and the passive intraatrial pressure rise are combined so that their peaks closely overlap (there is a delay between the onset of the two changes in intraatrial pressure that may not exactly coincide due to different durations). In other words, both the atrial pressure due to atrial contraction and the passive atrial pressure rise are approximately As can be seen, in this case, trace 207 shows the sum of the internal pressures reaching a single peak of about 3.5 mmHg. Similarly, with a delay of 10 ms (trace 206), A single peak was observed at trace 205 (20 ms delay) that was slightly delayed from trace 207 and had a lower peak than the peak of trace 207. As the time delay was increased, At this point, the traces begin to separate but still produce a single maximum (between 2.5 mmHg and 3 mmHg). Trace 204 (the same 30 ms delay as the trace shown in FIG. 20B) clearly shows two maximums. Although the atrial pressures are still well overlapped, the sum of the atrial pressures is at the top of tracing 201. Finally, even with the smaller degree of overlap, in trace 203 (40 ms delay) and trace 202 (50 ms delay) there is some overlap between the atrial contraction and the passive pressure rise, whereas in each trace the two peaks are more than 30 ms apart. 201, and the maximum internal pressure is approximately the same as trace 201, which does not show any overlap.

[0238] In some embodiments, the stimulation pattern can be used to deliver one or more AC pulses. Blood pressure may be reduced by exclusively applying intermittent stimulation patterns including or consisting of AC pulses. For example, by applying intermittent AC pulses, natural beating may occur between pulses where the AC pulses and / or the atrial pressure due to atrial contraction and the atrial pressure due to passive pressure rise are not configured to overlap (or the peaks of each do not overlap), thereby providing a higher atrial pressure in the atrium than the atrial pressure in the atrium in the absence of stimulation due to the combination of the atrial pressure caused by atrial contraction and the passive pressure rise. If desired, the time between the application of AC pulses may be selected according to the time constant of secretion and / or absorption of natriuretic peptides so that sufficient stimulation is delivered to essentially provide the desired effect, but not excessive stimulation. This may have the benefit of reducing the power used by the implanted device and / or reducing the degree of manipulation of the heart.

[0239] An exemplary method 230 for controlling intra-atrial pressure is illustrated generally in FIG. 23. Method 230 may be performed by an implantable device as described herein. Thus, the device may be configured to perform any or all of the steps of method 230. Similarly, , the method 230 may include any step that the device is configured to perform. For example, the method 230 may include any of the features discussed below with respect to the device 50 of FIG. It's okay to do that.

[0240] In some embodiments, method 230 may include sensing a cardiac event, as shown at step 231. The event(s) may include electrical and / or mechanical events, and may be sensed as known in the art and as described in more detail herein. For example, sensing The detected events may be the timing of the steps of atrial and / or ventricular excitation and / or mechanical activity of the heart, e.g., the opening and / or closing of one or more heart valves. The detected events may include an estimation of the relative timing between cardiac events. In some embodiments, step 231 may include triggering one or more cardiac events, e.g., atrial or ventricular activation. Optionally, step 231 may include detecting an intrinsic heart rate or triggering a heart rate. For example, step 231 may include setting a number to detect AV valve closure. Step 231 may include detecting ventricular activation or stimulation and AV valve closure defining the beginning of the isovolumic phase, thereby defining the beginning of the isovolumic phase, and / or detecting an opening of the aortic valve, thereby defining when the rapid ejection phase begins. The method may further include determining a time difference between the

[0241] The method 230 may include a step 232 in which a pulse setting is selected. Setting may include or include setting a time interval between atrial and ventricular activation. Setting may include selecting a ratio of atrial to ventricular activation for a given stimulation pulse. Setting may include a power setting based on timing of a sensed or estimated delivery of an excitatory pulse on a relative refractory period of the target chamber.

[0242] Method 230 may include step 233 of delivering at least one stimulation pulse using a pulse setting that may have been set in step 232, and that may be selected based on the timing of the event detected in step 231. In some embodiments, excitatory current may be applied to both ventricles, either simultaneously or sequentially. In some embodiments in which both ventricles are paced sequentially, at least one atrium (e.g. For example, the time interval from the onset of activation of a paced ventricle (e.g., the right atrium) to the onset of activation of the corresponding paced ventricle (e.g., the right ventricle) may be measured. The time interval may be set to zero or negative. In some configured embodiments, step 233 may be performed prior to or simultaneously with step 231. In some embodiments, the time interval is measured in milliseconds. This is also fine.

[0243] The pulse setting selected in step 232 may be selected based on feedback. In such a case, method 230 may include sensing intra-atrial pressure, as shown at step 234. Feedback information may be obtained on an ongoing and / or periodic basis, e.g., during implantation and / or during routine testing, for example, by using an implantable sensor for feedback and adjustment of pulse settings. Method 230 may include sensing intra-atrial pressure, as shown at step 234. The method may include a step 235 of estimating the overlap in time between the resulting atrial pressure (preferably the maximum atrial pressure) and the passive atrial pressure rise (preferably the maximum passive atrial pressure rise). For example, the estimation of step 235 may involve estimating the number of intraatrial pressure peaks and their duration. The method may include detecting the length and / or distance in time between peaks, and / or detecting the number of peaks and valleys in the atrial pressure and estimating the duration of contraction or change in atrial pressure based on the time between the peaks and valleys, and / or detecting the peak value of the atrial pressure compared to the atrial pressure of the same heart in the absence of stimulation. This comparison may be performed using a stored value corresponding to the atrial pressure measured before the start of therapy, and / or may include sensing the atrial pressure of at least one beat without delivering a stimulation pulse according to method 230.

[0244] The method 230 selects in step 232 based on the detected overlap estimated in step 235. Step 236 may include adjusting the selected pulse settings. For example, step 236 may include adjusting the time intervals to provide the greatest degree of overlap observed between the settings. Optionally, the greater degree of overlap may be achieved by adjusting the time intervals to provide the greatest degree of overlap observed between the settings. It may be defined as a function of the closeness of the intraatrial pressures, i.e., the closer the vertices are to each other, the greater the degree of overlap until the vertices completely overlap and a single peak intraatrial pressure is observed. Optionally, the degree of overlap is a function of the maximum atrial pressure sensed, with higher pressures being characterized by a greater degree of overlap.

[0245] As shown by the arrow from step 236 to step 231 in FIG. Step 232, step 233, step 234, and / or step 235 may be replaced by step 236. In some embodiments, the time pulse setting may be initially set to a first value in step 231, and based on feedback sensing performed during steps 234 and 235, the pulse setting is adjusted during step 236 until the degree of overlap is within a given range (or above or below a given value). may be increased or decreased (eg, the time interval may be decreased or increased).

[0246] The steps of method 230 may be performed in any order. For example, the steps may be performed in the manner shown in FIG. In another embodiment, step 232 may be performed in the order indicated by the arrows in the figure. This may be performed before step 231.

[0247] the timing of atrial contraction, atrial activation, ventricular contraction, AV valve closure and / or opening, and / or the flow or lack of blood from one or more atria to the corresponding ventricles; and / or blood pressure may be detected by any method known in the art and used as feedback control. In some embodiments, the onset of activation is determined by the onset of activation of one or more cardiac chambers (e.g., one or two ventricles, or the atrium). The sensed information may be used as a trigger for delivery of excitatory stimuli to the ventricles (the ventricles and the ventricles). The sensed information may additionally or instead be used in adjusting the timing intervals of the device.

[0248]

[0010] Embodiments may provide a method for adjusting a pulse setting of a system for controlling blood pressure, the method comprising: The atrial pressure data may include receiving a pulse signal having a first pulse setting. The atrial pressure may result from the system delivering a stimulation pulse to the heart. The method may further include analyzing the intra-atrial pressure data and providing a second pulse setting, different from the first pulse setting, adjusted according to the analysis. The analyzing may include analyzing the intra-atrial pressure data to estimate a time overlap between the intra-atrial pressure caused by the atrial contraction and a passive increase in intra-atrial pressure in the atrium. The analyzing may further include plotting the intra-atrial pressure data and / or mathematically analyzing the intra-atrial pressure data.

[0249] An embodiment may provide a system for lowering blood pressure. The system may include components such as those shown in FIG. 14. The system includes a means for providing information about the internal pressure variations in the atrium during at least one cardiac cycle of the heart, a stimulation pulse. means for generating a stimulation pulse to at least one cardiac chamber; and means for applying a stimulation pulse to at least one cardiac chamber. The means for generating stimulation pulses may be configured to generate stimulation pulses to control the timing of atrial contractions relative to the timing of ventricular contractions during a single cardiac cycle according to information about internal pressure variations in the atrium. In one embodiment, the means for providing information may first sense information (e.g., internal pressure and the time between internal pressure changes) and the means for generating stimulation pulses may then time the stimulation based on this information.

[0250] The information about pressure variations in the atria may include information about the occurrence of atrial contractions and / or information about the occurrence of ventricular contractions, including information about the relative timing of peak atrial pressure caused by atrial contraction and peak passive atrial pressure rise. The information may be, for example, one or more of atrial contraction, ventricular contraction, atrioventricular valve opening, atrioventricular valve closing, atrial electrical activity, ventricular electrical activity, blood flow, atrial refractory period, and heart rate. The occurrence of one or more cardiac events as described herein, including a plurality of The information may include information related to the time and / or timing.

[0251] The means for generating a stimulation pulse causes an atrial contraction for at least one cardiac cycle. The means for generating stimulation pulses may be configured to generate at least one atrial stimulation pulse and / or at least one ventricular stimulation pulse causing a ventricular contraction. The means for generating stimulation pulses may generate the at least one atrial stimulation pulse based on information about the occurrence of an atrial contraction and / or information about the occurrence of a ventricular contraction in a timed relationship to the occurrence of an atrial contraction and / or the occurrence of a ventricular contraction, and / or generate the at least one atrial stimulation pulse based on information about the occurrence of atrial contraction and / or information about the occurrence of a ventricular contraction in a timed relationship to the occurrence of atrial contraction and / or the occurrence of a ventricular contraction. The at least one ventricular stimulation pulse may be configured to be generated based on the information about the occurrence of a ventricular contraction and / or the information about the occurrence of an atrial contraction in a timed relationship to the occurrence of an atrial contraction. The information contained information about the occurrence of P-wave patterns in the natural stimulation pattern of the cardiac cycle. The information about the occurrence of ventricular contractions may include information about the occurrence of QRS complexes in the natural stimulation pattern of the cardiac cycle.

[0252] The timing of atrial contraction relative to ventricular contraction corresponds to an AV delay ranging from approximately 30 ms to approximately 0 ms. The means for generating a stimulation pulse may be configured to generate a stimulation pulse within a range of about 30 ms to about 0 ms before ventricular excitation occurs. Provides an excitatory stimulus to the atrium, and excitatory stimulation occurs within a range of approximately 30 ms to 0 ms after atrial excitation occurs. The stimulation pulse is configured to generate a stimulation pulse to provide a stimulation to a ventricle and / or to provide an excitatory stimulation to an atrium and then provide an excitatory stimulation to a ventricle within a range of about 30 ms to about 0 ms. This may also be the case.

[0253] Other embodiments may provide a different system for lowering blood pressure. The system may include components such as those shown in FIG. 14. In these other embodiments, the system for lowering blood pressure may include one or more cardiac activity indicators. The cardiac activity monitoring device may include means for providing information about timing of vents, means for generating stimulation pulses, and means for applying stimulation pulses to at least one cardiac chamber. The information about timing of the one or more cardiac activity events may include at least one of: occurrence of atrial contraction of the atrium, occurrence of ventricular contraction of the ventricle, opening of an atrioventricular valve, closing of an atrioventricular valve, electrical activity of the atrium, electrical activity of the ventricle, blood flow, intraatrial pressure of the atrium, change in intraatrial pressure of the atrium, atrial refractory period, and heart rate. The means for generating stimulation pulses determines ventricular contraction based on the information. The stimulation pulse may be configured to generate a stimulation pulse to time atrial contraction relative to the systole.

[0254] The timing of atrial contraction relative to ventricular contraction corresponds to an AV delay ranging from approximately 30 ms to approximately 0 ms. The means for generating a stimulation pulse may be configured to generate a stimulation pulse within a range of about 30 ms to about 0 ms before ventricular excitation occurs. Provides an excitatory stimulus to the atrium, and excitatory stimulation occurs within a range of approximately 30 ms to 0 ms after atrial excitation occurs. The stimulation pulse is configured to generate a stimulation pulse to provide a stimulation to a ventricle and / or to provide an excitatory stimulation to an atrium and then provide an excitatory stimulation to a ventricle within a range of about 30 ms to about 0 ms. This may also be the case.

[0255] Information about the timing of one or more cardiac activity events is collected during a single cardiac cycle. It contains information about the timing between two or more cardiac activity events. Good too.

[0256] The means for generating a stimulation pulse causes an atrial contraction for at least one cardiac cycle. at least one atrial stimulation pulse and / or at least one ventricular contraction The means for generating the stimulation pulse may be configured to generate at least one atrial stimulation pulse based on information about the occurrence of an atrial contraction and / or information about the occurrence of a ventricular contraction in a timed relationship to the occurrence of an atrial contraction and / or the occurrence of a ventricular contraction, and / or to generate at least one atrial stimulation pulse based on information about the occurrence of atrial contraction and / or information about the occurrence of a ventricular contraction in a timed relationship to the occurrence of atrial contraction and / or the occurrence of a ventricular contraction. The at least one ventricular stimulation pulse may be configured to be generated based on the information about the occurrence of a ventricular contraction and / or the information about the occurrence of an atrial contraction in a timed relationship to the occurrence of an atrial contraction. The information contained information about the occurrence of P-wave patterns in the natural stimulation pattern of the cardiac cycle. The information about the occurrence of ventricular contractions may include information about the occurrence of QRS complexes in the natural stimulation pattern of the cardiac cycle.

[0257] Control of tufted stimulation In some embodiments, stimulating the heart in such a way that the contribution of atrial contraction to the filling of the ventricles (atrial stimulation) is reduced or even prevented reduces cardiac filling at the end of diastole, resulting in a reduction in blood pressure. For simplicity, in the following description, such stimulation is referred to as "Blood Pressure Reducing (BPR) stimulation." BPR stimulation is an atrial stimulation. At least one chamber of the heart is provided with at least one small insufficiency region so that the occurrence of hypercalcaemia is reduced or even prevented. Such a pulse may include delivering at least one stimulation pulse. In the present specification, the term "stimulation pulse" is referred to as a "BPR stimulation pulse" or "BPR pulse." As discussed above, a "stimulation pulse" may include a sequence of one or more electrical pulses delivered to one or more chambers of the heart within the time frame of a single beat or cardiac cycle. For example, in some embodiments, a stimulation pulse may include one or more electrical pulses delivered to one or more locations in the ventricles and / or one or more electrical pulses delivered to one or more locations in the atria. Thus, in some embodiments, a stimulation pulse may include a first electrical pulse delivered to an atrium and a second electrical pulse delivered to a corresponding ventricle. In some embodiments, a stimulation pulse may include a first electrical pulse delivered to a corresponding atrium and a second electrical pulse delivered to a corresponding ventricle. It may involve a single pulse being delivered to multiple locations.

[0258] Stimulation settings refer to one or more parameters of one or more stimulation pulses delivered in a single cardiac cycle. For example, these parameters may include power, (power), the time interval between electrical pulses contained in a single stimulation pulse (e.g. AV delay ), the duration of the delivery relative to the natural rhythm of the heart, the length of the stimulation pulse or a portion thereof, and the location of the delivery between two or more chambers and / or within a single chamber. A BPR stimulation configuration or "BPR configuration" may include a configuration of one or more BPR pulses.

[0259] A stimulation pattern may include a series of pulses having the same stimulation setting, or a stimulation pattern may include multiple pulses, each having a different stimulation setting. For example, a stimulation pattern may have one or more pulses having a first setting and one or more pulses having a second setting that is different from the first setting. When a stimulation pattern is said to be in a state where it is ... It is understood to mean that in some embodiments, a stimulation pattern may include one or more cardiac cycles during which no stimulation pulse is delivered. In that case, the pulses can be considered to be delivered with zero power. A stimulation pattern can be a sequence of multiple identical pulses or pulses containing two or more different settings. Two stimulation sequences in one pattern may be included in one setting. The two or more stimulation sequences may differ in the order of the pulses provided. Preferably, they may differ in length (in duration and / or number of beats). In some embodiments, the stimulation pattern includes pulses having a BPR setting. In some embodiments, the stimulation pattern may include pulses that do not have a BPR setting. It's fine.

[0260] Example of stimulation settings configured to reduce or prevent atrial kicks in at least one ventricle. may include stimulation settings disclosed herein configured to cause a reduction in the patient's ventricular filling volume from a pre-treatment ventricular filling volume. This may be caused by causing at least some atrial contraction to occur against a closed AV valve. Some such examples may include:

[0261] a. Deliver one or more stimulation pulses to the patient between 0 and 50 ms before the onset of excitation in the patient's atrium. and delivering one or more stimulation pulses to the atrium. Preferably, this delay is set based on an atrial activation setting. Preferably, this includes delivering one or more stimulation pulses to the atrium 0-50 ms after delivery of the stimulation pulse to the ventricle. Preferably, this is done at a rate slightly higher than the patient's natural heart rate.

[0262] b. Deliver one or more stimulation pulses to the patient 0–70 ms after activation of the patient's atrium. and delivering to the ventricle. Preferably, the delay is set based on sensing of atrial activation. Preferably, this includes delivering one or more stimulation pulses to the atrium 0-70 ms prior to delivery of the stimulation pulse to the ventricle. Preferably, this is done at a rate slightly higher than the patient's natural heart rate.

[0263] Some embodiments may provide a system for reducing blood pressure that is configured to deliver stimulation at a rate higher than the natural heart rate based on a detected natural heart rate or natural activation. For example, the system may be configured to detect natural activation during the delivery of stimulation pulses, and if natural activity is detected, the system may be configured to inhibit delivery of stimulation pulses to the chamber. If the amount of detected activation exceeds a threshold within a given time frame, the natural heart rate may be considered to be higher than the number of stimulation pulse deliveries, in which case the number of deliveries may be increased, for example to accommodate the patient's increased heart rate. On the other hand, if the amount of detected activation exceeds a threshold within a given time frame, the natural heart rate may be considered to be higher than the number of stimulation pulse deliveries, in which case the number of deliveries may be increased, for example to accommodate the patient's increased heart rate. If the amount of activation received is below a threshold (which may be 0), the natural heartbeat is suppressed by the stimulation. It may be considered that the number of deliveries of the instimulating pulse is lower than the number of deliveries of the instimulating pulse, in which case the number of deliveries may be reduced to avoid, for example, excessive excitation of the patient's heart.

[0264] To achieve this effect, according to one embodiment, a system for reducing blood pressure senses the excitation rate of at least one of the atria and ventricles of a patient's heart. The cardiac stimulation device may include a sensor for sensing an activation rate of at least one of the atria and ventricles, a stimulation circuit configured to deliver stimulation pulses to the atria and ventricles, and a processor circuit coupled to the stimulation circuit. Preferably, the sensor for sensing an activation rate of at least one of the atria and ventricles may include an electrode for sensing atrial activation. The processor circuit may be configured to detect a patient's heart rate based on the sensing and to operate in a mode of operation in which stimulation pulses are delivered to each of the atria and at least one of the ventricles. The stimulation pulses may be delivered at a rate higher than the sensed activation rate and may be configured to stimulate the ventricles at a time between about 50 ms before and about 70 ms after stimulation of the atrium.

[0265] Reducing atrial kick may have an immediate effect on blood pressure, while hormone mediated mechanisms may take longer periods. Some devices may be configured to have both immediate and hormone mediated effects, but preferably some of the BPR settings and / or stimulation patterns may be configured to reduce or prevent atrial kick without a significant increase in atrial expansion. For example, if the AV valve closes at or after the atrial contraction is at peak pressure, there will be no increase in atrial expansion due to premature closure of the valve.

[0266] Thus, in some embodiments, the device may be configured to produce relative timing of atrial and ventricular activation comparable to an AV delay at least 40 ms long or at least 50 ms long. Atrial stretch may be measured, calculated and / or estimated in a manner known in the art. In some embodiments, the atrial stretch determination may include measuring atrial pressure. In some embodiments, the atrial expansion calculation may include measuring or estimating atrial dimensions (e.g., diameter, size or circumference).

[0267] In some embodiments, the atrial kick may be reduced because the BPR stimulation settings may be set such that the atrial contraction of the cardiac cycle is incomplete when the AV valve is open. In some embodiments, atrial contraction may occur completely or partially against a closed AV valve, hi some embodiments, atrial contraction may be effectively prevented or reduced in pressure and / or force.

[0268] In some embodiments, only one or more ventricles may be stimulated, and the stimulation pulses may be delivered to different Even if the pulse is timed to have a normal AV delay (e.g., 50 ms before and 120 ms after atrial activation), In some embodiments, the BPR stimulation settings include at least one electrical current to one or more atria. In some embodiments, the at least one atrial stimulus may include delivery of an electrical pulse or stimulus. In some embodiments, the at least one atrial stimulus may cause an atrial contraction. At least one atrial stimulus may interfere with atrial contraction. At least one atrial pulse may cause an atrial spasm or other type of inefficient atrial contraction. There is a match.

[0269] The reduction in blood pressure resulting from BPR stimulation may be observed virtually immediately upon application of the stimulation signal (e.g., within 1 or 3 seconds or within 1, 3 or 5 beats), and may be observed within 5 beats from the onset of stimulation. A minimum blood pressure value may be reached within less than one minute.

[0270] By controlling the settings of the BPR stimulation, the degree to which BP is reduced may be controlled. The degree may in some cases be patient specific and / or related to the exact location of one or more stimulating and / or sensing electrodes in or on the heart.

[0271] The extent to which BP is lowered may be controlled by controlling the settings of the BPR stimulation. The degree of injury may sometimes be patient specific and / or may involve one or more This relates to the precise placement of the stimulating and / or sensing electrodes. The degree to which BP changes can be a function of, for example, the AV delay, and so this functional relationship may be used to select an AV delay that provides a desired change in BP, or vice versa. An example of this functional relationship is shown in FIG. 24, which is described in more detail below.

[0272] Adaptation a. The inventors have demonstrated that while stimulation is maintained, blood pressure increases after a period of time. They found that blood pressures could show adaptive patterns (some of which often occurred over short periods of time, less than 5 or even 1 minute) and could reach levels close to or even higher than pre-stimulus values ​​(at least due to baroreflex in some cases). Adaptation was due, at least in part, to changes in the properties of the cardiovascular system, such as an increase in total peripheral resistance. The inventors further discovered that termination of stimulation results in a rapid return of blood pressure to pre-stimulation values ​​or even higher values, and that the heart thereafter responds to the blood pressure reducing stimulation signal to a degree similar to a heart that was not so stimulated. Additionally, different stimulation patterns with multiple BPR stimulation settings may result in different blood pressure reductions. This has been found to lead to a pressure-adaptive pattern.

[0273] b. The stimulation pattern may, for example, comprise at least one first stimulation setting and a second stimulation setting different from the first stimulation setting, the first stimulation setting and the second stimulation setting being an atrial kit. The stimulation pattern may be configured to reduce or prevent atrial pressure, atrial dilation, or both. In some embodiments, the second setting may include a longer AV delay than the first setting (e.g., about 80 ms to about 160 ms). In some embodiments, the second setting may not be configured to reduce atrial kick and / or control intra-atrial pressure, atrial expansion.

[0274] In Figure 1, the systolic blood pressure of a hypertensive patient receiving a stimulation signal is plotted against time. The crosses along the plotted line indicate the peak systolic blood pressure for each beat. The plot shows the pressure. During approximately the first 2 minutes of the plot, no stimulation signal was delivered. As can be seen, the initial blood pressure of the patients averaged over 150 mmHg. The blood pressure oscillations (approximately ±10 mmHg) are due to the respiratory cycle, as is known in the art.

[0275] A first stimulation pattern is then applied during time interval a-a' and a second stimulation pattern is applied during time interval a-a'. A first stimulation pattern was applied during time interval b-b', and a third stimulation pattern was applied during time interval c-c'. After the middle and third stimulation patterns of the line, the heart was not stimulated.

[0276] Attention is now directed to FIG. 2, which shows an enlarged portion of the portion of FIG. 1 designated by dashed rectangle A. During the time designated by the dashed rectangle in FIG. 2, which corresponds to time interval a-a' in FIG. 1, stimulation begins and is delivered to the patient's right atrium and right ventricle, such that the atrium receives the BPR stimulation signal (pulse) 2 ms before the ventricle. Stimulation ends at the time designated a' in FIGS. 1 and 2. During time interval a-a', the patient's systolic pressure first decreases to a minimum of less than 110 mmHg, then increases to an initial blood pressure of less than 110 mmHg. and the minimum value achieved. At point a', the stimulation was stopped and an immediate overshoot of the blood pressure was observed to a value in excess of 170 mmHg. Within about a dozen beats, the blood pressure Back to that original range.

[0277] The blood pressure changes shown in Figures 1 and 2 are indicative, at least in part, of the cardiovascular system's response to changes in blood pressure, known as the baroreflex. The baroreflex modulates blood pressure to a given stimulus by altering cardiovascular characteristics (e.g., peripheral resistance and / or myocardial contractility). It may be assumed that the reduction in blood pressure resulting from the reduction in ventricular filling elicits a baroreflex response directed towards restoring the pre-stimulus blood pressure. The effect of the baroreflex on the cardiovascular system is evident, for example, at point a' in FIG. 2. At this point, the stimulus that affected ventricular filling has been withdrawn and the blood pressure immediately exceeds the pre-stimulus blood pressure. This may be taken to indicate a baroreflex change on the cardiovascular system (e.g., increased peripheral resistance and increased contractility). At point a', when the stimulus has ceased and the blood pressure has peaked, in this case The baroreflex acts on one or more features of the cardiovascular system to reduce blood pressure to its pre-change level. The stimulation pattern responded to the increase in blood pressure by again changing the stimulation pattern. As can be clearly seen, the response of the baroreflex feedback to increases and decreases in blood pressure is asymmetric in that the response to increases in blood pressure is much faster than the response to decreases in blood pressure. In some embodiments, this asymmetry of the baroreflex may be exploited, for example, by controlling the stimulation pattern accordingly, as detailed herein, to reduce or even prevent adaptation of reduced blood pressure due to reduced filling.

[0278] FIG. 3A shows an expanded view of the curve of FIG. 1 between time points a and a'. In FIG. 3A, the exponential function The data were fitted to a plotted curve showing the adaptation response. The numbers describe the relationship between time and SysBP and have the following formula:

[0279] P = Pi + DP(1-e -t / k ) where P (in mmHg) represents the systolic blood pressure, Pi (mmHg) is the first average reduced blood pressure at the start of BPR stimulation, and DP (mmHg) is the mean reduced blood pressure after the initial drop to a new steady-state level. where k (seconds) is the response time constant, e is a mathematical constant that is the base of the natural logarithm, and t (seconds) is time.

[0280] In FIG. 3A, the matching function was:

[0281] P = 115 + 23(1-e -t / 15.5 ) Where Pi was found to be 115mmHg. DP was 23mmHg. K was 15.5 seconds.

[0282] FIG. 3B shows an expanded view of the portion of FIG. 1 indicated by the dashed rectangle A'. In FIG. 3B, an exponential function was fitted to the plotted curve showing the adaptation response to the end of delivery of the BPR stimulus. As can be seen, this response in terms of blood pressure reduction was faster than the response to BPR stimulation. .

[0283] In FIG. 3B, the matching function was:

[0284] P=190-35(1 - e -t / 4.946 ) where Pi was found to be 190mmHg. DP was -35mmHg. K was 4.946 seconds.

[0285] As mentioned above, the baroreflex response to a reduction in blood pressure is much slower than the baroreflex response to an increase in blood pressure. This is shown as the ratio of the time constant k (about 15 seconds to about 5 seconds) mentioned above to the much faster response to an increase in blood pressure. This asymmetry in the speed of the baroreflex response may provide a means to design stimulation patterns that produce mean blood pressure reductions and reduced or even prevented adaptation. For example, in a preferred embodiment, the stimulation pattern may alternate between two stimulation settings in a manner where the weighted response favors the cardiovascular changes caused by an increase in blood pressure. In this embodiment, the stimulation pattern may alternate between two stimulation settings in a manner where the weighted response favors the cardiovascular changes caused by an increase in blood pressure. The first setting is designed to reduce blood pressure and the second setting allows normal ventricular filling or at least Two stimulations were performed with the second setting designed to have a higher ventricular filling than the first setting. The heart may be stimulated using a stimulation pattern having a setting that may include pulses having a first setting (BPR) that are delivered for a period shorter than the time constant of the baroreflex response to a decrease in blood pressure. In such a case, adaptation may begin to become evident and blood pressure may increase from a reduced level, but may not reach its pre-stimulation level.

[0286] The stimulation pattern may also include pulses having a second setting (e.g., the natural AV delay) that are delivered for a period longer than the time constant of the baroreflex response to an increase in blood pressure. In some cases, it may even be possible to take advantage of the baroreflex-induced reduction in blood pressure, and blood pressure may even return to its level before the stimulation pattern was switched to this second setting. The weighted response of the baroreflex in such a pattern may reduce or prevent adaptation, but the average pressure may be lower than the pre-stimulation level. The relationship between the time constant and the duration assigned to the delivery of pulses with different settings may determine the level of baroreflex response that is in effect during the entire stimulation pattern. For a given stimulation setting, if the duration of delivery is selected to be shorter than the time constant of the response, the baroreflex may not be able to alter the cardiovascular system back to the pre-stimulation level, and if the selected duration is greater than the time constant, the baroreflex effect may be more pronounced.

[0287] As can be seen in FIG. 1, in the interval between points b and b′, ​​a second stimulation pattern was delivered. FIG. 4 shows an expanded version of this portion of FIG. 1 (indicated by dashed rectangle B in FIG. 1). In the second stimulation pattern, a sequence of 12 BPR pulses is delivered to the atrial and contraventricular ventricles with an AV delay of 2 ms. During this period, the atrial impulse was delivered to both the corresponding ventricles, followed by three beats in which only the atrial impulse was artificially delivered and no ventricular impulse was delivered. During these last three beats, ventricular activation occurred via natural conductance through the AV node resulting in an AV delay of ~180 ms. This second stimulation pattern was repeated for the duration of the time interval previously mentioned. In FIG. 4, an exponential function fit to the curve was found to be:

[0288] P = 112 + 30(1-e -t / 25.5 ) As can be seen, Pi and also DP were comparable to the corresponding values ​​of the first stimulation pattern (a-a' in FIG. 3A). However, k of the second pattern was nearly twice the time constant of the first stimulation pattern. In this time interval, adaptation occurred at a slower rate than in FIG. 3A, but blood pressure rose more rapidly when the pattern switched between stimulation pulses than in FIG. 3A. This result demonstrates that the use of stimulation patterns with alternating stimulation settings reduces adaptation.

[0289] A third stimulation pattern was similarly delivered between points c and c' as seen in Figure 1. Figure 5A shows an enlarged view of the portion of Figure 1 indicated by dashed rectangle C, including the portion of the curve between points c and c'. In the third stimulation pattern, a sequence of 12 BPR pulses was delivered with an AV delay of 2 ms, followed by three BPR pulses each with an AV delay of 120 ms. This was repeated for the duration of the time interval previously mentioned.

[0290] The portion of the curve in FIG. 5A indicated by the dashed rectangle is plotted in FIG. 5B. In FIG. 5B, the plotted curve shows the adaptation response to delivery of a stimulation pattern of 12 BPR pulses delivered with an AV delay of 2 ms, followed by three BPR pulses each with an AV delay of 120 ms. , an exponential function was fitted.

[0291] In FIG. 5B, the exponential function was:

[0292] P = 109.7 + 22.3(1 - e -t / 45.4 ) where Pi was found to be 109.7 mmHg. DP was 22.3 mmHg. K was 45.4 seconds. As can be seen, the initial reduction in blood pressure was comparable to that shown in Figure 3A (Pi = 115 or 109.5), but the adaptation time constant (k) was higher (45.4 seconds vs. 15.5 seconds). This is consistent with the results shown in Figure 3A. This means that low blood pressure was maintained for a period approximately three times longer than in the control group.

[0293] Attention is now directed to Figure 6, in which a hypertensive patient's heart was stimulated with a stimulation pattern having a sequence of 12 BPR pulses delivered with an AV delay of 2 ms, followed by three BPR pulses each with an AV delay of 80 ms.

[0294] As can be seen, in this case the adaptation rate was very low and barely detectable in the allotted time interval. The exponential formula could not be fitted. This suggests that adaptation was extremely slow or nonexistent.

[0295] In Figure 7, a stimulation pattern was created with a sequence of 12 BPR pulses delivered with an AV delay of 2 ms. In this study, the heart of a hypertensive patient was stimulated with three BPR pulses, each with an AV delay of 40 ms. The stimulation was performed at point t 1 It starts at point t 2 There was no measured adaptive response, the fitted curve was indeed linear, and the time interval t 1 -t 2 31mmHg higher than the blood pressure immediately before and after The patient had a fixed mean reduced blood pressure of approximately 112 mmHg.

[0296] As is evident from the different stimulation patterns described above, a stimulation pattern comprising at least one BPR stimulus can be configured to at least approximate one or more targets. For example, in some embodiments, the stimulation pattern may be configured to cause an initial reduction in blood pressure (systolic and / or diastolic) that exceeds a predetermined threshold or falls within a predetermined range. In more particular embodiments, the blood pressure may be increased by at least a given percentage or by at least a given measure (e.g., by 10% or more). The blood pressure may be reduced by a given amount (e.g., SysBP of 90-130 mmHg) or may be reduced to within a given range (e.g., SysBP of 90-130 mmHg) or below a given target (e.g., SysBP of 130 mmHg or less). In some embodiments, the target may include maintaining the reduced blood pressure within a reduced average range for an extended period of time. For example, a given blood pressure may be reduced to a given average blood pressure for a period of time or for a number of beats.

[0297] In another embodiment, the goal is to reduce a given percentage of beats to a reduced range / threshold. In some embodiments, the goal may include reducing blood pressure while also reducing the level of spikes between stimulation pulses. For example, a stimulation pattern may be used to reduce blood pressure to a constant blood pressure for a predetermined time interval. In some embodiments, a stimulation pattern may be used to reduce blood pressure without significantly affecting cardiac output. For example, intermittent BPR pulses may be used to reduce blood pressure to a constant blood pressure for a predetermined time interval. By applying a higher atrial kick, a pulse with a higher (or even sufficient) atrial kick may occur during the BPR pulse. Pulses with a throttling mechanism can prevent BPR pulses from significantly reducing cardiac output. .

[0298] In another embodiment, cardiac output can be dynamically affected by affecting flow through the vasculature by reducing the adaptations associated with lowering total peripheral resistance along with reducing blood pressure (afterload). In yet another embodiment, pacing at a higher rate than the patient's natural rhythm can avoid the negative effects on cardiac output that may be associated with lower stroke volumes.

[0299] When configuring stimulation patterns to approach one or more targets, different values ​​of blood pressure hypotension Providing a reduction may include adjusting stimulation parameters that affect the AV delay. For example, stimulation parameters that provide a shorter AV delay may reduce blood pressure to a greater extent than stimulation parameters that provide a longer AV delay. In embodiments, stimulation settings that reduce atrial stimulation vary from about 5 ms to about 30 ms (e.g., between daytime and nighttime, or between nighttime and daytime). An AV delay (between vigorous and light activity) may be provided, with a shorter AV delay resulting in a greater reduction in blood pressure.

[0300] Providing different amounts of blood pressure reduction may include varying stimulation parameters other than the short AV delay duration. For example, in some embodiments, the ratio of short AV delays to longer AV delays may be adjusted. As another example, other embodiments may adjust the heart rate where pulses with short AV delays are delivered compared to heart rates with longer AV delays.

[0301] In some embodiments, a time constant for a given pattern of blood pressure change may be calculated, and the stimulation pattern may be configured to have one or more BPR stimulation parameters for the amount of time or number of beats set as a particular percentage of the calculated time constant. For example, in FIGs. 3A and 3B, k was measured to be about 15 seconds for the rate of increase in blood pressure during delivery of the BPR pulse, and about 4.9 seconds for the rate of adaptation to the end of delivery of the BPR pulse. In some embodiments, it may be desirable to prevent blood pressure from increasing beyond a given value, in which case the period of delivery of the BPR pulse will be significantly less than k (e.g., 30% to 6% of k). In this embodiment, the interval is selected to be less than 15 seconds. Such intervals may be about 6 to 10 seconds or 8 seconds, which results in a heart rate of about 80 beats per minute. May contain ~14 beats.

[0302] Preferably, an adaptive response to the delay of the BPR pulse is utilized. In such cases, a larger fraction of k may be applied. For example, based on FIG. 3B, 3 to 5 drums A period of motion may be selected where k is approximately 4.9 seconds. Thus, for example, based on Figures 3A and 3B, the inventors applied the stimulation pattern of Figure 4.

[0303] The stimulation pattern may be set, for example, to be the best of multiple stimulation patterns (i.e., the one closest to the set target parameters) and / or to be the best of the set target parameters. may be selected as the first tested stimulation pattern that matches.

[0304] Slow Baroreflex Response-Based Embodiments In experiments with dogs, the inventors found that if treatment is terminated after several days of treatment, it may take a relatively long time for blood pressure to return to its pre-treatment value. This slow baroreflex response can be exploited. In particular, in embodiments, treatment (e.g., normal pacing or no pacing at all) can be suspended for long periods of time, thereby allowing for battery power savings and longer service life of the stimulator.

[0305] As an example of a slow baroreflex response, see FIG. 27, which is a graph showing the effect of blood pressure lowering treatment in dogs as disclosed herein, plotting the change in systolic blood pressure (mmHg) over time (days). As shown in the graph, blood pressure values ​​before treatment are indicated by the baseline ("BL") marked with diamond data points, values ​​during the treatment period are indicated by the treatment line marked with square data points, and values ​​after treatment are indicated by the device off ("Dev Off") line marked with triangle data points. In this experiment, convergence Systolic blood pressure was measured continuously over a 24-hour period using an implantable sensor that transmitted systolic pressure to a receiver, with each data point on the graph representing the average measurement over the 24-hour period.

[0306] The canine subjects exhibited a blood pressure of approximately 210 mmHg, as shown by the baseline in FIG. Immediately upon application of the blood pressure lowering treatment disclosed throughout this disclosure, the dog's blood pressure was reduced to approximately 170 mmHg, as shown by the treatment line in Figure 27. During the treatment period, the dog's blood pressure ranged between about 150 mmHg and about 175 mmHg (i.e., about 35-60 mmHg lower than pretreatment values). The treatment was applied for 30 days.

[0307] When the treatment was stopped (pacing was no longer applied to the dog's heart), the dog's blood pressure increased slightly to about 180 mmHg as shown by the device offline in FIG. The blood pressure of the dogs remained at that level for about 20 days, after which it gradually began to rise back to nearly pre-treatment levels.

[0308] Considering the mechanism of a slow baroreflex response, such as the response illustrated in FIG. 27, an embodiment provides a first stimulation pattern (i.e., a therapeutic stimulation pattern) configured to reduce blood pressure. and a second stimulation pattern (i.e., In one embodiment, the present invention provides a method for treating hypertension that includes alternating a "stimulation" pattern with a "rest" pattern of stimulation, each of which may be appropriately administered over a period of days, weeks, or longer. In embodiments, each of the two patterns may be applied for at least one week, providing treatment over a weekly timescale. The resting stimulation pattern may involve stimulation or no stimulation at all.

[0309] In an embodiment, the duration of the first stimulus and the second stimulus pattern may be the same or different.

[0310] For example, the duration of the resting stimulation pattern may be shorter than the duration of the therapeutic stimulation pattern, for example, 25% to 90%, or in some cases 50% to 80% thereof. In one embodiment, the duration of the resting stimulation pattern may be about 2 / 3 of the duration of the therapeutic stimulation pattern.

[0311] The duration of the pause stimulation pattern may be dependent on or proportional to the extent of the reduction in blood pressure caused by the therapeutic stimulation pattern, for example, if the therapeutic stimulation pattern is configured to reduce blood pressure by at least 50 mmHg, the pause stimulation pattern may last longer than if the therapeutic stimulation pattern is configured to reduce blood pressure by only 30 mmHg.

[0312] If desired, the duration of the resting stimulation phase may be 2 weeks to 1 month (eg, 14 to 31 days) or less, regardless of the duration of the therapeutic stimulation pattern.

[0313] Each stimulation pattern may include multiple stimulation patterns, at least some of which may include one or more facilitatory stimulation reduction pulse settings, e.g., according to one or more of the patterns described in this disclosure. For example, during a therapeutic stimulation pattern phase, the treatment may include variations as needed (e.g., alternating between day and night settings).

[0314] In an embodiment, the resting stimulation pattern includes (1) no application of pacing, (2) pacing without atrial stimulation reduction, and (3) a stimulation pattern that provides a greater overall and / or average stimulation effect than the therapeutic stimulation pattern. A small reduction in atrial stimulation may be selected from pacing. Optionally, the rest stimulation pattern may include switching from one rest stimulation pattern to another. The rest stimulation pattern may not necessarily completely stop the blood pressure reduction, and may include, for example, applying very few atrial stimulation reduction pulses (e.g., no more than 10 pulses in a 20 minute period), or alternating one degree of blood pressure reduction with another different degree of blood pressure reduction.

[0315] In other embodiments, more than two stimulation patterns may be used for one or more of the therapeutic stimulation and resting periods. For example, a first stimulation pattern providing an AV delay of 2 ms may be used in the first week. Apply pacing to the patient, followed by no pacing for 1 week, and then provide an AV delay of approximately 0–20 ms for 1 month. After that, for 3 or 6 weeks, the stimulation pattern was changed to a 140 ms AV A stimulation pattern providing a delay may also be performed, providing a stimulation phase of approximately 30 ms AV delay once per day for the three or six week period.

[0316] Such a stimulation approach may minimize the duration and degree of electrical stimulation applied to the heart while still maintaining desired long-term blood pressure levels. Method embodiments for setting and / or selecting stimulation patterns A method 600 for setting and / or selecting a stimulation pattern is shown diagrammatically in FIG. Method 600 includes, during implantation of a device for performing BPR and / or AC stimulation, and / or Performed periodically and / or continuously during operation to adjust equipment operating parameters Method 600 may be performed by system 700, which is described below. Thus, system 700 may be configured to perform the steps of method 600. Similarly, method 600 may include steps that system 700 is configured to perform. For example, method 600 may include the functionality described below for system 700. Additionally, method 600 may include the functionality described below for system 700. The method 600 may be performed by the apparatus 50 described below with reference to FIG. The method may include a step configured to:

[0317] Throughout this disclosure, the terms "first," "second," and "third" refer to a sequence of events. No ordering is always meant to be implied. In some cases, these terms are used to distinguish individual events from one another without any reference to an order.

[0318] In some embodiments, step 601 may include setting a target blood pressure value. The goals may include absolute blood pressure values ​​(e.g., target blood pressure ranges, target spike thresholds, and / or or the number or fraction of spikes in a given time frame), a relative value (e.g., compared to the patient's pre-treatment blood pressure or as a comparison between multiple tested stimulation patterns), or both. The target blood pressure value may be associated with a blood pressure value (e.g., measured in mmHg) and / or a formula calculated to fit the stimulation pattern to the blood pressure measurement, etc. This target blood pressure value may be set before, during and / or after other method steps. It may be determined, for example, that the desired response is reached and may be corrected if it is not reached by a tested stimulation pattern.

[0319] Step 602 may include delivering one or more stimulation patterns, including the first stimulation pattern, to one or more chambers of the patient's heart. The first stimulation pattern may be a generic stimulation pattern, or the first stimulation pattern may be a stimulation pattern that is specific to the patient (e.g., implanting a replacement device). The first stimulus may already be selected to suit a given patient (when the first stimulus is inserted). The patterns may include at least one stimulation pattern configured to reduce or prevent atrial kicks in at least one ventricle during a first time interval and / or to control intra-atrial pressure, atrial expansion, or both.

[0320] Step 603 is performed prior to each delivery of one or more stimulation patterns (step 602). and / or after the detection of one or more parameters. The sensed parameters may include sensing intra-atrial pressure to assess overlap between peak atrial pressure values ​​due to contraction and peak atrial pressure values ​​due to ventricular contraction. The sensed parameters may include sensing intra-atrial pressure as a result of delivery of each of the one or more stimulation patterns (step 602) to assess the atrial pressure resulting from the stimulation and, optionally, comparing this atrial pressure to one or more of the atrial pressures resulting from different stimulations or no stimulation. Optionally, the parameter may include a blood pressure value or a parameter related to blood pressure (e.g., a change in blood pressure). In some embodiments, the sensed parameter may include information related to the timing and / or degree of closure and / or opening of the AV valve. In some embodiments, the sensed parameter may include information related to the timing and / or rate of blood flow between the atria and ventricles of the heart. In some embodiments, the sensed parameter may include sensing pressure inside the heart chambers (e.g., the atria and / or ventricles). In some embodiments, sensing the state or position (i.e., open or closed) of the patient's AV valve may include sensing heart sounds, for example, using an audio sensor. In some embodiments, sensing the state of the patient's AV valve may include Doppler sensing and / or imaging of heart motion. In some embodiments, the state of the patient's AV valve may be sensed by a blood flow sensor.

[0321] In some embodiments, blood flow sensing may be performed by one or more implanted sensors in one or more cardiac chambers. For example, one or more pressure sensors may be placed in the right ventricle. In some embodiments, multiple pressure sensors may be located in multiple chambers. Preferably, measurements from multiple sensors may be combined. Preferably, pressure changes, trends in pressure changes, and / or pressure change patterns are used to provide information related to blood flow. In some embodiments, the relative distance between two or more sensors in different chambers may be Comparing the changes may be used.

[0322] Once the stimulation pattern is delivered to the heart (step 602), at least One or more parameters may be measured at any one time, or multiple times, or even continuously. Each stimulation pattern may be delivered more than once.

[0323] Step 604 may include analyzing the sensed parameters. In one embodiment, at least one stimulation pattern is delivered and a corresponding parameter is sensed. Once determined, an analysis may be performed 604. In embodiments where multiple parameters are sensed, comparing the sensed parameter value with a target; and Comparison between stimulation patterns, calculated values ​​related to two or more stimulation patterns (e.g. Step 604 may include comparing a constant (e.g., k) and comparing additional sensed parameters between the two or more stimulation patterns. This last function may be performed to determine and select which stimulation pattern will produce a higher ejection fraction, stroke volume, cardiac output, and / or lower battery usage. .

[0324] Step 605 may include setting a pacing (stimulation) pattern. If more than one parameter is sensed, multiple parameters, multiple targets, and / or multiple stimulation patterns may be set. Based on the target range of numbers, the stimulation pattern used in step 605 may be selected.

[0325] In some embodiments, the steps shown in FIG. 8 may be performed in the order indicated by the arrows in FIG. 8. In other embodiments, the steps may be performed in a different order. For example, step 602 may be performed before setting the target blood pressure value according to step 601. In some embodiments, the stimulation pattern may be set to be performed indefinitely. In some embodiments, the stimulation pattern may be set to be performed for a predetermined period of time. For example, in some embodiments, the stimulation pattern set during step 605 may be performed for a predetermined period of time. Steps 602, 603 and 604 may then be repeated to generate another It may be determined how the stimulation pattern affects the patient's blood pressure. Based on the analysis performed in step 604, step 605 may then also be repeated.

[0326] In some embodiments, the method 600 may include adjusting the first stimulation pattern, thus forming the first stimulation pattern into a second stimulation pattern. In some embodiments, the step 605 of setting the stimulation pattern may include adjusting the stimulation pattern. For example, step 605 may include adjusting a parameter of the first stimulation setting (e.g., the time interval from step 602). Step 605 may include adjusting parameters of a first stimulation setting configured to reduce or prevent atrial kicks in at least one ventricle and / or to control intra-atrial pressure, atrial expansion, or both. In some implementations, step 605 may include adjusting the first stimulation setting to a second stimulation setting configured to cause a reduction in blood pressure by at least a predetermined amount. In some embodiments, the predetermined amount may include, for example, about 8 mmHg to about 30 mmHg. In embodiments, the predetermined amount may be about 4% of the patient's pre-treatment blood pressure. This predetermined amount may be between about 4% and about 30% of the patient's pre-treatment blood pressure. good.

[0327] In some embodiments, step 605 modulates the stimulation pattern by at least a predetermined amount. This may include adjusting the stimulation pattern to be configured to cause an immediate reduction in blood pressure. For example, in some embodiments, step 605 may adjust the stimulation pattern to: The device is designed to cause a reduction in blood pressure by at least a predetermined amount within about 3 seconds of application of electrical current to the heart. In some embodiments, step 605 may include adjusting the stimulation pattern to be within at least five beats of the applied current. In some embodiments, adjusting the stimulation pattern during step 605 to a stimulation pattern configured to cause a reduction in blood pressure by at least a predetermined amount. The reduction in blood pressure resulting from the designed stimulation pattern may occur within 1 to 3 seconds of application of the current to the heart, or within 1, 3 or 5 beats of application of the current to the heart.

[0328] In some embodiments, the stimulation pattern set during step 605 results in The resulting reduction in blood pressure may be such that the patient's average blood pressure at rest is at least 8 mmHg lower than the patient's initial blood pressure at rest. In some embodiments, the reduction in blood pressure resulting from the stimulation pattern established during step 605 is maintained for at least one minute. In some embodiments, the result of the stimulation pattern set during step 605 may be The resulting reduction in blood pressure may be maintained for at least 5 minutes. In the present embodiment, the blood pressure may reach a minimum blood pressure value within less than five beats from the start of stimulation. For example, step 605 may combine a first stimulation pattern with a second stimulation pattern configured to cause a reduction in blood pressure. In some embodiments, step 605 may include adjusting the first stimulation pattern to a second stimulation pattern configured to cause a reduction in blood pressure for a predetermined time interval. For example, The interval may comprise at least 1 minute or at least 5 minutes.

[0329] In some embodiments, the second stimulation pattern is greater than a predetermined degree for a predetermined interval. The blood pressure monitor may be configured to maintain the blood pressure not exceeding a predetermined average value as much as possible. For example, the predetermined amount may be a difference of about 20 mmHg or less. In some embodiments, the predetermined amount may be a difference of about 1 mmHg to about 8 mmHg. In some embodiments, the patient's blood pressure may exceed the predetermined average value for some beats, but the patient's mean blood pressure may not exceed the predetermined average value.

[0330] In some embodiments, the second stimulation pattern may include second stimulation settings configured to reduce or prevent atrial kicks in at least one ventricle and / or control intra-atrial pressure, atrial expansion, or both. The second stimulation settings may be based on at least one blood pressure variability parameter calculated from input data sensed during application of the first stimulation pattern.

[0331] In some embodiments, the second stimulation pattern comprises a stimulation pattern for suppressing blood pressure spikes during the stimulation pattern. In some embodiments, the second stimulation pattern may be configured to reduce or limit the magnitude of the blood pressure spikes between stimulation pulses to a percentage of the basal blood pressure value. For example, the second stimulation pattern may be configured to prevent blood pressure from increasing by more than about 80% between pulses. That is, the second stimulation pattern may be configured to prevent blood pressure from spiking by more than about 80% between pulses. In the second stimulation pattern, the blood pressure is prevented from increasing by more than about 40% between pulses. In some embodiments, the second stimulation pattern may be configured to For example, in some embodiments, the second stimulation pattern may be configured to prevent blood pressure spikes of more than about 20 mmHg between pulses. The device may be configured to prevent a sudden rise in blood pressure caused by the

[0332] In some embodiments, the second stimulation pattern may comprise a plurality of stimulation pulses. At least one stimulation pulse of the plurality of stimulation pulses may have a first stimulation setting configured to reduce atrial kick in at least one ventricle and / or to control intra-atrial pressure, atrial expansion, or both. At least one stimulation pulse is delivered, and the increase in blood pressure between the stimulation pulses is limited to a predetermined value. In some embodiments, the second stimulation pattern may have a second stimulation setting configured to reduce atrial kick or reduce the baroreflex response to control of atrial expansion so as to reduce the atrial kick. The stimulation pattern may be configured to increase blood pressure for about 1 to 5 heartbeats to elicit a baroreflex response. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting and a plurality of stimulation pulses having a second stimulation setting. In some embodiments, between about 1% and multiple of the stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation setting may be present during about 40% of the pulses. The second stimulation pattern includes a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In such an embodiment, between about 1% of the plurality of stimulation pulses and about 40% of the plurality of stimulation pulses of the stimulation pattern may have the second stimulation setting.

[0333] In some embodiments, the stimulation pattern may include a ratio of stimulation pulses having a first stimulation setting to stimulation pulses having a second stimulation setting based on the ratio of time constants of responses to increases and decreases in blood pressure. The ratio of stimulation pulses having the first stimulation setting is In some embodiments, the first stimulation setting may include a first AV delay and the second stimulation setting may include a second AV delay, the first AV delay being shorter than the second AV delay. In some embodiments, the second stimulation pattern includes a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. and one or more stimulation pulses having a stimulation setting. The second stimulation pattern is a first stimulation pattern for about 2 to about 5 stimulation pulses having a second setting. In some embodiments, the stimulation pulse rate may include between about 8 and about 13 stimulation pulses having a constant rate. In the second stimulation pattern, a stimulation pattern is configured to elicit a hormonal response from the patient's body. In some embodiments, the stimulation pulse may include at least one stimulation pulse having a stimulation setting. The first stimulation pattern was configured to not elicit a hormonal response from the patient's body. The stimulation setting may include at least one stimulation pulse. In a given sequence of stimulation patterns, a second stimulation pattern may be applied before a first stimulation pattern.

[0334] In some embodiments, method 600 may include alternating between two or more stimulation patterns. For example, method 600 may include alternating between two to ten stimulation patterns.

[0335] In some embodiments, the blood pressure sensor and controller may be configured to operate at least partially as a closed loop.

[0336] In some embodiments, the method 600 applies a plurality of stimulation patterns and, during stimulation, The controller may include a controller configured to receive, for each of the stimulation patterns, corresponding input data related to a blood pressure of the patient. The stimulation patterns may include at least one cardiac stimulation pattern. At least one stimulator having stimulation settings configured to reduce or prevent atrial kicks in the chamber and / or to control intra-atrial pressure, atrial expansion, or both. The stimulation pattern may include at least two stimulation patterns each having an intense pulse. The two stimulation patterns may differ from each other by the number or length of time that the at least one stimulation pulse is delivered in succession. The stimulation settings may differ from each other by the number or length of time that the AV delays occur consecutively. In some embodiments, the stimulation settings are In some embodiments, the stimulation settings may be the same for at least two stimulations. Each of the patterns may include the same AV delay. In some embodiments, the at least two stimulation patterns may differ from one another by one or more stimulation settings included within each of the at least two stimulation patterns.

[0337] In some embodiments, the method 600 includes, for each of a plurality of stimulation patterns, and a controller for calculating at least one blood pressure variability parameter associated with the data. The method 600 may include a controller that adjusts the stimulation pattern according to the blood pressure variability parameter. In some embodiments, the method 600 may include selecting the patient having the best blood pressure variability parameters. The stimulation pattern may include a controller that adjusts the stimulation pattern to result in a stimulation pattern. For example, the best blood pressure variability parameter may include a blood pressure variability parameter that is indicative of a lowest degree of baroreflex. The best blood pressure variability parameter may include a blood pressure variability parameter that is indicative of a baroreflex within a predetermined range.

[0338] In some embodiments, the second stimulation pattern elicits a hormonal response from the patient's body. At least one stimulation pulse having a stimulation setting configured to stimulate In some embodiments, the first stimulation pattern elicits a hormonal response from the patient's body. At least one stimulation pulse having a stimulation setting configured to prevent interference with the stimulation. stomach.

[0339] In some embodiments, the plurality of stimulation patterns may include a first stimulation pattern and a second stimulation pattern administered after the first stimulation pattern, the second stimulation pattern being determined by an algorithm using blood pressure variability parameters associated with input data of the first stimulation setting. The stimulation setting may include at least one stimulation setting that is set based on the stimulation setting.

[0340] System for reducing blood pressure FIG. 9 illustrates a schematic of a system 700 for reducing blood pressure, according to some embodiments. The system 700 may be a single device or may comprise multiple devices, preferably associated by wired or wireless communication. The device may have multiple components disposed within a housing and / or connected to the housing electrically and / or by wires. As shown in FIG. 9, a heart 701 is connected to the system 700 by one or more stimulation electrodes 702. The stimulation electrodes may be configured to stimulate at least one chamber of the patient's heart with a stimulation pulse.

[0341] In some embodiments, each of the multiple electrodes 702 is positioned in a different chamber of the heart. For example, one electrode may be placed in the atrium and another in the ventricle. In some embodiments, multiple electrodes 702 may be disposed in a single chamber. For example, two electrodes may be placed in the atrium and / or two electrodes may be placed in the ventricle. In some embodiments, one electrode may be placed in the first chamber and multiple electrodes may be placed in the second chamber.

[0342] In this embodiment, the electrodes 702 may include common cardiac pacemaker leads, such as Medtronic Capsure® pacing leads. The pacing lead is used to connect the pacing lead to the system 700. The pacing lead consists of an industry standard IS-1 B1 connector (reference standard ISO 5148-3:2013) on one end and an electrode on the other end with insulation between them. In some embodiments, the IS-1 B1 connector may be configured with a conductor system. The quartz crystal uses stainless steel for the two electrode contacts and silicon as the insulating material. Some embodiments may use polyurethane as the insulating material.

[0343] Stimulation of one or more cardiac chambers may be achieved by placing a voltage between two electrodes of the atrial or ventricular cardiac pacing leads described above. The stimulation circuit uses a network of transistors (e.g., MOSFETs) to change a capacitor to a specific programmable voltage, such as 2.0 V, and then to switch the voltage across the electrode for a programmable time of a fixed duration, such as 0.5 ms. The same network may also manage the discharge of residual charge that may accumulate in the electrodes after stimulation is completed. The type of stimulation applied, such as unipolar (between one electrode and the stimulator housing) or unipolar (between one electrode and the stimulator housing) The type of may be controlled.

[0344] As is known in the art, one or more electrodes may be positioned in contact with one or both ventricles and / or one or both atria. Such electrodes may be used to sense and / or deliver stimuli to the respective cardiac chambers. For example, one electrode may be implanted in the right ventricle and an additional electrode may be implanted in the left ventricle through the coronary sinus. and with the system 700 including means for generating biventricular stimulation of both ventricles to reduce dyssynchrony caused by ventricular stimulation. Pacing electrodes can be introduced into both ventricles.

[0345] The system 700 includes a controller 703. The system 700 may be an electrical stimulator that includes a power source 704 (e.g., a battery as known in the art of electrical stimulators). And / or the electrodes 702 may draw power from the power source 704 .

[0346] Preferably, the electrical stimulator of the system 700 is provided in a sealed housing and header. The housing may be made of titanium or other biocompatible materials and may contain the power source 704, electronics, and a telemetry coil or communication module 707 for communication with external devices. The power source 704 may be implantable. The battery chemistry may be a graded sealed primary battery. In some embodiments, the battery may be a lithium-iodine battery. In other embodiments, larger or smaller batteries may be used. In other embodiments, rechargeable batteries, such as Li-ion rechargeable batteries, may be used. The electronics of some embodiments may use standard off-the-shelf electronics (e.g., transistors and diodes) and / or custom-made electronics. It may be composed of a child device (e.g., ASIC).

[0347] To detect the onset of atrial and / or ventricular activation, one or more sensing electrodes may be implanted at or near a location of interest in the heart. These sensing electrodes may be the same electrodes used to deliver pulses to the heart or may be dedicated sensing electrodes. The electrical activity may be band-pass filtered to remove undesired noise with a programmable cut-off frequency and may comply with international standards for cardiac pacemakers (reference EN45502-2-1:2003). Electrical circuitry may be used to amplify the electrical signal generated by the propagating activation of the cardiac chambers and to determine the onset of activation when the electrical signal meets certain criteria, for example the crossing of a predefined threshold. The signal may be amplified, for example by a programmable gain and then measured to a level below 0.2 mV (cardiac activation threshold). for threshold detection, with programmable detection thresholds in steps of 0.4 mV (atrium) and 0.4 mV (ventricle); These means of detecting excitation may introduce a delay between the actual onset of activation in the chamber and its detection. This is because the detection electrode may be far from the origin of excitation and the time it takes for the signal to meet the detection criteria may be non-negligible, in the range of 5-50 ms or even more. In such cases, the timing of the onset of activation may be estimated based on the timing of sensed activation, and delivery of the stimulation pulse would be timed to account for this delay.

[0348] Preferably, the controller 703 is coupled to an accelerometer to measure the patient's activity level. This patient activity level is used to determine the degree of pacing and / or Or BPR settings and / or stimulation patterns may be adjusted. Activity level may also be used to control the effect of the desired level on blood pressure. For example, blood pressure reduction may be reduced at high activity levels to allow better performance when increased blood pressure is required. Alternatively, blood pressure may naturally decrease when the patient is inactive (e.g., sleeping), in which case pacing may be adjusted to avoid reducing blood pressure below a desired threshold. Activity level may also be used to adjust settings based on baroreflex, if necessary, to allow for better response. The sensor may be, for example, a piezoelectric sensor. In other embodiments, a MEMS-based accelerometer sensor may be used. In other embodiments, a fine ventilation sensor may be used, preferably in combination with an accelerometer.

[0349] The controller 703 may be configured to deliver electrical current to the heart 701 via one or more electrodes 702. The controller 703 may be configured to generate stimulation pulses according to any embodiment of the present disclosure. In some embodiments, the stimulation pulses may be delivered to at least a ventricle of the heart. In some embodiments, the stimulation pattern may include a first stimulation setting and a second stimulation setting different from the first stimulation setting. Advantageously, the first and second stimulation settings are configured to reduce or prevent atrial stimulation and / or control the atrial pressure and / or expansion. In some embodiments, the first stimulation setting has a different AV delay than the second stimulation setting. In some embodiments, the first and / or second stimulation setting may be configured such that the atrial pressure caused by the atrial contraction of the atrium overlaps in time with the passive pressure rise of the atrium, thereby providing a higher atrial pressure in the atrium than the atrial pressure in the atrium in the absence of stimulation due to the combination of the atrial pressure caused by the atrial contraction and the passive pressure rise. In some embodiments, the first and / or second stimulation setting may be configured such that the maximum atrial expansion is approximately equal to or less than the maximum atrial expansion of the same heart when not stimulated. In some embodiments, the first and / or second stimulation setting is configured such that the atrial contraction force is highest when the AV valve is open. In some embodiments, the first stimulation setting and / or the second stimulation setting are at least partially altered such that the mechanics of at least one atrial contraction are different from the mechanics of a preceding natural atrial contraction. In some embodiments, the cardiac muscle is adapted to alter the mechanics of at least one atrial contraction. the first stimulation setting and / or the second stimulation setting reduce the force of at least one atrial contraction. In some embodiments, the first stimulation setting and / or The second stimulation setting is configured to prevent at least one atrial contraction.

[0350] In some embodiments, the controller 703 is configured to deliver a variety of different AV delays. The controller 703 may be configured to determine when an atrial contraction or excitation occurs (as described herein). The controller 703 may be configured to sense when an atrial activation or contraction occurs and then deliver a ventricular stimulus at a fixed interval thereafter or prior to a future anticipated atrial activation or contraction. This interval may be programmable. The controller 703 may also stimulate the atrium and then deliver a ventricular stimulus, also via a programmable The programmable intervals may be configured to deliver at fixed intervals thereafter, which may be programmable. The programmable intervals may be, for example, configured to accommodate a desired therapeutic effect. , or may even be varied between 2ms and 70ms to give a negative AV delay of up to -50ms.

[0351] In some embodiments, the controller 703 is configured to repeat the stimulation pattern multiple times. For example, the controller 703 may repeat the stimulation pattern twice. In another embodiment, the controller 703 is configured to repeat the stimulation pattern at least twice during a one hour period. The stimulation pattern repeated by the controller 703 may be any type of stimulation pattern. For example, the stimulation pattern may include an atrial kit in at least one ventricle. In another embodiment, the stimulation pattern may include stimulation settings configured to reduce or prevent atrial kicks in at least one ventricle and / or to control intra-atrial pressure, atrial expansion. The stimulation may include two different stimulation settings, each configured to control either intra-atrial pressure, atrial expansion, or both. The inputs may differ by one or more parameters, for example by AV delay.

[0352] In some embodiments, the controller 703 may be configured to apply one or more successive stimulation patterns for a predetermined time interval. For example, in some embodiments, the time interval may be 10 minutes or more. In other embodiments, the time interval may be 30 minutes or more, 1 hour or more, or 24 hours or more. In some embodiments, the time interval may be a period of time that is longer than a month, such as one month to one year. In some embodiments, the time interval may be one year or more.

[0353] In some embodiments, the one or more successive stimulation patterns include, for a portion of the time interval: To reduce or prevent atrial kicks in at least one ventricle and / or in the atrium a first stimulation setting configured to control either or both of atrial pressure and atrial expansion; For example, one or more consecutive stimulation patterns may be continuous for about 50% to about 100% of the time interval. In another embodiment, the one or more successive stimulation patterns may include a first stimulation setting configured to reduce or prevent atrial kicks in at least one ventricle for about 100% of the time interval and / or to control intra-atrial pressure, atrial expansion, or both. In another embodiment, the one or more successive stimulation patterns may include a first stimulation setting configured to reduce or prevent atrial kicks in at least one ventricle for about 50% of the time interval and / or to control intra-atrial pressure, atrial expansion, or both. In some implementations, the stimulation setting may include a first stimulation setting configured to reduce or prevent atrial pressure, atrial dilation, or both. In an embodiment, the one or more successive stimulation patterns may include a second stimulation setting having a longer AV delay than the first stimulation setting for at least one beat during the time interval.

[0354] In another embodiment, the one or more successive stimulation patterns include a second stimulation setting and / or and a third stimulation setting. The second stimulation setting and / or the third stimulation setting may each be different from the first stimulation setting. In some embodiments, the second stimulation setting and / or the third stimulation setting each reduce or prevent atrial kick in at least one ventricle. In some embodiments, the second stimulation setting and / or the third stimulation setting may each be configured not to reduce or prevent atrial kicks in at least one ventricle and / or not to control intra-atrial pressure, atrial expansion, or both. In some embodiments, the second stimulation setting and / or the third stimulation setting may each be configured not to reduce or prevent atrial kicks in at least one ventricle and / or not to control intra-atrial pressure, atrial expansion, or both. The stimulation settings may include from about 0% of the time interval to about 50% of the time interval. In some embodiments, the second stimulation setting and / or the third stimulation setting may comprise between about 0% of the time interval and about 30% of the time interval. The stimulation settings may include from about 0% of the time interval to about 20% of the time interval. In an embodiment, the second stimulation setting and / or the third stimulation setting may comprise between about 5% of the time interval and about 20% of the time interval.

[0355] Blood pressure is known to vary over a circadian cycle, and in some cases, abnormally high blood pressure prevails only during a portion of the 24-hour period (e.g., during night or day or a portion thereof), or for most of the 24-hour period. In addition, blood pressure is known to vary according to physical activity, and active people have higher blood pressure than at rest. Thus, in some cases, it may be desirable to control the delivery of therapy as needed, for example, by changing therapy parameters to lower blood pressure, or even by not providing cardiac stimulation delivery. In other words, cardiac stimulation may be changed to adjust stimulation parameters or simply turned on / off at different times of the day and / or when the patient is active or at rest. If desired, the delivery of such stimulation may be controlled according to time of day and adjusted to the patient's circadian BP rhythm.

[0356] Example 1 FIG. 21 shows systolic BP in untreated patients monitored over a 24-hour period. Time averages are presented. As shown, the patient's BP was abnormally high during the day (approximately 10:00 a.m. to 6:00 p.m.). In these types of cases, it may be preferable to configure the device to deliver pulses configured to reduce afferent stimulation and / or provide AC stimulation only during times when BP is expected to be abnormally high (i.e., when there is a need or when the need is anticipated).

[0357] Example 2 Another example is shown in FIG. 22. Here, the untreated blood pressure of a patient (data "x" in FIG. 22) is Optionally, the patient's BP (represented by a line with dots) is found to be abnormally high at night (2 pm to 7 am). The rise in daytime BP is within the normal range and may be due to increased patient activity. Optionally, the patient may be assumed to be in need of therapy only at night and the device may be set to deliver stimulation accordingly. Optionally, the patient may be assumed to be in need of therapy during the day and the device may be set such that even if an increase in blood pressure is measured during the day, such an increase should not trigger the delivery of a therapy to lower blood pressure. Optionally, the device may be set not to measure daytime blood pressure.

[0358] In the example shown in FIG. 22, the patient then paces both the atrium and ventricle with a 15 ms AV delay for 10 beats, then paces both the atrium and ventricle with a 40 ms AV delay for 3 beats. The patients were treated with a blood pressure reducing pulse with a setting of pacing BP of 1.2 mmHg. The delivery of therapy was initiated at 3:00 pm each day and continued for 13 hours. The resulting BP was plotted. As can be seen (represented by a line with round data points in FIG. 22), BP was essentially within the normal range throughout the day, showing much smaller fluctuations than before treatment (under treatment, , BP fluctuated by approximately 30mmHg or less, whereas the untreated BP range fluctuated by more than 40mmHg).

[0359] In some embodiments, a patient-specific (absent stimulation) blood pressure profile is first determined, and stimulation parameters that produce the desired blood pressure reduction are then determined based on that specific profile. FIG. 22 shows one example of such an approach. In an embodiment, blood pressure is measured continuously or intermittently during operation of the device and stimulation parameters that produce the desired reduction in blood pressure are then determined accordingly.

[0360] Rather than alternating periods of cardiac stimulation with periods of no cardiac stimulation, as discussed with respect to the exemplary approaches of Examples 1 and 2 of FIGS. 21 and 22, other approaches adjust stimulation parameters to provide different stimulation periods during each of two or more periods of a time interval. The stimulation parameters for each time period may be selected to achieve a different degree of blood pressure reduction based on the needs during that particular time period, such as blood pressure sensing feedback, time of day, patient activity, or a particular patient's unique blood pressure pattern.

[0361] For example, a first stimulation setting may achieve a greater degree of blood pressure reduction during the day, followed by A second stimulation setting is provided during the night that may achieve a lower degree of blood pressure reduction than the first stimulation setting, and further reduces blood pressure from the blood pressure level when no stimulation is applied. As another example, the first stimulation setting may achieve a higher degree of blood pressure reduction during periods of low patient activity, and subsequently During high activity in patients who can achieve a lower degree of blood pressure reduction than the first stimulation setting A second stimulation setting is applied to reduce blood pressure from the blood pressure level when no further stimulation is applied. Can.

[0362] When alternating between periods of different stimulation settings, embodiments may adjust the degree of blood pressure change gradually, either by temporary incremental adjustments to parameters that affect the degree of blood pressure change, or by continuous adjustments. For example, a first stimulation setting may use an AV delay of 30 ms and a second stimulation setting may use an AV delay of 30 ms. If a setting uses a 60 ms AV delay, when switching from the first stimulus setting to the second stimulus setting, the AV delay increases by 5 ms from the first stimulus setting with a 30 ms AV delay to the second stimulus setting with a 60 ms AV delay. The stimulation setting may be adjusted incrementally over minutes (e.g., to 35 ms, then to 40 ms, etc.). Similar incremental adjustments may be used to switch from the second stimulation setting back to the first stimulation setting. In other embodiments, the adjustment may be continuous in that the rate of change of the parameter affecting blood pressure (e.g., AV delay) is constant when switching from the first stimulation setting to the second stimulation setting.

[0363] As discussed above, providing different values ​​of blood pressure reduction may include adjusting stimulation parameters that affect AV delay, which adjustments may be used to switch between stimulation settings. For example, stimulation parameters that provide a shorter AV delay may reduce blood pressure to a greater extent than stimulation parameters that provide a longer AV delay. In embodiments, the stimulation setting that reduces atrial stimulation varies from about 5 ms to about 30 ms (e.g., between daytime and nighttime, or between nighttime and daytime). An AV delay may be provided (between vigorous activity and light activity), with a shorter AV delay resulting in a greater reduction in blood pressure.

[0364] FIG. 24 shows the relationship between AV delay (in this example, 100 ms or less) and the decrease in systolic blood pressure in a specific patient. 1 is a graph showing an embodiment of the relationship between AV delay and blood pressure reduction. As shown, stimulation parameters may be selected that achieve an AV delay that produces a desired reduction in systolic blood pressure. Thus, based on the relationship between AV delay and blood pressure reduction, blood pressure reduction therapy may be tailored to reduce the duration of a given time interval, as shown in the following two examples. During a specific period (e.g., a period of minutes or hours over a time interval of a day), It may be adjusted to achieve the desired blood pressure reduction based on need.

[0365] Example 3 FIG. 25 is a graph of systolic blood pressure over a 24-hour period for a particular outpatient patient. As shown, the patient in FIG. 25 has very high blood pressure early in the day (about 140-160 mmHg from about 6:00 a.m. to about 2:00 p.m.) and very low blood pressure later in the night (about midnight to about Between 2:00 and 3:00 AM, they have low blood pressure (less than 100 mmHg), and in between they have intermediate blood pressure values ​​(approximately 120-140 mmHg from approximately 3:00 PM to approximately 11:00 PM).

[0366] For the patient type of Figure 25, it may be useful to apply therapy with different sets of stimulation parameters throughout the day. For example, in one embodiment, a first set of stimulation parameters that significantly reduce blood pressure may be applied from about 6:00 AM to about 2:00 PM (with a relatively very short AV delay), and a second set of stimulation parameters that still reduce blood pressure slightly may be applied from about 2:00 PM to about midnight, with a longer AV delay. provide a second set of stimulation parameters (e.g., no stimulation or normal AV delay) The stimulation (stimulus providing a stimulation) may be applied from about midnight to about 6:00 a.m. Accordingly, different stimulation parameters will reduce or prevent atrial stimulation depending on the patient's needs at different periods during this time interval, lowering blood pressure and providing an overall more normalized and controlled blood pressure for the patient.

[0367] Example 4 FIG. 26 is a graph of systolic blood pressure over a 24-hour period for another particular outpatient patient, different from the patient in FIG. 25. The patient in FIG. 26 has high blood pressure during the night (from about midnight to about 7 a.m.). The blood pressure is over 140 mmHg until dusk, but is unstable during the day.

[0368] The patient type of FIG. 26 may benefit from a different set of stimulation parameters than the patient type of FIG. 25. For example, during the night, a long AV delay may be applied. Thereafter, the AV delay may be increased periodically, from about 9:00 a.m. to about 2:00 p.m. (when blood pressure is below 120 mmHg). After that, it reaches normal levels from about 9 p.m. to about midnight. Further increases (or sets of increases) in AV delay until mid-night lead to longer AV delays (e.g., (same as or slightly shorter than that applied) may be applied.

[0369] All of the above example stimulation patterns may include a feedback loop and / or may be pre-programmed based on the patient's known circadian blood pressure variations.

[0370] In some embodiments, the controller 703 programs a sequence of 10 to 60 stimulation pulses having a first stimulation setting configured to reduce or prevent atrial kick in at least one ventricle and / or to control intra-atrial pressure, atrial expansion, or both. In some implementations, the stimulation device may be configured to deliver one or more sequential stimulation patterns, including In some embodiments, the controller 703 may be configured to administer one or more sequential stimulation patterns including a sequence of 1-10 beats embedded within 10-60 stimulation pulses, and the sequence of 1-10 beats may have a longer AV delay than the first stimulation setting. For example, 10 to 60 stimulation pulses may include 5 stimulation pulses with a first stimulation setting, followed by 1 beat with a longer AV delay than the first stimulation setting, followed by 1 beat with a longer AV delay than the first stimulation setting. The sequence of 1 to 10 beats may include at least 50 stimulation pulses having the same frequency. to reduce or prevent atrial kicks in at least one ventricle, and / or to reduce intraatrial pressure, a first stimulation setting configured to control either or both of atrial expansion and atrial distension; The sequence of 1 to 10 beats may include at least one stimulation pulse that occurs without stimulation. The sequence of 1 to 10 beats may include a natural AV delay. Good too.

[0371] The system 700 may further include one or more sensors 705. In some embodiments, such a sensor 705 may include one or more sensing electrodes for sensing electrical activity of the heart. In some embodiments, the one or more sensing electrodes may include one or more stimulation electrodes 702. In some embodiments, the sensor 705 may include one or more sensors (such as implanted In some embodiments, the sensor may include one or more sensors. The pressure sensor 705 may include one or more pressure sensors implanted in the heart (e.g., in the atrium and / or ventricle). In some embodiments, the sensor 705 may include one or more blood flow sensors (implanted or external). For example, the one or more sensors 705 may include ultrasonic sensing of blood flow through an AV valve. In some embodiments, the sensor 705 may include one or more sensors (implanted or external) that sense blood flow through an AV valve. The device may include one or more sensors configured to monitor the timing of closure of the valve. One or more of these sensors are configured to operate in a closed loop with a controller. Good too.

[0372] Information from the sensors 705 may be provided to the controller 703 by some form of communication, including wired and / or wireless communication. Preferably, the system 700 includes one or more communication modules 707 for receiving and / or transmitting information between system components and / or to devices external to the system. In some embodiments, the controller 703 may be configured to receive input data related to the patient's blood pressure. For example, input data relating to a patient's blood pressure may represent BP measured at one or more time points. or BP variability (e.g., degree of change and / or rate of change or time course) Data showing the BP or BP fluctuation, maximum and / or statistical data relating to the minimum BP value.

[0373] Preferably, the system 700 may include one or more user interfaces 708 for providing information and / or allowing input of information. Providing information may include, for example, displaying operational information related to the system and / or inputting information about the system during operation. including a representation of data recorded by and / or received by the system. This may be achieved by determining the parameters sensed and / or the relationship between the sensed parameters and the operation. Information (stimulation pattern settings and / or correlation between a given pace and the detected information) The relationship may include relationships between the

[0374] Preferably, the user interface 708 is a user interface for executing software applications. A commercially available laptop computer (e.g., a Windows®-based computer) that supports The software application may be connected to a handheld wand that contains a telemetry circuit for communication with the implantable stimulator. The wand may also function to generate commands to be communicated to a selected interface. The commands sent to the wand may be for setting stimulation parameters and / or for generating diagnostic messages for the device. The wand may be used to retrieve diagnostic, device data, cardiac data, and real-time cardiac sensing. The interface also allows for connection of a 3-lead ECG, and this data is displayed on a laptop computer screen by a software application. In other embodiments, the 3-lead ECG electronics may not be included, or 12-lead ECG electronics may be included. In other embodiments, the wand, interface, and and laptop computer functionality with a dedicated piece of hardware that serves all three functions. In other embodiments, printing capabilities may also be added to the user interface 708.

[0375] In some embodiments, the interface 708 allows a user (e.g., a physician) to Preferably, the interface 708 is configured to allow a user to provide a set of control instructions (e.g., target values ​​and / or ranges, and / or other limits or instructions) for the system. and / or ultrasound monitoring results).

[0376] Preferably, the one or more user interfaces 708 allow the user to select a stimulation pattern (e.g., from a set of stimulation patterns stored in the system 700) or to select a stimulation pattern. It may be possible to apply constraints to the setting and / or selection of patterns.

[0377] Preferably, the system 700 may include one or more processors 706. The parameters detected by the sensor 705 and / or the input from the interface 708 are used to configured to process the force data to select a stimulation pattern for delivery by the system 700. Preferably, the processor 706 is adapted to analyze the sensed parameters by: and may be configured to extract information and / or formula constants to be used in selecting and / or evaluating stimulation patterns.

[0378] One or more components of system 700, or portions of such components, may be implanted in a patient, while some components of system 700, or portions of such components, may be external to the patient. When some components (or parts thereof) are implanted and others are not, communication between the components may essentially be by wired and / or wireless means as known in the art. For example, some of both the controller 703 and / or the processor 706 may Some or all of the functions may be performed outside the body. By placing it outside the patient's body, the size and / or energy requirements of the implanted device can be reduced. This may help reduce and / or improve the computational power of the system.

[0379] The system 700 may provide additional functions related to cardiac function and the overall performance of the cardiovascular system. For example, system 700 may include one or more algorithms and / or electrodes to enable biventricular pacing or cardiac resynchronization therapy to reduce asynchrony that may be caused by ventricular stimulation. In some embodiments, system 700 may include one or more algorithms to counteract possible reductions in cardiac output. Such algorithms may implement other methods known in the art to increase cardiac output or to control cardiac output. In some embodiments, the system 700 may change the heart rate to Rate response algorithms that affect how your heart rate changes in response to a situation. For example, system 700 may include a rate response algorithm that affects changes in heart rate in response to changes in levels of exercise, ventilatory activity, and / or oxygen consumption.

[0380] In some embodiments, the system 700 may include a sensor to detect activity. Alternatively, the algorithm may turn off stimulation when the patient is exercising and the patient's blood pressure is not reduced. In some embodiments, the system 700 may include a real-time clock ( Such a clock may be used to control the timing of stimulation. For example, system 700 may be configured to turn stimulation on and off depending on the time of day. Such algorithms may be used to prevent hypotension during the night while the patient is asleep.

[0381] In some embodiments, a kit including one or more components of the system 700 and a set of instructions for adjusting the stimulation pattern based on inputs related to the patient's blood pressure may be provided.

[0382] In some embodiments, a system for reducing blood pressure may be provided that is configured to deliver stimulation at a rate higher than the natural heart rate based on a detected natural heart rate or natural activation. For example, the system may be configured to detect natural activation during the delivery of the stimulation pulses, and if natural activity is detected, the system may be configured to inhibit delivery of the stimulation pulses to the chamber. If the amount of detected activation exceeds a threshold within a given time frame, the natural heart rate may be considered to be higher than the transmission rate of the stimulation pulses, in which case the transmission rate may be increased, for example, to accommodate the increased heart rate of the patient. On the other hand, if the amount of detected activation is lower than a threshold (which may be 0) within a given time frame, the natural heart rate may be considered to be lower than the transmission rate of the stimulation pulses. and in that case, for example, the conductance may be reduced to avoid overexcitation of the patient's heart.

[0383] To achieve this effect, according to one embodiment, a system for lowering blood pressure includes a sensor for detecting the activation rate of at least one of the atria and the ventricles of a patient's heart, and a cardiac The device may include a stimulation circuit configured to deliver stimulation pulses to the atria and ventricles, and a processor circuit coupled to the stimulation circuit. The processor circuit may be configured to detect a patient's heart rate based on sensing and to operate in a mode of operation in which stimulation pulses are delivered to each of at least one of the atria and ventricles. The stimulation pulses may be delivered at a rate greater than the sensed activation rate and may be configured to stimulate the ventricles at a time between about 50 ms before and about 70 ms after stimulation of the atria.

[0384] In some embodiments, a system for reducing blood pressure based on a predicted next atrial contraction may be provided. For example, the system for reducing blood pressure may include a sensor for sensing an activation rate of at least one of an atrium and a ventricle, a stimulation circuit configured to deliver a stimulation pulse to at least one of the atrium and a ventricle, and a processor circuit coupled to the stimulation circuit. The processor circuit may be configured to: predict timing of a next atrial activation based on the detected activation rate of a preceding atrial activation; and determine whether at least one ventricle is activated based on the predicted next atrial activation. The device may be configured to operate in a mode of operation in which the device stimulates at a time between about 50 ms before and about 10 ms after an atrial activation. The predicted timing may be the time between two preceding sensed atrial activations. The atrial activation time may be based on a function that is based on the time interval between the atrial activations and on previously sensed time intervals between the atrial activations, the change in the time interval, the rate of change of the time interval, and / or This may include detecting periodic variations in the time interval (e.g., periodic variations due to breathing). .

[0385] Preferably, the sensor for sensing atrium and / or ventricle activation rate may include an electrode for sensing atrial activation.

[0386] In a further aspect, prediction of the next atrial activation may be based on functions of the preceding sensed activation, including the interval and rate of change of cyclic variation.

[0387] In a further aspect, the timing of the predicted next atrial activation may be adjusted to reflect the delay between atrial activation and sensed atrial activation.

[0388] In a further aspect, the system may further comprise an additional sensor for sensing a parameter related to the activity of the heart and for adjusting the time at which the ventricle is stimulated accordingly. The parameter may be one of the group consisting of blood pressure, blood flow, the state of the AV valve, and data related to wall motion of the heart or a portion thereof. The additional sensor may be a pressure sensor. , an impedance sensor, an ultrasonic sensor, and / or one or more sound sensors, and / or or one or more blood flow sensors. The additional sensors may be embedded It may be possible to include the

[0389] <Reducing atrial kick> Some embodiments stem from the inventors' realization that blood pressure can be reduced by causing closure of at least one AV valve during at least a portion of the atrial activation. This reduces or even prevents the contribution of atrial contraction to ventricular filling, resulting in reduced cardiac filling at the end of occlusion and therefore reduced blood pressure.

[0390] In some embodiments, at least a portion of the atrial contractions may occur against a closed AV valve. For example, in some embodiments, 40% or more of the atrial contractions may occur against a closed AV valve. In some embodiments, 80% or more of the atrial contractions may occur against a closed AV valve. For example, the contractions may begin within about 20 ms before the ventricular contraction, and atrial activation may occur within 20 ms before the ventricular contraction. In some embodiments, 100% of the atrial contractions may occur against a closed AV valve, in which case ventricular activation occurs at a time when the ventricular contraction is not initiated. The stimulation is timed to begin before the onset of atrial contraction. This may include ventricular excitation before the onset of atrial activation. The higher the percentage of atrial activation that occurs with the AV valve closed, the more the atrial kick is reduced. Stimulation of both the atrial and ventricular chambers may provide better control of the percentage of atrial contraction that occurs with the valve closed.

[0391] Various embodiments may be implemented to cause at least a portion of the atrial contraction to occur with the valve closed. For example, the AV valve may be opened within 70 ms after the onset of the atrial mechanical contraction, or within 40 ms after the onset of the atrial mechanical contraction, or within 5 or 6 ms after the onset of the atrial mechanical contraction. In some embodiments, the AV valve may be closed within 10 ms or even less before the onset of mechanical contraction of the atrium. For example, the AV valve may be closed within 5 ms before the onset of mechanical contraction of the atrium. In some embodiments, the AV valve may be closed simultaneously with the onset of a mechanical contraction. In some embodiments, the AV valve may be closed after the onset of an atrial mechanical contraction. For example, the AV valve may be closed within 5 ms after the onset of an atrial mechanical contraction. Good too.

[0392] In some embodiments, the onset of contraction of the chamber may be sensed and the stimulation pulse may be timed to the sensed onset of contraction. The onset of contraction in the chamber is the onset of active generation of contractile force in the chamber. The onset of contraction is the onset of blood flow into the chamber. The onset of contraction can be detected by a sudden change in pressure not related to the onset of contraction. The onset of contraction may also be detected by measuring the movement of the walls of the heart chamber using ultrasound or by measuring a reduction in the volume of the chamber. These methods of detecting the onset of contraction may have a delay between the actual onset of contraction and the detection of the onset of contraction.

[0393] In some embodiments, the AV valve is closed after the onset of at least one atrial contraction. For example, the AV valve may be closed from about 0 ms to about 70 ms after the onset of contraction of at least one atrium. In some embodiments, the AV valve may be closed from about 0 ms to about 40 ms after the onset of contraction of at least one atrium. In some embodiments, the AV valve may be closed from about 0 ms to about 40 ms after the onset of contraction of at least one atrium. In some embodiments, the AV valve may be closed from about 0 ms to about 10 ms after the onset of contraction. The valve may be closed about 0 ms to about 5 ms after the onset of contraction of at least one atrium.

[0394] Typically, atrial contraction may begin about 40 ms to about 100 ms after the onset of atrial excitation. In some embodiments, the AV valve may be closed after the onset of atrial activation. For example, the AV valve may be closed from about 40 ms to about 170 ms after the onset of atrial activation. In another embodiment, the valve may be closed about 40 ms to about 110 ms after the onset of atrial activation. For example, the AV valve may be closed from about 40 ms to about 75 ms after onset of atrial activation. For example, the AV valve may be closed from about 40 ms to about 50 ms after onset of atrial activation.

[0395] In some embodiments, the onset of excitation in the chamber may be detected and the stimulation pulse may be timed to the detected onset of excitation. The onset of excitation is the onset of an action potential propagating through the chamber. The onset of excitation may be detected by sensing local electrical activity in the chamber using a sensing electrode connected to an amplifier. The onset of excitation may also be detected by electrocardiography.

[0396] In some embodiments, the method of detecting onset of activation may include a delay between the actual onset of activation and the detection of the onset of activation. The timing of detected atrial activation may be determined by taking into account the delay between the actual onset of activation and its detection. For example, if the detection delay is estimated to be 20-40 ms and the stimulation pulse is delivered 0-70 ms after the onset of atrial activation, If the system is to transmit a pulse between 40 ms before the next expected detection event and 30 ms after the next expected detection event, or 30 ms after the next expected detection event, Similarly, a stimulation pulse may be set to initiate atrial activation 0-50 ms before the onset of atrial activation. If a pulse is to be delivered to the chamber and the same 20-40 ms sensing delay is assumed, the system may be configured to deliver a pulse between 40 ms before the next expected sensed event and 90 ms before the next expected sensed event. The sensing delay may be due to one or more of the distance between the location of the onset of activation and the sensing electrode, the level of the electrical signal, the characteristics of the sensing circuitry, and a threshold set for the sensed event. The delay may be, for example, a duration related to the duration of signal propagation from the origin of excitation to the electrode location, a duration related to the frequency response of the sensing circuitry, and / or a duration related to the time at which the signal propagation energy is detectable by the sensing circuitry. The delay may be significant and may vary, for example, between about 5 ms and about 100 ms.

[0397] One method to estimate the delay is to use the AV delay measured when both the atrial and ventricular chambers are sensed. One approach is to use the time difference between the AV delay when the atrium is paced and the ventricle is sensed and the AV delay when the atrium is paced. Another approach may use a calculation of the amplifier response time based on set thresholds, signal strength and frequency content.

[0398] In other embodiments, if the delay between atrial activation and sensing of activation is longer than the desired AV delay (e.g., the sensing delay is 50 ms and the desired AV delay is 40 ms), then both the atrium and ventricle may be paced to achieve the desired AV delay.

[0399] In other embodiments, an algorithm may also be used to track the intrinsic rhythm. For example, to track the intrinsic rhythm, the atrial intrinsic rate may first be sensed. Then, the base rate may be set a few beats above the sensed rate. If there is a sensed event, the base rate may be increased to a rate above the newly sensed rate. If there is no sensed event after a certain number of paced beats, the base rate may be decreased in steps until a sensed event is detected or the rate reaches the minimum allowed base rate. This approach may always produce pacing.

[0400] Other approaches may include varying the delay used with atrial sensing until the effect on blood pressure is the same as that obtained by pacing both the atrium and ventricle with the desired AV delay. In these experimental approaches, rather than estimating the AV delay, the practitioner may determine a preferred AV delay by observing the effect of pacing on the obtained blood pressure and adjusting the AV delay until the desired blood pressure is obtained. For example, according to these approaches, the practitioner may first pace the atrium and pace the ventricle with a given (arbitrarily predetermined) delay to obtain a desired blood pressure change. The practitioner may then sense the atrium and pace the ventricle, observe the resulting blood pressure change, and compare the resulting blood pressure change to the desired blood pressure change of the paced atrium-paced ventricle. If these blood pressure changes are not substantially equal, based on this comparison, the practitioner may adjust the stimulation timing of the sensed atrium-paced ventricle, observe the newly altered resulting blood pressure change, and compare the altered blood pressure change to the desired blood pressure change of the paced atrium-paced ventricle. If necessary, the practitioner may then repeat the adjustment and observation until the sensed atrial-paced ventricular stimulation timing achieves the same blood pressure change as the desired blood pressure change of paced atrial-paced ventricular stimulation.

[0401] Some embodiments provide a 0 ms AV delay between the sensed atrium and the paced ventricle. Even if the atrial activation is not activated, the delay between atrial activation and atrial sensing may be too long to cause a sufficient drop in blood pressure. In these cases, embodiments may pace the ventricle based on the delay from the previous atrial sensing to produce the desired drop in blood pressure. In these cases, the delay will be shorter than the expected AA interval (the interval between two atrial contractions).

[0402] In other embodiments, the difference between the sensed atria-paced ventricular AV delay and the paced atria-paced ventricular AV delay that results in the same blood pressure drop may be used to set the difference if other values ​​of AV delay are selected instead of performing separate empirical measurements. In other embodiments, the difference may be corrected based on rate using the pacemaker's standard algorithms that vary the AV delay based on rate.

[0403] Typically, the delay between sensing atrial activation and pacing the ventricle is reduced to induce a lower blood pressure in the patient (e.g., as might be expected based on FIG. 24). In some cases, however, a correlation may be derived between adjustments by making changes, observing the resulting blood pressure changes, and making further adjustments accordingly.

[0404] In some embodiments, the AV valve is adapted to circulate the at least one atrium prior to the onset of activation or contraction of the atrium. For example, the AV valve may be closed within about 0 ms to about 5 ms prior to the onset of activation or contraction of at least one atrium. In some embodiments, the AV valve may be closed simultaneously with the onset of activation or contraction of at least one atrium.

[0405] In some embodiments, direct mechanical control of AV valve closure may be provided. In such embodiments, a mechanical device, or a portion thereof, may be implanted in the patient and actuated to cause closure of the valve between the atrium and the ventricle. For example, an artificial valve may be implanted in the patient's heart. A stimulation pattern may be implanted in the AV valve and actuated to mechanically close according to some embodiments. In such embodiments, such closure of the AV valve may be achieved by controlling the function of the implanted valve, instead of or in addition to delivering a stimulation pattern.

[0406] In some embodiments, a shortened, or even negative, time interval between the onset of atrial activation and the onset of ventricular activation is used to reduce cardiac filling and thereby reduce blood pressure. As used herein, a negative time interval between the onset of atrial activation and the onset of ventricular activation means that in a single cardiac cycle, the onset of activation for at least one ventricle occurs before the onset of atrial activation. In this case, atrial contraction may occur at least partially against a closed AV valve. This is because the pressure generated in the ventricle may be greater than the pressure in the atrium. A short time after the onset of ventricular contraction, the ventricular pressure may exceed the atrial pressure, leading to passive closure of the valve. This valve closure may reduce or even eliminate the atrial kick, which may then reduce ventricular filling. As a result, the force of ventricular contraction may be reduced and blood pressure may drop.

[0407] The time between the onset of excitation in each cardiac chamber and the onset of mechanical contraction is not fixed. Therefore, the timing of excitation does not guarantee the same effect on the timing between contractions. However, in some embodiments, the timing between excitation is used as a frame of reference for practical reasons. The ultimate goal of controlling the timing of excitation is to control the timing of contractions.

[0408] In some embodiments, a shortened, or even negative, time interval between the onset of atrial activation and ventricular activation may be used to reduce cardiac filling and thereby reduce blood pressure, in which case better control over the atrial contribution can be obtained, since the onset of ventricular contraction results in valve closure.

[0409] In some embodiments, 40% or more of atrial contraction may occur during ventricular contraction. For example, atrial contraction may begin about 60 ms or less before ventricular contraction, or atrial activation may occur about 60 ms or less before ventricular activation. In some embodiments, 80% or more of atrial contraction may occur during ventricular contraction. For example, contraction may begin about 20 ms or less before ventricular contraction, or atrial activation may occur about 20 ms or less before ventricular activation. In some embodiments, 100% of atrial contraction may occur during ventricular contraction, in which case ventricular activation may occur about 20 ms or less before ventricular activation. The contraction is timed to begin before the onset of atrial contraction, which may include ventricular excitation before the onset of atrial activation.

[0410] In some embodiments, at least one ventricle contracts during or before the corresponding atrium contracts. A method is provided for inducing contraction of at least one ventricle of a heart to contract. One method to achieve this goal is to use a pulse train that is pulsed between approximately 50 ms before and 70 ms after the onset of corresponding atrial activation. In some embodiments, the method comprises exciting the ventricle at a time point. The time interval between the onset of activation of at least one ventricle and the onset of activation of the corresponding atrium may be zero, i.e., the onset of activation for at least one ventricle is equal to or greater than the onset of activation of the corresponding atrium. In some embodiments, the onset of ventricular activation may occur between about 0 ms and about 50 ms before the onset of atrial activation. In some embodiments, the onset of ventricular activation may occur between about 0 ms and about 50 ms before the onset of atrial activation. , occurring at least about 2 ms before to at least about 2 ms after the onset of excitation of at least one atrium In some embodiments, the onset of ventricular activation may be preceded by at least one atrial activation. In some embodiments, the onset of ventricular activation may occur at least about 20 ms before to at least about 10 ms after the onset of at least one atrial activation. In some embodiments, the onset of ventricular activation may occur at least about 40 ms before to at least about 40 ms after the onset of at least one atrial activation. stomach.

[0411] In some embodiments, a method includes delivering a stimulation pulse from a stimulation circuit to at least one of an atrium and a ventricle, stimulating the ventricle to induce atrial activation in at least one atrium. The ventricular excitation is started between about 0 ms and about 50 ms before the start of the treatment, thereby increasing the ventricular filling volume to the pre-treatment volume. and operating a processor circuit coupled to the stimulation circuit in an operating mode that reduces ventricular filling from a pre-treatment blood pressure and reduces the patient's blood pressure from a pre-treatment blood pressure. In such an embodiment, atrial activation may be sensed to determine the onset of atrial activation. The time interval between the onset of atrial activation and the moment atrial activation is sensed may be known and used to calculate the timing of the onset of atrial activation. For example, if atrial activation is sensed 20 ms after the onset of atrial activation and it is known that the ventricle will be stimulated 40 ms before the onset of atrial activation, then the ventricle will be stimulated 60 ms before the expected sensing of atrial activation.

[0412] In another embodiment, the method includes stimulating the atrium to induce ventricular activation in at least one ventricle. The atrial excitation is initiated between approximately 0 ms and approximately 50 ms before the start of the treatment, thereby decreasing the ventricular filling volume to the amount before the treatment. The method may include operating a processor circuit coupled to the stimulation circuit in an operating mode in which the stimulation circuit reduces ventricular filling volume from a pre-treatment volume and reduces the patient's blood pressure from a pre-treatment blood pressure. For example, the processor circuit may be configured to operate in an operating mode in which the one or more excitatory pulses are delivered to the atrium about 0 ms to about 50 ms before the one or more excitatory pulses are delivered to the patient's ventricle. In such embodiments, pacing may be timed without relying on sensing atrial activation. Preferably, in such embodiments, pacing is timed by sensing atrial activation to ensure that one or more excitatory pulses are delivered to the atrium before natural activation occurs. Activation is detected. Preferably, atrial activation is configured to commence between about 0 ms and about 50 ms after onset of ventricular activation when the intrinsic atrial activation rate is less than the intrinsic ventricular activation rate.

[0413] In some embodiments, the device may include a stimulation circuit configured to deliver stimulation pulses to at least one of the atria and the ventricles. The device may include a processor circuit coupled to the stimulation circuit. In some embodiments, the processor circuit may be configured to operate in an operating mode that stimulates the ventricles to initiate ventricular activation between about 0 ms and about 50 ms before the onset of atrial activation in at least one atrium, thereby reducing ventricular filling volume from a pre-treatment ventricular filling volume and reducing the patient's blood pressure from a pre-treatment blood pressure. In such embodiments, atrial activation may be detected to determine the onset of atrial activation. The time interval between the onset of atrial activation and the moment the atrial activation is detected may be known and may be used to calculate the timing of the onset of atrial activation. For example, if atrial activation is detected 20 ms after the onset of atrial activation and it is known or estimated that the ventricle shall be stimulated 40 ms before the onset of atrial activation, the ventricle will be stimulated 60 ms before the expected detection of atrial activation.

[0414] In another embodiment, the processor circuitry is adapted to stimulate the atrium and stimulate at least one ventricle. Atrial excitation is initiated between approximately 0 ms and approximately 50 ms after the onset of ventricular excitation, thereby controlling the ventricular filling volume. The processor circuit may be configured to operate in a mode of operation to reduce a ventricular filling volume from a pre-treatment volume and to reduce a patient's blood pressure from a pre-treatment volume. The pacing device may be configured to operate in a mode of operation in which one or more excitatory pulses are delivered to the atrium between about 0 ms and about 50 ms after an excitatory pulse is delivered to the patient's ventricle. In such embodiments, pacing may be timed without relying on sensing atrial activation. Preferably, in such embodiments, one or more excitatory pulses are delivered to the atrium before natural activation occurs. Atrial activation is sensed to ensure that the pulse is delivered to the atrium. Preferably, atrial activation is timed to commence between about 0 ms and about 50 ms after onset of ventricular activation when the intrinsic atrial activation rate is less than the intrinsic ventricular activation rate.

[0415] 10A and 10B show the heart of a healthy anesthetized dog over a period of time. 10A shows the electrocardiogram (ECG), left ventricular pressure (LVP) and arterial (blood) pressure (AP) traced at different points in FIG. 10A. Prior to point 101, the heart was allowed to beat naturally and the ECG, LVP and AP were traced. At point 101, ventricular pacing was initiated. The ventricles were paced 2 ms after the onset of atrial activation. This pacing caused an immediate change in the ECG that was accompanied by a drop in both LVP and AP. Pacing continued with a time interval of 2 ms between the onset of atrial contraction and the onset of ventricular pacing until point 103 in FIG. 10B, where pacing ceased. As can be seen, the pacing As soon as pacing was stopped, ECG, LVP, and BP all returned to essentially the same values ​​as before pacing.

[0416] 11A and 11B show the ventricular contraction in a natural state (FIG. 11A) and the onset of atrial contraction and the ventricular contraction in a normal state (FIG. 11B). The figures show the heart of a hypertensive dog when paced with a time interval of 2 ms between the onset of pacing and the onset of pacing (Fig. 11B). These figures show the cardiac ECG, right ventricular pressure (RVP), and RVP diastolic pressure, respectively. Shown are tracings of majority and right atrial pressure (RAP).

[0417] In Figure 11A, the P waves and QRS of a natural beat are clearly visible. By following the P waves as a result of atrial contraction, the increase in atrial pressure is visible. In the RVP tracing, by following the QRS complex against the ECG, A rapid increase in RVP is seen at higher magnification, which indicates ventricular contraction. In Fig. 11B, this sudden increase in RVP is preceded by an earlier, smaller increase in RVP that occurs simultaneously with atrial contraction and a reduction in blood pressure, and is the result of blood shifting from the atrium to the chambers. This is the atrial kick. In Fig. 11B, where pacing is at a time interval of 2 ms, the P-wave is essentially unnoticeable in the ECG, and electrical stimulator artifacts are discernible. The atrial kick in this case is not discernible on the zoomed tracing of right ventricular pressure, because the atrial contraction occurs simultaneously with, or even shortly after, the onset of ventricular contraction.

[0418] In Figure 12, a hypertensive dog heart shows a 60 ms time interval between atrial and ventricular pacing (trace points 105 and 107) or between atrial and ventricular pacing (trace point 109). The pacemaker was paced at a time interval of 120 ms. Tracking included ECG, left ventricular pressure (LVP), right ventricular pressure (RVP), and The left ventricular pressure (RVP), the magnification of RVP, and the right atrial pressure (RAP) are shown for follow-up points 105 and 107. As can be seen in the correspondingly enlarged trace of the RVP, the pacing time interval of 60 ms was The atrial kick is very slight, and the ventricular contraction begins shortly after the peak of the atrial contraction. In this case, the contribution of the atrial kick to ventricular filling is significantly reduced, but not completely eliminated, while the peak of the atrial contraction does not occur against a closed valve and atrial dilation is not increased. During pacing with a time interval of 120 ms, the atrial kick is clearly visible (enlarged). 109) in tracing RVP, but the onset of ventricular contraction and closure of the AV valves occurs before the completion of atrial contraction, thereby slightly reducing the contribution of the atrial kick to ventricular filling.

[0419] In FIG. 16, the heart of a hypertensive patient was paced with different AV delays. This example shows the results obtained by pacing both the atrium and the corresponding ventricle versus pacing only the ventricle based on an atrial sensed pulse. During the interval d-d', the atrium A pulse was sensed and the ventricular pulse was paced with an AV delay of 2 ms. During interval e-e', both the atrium and ventricle were paced with an AV delay of 2 ms. During interval f-f', both the atrium and ventricle were paced with an AV delay of 40 ms. During interval g-g', both the atrium and ventricle were paced with an AV delay of 20 ms. During the interval h-h', both the atrium and ventricle were paced with an AV delay of 80 ms. As shown in this example, comparing interval d-d' to interval e-e', blood pressure is lower when the atrium is paced during interval e-e' than when atrial activity is just sensed. As further shown in this example, comparing intervals e-e', f-f', g-g', and h-h', shorter AV delays caused a greater reduction in blood pressure than longer ones. For example, interval g-g' (20 ms AV delay) caused a greater reduction in blood pressure than interval e-e' (2 ms AV delay). As can be seen from the results of this example, the change in blood pressure may be caused at least in part by different AV delays, which are the atrial contractions relative to the closed valves. This leads to different percentages of

[0420] Method embodiments for reducing atrial kick Method 40 for reducing blood pressure is shown diagrammatically in FIG. 13. Method 40 may be performed by device 50 of FIG. 14, described below. Thus, device 50 may be configured to perform any or all of the steps of method 40. Similarly, method 40 may include any step that device 50 is configured to perform. For example, method 40 may include any of the functions described above with respect to device 50. Method 40 may include any step from method 600. Similarly, method 600 may include any step from method 40. Method 40 may include any step that system 700 is configured to perform. The system 700 may be configured to perform any or all of the steps of the method 40. It may be possible.

[0421] In some embodiments, method 40 may include step 41 of an atrial contraction. In some embodiments, step 41 includes sensing atrial activation. For example, step 41 may include sensing natural atrial activation. In some embodiments, method 40 includes inducing atrial activation. Method 40 may include step 42, in which a time interval is applied. Method 40 may include step 43, inducing AV valve closure. In some embodiments, step 43 may include inducing an excitatory current to at least one ventricle. This may be accomplished by applying an excitation current to both atria and / or actuating a prosthetic valve between at least one atrium and the corresponding ventricle to close. In some embodiments, steps 41, 42 and 43 may be repeated as indicated by the reverse arrow from step 43 back to step 41. In some embodiments, excitatory current may be applied to both ventricles simultaneously or sequentially. In some embodiments where both ventricles are paced sequentially, the initiation of activation of at least one atrium (e.g., the right atrium) and the start of activation of the paced atrium are sequentially determined. A time interval may be measured between the onset of activation of the corresponding ventricle (e.g., the right ventricle) that will be activated when the pulse is released from the ventricle and the onset of activation of the corresponding ventricle (e.g., the right ventricle). In some embodiments, step 43 may occur before or simultaneously with step 41, where the time interval is set to zero or negative. In some embodiments, the time interval may be measured in milliseconds.

[0422] Preferably, contraction of the atria and ventricles may be caused by controlling the contraction of both (e.g., by controlling the excitation leading to the contraction). Preferably, the onset of atrial activation is sensed, which triggers valve closure at a predetermined timing interval. Preferably, both atria are paced. In some embodiments where both AV valves are closed sequentially (e.g., when both ventricles are paced sequentially), a timing interval is determined between the onset of activation of the first atrium to be paced, and the onset of valve closure. Preferably, the timing of activation of one or more chambers (e.g., the onset of activation) is measured from the onset of activation of one or more preceding cardiac chambers, e.g., from the onset of activation of one or more preceding cardiac chambers. Based on the timing of the cycle, one or more excitation stimuli are The mixture may be delivered to the same and / or different chambers at desired time intervals before and / or after mixing.

[0423] In some embodiments, method 40 may be repeated for each heartbeat. In some embodiments, method 40 may be performed intermittently. For example, the method may be applied every few heartbeats. Alternatively, method 40 may be applied for a few heartbeats and then repeated for one or more heartbeats. For example, method 40 may be applied for 5-15 beats. In some embodiments, the application / avoidance pattern may be more complex, preferably based on a predefined algorithm. For example, the algorithm may adjust parameters of the stimulation rather than simply stopping and starting the stimulation. This reduces ventricular filling between beats, potentially reducing the ejection profile. As used herein, the ejection profile of the heart is the total volume of blood pumped by the heart in a given period of time. In some embodiments, intermittent application of method 40 may be applied to counteract the reduction in the ejection profile of the heart.

[0424] In some embodiments, the time interval applied in step 42 may be selected based on feedback. In such cases, method 40 may include: Detecting feedback parameters from the part and / or the patient's body, step 44 For example, one or more of atrial kick, blood pressure (e.g., in the arteries), and ventricular pressure. and / or atrial pressure, either directly or indirectly, to provide feedback information. In some embodiments, the feedback information may additionally or alternatively include the time when the atrium contracts and the AV valve closes and / or the time when the ventricle contracts. For example, an ultrasound sensor may be used to sense cardiac activity, for example, by ultrasound imaging of cardiac activity or by generating an echocardiogram (ECHO).

[0425] In some embodiments, step 44 includes using pulsed wave or continuous wave Doppler ultrasound to sense blood flow (e.g., flow velocity) and / or cardiac tissue motion at any point. Preferably, step 44 includes using an ultrasound sensor to detect A-waves, which correspond to contractions of the left atrium and blood flow to the left ventricle. It may include the following.

[0426] The method may include step 45, adjusting the time interval from step 42 based on feedback information from step 44. For example, step 45 may include adjusting the time interval based on sensed blood pressure. As shown in FIG. 13 by the arrow pointing from step 45 to step 41, steps 41, 42, 43 and / or 44 may be repeated after performing step 45. Some embodiments Then, the time interval may be initially set to a first value during step 41, and then during step 44 Based on the feedback sensing performed, the time interval may be decreased or increased during step 45 until the feedback value is within a given range (or above or below a given value). For example, the time interval may be increased until the systolic blood pressure is above 100 mmHg and / or below 140 mmHg and / or the diastolic blood pressure is below 90 mmHg and / or above 60 mmHg. The spacing may be adjusted.

[0427] In some embodiments, steps 44 and 45 may be performed for each application of step 43 (e.g., application of a ventricular pacing stimulus) during operation of method 40. In some embodiments, alternatively or additionally, a device may be installed (e.g., installed) on a patient in accordance with one or more embodiments. Steps 44 and 45 may be performed when the cardiac pacing device is provided (by implantation of a cardiac pacing device). The adjusting steps may be repeated periodically (e.g., by a caregiver during testing) and / or intermittently (e.g., once an hour or every 2-3 applications of ventricular pacing stimulation). In some embodiments, the adjusting steps may be performed based on one or more sensed parameters. Step 45 may be performed when feedback information indicates that the meter has exceeded a preset range for more than a predetermined period of time.

[0428] The steps of method 40 may be performed in any order, for example, the steps may be performed in the order indicated by the arrows shown in Figure 13. In another embodiment, step 42 may be performed before step 41.

[0429] the timing of atrial contraction, atrial activation, ventricular contraction, AV valve closure and / or opening, and / or the flow or lack thereof of blood from one or more atria to the respective ventricles; , and / or blood pressure may be sensed using any method known in the art and may be used as a feedback control. In some embodiments, the onset of excitation may be used as a trigger for delivery of an excitatory stimulus to one or more ventricles. The sensed information may additionally or alternatively be used in adjusting the timing intervals of the device.

[0430] Preferably, the feedback parameters may allow for responses to conditions requiring additional throughput from the heart, and these may be used to automatically stop causing valve closure at shortened time intervals instead of adjusting the timing interval. For example, the feedback parameters may lead to adjustments during exercise. In this example, a heart rate sensor may be used to provide feedback information regarding the patient's heart rate. If the heart rate is above a given threshold, the feedback may be used to stop the device. The device may, for example, stop the device when the heart rate is below a given threshold and / or for a predefined period of time. After a certain period of time has elapsed, it may be triggered again based on sensed feedback information.

[0431] Device for reducing blood pressure Reference is now made to FIG. 14, which shows a schematic diagram of a device 50 according to one embodiment. The device 50 may be constructed essentially in a manner known in the art, with certain modifications as described herein, and may have components similar to a cardiac pacemaker. Preferably, the device is implantable. Preferably, the device is adapted to provide additional and / or additional cardiac stimulation to the heart. or includes components capable of providing alternative electrical therapy (e.g., defibrillation). Device 50 may be configured for implantation in a patient's body in a manner essentially known in the art for implantable pacemakers, preferably with certain modifications as described herein. Device 50 may include components of system 700, and system 700 may include components of device 50.

[0432] The device 50 comprises a biocompatible body 51, one or more controllers 52, a power source 53, and The body 51 may include a telemetry unit 56. The body 51 may include a housing for housing multiple components of the device. The controller 52 may be configured to control the operation of the device and may implement any of the embodiments and methods disclosed herein. For example, the controller 52 may control the delivery of stimulation pulses. In some embodiments, the power source 53 may include a battery. For example, the power source 53 may include a rechargeable battery. In some embodiments, the power source 53 may include an inductively rechargeable battery. In some embodiments, the telemetry unit 56 may include one or more or multiple other units and / or components. For example, telemetry unit 56 may be configured to communicate with an external programmer and / or a receiving unit for receiving data recorded by device 50 during operation.

[0433] In some embodiments, device 50 may be configured to be attached to one or more electrodes and / or sensors. The electrodes and / or sensors may be integrated into device 50. whether attached to and / or connectable with In some embodiments, the electrodes are configured to pace at least one ventricle. Additionally or alternatively, the device preferably includes a ventricular electrode 561 formed thereon. The atrium 562 may be connected, by wire or wirelessly, to at least one implanted prosthetic valve 562. Additionally, the device 50 may include one or more atrial electrodes 57 for pacing one or more atria, and / or one or more atrial sensors 58 for detecting the onset of atrial activation, and / or other The system may include one or more sensors 59 for providing feedback parameters of the system.

[0434] In some embodiments, the sensor 59 may include one or more of a pressure sensor, an electrical sensor (e.g., an ECG The sensors 59 may include mechanical and / or electronic sensors (e.g., For example, ultrasonic sensors, electrodes and / or RF transceivers. In some embodiments, the sensor 59 may communicate with the device 50 via telemetry.

[0435] In some embodiments, the ventricular electrode 561 and / or the atrial electrode 57 may be standard pacing electrodes. The ventricular electrode 561 may be placed in a position known in the art for ventricular pacing. For example, a ventricular electrode may be positioned relative to the heart. In some embodiments, the atrial electrode 57 may be located near In some embodiments, the atrial electrode 57 may be positioned in and / or near one or more of the atria. For example, in some embodiments, the atrium may be attached to one or more of the atria at a An atrial electrode 57 may be attached to the right atrium near the location of the sinoatrial (SA) node.

[0436] One location of the ventricular electrode 561 is such that when the heart is paced, the pacing reduces or minimizes QRS prolongation in order to reduce or even minimize asynchrony. In some embodiments, this location is in the ventricular septum near the His bundle. The ventricular electrode 561 may additionally or alternatively be located on the epicardial or coronary It may be placed in a coronary vein, preferably to reduce asynchrony. More than one electrode can be placed in the ventricle to provide biventricular pacing.

[0437] The device 50 includes a pulser configured to deliver stimulation pulses to at least one heart chamber. The pulse generator or stimulation circuitry may include some or all of the standard capabilities of a conventional pacemaker. The controller 52 may be configured to control the pulse generator or stimulation circuitry. The atrial sensor 58 (and preferably other electrode sensors configured to sense other cardiac chambers) may be connected to the device 50 via specific circuitry that amplifies the electrical activity of the heart and allows sampling and detection of activation of specific chambers. Other circuitry may be configured to deliver stimuli to specific electrodes to pace the heart and generate propagating electrical activation.

[0438] In some embodiments, one or more additional sensors 59 are located in or on one or more of the atria and / or in or on one or more of the ventricles and / or preferably adjacent to the heart. For example, one or more sensors may be located on and / or in a vena cava, and / or on and / or in one or more arteries, and / or on and / or in one or more cardiac chambers. These sensors may measure pressure, or may measure other indices such as impedance and / or flow.

[0439] In some embodiments, controller 52 may include or be a microprocessor powered by power supply 53. In some embodiments, device 50 may include a clock 54, for example generated by a crystal. Device 50 may include internal memory 55 and / or may be connected to an external memory, for example The device may be connected to an external memory via a telemetry unit 56. In some embodiments, the telemetry unit 56 may be configured to allow communication with an external device, such as a programmer and / or one or more of the sensors 59. Any or all feedback information and / or a log of the operation of the device may be stored in an internal memory 55. and / or may be stored in an external memory unit by the telemetry unit 56. The information may be relayed to the

[0440] In some embodiments, the controller 52 may be configured to perform at least one of the methods described herein. It may operate according to the embodiment.

[0441] In some embodiments, the device 50 senses one or more feedback parameters. , may include one or more sensors for controlling the application and / or magnitude of the AV delay.

[0442] Artificial valves Additionally or alternatively, device 50 may be configured to directly control the operation of at least one implanted prosthetic valve 562. Attention is now directed to Fig. 15, which illustrates a schematic of a prosthetic valve 60 according to an embodiment of the present invention. Valve 60 shown in this example is bileaflet, as is known per se in the art for prosthetic valves. Although the following example relates to a bileaflet valve, the embodiment may also be implemented with other prosthetic valves, such as, for example, caged ball valves and disc valves.

[0443] As shown in Figure 15, the valve 60 may include a ring 61 for suturing the valve in place when implanted in a patient's heart. The valve 60 may include two semicircular leaflets 62 that rotate about posts 63 attached to the ring 61. In this schematic depiction, another device part is shown diagrammatically as a body 64, which corresponds to the body 51 shown in Figure 14. The body 64 may receive feedback information from a heart 65 in which the valve 60 is implanted.

[0444] Valve 60 differs from conventional prosthetic valves in that its closure may be directly controlled by device 50. Valve 60 may be slid open (e.g., by rotating struts 63 or by closing one or more leaflets 62). The valve may include a mechanism (e.g., a coil or hydraulic mechanism) configured to dynamically cause the valve to close (by inflating a portion of the valve). , and may later be returned to a relaxed position to allow the valve to open and, if desired, to be repeatedly closed. Relaxation may occur at a predetermined time after closure. Additionally or alternatively, relaxation may be affected in response to a sensor (e.g., a pressure sensor) reading ventricular activity. Control of valve 60 may be performed wirelessly (using a telemetry unit associated with the valve) or by wired communication with components in body 64. In some embodiments, valve 60 may be a valve configured to be opened and closed independently of fluid pressure acting on the valve. For example, valve 60 may be a ball valve.

[0445] Effect of the embodiment on reducing blood pressure Generally, some of the disclosed method and system embodiments include at least one The present invention provides a different approach to reducing the filling of the ventricles of the heart, thereby reducing blood pressure. Unlike previous mechanical methods for reducing blood pressure, some of the embodiments described herein achieve this goal without increasing pressure within at least one corresponding atrium. The reduction in blood pressure can be mechanically controlled without an increase in atrial pressure that would induce the secretion of atrial natriuretic hormone or atrial natriuretic peptide. The disclosed embodiment can prevent undesirable effects on heart rate and can reduce the possibility of canon atrial waves. This can reduce the risk of

[0446] Some of the disclosed embodiments may increase atrial expansion while causing the release of atrial natriuretic peptides to reduce atrial stimulation. For example, disclosed embodiments may include a method that includes stimulating the heart to contract the atrium while closing a heart valve associated with the atrium such that the contraction expands the atrium. Some embodiments as described above may reduce blood pressure as described above using cardiac stimulation to reach a peak atrial pressure caused by atrial contraction at a time that overlaps with a peak passive increase in atrial pressure. Some embodiments, such as those described above, may increase intra-atrial pressure and atrial dilation by causing the release of atrial natriuretic hormone or atrial natriuretic peptide. Some embodiments, such as those described above, may increase intra-atrial pressure and atrial dilation by using cardiac stimulation configured to have atrial contraction such that the intra-atrial pressure caused by atrial contraction of the atrium overlaps in time with the passive intra-atrial pressure increase of the atrium, thereby causing increased atrial dilation of the atrium that provides an intra-atrial pressure in the atrium that is higher than the intra-atrial pressure in the atrium in the absence of stimulation, thereby lowering blood pressure through hormonal or neuronal pathways. Reducing atrial stimulation and simultaneously causing the release of atrial natriuretic peptide may have a synergistic effect on lowering blood pressure. In some embodiments, control of the timing of valve closure relative to atrial contraction may be achieved by one or The amount by which the multiple atria expand may be controlled.

[0447] Unlike previous pharmaceutical or mechanical methods for reducing blood pressure, some of the disclosed embodiments achieve the goal of immediately reducing blood pressure. For example, reduction in blood pressure may occur within 1-3 seconds or within 1, 3, or 5 heartbeats of application of electrical current, and blood pressure may be increased immediately following stimulation. The lowest blood pressure value may be reached within less than 5 seconds of the start of the test.

[0448] The above example combines mechanical therapy with neuronal feedback and natural release of hormones that induce adaptation. Mechanical therapy and natural release of hormones may be additive or even synergistic mechanisms. While hormone release affects the cardiovascular system, mechanical therapy affects the heart itself. Reducing blood pressur...

Claims

1. 1. A system for delivering blood pressure reducing electrical stimulation to a patient's heart, comprising: a stimulation circuit configured to deliver stimulation pulses to at least one chamber of the patient's heart; at least one sensor configured to sense activation of the heart; At least one controller, pacing a first chamber of the heart and, after a first delay, pacing a second chamber of the heart to produce a desired change in blood pressure; receiving a first signal from the at least one sensor indicative of intrinsic activation of the first chamber and pacing the second chamber after a second delay; measuring a first blood pressure change resulting from the second delay; Comparing the first blood pressure change to the desired blood pressure change; adjusting the second delay to a third delay intended to adjust the first blood pressure change closer to the desired blood pressure change; receiving a second signal from the at least one sensor indicative of intrinsic activation of the first chamber and pacing the second chamber after the third delay; determining a second blood pressure change resulting from the third delay; determining that the second blood pressure change is substantially equal to the desired blood pressure change; the at least one controller configured to deliver a stimulation pattern to the heart including pulses having the third delay between sensing intrinsic activation of the first chamber and delivery of a stimulation pulse to the second chamber; A system comprising:

2. The system of claim 1 , wherein the first chamber is an atrium and the second chamber is a ventricle.

3. 3. The system according to claim 1, wherein the time required for the second delay is shorter than the time required for the first delay and longer than 0 msec.

4. 4. The system of claim 1, wherein in the step of receiving a first signal indicative of intrinsic excitation of the first chamber from the at least one sensor, the first signal is a signal indicative of intrinsic excitation that occurred in the cardiac cycle in which the first signal occurs.

5. 3. The system of claim 1 or claim 2, wherein in the step of receiving a first signal indicative of intrinsic activation of the first chamber from the at least one sensor, the first signal is a signal indicative of intrinsic activation that occurred in a previous cardiac cycle.

6. 6. The system of claim 1, further comprising a memory, wherein a difference between the time taken for the first delay and the time taken for the third delay is stored in the memory, and this difference is used to set other differences when other AV delay values ​​are selected to obtain other desired blood pressure changes instead of performing another experimental measurement.

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