System for controlling 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 functions including filling and contraction. Certain embodiments of the present invention include the application of local electrical stimulation to the heart.

Background Art

[0002] Blood pressure fluctuations are typically known to occur, for example, due to an increase in 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 decreased blood pressure affects the function of the heart and the characteristics of the cardiovascular system through a feedback loop. Such feedback control is achieved by the nervous system and the endocrine system (e.g., natriuretic peptides). In people with hypertension, although the baroreflex is functioning, the blood pressure remains elevated.

[0003] Hypertension (e.g., blood pressure of 140 / 90 mmHg or higher) is a serious health problem that affects many people. For example, approximately 74.5 million people aged 20 and over living in the United States have hypertension. Hypertension can lead to life-threatening conditions such as stroke, heart attack, and / or congestive heart failure. Among people with hypertension who are receiving current treatment, approximately 44.1% are controlling their hypertension in a satisfactory manner. In contrast, 55.9% of the same people are not able to control it well.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0005] Traditionally, the treatment of hypertension has included medication and lifestyle changes. These two types of treatment are not effective for all patients. In addition, due to side effects, certain patients may not be able to receive medication. Therefore, the need for additional techniques to lower blood pressure remains.

Means for Solving the Problems

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

[0007] The present invention applies focal electrical stimulation to the heart, including at least two different stimulation patterns configured to lower blood pressure to different extents respectively. The cardiac stimulation may alternately perform the stimulation patterns based on the needs of the patient. For example, a certain degree of blood pressure reduction during a part of the 24-hour cycle (e.g., daytime or a part thereof) and another different degree of blood pressure reduction during another part of the 24 hours (e.g., nighttime or a part thereof) are alternately performed. As another example, the cardiac stimulation may alternately perform a first stimulation pattern that provides a first degree of blood pressure reduction during a period of intense activity by the patient and a second stimulation pattern that provides a second different degree of blood pressure reduction during a period of light activity by the patient.

[0008] In some embodiments, rather than or in addition to pharmacologically treating hypertension, hypertension is mechanically treated. In some embodiments, an electrical stimulation device, such as a pacemaker or other types of devices having a pulse generator, may be used to stimulate a 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 stimulation pattern may be configured such that the baroreflex can be adjusted to reduce or even prevent the adaptation response of the cardiovascular system.

[0009] Some embodiments may utilize the slow baroreflex response that occurs after treatment has been discontinued or reduced. Under such circumstances, it may take a long time for the blood pressure level to return to its pre-treatment value, and treatment may be interrupted or reduced for a long period. Subsequently, treatment may be resumed at the treatment level applied before treatment was interrupted or reduced, before the blood pressure level reaches its pre-treatment value and before treatment is interrupted or reduced for a long period.

[0010] In some embodiments, an electrical stimulation device may be used to stimulate a patient's heart such that at least a portion of atrial contraction is induced with the atrioventricular valve closed. In such atrial contractions, less blood may enter the corresponding ventricle than when the atrioventricular valve is open during atrial contraction, which achieves an immediate decrease in blood pressure.

[0011] In some embodiments, the intracardiac pressure generated by atrial contraction of the atrium may overlap in time with the passive intracardiac pressure increase of the atrium, thereby providing an intracardiac pressure of the atrium that is a combination of the intracardiac pressure generated by atrial contraction and the passive pressure increase, and is higher than the intracardiac pressure of the atrium in the absence of stimulation. This may cause an increase in atrial dilation, thereby reducing blood pressure through the hormonal pathway and / or the neuronal pathway. This decrease in blood pressure may take some time to appear, and that time depends on the hormonal pathway and / or the neuronal pathway.

[0012] The intracardiac pressure generated by atrial contraction may reach the maximum intracardiac pressure generated by atrial contraction. The passive intracardiac pressure increase of the atrium may reach the maximum passive intracardiac pressure increase of the atrium. Alternatively, or in addition thereto, the time overlap between the intracardiac pressure generated by atrial contraction of the atrium and the passive intracardiac pressure increase of the atrium may include the time overlap of the maximum intracardiac pressure and the maximum passive pressure increase generated by atrial contraction. In some embodiments, the overlap of the above-mentioned maximum intracardiac pressure and the maximum passive pressure increase may result in a combined intracardiac pressure (of the intracardiac pressure generated by atrial contraction and the passive pressure increase) that is higher than the intracardiac pressure of the atrium in the absence of stimulation.

[0013] In some embodiments, an electrical stimulation device may be used to stimulate the patient's heart to cause at least some atrial contractions while keeping the atrioventricular valve closed within a single cardiac cycle, and / or to stimulate the patient's heart such that the intracardiac pressure generated by atrial contraction of the atrium overlaps in time with the passive intracardiac pressure increase of the atrium, thereby providing an intracardiac pressure of the atrium that is a combination of the intracardiac pressure generated by atrial contraction and the passive pressure increase, and is higher than the intracardiac pressure of the atrium in the absence of stimulation.

[0014] In some embodiments, an artificial valve may be used during the treatment of hypertension. One or more atrioventricular (AV) valves are malfunctioning, in some medical conditions In some cases, the valve may be replaced by implanting an artificial (prosthetic) valve. These artificial valves may typically be configured to open and close passively in response to the pressure difference between the atrium and ventricle, similar to natural valves. Passive artificial valves are typically classified into three types based on their mechanical structure: cage-type ball valves, tilting disk valves, and bileaflet valves. As another method In some embodiments, an active artificial valve configured to open and close actively may be used.

[0015] In one aspect of the present 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 the patient's heart with stimulation pulses. The system may include at least one controller configured to apply a stimulation pattern of stimulation pulses to at least one chamber of the heart. The stimulation pattern 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 may be configured to reduce or prevent an atrial kick and / or to control either or both of the atrial pressure and atrial dilation.

[0016] In one aspect of the present 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 the patient's heart. The system may include at least one controller configured to apply a stimulation pattern comprising a plurality of stimulation pulses. At least a portion of the plurality of stimulation pulses At least one stimulation pulse may have a first stimulation setting configured to reduce an atrial kick in at least one ventricle. At least one stimulation pulse of a plurality of stimulation pulses may have a second stimulation setting configured to reduce a baroreflex response to the reduction of the atrial kick so as to limit an increase in a blood pressure value occurring between the stimulation pulses to a predetermined value or a range of values.

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

[0018] In some embodiments, the apparatus processor circuit may be configured to operate in an operating mode in which the apparatus controls an AV delay. The AV delay may be understood to mean, as used herein, the delay that occurs in a single heartbeat between ventricle excitation and / or contraction and atrial excitation and / or contraction. Additionally, as used herein, the AV delay in a system or method may be understood to mean the time delay between the delivery of at least one excitatory stimulus to the ventricle within one heartbeat and the detection of the onset of atrial excitation, the expected timing of the onset of atrial excitation, and one of the delivery of at least one excitatory stimulus to the atrium.

[0019] This AV delay may be set by delivering at least one stimulation pulse to both at least one atrium and at least one ventricle. This stimulation is preferably performed to a greater degree than the natural activity of the heart of. Such a degree may be, for example, using at least one sensing electrode for detecting the natural activity in the right atrium when there is no stimulation Moreover, the degree of stimulation pulse transmission may be adjusted and set accordingly.

[0020] Preferably, if ventricular excitation is time-adjusted such that it starts before the transmission of one or more stimulation pulses to the atrium, the transmission of the stimulation pulse to the heart is time-adjusted such that one or more excitatory pulses are transmitted to the atrium at a time earlier than the expected next natural onset of atrial excitation. In some embodiments, the AV delay may be set by transmitting at least one stimulation pulse to one or more ventricles rather than to the atrium. In such a case, one or more natural activities of the atrium may be detected, and the ventricular excitation and / or contraction timing may be set to precede its natural expected timing based on the detected degree of atrial activity. In some embodiments, the processor circuit may be configured to operate in an operating mode that stimulates the ventricle such that ventricular excitation starts about 0 milliseconds (ms) to about 50 ms before the start of atrial excitation in at least one atrium, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume and reducing the patient's blood pressure from the pre-treatment blood pressure. In such an embodiment, atrial excitation may be detected to determine the start of atrial excitation. For example, the processor circuit may be configured to operate in an operating mode that transmits one or more excitatory pulses to the ventricle about 0 ms to about 50 ms before the next atrial excitation is expected to occur. The time interval between the start of atrial excitation and the moment when atrial excitation is detected may be known or estimated and may be used to calculate the timing of the start of atrial excitation. For example, it is known or estimated that atrial excitation is detected 5 ms after the start of atrial excitation, and the start of atrial excitation

[0021] In some embodiments, the AV delay may be set by transmitting at least one stimulation pulse to one or more ventricles rather than to the atrium. In such a case, one or more natural activities of the atrium may be detected, and the ventricular excitation and / or contraction timing may be set to precede its natural expected timing based on the detected degree of atrial activity. In some embodiments, the AV delay may be set by transmitting at least one stimulation pulse to one or more ventricles rather than to the atrium. In such a case, one or more natural activities of the atrium may be detected, and the ventricular excitation and / or contraction timing may be set to precede its natural expected timing based on the detected degree of atrial activity. In some embodiments, the AV delay may be set by transmitting at least one stimulation pulse to one or more ventricles rather than to the atrium. In such a case, one or more natural activities of the atrium may be detected, and the ventricular excitation and / or contraction timing may be set to precede its natural expected timing based on the detected degree of atrial activity. In some embodiments, the AV delay may be set by transmitting at least one stimulation pulse to one or more ventricles rather than to the atrium. In such a case, one or more natural activities of the atrium may be detected, and the ventricular excitation and / or contraction timing may be set to precede its natural expected timing based on the detected degree of atrial activity.

[0022] In some embodiments, the processor circuit may be configured to operate in an operating mode that stimulates the ventricle such that ventricular excitation starts about 0 milliseconds (ms) to about 50 ms before the start of atrial excitation in at least one atrium, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume and reducing the patient's blood pressure from the pre-treatment blood pressure. In such an embodiment, atrial excitation may be detected to determine the start of atrial excitation. For example, the processor circuit may be configured to operate in an operating mode that transmits one or more excitatory pulses to the ventricle about 0 ms to about 50 ms before the next atrial excitation is expected to occur. The time interval between the start of atrial excitation and the moment when atrial excitation is detected may be known or estimated and may be used to calculate the timing of the start of atrial excitation. For example, it is known or estimated that atrial excitation is detected 5 ms after the start of atrial excitation, and the start of atrial excitation In some embodiments, the processor circuit may be configured to operate in an operating mode that stimulates the ventricle such that ventricular excitation starts about 0 milliseconds (ms) to about 50 ms before the start of atrial excitation in at least one atrium, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume and reducing the patient's blood pressure from the pre-treatment blood pressure. In such an embodiment, atrial excitation may be detected to determine the start of atrial excitation. For example, the processor circuit may be configured to operate in an operating mode that transmits one or more excitatory pulses to the ventricle about 0 ms to about 50 ms before the next atrial excitation is expected to occur. The time interval between the start of atrial excitation and the moment when atrial excitation is detected may be known or estimated and may be used to calculate the timing of the start of atrial excitation. For example, it is known or estimated that atrial excitation is detected 5 ms after the start of atrial excitation, and the start of atrial excitation In some embodiments, the processor circuit may be configured to operate in an operating mode that stimulates the ventricle such that ventricular excitation starts about 0 milliseconds (ms) to about 50 ms before the start of atrial excitation in at least one atrium, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume and reducing the patient's blood pressure from the pre-treatment blood pressure. In such an embodiment, atrial excitation may be detected to determine the start of atrial excitation. For example, the processor circuit may be configured to operate in an operating mode that transmits one or more excitatory pulses to the ventricle about 0 ms to about 50 ms before the next atrial excitation is expected to occur. The time interval between the start of atrial excitation and the moment when atrial excitation is detected may be known or estimated and may be used to calculate the timing of the start of atrial excitation. For example, it is known or estimated that atrial excitation is detected 5 ms after the start of atrial excitation, and the start of atrial excitation If the ventricles are to be stimulated 20 ms prior to that, the ventricles will be stimulated 25 ms prior to the next expected detection of atrial excitation.

[0023] In other embodiments, the processor circuitry is configured to operate in an operating mode in which, when the atria are stimulated, atrial excitation is initiated about 0 ms to about 50 ms after the initiation of ventricular excitation in at least one ventricle, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume and reducing the patient's blood pressure from the pre-treatment blood pressure. For example, the processor circuitry may be configured to operate in an operating mode in which one or more excitatory pulses are transmitted to the atria about 0 ms to about 50 ms after one or more excitatory pulses are supplied to the patient's ventricles. In such embodiments, pacing may be time-regulated without relying on detecting atrial excitation. Preferably, in such embodiments, atrial excitation is detected to ensure that one or more excitatory pulses are transmitted to the atria before a natural excitation occurs. Preferably, atrial excitation is set to start about 0 ms to about 50 ms after the start of ventricular excitation when the original atrial excitation rate is lower than the original ventricular excitation rate. after the start of ventricular excitation in at least one ventricle, atrial excitation is initiated, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume and reducing the patient's blood pressure from the pre-treatment blood pressure. For example, the processor circuitry may be configured to operate in an operating mode in which one or more excitatory pulses are transmitted to the atria about 0 ms to about 50 ms after one or more excitatory pulses are supplied to the patient's ventricles. In such embodiments, pacing may be time-regulated without relying on detecting atrial excitation. Preferably, in such embodiments, atrial excitation is detected to ensure that one or more excitatory pulses are transmitted to the atria before a natural excitation occurs. Preferably, atrial excitation is set to start about 0 ms to about 50 ms after the start of ventricular excitation when the original atrial excitation rate is lower than the original ventricular excitation rate. In such embodiments, pacing may be time-regulated without relying on detecting atrial excitation. Preferably, in such embodiments, atrial excitation is detected to ensure that one or more excitatory pulses are transmitted to the atria before a natural excitation occurs. Preferably, atrial excitation is set to start about 0 ms to about 50 ms after the start of ventricular excitation when the original atrial excitation rate is lower than the original ventricular excitation rate. In such embodiments, pacing may be time-regulated without relying on detecting atrial excitation. Preferably, in such embodiments, atrial excitation is detected to ensure that one or more excitatory pulses are transmitted to the atria before a natural excitation occurs. Preferably, atrial excitation is set to start about 0 ms to about 50 ms after the start of ventricular excitation when the original atrial excitation rate is lower than the original ventricular excitation rate. In such embodiments, pacing may be time-regulated without relying on detecting atrial excitation. Preferably, in such embodiments, atrial excitation is detected to ensure that one or more excitatory pulses are transmitted to the atria before a natural excitation occurs. Preferably, atrial excitation is set to start about 0 ms to about 50 ms after the start of ventricular excitation when the original atrial excitation rate is lower than the original ventricular excitation rate.

[0024] In some embodiments, the timing of the mechanical contraction related to the electrical excitation of the chambers for the patient may be determined, for example, by detecting changes in atrial and ventricular pressures, using ultrasound to detect wall motion (e.g., echocardiography or cardiac echo), and / or detecting impedance changes or the opening and closing of heart valves using embedded and / or or external sensors known in the art. Such sensors may include, for example, pressure sensors, impedance, ultrasonic sensors, and / or one or more acoustic sensors and / or one or more blood flow sensors.

[0025] One or more excitatory pulses will be at a timing that will produce the desired pattern of contractions The timing of mechanical contraction related to the electrical excitation of the chamber for the patient may be considered so as to be transmitted to the heart, and the processor circuit may be configured accordingly. This may be done in a closed-loop mode using one or more embedded sensors and / or, for example, using an interface having an external measuring device, sometimes (e.g., at the time of device implantation and / or inspection).

[0026] The operating mode may include stimulating the ventricle to initiate contraction of the ventricle before the onset of contraction of at least one atrium. and may include causing the AV valve to close during at least a portion of the contraction of at least one atrium by stimulating the ventricle to initiate contraction of the ventricle before the end of the contraction of at least one atrium.

[0027] The operating mode may include stimulating the ventricle to initiate contraction of the ventricle within less than 100 ms after the onset of contraction of at least one atrium. and thereby causing the AV valve to close during at least a portion of the contraction of at least one atrium. and may include causing the AV valve to close during at least a portion of the contraction of at least one atrium by stimulating the ventricle to initiate contraction of the ventricle before the end of the contraction of at least one atrium.

[0028] The operating mode may include stimulating the ventricle to initiate contraction of the ventricle within less than 100 ms after the onset of contraction of at least one atrium.

[0029] Optionally, care is taken to ensure that atrial contraction starts before ventricular contraction reaches peak internal pressure. Since atrial contraction is usually faster than ventricular contraction, this is possible even if ventricular contraction has started before the onset of atrial contraction. Therefore, one of the following settings may be selected.

[0030] a. The operating mode may include stimulating the ventricle to initiate contraction of the ventricle at any point during atrial contraction but before the atrium reaches its maximum internal pressure due to atrial contraction.

[0031] b. The operating mode may include stimulating the ventricle to initiate contraction of the ventricle at any point during atrial contraction but after the atrium has reached its maximum internal pressure due to atrial contraction.

[0032] c. The actuation mode includes stimulating the ventricles at a timing when contraction begins at essentially the same time (e.g., within 5 ms of each other) in both the atria and ventricles. This is also acceptable.

[0033] d. The actuation mode may include stimulating the ventricles at a timing such that peak atrial contraction occurs when the ventricles are near or at maximum dilation, thereby causing an increase in the dilation of the atrial wall that is further detailed below with respect to the isovolumetric and rapid ejection phases of the ventricles, and starting contraction in the ventricles.

[0034] The actuation mode includes stimulating the ventricles to contract at least partially prior to the start of contraction of at least one atrium, thereby causing the AV valve to close during the start of contraction of at least one atrium. This may be included. This may be included.

[0035] Preferably, the processor circuit is configured to operate in an actuation mode in which one or more excitatory pulses are transmitted to the patient's atria between about 0 ms and about 50 ms after one or more excitatory pulses are transmitted to the patient's ventricles. This may be included.

[0036] In another aspect, an embodiment of a method for reducing the blood pressure of a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume is provided. The method includes transmitting a stimulation pulse from a stimulation circuit to at least one of the atria and ventricles, and operating a processor circuit coupled to the stimulation circuit in an actuation mode such that ventricular excitation is started about 0 ms to about 50 ms before the start of atrial excitation in at least one atrium, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume and reducing the patient's blood pressure from the pre-treatment blood pressure. This may be included. This may be included.

[0037] In such an embodiment, atrial excitation may be detected to determine the onset of atrial excitation. For example, the method may include delivering one or more excitatory pulses to the ventricles about 0 ms to about 50 ms before the next atrial excitation is expected to occur. The time interval between the onset of atrial excitation and the moment when atrial excitation is detected may be known and may be used to calculate the timing of the onset of atrial excitation. For example, it is known or estimated that atrial excitation is detected 5 ms after the onset of atrial excitation, and if the ventricles are to be stimulated 20 ms before the onset of atrial excitation, the ventricles will be stimulated 25 ms before the expected next detection of atrial excitation. becomes.

[0038] In other embodiments, the method stimulates the atria to initiate atrial excitation between about 0 ms and about 50 ms after the onset of ventricular excitation in at least one ventricle, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume and reducing the patient's blood pressure from the pre-treatment blood pressure, and may include operating a processor circuit coupled to a stimulation circuit to operate in an operating mode. For example, the method may include delivering one or more excitatory pulses to the atria between about 0 ms and about 50 ms after one or more excitatory pulses have been delivered to the patient's ventricles. In such an embodiment, pacing may be time-adjusted without relying on detecting atrial excitation. Preferably, such an embodiment includes detecting atrial excitation to ensure that one or more excitatory pulses are delivered to the atria before a natural excitation occurs. Preferably, when the original atrial excitation rate is lower than the original ventricular excitation rate, atrial excitation is set to start between about 0 ms and about 50 ms after the onset of ventricular excitation.

[0039] ​​​​In some embodiments, the timing of mechanical contraction related to electrical excitation of the chamber for the patient may be evaluated using, for example, ultrasound (such as echocardiography or cardiac echo) or other known means. The timing of mechanical contraction related to electrical excitation of the chamber for the patient may be considered to generate a desired pattern of contraction, and the timing at which one or more excitatory pulses are transmitted to the heart may be selected.

[0040] The operating mode may include stimulating the ventricles to contract the ventricles before at least one atrium begins to contract. It may include causing the ventricles to contract so as to close the AV valve during at least a portion of the contraction of at least one atrium.

[0041] The operating mode may include stimulating the ventricles to contract the ventricles before at least one atrium begins to contract. It may include causing the ventricles to contract so as to close the AV valve during at least a portion of the contraction of at least one atrium. It may include causing the ventricles to contract so as to close the AV valve during at least a portion of the contraction of at least one atrium.

[0042] The operating mode may include stimulating the ventricles to contract the ventricles before at least one atrium ends its contraction. It may include causing the ventricles to contract so as to close the AV valve during the start of the contraction of at least one atrium. It may include causing the ventricles to contract so as to close the AV valve during the start of the contraction of at least one atrium.

[0043] Preferably, the method may include transmitting one or more excitatory pulses to the atria between about 0 ms and about 50 ms after one or more excitatory pulses are transmitted to the ventricles of the patient. .

[0044] In another aspect, an embodiment of an apparatus for reducing the blood pressure of a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume is provided. The apparatus includes a stimulation circuit configured to transmit stimulation pulses to at least one cardiac chamber of the patient's heart. It is provided with a stimulation circuit configured to transmit stimulation pulses to at least one cardiac chamber of the patient's heart. This may also be the case. This device may comprise a processor circuit coupled to a stimulation circuit. The processor circuit may cause a contraction of about 40% of the atrium and about 100% of the atrial contraction when the atrioventricular valve associated with the atrium is closed, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume and reducing the patient's blood pressure from the pre-treatment blood pressure, and at least one heart chamber is configured to operate in an operating mode that stimulates. This can be achieved, for example, by initiating atrial contraction about 60 ms or less before the closure of the AV valve. 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 embedded sensors.

[0045] In another aspect, an embodiment of a device for reducing the blood pressure of a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume is provided. This device may comprise a stimulation circuit configured to deliver stimulation pulses to at least one heart chamber. This device may comprise a processor circuit coupled to the stimulation circuit. The processor circuit may cause about 50% to about 95% of the atrial contraction during ventricular systole, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume and reducing the patient's blood pressure from the pre-treatment blood pressure, and at least one heart chamber is configured to operate in a pacing mode that paces. This can be achieved, for example, by initiating atrial contraction about 50 ms to 5 ms before the start of ventricular systole. Preferably, the timing of the start of ventricular systole may be set according to the timing of the closure of the AV valve. 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 embedded sensors.

[0046] In another aspect, one embodiment provides a method implemented using an implantable myocardial stimulation device 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 such that the atria contract while the heart valves associated with the atria remain closed and such that ventricular dilation due to contraction causes the patient's blood pressure to drop below the pre-treatment blood pressure. This can be achieved, for example, by contracting the atria at the time when the ventricular internal pressure is at its maximum such that the force of atrial contraction increases the atrial internal pressure and atrial dilation beyond the maximum passive internal pressure and dilation caused by the contraction of the associated ventricle. In such a case, the timing of the maximum atrial contraction must either coincide with the end of the isovolumic period or must be during the rapid ejection phase of the ventricle. Optionally, this timing may be set periodically (e.g., at implantation) based on data from an external sensor and / or using one or more implantable sensors in a closed loop.

[0047] In another aspect, one embodiment provides a system for reducing a patient's blood pressure by controlling atrial internal pressure and atrial dilation. The system may include a stimulation circuit configured to deliver stimulation pulses to at least one heart chamber of the patient's heart and at least one controller configured to effect 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 stimulate the heart such that the atrial internal pressure caused by the stimulation is higher than the atrial internal pressure without stimulation, and such that the patient's blood pressure drops, by causing the atrial internal pressure caused by atrial contraction to coincide in time with the passive increase in atrial internal pressure, and by causing the atrial internal pressure caused by the stimulation to be a combination of the atrial internal pressure caused by atrial contraction and the passive increase in atrial internal pressure.

[0048] The atrial intracardiac pressure caused by the stimulus may cause an increase in atrial dilation of the atrium that lowers blood pressure through the hormonal pathway and / or the neural pathway.

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

[0050] At least one of the stimulation pulses may include stimulating the atrium of the heart. At least one of the stimulation pulses may include stimulating the ventricle of the heart. At least one of the stimulation pulses may further pace the atrium and ventricle at a substantially equal rate if desired, or pace the atrium at a rate faster than the rate at which the ventricle is paced.

[0051] At least one of the stimulation pulses may include stimulating the atrium so that the atrium 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] If desired, 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. It may further include exciting.

[0054] One or more stimulation patterns may further include stimulating the heart to reduce or prevent atrial stimulation. At least one of the stimulation patterns may include stimulating the heart in a plurality of beats, and at least a part of the stimulation pulses is such that the intracardiac pressure generated in the atrium by atrial contraction overlaps in time with the passive intracardiac pressure rise in the atrium, so that the intracardiac pressure in the atrium generated by stimulation is higher than the intracardiac pressure in the atrium without stimulation by the combination of the intracardiac pressure generated by atrial contraction and the passive pressure rise, and at least a part of the stimulation pulses is configured to reduce or prevent atrial stimulation. In a single beat, both atrial stimulations are reduced or prevented, and the intracardiac pressure generated in the atrium by atrial contraction overlaps in time with the passive intracardiac pressure rise in the atrium, so that the intracardiac pressure in the atrium generated by stimulation is higher than the intracardiac pressure in the atrium without stimulation by the combination of the intracardiac pressure generated by atrial contraction and the passive pressure rise, and stimulation pulses may be provided.

[0055] In a single beat, both atrial stimulations are reduced or prevented, and the intracardiac pressure generated in the atrium by atrial contraction overlaps in time with the passive intracardiac pressure rise in the atrium, so that the intracardiac pressure in the atrium generated by stimulation is higher than the intracardiac pressure in the atrium without stimulation by the combination of the intracardiac pressure generated by atrial contraction and the passive pressure rise, and stimulation pulses may be provided.

[0056] At least one stimulation pattern has a first atrial contraction that starts when the atrioventricular valve is open and ends after the atrioventricular valve closes in a single beat, such that the intracardiac pressure in the atrium generated by atrial contraction is higher than the intracardiac pressure in the atrium without stimulation by the combination of the intracardiac pressure generated by atrial contraction and the passive pressure rise, and includes at least one stimulation pulse set to induce a second atrial contraction in which the intracardiac pressure in the atrium generated by atrial contraction overlaps in time with the passive intracardiac pressure rise in the atrium. The first atrial contraction may be detected, and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced. At least one stimulation pattern has a first atrial contraction that starts when the atrioventricular valve is open and ends after the atrioventricular valve closes in a single beat, such that the intracardiac pressure in the atrium generated by atrial contraction is higher than the intracardiac pressure in the atrium without stimulation by the combination of the intracardiac pressure generated by atrial contraction and the passive pressure rise, and includes at least one stimulation pulse set to induce a second atrial contraction in which the intracardiac pressure in the atrium generated by atrial contraction overlaps in time with the passive intracardiac pressure rise in the atrium. The first atrial contraction may be detected, and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced. At least one stimulation pattern has a first atrial contraction that starts when the atrioventricular valve is open and ends after the atrioventricular valve closes in a single beat, such that the intracardiac pressure in the atrium generated by atrial contraction is higher than the intracardiac pressure in the atrium without stimulation by the combination of the intracardiac pressure generated by atrial contraction and the passive pressure rise, and includes at least one stimulation pulse set to induce a second atrial contraction in which the intracardiac pressure in the atrium generated by atrial contraction overlaps in time with the passive intracardiac pressure rise in the atrium. The first atrial contraction may be detected, and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced. At least one stimulation pattern has a first atrial contraction that starts when the atrioventricular valve is open and ends after the atrioventricular valve closes in a single beat, such that the intracardiac pressure in the atrium generated by atrial contraction is higher than the intracardiac pressure in the atrium without stimulation by the combination of the intracardiac pressure generated by atrial contraction and the passive pressure rise, and includes at least one stimulation pulse set to induce a second atrial contraction in which the intracardiac pressure in the atrium generated by atrial contraction overlaps in time with the passive intracardiac pressure rise in the atrium. The first atrial contraction may be detected, and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0057] Alternatively, at least one stimulation pattern is such that the intracardiac pressure of the atrium caused by the stimulation is higher than the intracardiac pressure of the atrium without stimulation by a combination of the intracardiac pressure of the atrium caused by atrial contraction and the passive pressure increase, in a single beat, starting when the atrioventricular valve is open and ending before the atrioventricular valve closes, having a first atrial contraction, and inducing a second atrial contraction in which the intracardiac pressure caused by the atrial contraction of the atrium overlaps in time with the passive pressure increase of the atrium. The first atrial contraction may be detected, and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced. It may include at least one stimulation pulse set to be. The first atrial contraction may be detected, and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced. such that the intracardiac pressure caused by the atrial contraction of the atrium overlaps in time with the passive pressure increase of the atrium. One or more stimulation patterns may include (1) a first stimulation pulse that stimulates the heart such that the intracardiac pressure of the atrium caused by the stimulation is higher than the intracardiac pressure of the atrium without stimulation by a combination of the intracardiac pressure of the atrium caused by atrial contraction and the passive pressure increase, due to the intracardiac pressure of the atrium caused by atrial contraction overlapping in time with the passive pressure increase of the atrium, and (2) a second stimulation pulse that stimulates the heart such that atrial stimulation is reduced or prevented, and alternatingly performing a plurality of stimulation patterns having different ratios. Optionally, one or more stimulation patterns reduce or prevent atrial stimulation and include at least one stimulation pulse configured to stimulate the heart such that the intracardiac pressure of the atrium caused by the atrial contraction of the atrium overlaps in time with the passive pressure increase of the atrium, and the intracardiac pressure of the atrium caused by the stimulation is higher than the intracardiac pressure of the atrium without stimulation by a combination of the intracardiac pressure of the atrium caused by atrial contraction and the passive pressure increase (both in a single cardiac cycle).

[0058] It may include alternately performing a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that the intracardiac pressure of the atrium caused by the stimulation is higher than the intracardiac pressure of the atrium without stimulation by a combination of the intracardiac pressure of the atrium caused by atrial contraction and the passive pressure increase, due to the intracardiac pressure of the atrium caused by atrial contraction overlapping in time with the passive pressure increase of the atrium, and (2) a second stimulation pulse that stimulates the heart such that atrial stimulation is reduced or prevented. Optionally, one or more stimulation patterns reduce or prevent atrial stimulation and include at least one stimulation pulse configured to stimulate the heart such that the intracardiac pressure of the atrium caused by the atrial contraction of the atrium overlaps in time with the passive pressure increase of the atrium, and the intracardiac pressure of the atrium caused by the stimulation is higher than the intracardiac pressure of the atrium without stimulation by a combination of the intracardiac pressure of the atrium caused by atrial contraction and the passive pressure increase (both in a single cardiac cycle). Optionally, one or more stimulation patterns reduce or prevent atrial stimulation and include at least one stimulation pulse configured to stimulate the heart such that the intracardiac pressure of the atrium caused by the atrial contraction of the atrium overlaps in time with the passive pressure increase of the atrium, and the intracardiac pressure of the atrium caused by the stimulation is higher than the intracardiac pressure of the atrium without stimulation by a combination of the intracardiac pressure of the atrium caused by atrial contraction and the passive pressure increase (both in a single cardiac cycle).

[0059] One or more stimulation patterns include alternately performing a plurality of stimulation patterns having different ratios of: (1) a first stimulation pulse that stimulates the heart such that the intracardiac pressure generated by atrial contraction of the atrium causes the intracardiac pressure of the atrium generated by the stimulation to be higher than the intracardiac pressure of the atrium without stimulation by a combination of the intracardiac pressure generated by atrial contraction and the passive pressure increase of the atrium, where the intracardiac pressure generated by atrial contraction overlaps in time with the passive pressure increase of the atrium; and (2) a second stimulation pulse that does not provide the intracardiac pressure generated by atrial contraction of the atrium that overlaps in time with the passive pressure increase of the atrium. This is also acceptable.

[0060] At least one stimulation pulse includes pacing at least one of the atrium of the heart and the ventricle of the heart such that the relative timing of excitation corresponds to an atrioventricular delay of about 2 ms. This may also be included.

[0061] At least one stimulation pulse includes pacing at least one of the atrium 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. This may also be included.

[0062] In another aspect, one embodiment provides a method for lowering a patient's blood pressure by controlling intracardiac pressure and atrial dilation. The method may be implemented using an implantable myocardial stimulation device associated with the patient's heart. The method includes stimulating the heart to provide an intracardiac pressure generated by atrial contraction that overlaps in time with the passive pressure increase of the atrium such that the combination of the intracardiac pressure generated by atrial contraction and the passive pressure increase causes an intracardiac pressure higher than the intracardiac pressure of the atrium without stimulation and such that the patient's blood pressure decreases.

[0063] The intracardiac pressure of the atrium generated by the stimulation may cause an increase in atrial dilation of the atrium that lowers blood pressure through a hormonal pathway or a neuronal pathway.

[0064] The atrial pressure generated by atrial contraction may reach the maximum atrial pressure generated by atrial contraction. The passive pressure rise in the atrium may reach the maximum passive pressure rise in the atrium. Alternatively, or in addition, the time overlap between the atrial pressure generated by atrial contraction in the atrium and the passive pressure rise in the atrium may include the time overlap of both the maximum atrial pressure and the maximum passive pressure rise generated by atrial contraction. In some embodiments, the overlap of the above-mentioned maximum atrial pressure and the maximum passive pressure rise results in a combined atrial pressure (the atrial pressure generated by atrial contraction and the passive pressure rise) that is higher than the atrial pressure in the atrium without stimulation. Therefore, the method may include stimulating the heart such that the maximum value of the atrial pressure generated by atrial contraction in the atrium overlaps in time with the maximum passive pressure rise in the atrium.

[0065] The method may include stimulating the atrium of the heart. The method may alternatively or in addition include stimulating the ventricle of the heart. The method may further include pacing the atrium and ventricle at substantially the same rate, 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, further include stimulating the atrium to contract twice during a single cardiac cycle by stimulating the atrium twice during a single cardiac cycle or stimulating the atrium once during a single cardiac cycle.

[0067] Optionally, the method may include stimulating the atrium such that the atrium contracts only once during a single cardiac cycle.

[0068] ​The method may further include stimulating the heart to reduce or prevent atrial stimulation. Stimulating the heart may include transmitting a stimulation pattern to the heart in a plurality of beats, wherein at least some of the stimulation pulses of the stimulation pattern are such that the intracardiac pressure generated by atrial contraction of the atrium overlaps in time with the passive intracardiac pressure rise of the atrium, so that the intracardiac pressure of the atrium generated by the stimulation is higher than the intracardiac pressure of the atrium without stimulation by the combination of the intracardiac pressure generated by atrial contraction and the passive intracardiac pressure rise, and at least some of the stimulation pulses are configured to reduce or prevent atrial stimulation. Both atrial stimulations are reduced or prevented in a single beat, and the intracardiac pressure generated by atrial contraction of the atrium overlaps in time with the passive intracardiac pressure rise of the atrium, so that the intracardiac pressure of the atrium generated by the stimulation is higher than the intracardiac pressure of the atrium without stimulation by the combination of the intracardiac pressure generated by atrial contraction and the passive intracardiac pressure rise, and a stimulation pulse may be provided.

[0069] Stimulating the heart includes having a first atrial contraction that starts when the atrioventricular valve is open and ends after the atrioventricular valve closes in a single beat such that the intracardiac pressure generated by the stimulation of the atrium is higher than the intracardiac pressure of the atrium without stimulation by the combination of the intracardiac pressure generated by atrial contraction and the passive intracardiac pressure rise. It may include transmitting at least one stimulation pulse set to induce a second atrial contraction in which the intracardiac pressure generated by atrial contraction of the atrium overlaps in time with the passive intracardiac pressure rise of the atrium. The first atrial contraction may be detected, and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0070] Alternatively, stimulating the heart may include transmitting at least one stimulation pulse configured such that, in a single beat, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase, starting when the atrioventricular valve is open and ending before the atrioventricular valve closes, and having a first atrial contraction that induces a second atrial contraction in which the atrial intracardiac pressure resulting from the atrial contraction of the atrium overlaps in time with the passive pressure increase of the atrium. The first atrial contraction may be detected, and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced. The method may further include alternately performing a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase, 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 include at least one stimulation pulse configured to reduce or prevent atrial stimulation and to stimulate the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase (both in a single cardiac cycle). The method may further include alternately performing a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase, 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 include at least one stimulation pulse configured to reduce or prevent atrial stimulation and to stimulate the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase (both in a single cardiac cycle).

[0071] The method may further include alternately performing a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase, 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 include at least one stimulation pulse configured to reduce or prevent atrial stimulation and to stimulate the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase (both in a single cardiac cycle). The method may further include alternately performing a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase, 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 include at least one stimulation pulse configured to reduce or prevent atrial stimulation and to stimulate the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase (both in a single cardiac cycle). Optionally, one or more of the stimulation patterns include at least one stimulation pulse configured to reduce or prevent atrial stimulation and to stimulate the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase (both in a single cardiac cycle). Optionally, one or more of the stimulation patterns include at least one stimulation pulse configured to reduce or prevent atrial stimulation and to stimulate the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase (both in a single cardiac cycle).

[0072] The method may further include alternately performing a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase, 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 include at least one stimulation pulse configured to reduce or prevent atrial stimulation and to stimulate the heart such that, due to the atrial intracardiac pressure resulting from atrial contraction of the atrium overlapping in time with the passive pressure increase of the atrium, the atrial intracardiac pressure resulting from the stimulation is higher than the atrial intracardiac pressure in the absence of stimulation, due to a combination of the atrial intracardiac pressure resulting from atrial contraction and the passive pressure increase (both in a single cardiac cycle). By overlapping, the intracardiac pressure of the atrium caused by the stimulus becomes higher than the intracardiac pressure of the atrium without the stimulus by a combination of the intracardiac pressure of the atrium caused by atrial contraction and the passive pressure increase. A first stimulation pulse for stimulating the heart, and (2) a second stimulation pulse that does not provide the intracardiac pressure caused by atrial contraction that overlaps in time with the passive pressure increase of the atrium. It may further include alternately performing a plurality of stimulation patterns having different ratios.

[0073] This method paces at least one of the atrium of the heart and the ventricle of the heart such that the relative timing of excitation corresponds to an atrioventricular delay of about 2 ms. It may further include pacing at least one of the atrium of the heart and the ventricle of the heart. Yes.

[0074] This method paces at least one of the atrium 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. It may further include pacing at least one of the atrium of the heart and the ventricle of the heart. Yes.

[0075] In another aspect, one embodiment provides a method for lowering a patient's blood pressure. The method may be implemented using an implantable myocardial stimulation device associated with the patient's heart. The method may include delivering stimulation pulses of one or more stimulation patterns to at least one heart 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. At least one of the first stimulation setting and the second stimulation setting May be configured to reduce or prevent atrial stimulation. Stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation may be delivered as needed. Yes.

[0076] Delivery of the stimulation pulses as needed may include one or more of the following.

[0077] a. Limit the treatment when necessary, for example, limit the delivery of a stimulation setting configured to reduce or prevent atrial stimulation when the patient's blood pressure is known or predicted to be abnormally high. This may include using real-time feedback measurements of one or more blood pressure-related parameters, or basing the required prediction pattern on past measurements of the same patient. For example, for some patients, BP may be high for 24 hours a day, while for other patients, BP may be high only during a part of the 24 hours (e.g., daytime or nighttime). b. Do not treat when high BP is required, for example, when the increase in BP is healthy and thus may be in a desired state, do not deliver a stimulation setting configured to reduce or prevent atrial stimulation. For example, BP is known to increase during activity and decrease again when activity decreases (e.g., during exercise or physical work which is naturally associated with an increase in BP). Stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation may be provided only for a part of the 24 hours, which may be at night or a part thereof, or during the day or a part thereof. Stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation may be provided only when the heart rate is below a predetermined threshold. The predetermined threshold may be 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 exceeding the average heart rate by 30 beats and exceeding the 80th percentile of the heart rate.

[0078]

[0079]

[0080]

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

[0082] Optionally, the patient may be considered "at rest" or "at a low activity level" when the patient's activity is low. For example, 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 respiration, etc.), the patient may be considered "at rest" or "at a low activity level". For example, sitting activities such as reading or talking, or movement around the house or in the office may be considered to be at a sufficiently low activity level to enable the delivery of stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation.

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

[0084] In another aspect, one embodiment includes 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 effect the delivery of stimulation pulses of one or more stimulation patterns to at least one heart chamber, for lowering the patient's blood pressure. A stem is provided. 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 be configured to reduce or prevent atrial stimulation. A stimulation pulse having a stimulation setting configured to reduce or prevent atrial stimulation may be transmitted as needed.

[0085] At least one controller may be configured to transmit a stimulation pulse having a stimulation setting configured to reduce or prevent atrial stimulation only during a part of 24 hours. The part of 24 hours may be at night or a part thereof, or during the day or a part thereof. At least one controller may be configured to transmit a stimulation pulse having a stimulation setting configured to reduce or prevent atrial stimulation only when the heart rate is below a predetermined threshold. The predetermined threshold may be an absolute value such as 90 bpm. The predetermined threshold may be set to a value related to the average heart rate of the patient. For example, the predetermined threshold may be at least one of a heart rate exceeding the average heart rate by 30 beats and exceeding the 80th percentile of the heart rate.

[0086] At least one controller may be configured to transmit a stimulation pulse having a stimulation setting configured to reduce or prevent atrial stimulation only when the patient is at rest or at a low activity level. The system may be configured to determine whether the patient is at rest or at a low activity level by detecting at least one of motion, posture, respiratory rate, and heart rate. activity level.

[0087]

[0088] ​​​​At least one controller may be configured to select one or more stimulation patterns based on the measured blood pressure parameters. At least one controller may also be configured to change one or more stimulation patterns when a baroreflex is detected.

[0089] In another aspect, one embodiment may provide a method for adjusting the pulse settings of a system for controlling blood pressure. The method may include receiving atrial pressure data related to the atrium of the patient's heart during at least one cardiac cycle. The atrial pressure data may result from the system transmitting a stimulation pulse having a first pulse setting to the heart. The method may further include analyzing the atrial pressure data and providing a second pulse setting different from the first pulse setting adjusted according to this analysis. Analyzing may include analyzing the atrial pressure data to estimate the time overlap between the atrial pressure generated by atrial contraction and the passive atrial pressure increase. Analyzing may further include analyzing the atrial pressure data to estimate the time overlap between the maximum atrial pressure generated by atrial contraction and the maximum passive atrial pressure increase of the atrium. Analyzing may include analyzing the atrial pressure data to compare the first atrial pressure (or maximum atrial pressure) obtained during the cardiac cycle in which the stimulation pulse was transmitted with the second atrial pressure of the atrium in the absence of stimulation. Analyzing may further include plotting the atrial pressure data and / or mathematically analyzing the atrial pressure data.

[0090] In another aspect, one embodiment may provide a system for lowering blood pressure. The system includes means for providing information about the pressure fluctuations in the atrium during at least one cardiac cycle of the heart, means for generating a stimulation pulse, and means for transmitting the stimulation pulse to at least one cardiac chamber ​​​​It may be provided with means for applying to the chamber. The means for generating the stimulation pulse may be configured to generate the stimulation pulse so as to control the timing of atrial contraction with respect to the timing of ventricular contraction during a single cardiac cycle according to the information about the intracardiac pressure fluctuation of the atrium.

[0091] The information about the intracardiac pressure fluctuation in the atrium may include the information about the occurrence of atrial contraction and / or the information about the occurrence of ventricular contraction. The means for generating the stimulation pulse may be configured to generate at least one atrial stimulation pulse for causing atrial contraction and / or at least one ventricular stimulation pulse for causing ventricular contraction for at least one cardiac cycle. The means for generating the stimulation pulse may be configured to generate at least one atrial stimulation pulse based on the information about the occurrence of atrial contraction and / or the information about the occurrence of ventricular contraction in such a relationship that the timing is adjusted with respect to the occurrence of atrial contraction and / or the occurrence of ventricular contraction. And / or, at least one ventricular stimulation pulse is generated based on the information about the occurrence of ventricular contraction and / or the information about the occurrence of atrial contraction in such a relationship that the timing is adjusted with respect to the occurrence of ventricular contraction and / or the occurrence of atrial contraction. The information about the occurrence of atrial contraction may include the information about the occurrence of the P wave pattern in the natural stimulation pattern of the cardiac cycle. The information about the occurrence of ventricular contraction may include the information about the occurrence of the QRS complex in the natural stimulation pattern of the cardiac cycle. It may be.

[0092] In another aspect, one embodiment may provide a system for lowering blood pressure. The system may include means for 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. Means, means for generating a stimulation pulse, and means for applying the stimulation pulse to at least one cardiac chamber It may be provided with. The timing of one or more cardiac activity events The information may include at least one of the occurrence of atrial contraction of the atrium, the occurrence of ventricular contraction of the ventricle, the opening of the atrioventricular valve, the closing of the atrioventricular valve, the electrical activity of the atrium, the electrical activity of the ventricle, blood flow, the atrial pressure in the atrium, the change in the atrial pressure in the atrium, and the heart rate. The means for generating the stimulation pulse may be configured to generate the stimulation pulse so as to set the timing of atrial contraction relative to ventricular contraction based on the information.

[0093] The timing of atrial contraction relative to ventricular contraction may correspond to an AV delay within the range of about 30 ms to about 0 ms The means for generating the stimulation pulse provides an excitatory stimulus to the atrium within the range of about 30 ms to about 0 ms before ventricular excitation occurs, and within the range of about 30 ms to about 0 ms after atrial excitation occurs, and / or provides an excitatory stimulus to the atrium, and then provides an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms later, so as to be configured to generate the stimulation pulse. generate the stimulation pulse. be configured.

[0094] The information about the timing of one or more cardiac activity events may include the information about the timing between two or more cardiac activity events in a single cardiac cycle. The means for generating the stimulation pulse causes atrial contraction for at least one cardiac cycle. be included.

[0095] The means for generating the stimulation pulse causes atrial contraction for at least one cardiac cycle. It may be configured to generate at least one atrial stimulation pulse and / or at least one ventricular stimulation pulse that causes ventricular contraction. The means for generating the stimulation pulses is in a relationship that synchronizes with the occurrence of atrial contraction and / or the occurrence of ventricular contraction, and generates at least one atrial stimulation pulse based on information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction, and / or is in a relationship that synchronizes with the occurrence of ventricular contraction and / or the occurrence of atrial contraction, and is configured to generate at least one ventricular stimulation pulse based on information about the occurrence of ventricular contraction and / or information about the occurrence of atrial contraction. The information about the occurrence of atrial contraction may include information about the occurrence of the P-wave pattern in the natural stimulation pattern of the cardiac cycle. The information about the occurrence of ventricular contraction may include information about the occurrence of the QRS complex in the natural stimulation pattern of the cardiac cycle.

[0096] In another aspect, one embodiment provides another method for lowering a patient's blood pressure by controlling atrial pressure and atrial dilation. The method may be implemented using an implantable myocardial stimulation device associated with the patient's heart. The method is to transmit stimulation pulses of one or more stimulation patterns to at least one heart chamber, wherein at least one of the stimulation pulses has a first stimulation setting, and at least one of the stimulation pulses has 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 contract the atrium such that the atrial pressure generated by atrial contraction of the atrium overlaps in time with the passive increase in atrial pressure, and by the overlap between the atrial pressure generated by atrial contraction and the passive increase in pressure, providing an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation by the combination of the atrial pressure generated by atrial contraction and the passive increase in pressure, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through a hormonal pathway or a neuronal pathway. Transmitting, wherein at least one of the stimulation pulses has a first stimulation setting, and at least one of the stimulation pulses has 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 contract the atrium such that the atrial pressure generated by atrial contraction of the atrium overlaps in time with the passive increase in atrial pressure, and by the overlap between the atrial pressure generated by atrial contraction and the passive increase in pressure, providing an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation by the combination of the atrial pressure generated by atrial contraction and the passive increase in pressure, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through a hormonal pathway or a neuronal pathway. At least one of which has a first stimulation setting, and at least one of the stimulation pulses has 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 contract the atrium such that the atrial pressure generated by atrial contraction of the atrium overlaps in time with the passive increase in atrial pressure, and by the overlap between the atrial pressure generated by atrial contraction and the passive increase in pressure, providing an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation by the combination of the atrial pressure generated by atrial contraction and the passive increase in pressure, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through a hormonal pathway or a neuronal pathway. At least one of which has a first stimulation setting, and at least one of the stimulation pulses has 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 contract the atrium such that the atrial pressure generated by atrial contraction of the atrium overlaps in time with the passive increase in atrial pressure, and by the overlap between the atrial pressure generated by atrial contraction and the passive increase in pressure, providing an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation by the combination of the atrial pressure generated by atrial contraction and the passive increase in pressure, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through a hormonal pathway or a neuronal pathway. And time, and by the overlap between the atrial pressure generated by atrial contraction and the passive increase in pressure, providing an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation by the combination of the atrial pressure generated by atrial contraction and the passive increase in pressure, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through a hormonal pathway or a neuronal pathway.

[0097] Optionally, at least one of the first stimulation setting and the second stimulation setting is atrial contraction configured to have an atrial contraction such that the maximum atrial pressure generated by the atrial contraction overlaps in time with the maximum passive atrial pressure rise of the atrium. The method may include providing an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation due to the overlap of the maximum atrial pressure and the maximum passive pressure rise generated by the atrial contraction, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through the hormonal or neuronal pathway.

[0098] In another aspect, one embodiment provides a system for lowering a patient's blood pressure by controlling atrial pressure and atrial dilation. The system includes a stimulation circuit configured to deliver stimulation pulses of one or more stimulation patterns to at least one heart chamber and at least one controller configured to effect delivery of stimulation pulses of one or more stimulation patterns to 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 is configured to contract the atrium of the heart such that the atrial pressure generated by the atrial contraction of the atrium provides an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation by the combination of the atrial pressure generated by the atrial contraction and the passive pressure rise, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through the hormonal or neuronal pathway. Optionally, at least one of the first stimulation setting and the second stimulation setting setting and the second stimulation setting is configured to contract the atrium of the heart such that the atrial pressure generated by the atrial contraction of the atrium provides an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation by the combination of the atrial pressure generated by the atrial contraction and the passive pressure rise, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through the hormonal or neuronal pathway. Optionally, at least one of the first stimulation setting and the second stimulation setting ​That is, the heart atrium may be contracted such that the maximum atrial pressure generated by atrial contraction overlaps in time with the maximum passive atrial pressure rise of the atrium, thereby providing an atrial pressure in the atrium that is higher than the atrial pressure in the atrium in the absence of stimulation, and causing an increase in atrial dilation of the atrium that lowers blood pressure through the hormonal or neuronal pathway.

[0099] In another aspect, one embodiment provides a method for treating a patient's blood pressure disorder by controlling atrial pressure and atrial dilation. The method may be implemented using an implantable myocardial stimulation device associated with the heart of a patient having a pre-treatment blood pressure. The method may include stimulating the heart to contract the atrium while the heart valve associated with the atrium is closed such that the atrium expands upon contraction, and by expanding the atrium, preferably, when the active force of atrial contraction exceeds the maximum passive pressure and dilation caused by ventricular contraction, contracting the atrium when the ventricular pressure is at its maximum, resulting in a decrease 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 stimulating electrode for stimulating at least one chamber of the patient's heart with a stimulation pattern comprising at least one stimulation pulse. The system may include at least one controller configured to receive an input related to the patient's blood pressure and to adjust the stimulation pattern based on the blood pressure. For example, the input may include receiving data sensed by one or more sensors (implanted or external), and / or receiving data supplied by the user. For example, during an implanted and / or periodic check, the user may supply data regarding the measured blood pressure. and / or receiving data supplied by the user. For example, during an implanted and / or periodic check, the user may supply data regarding the measured blood pressure.

[0101] Preferably, the system receives this input from a measurement sensor and / or a user interface via an input port for receiving the input by wired communication and / or wireless communication. The input may comprise blood pressure (BP), or data related to a change 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 detect pressure or a change in pressure within one or more heart chambers and adjust a stimulation pattern based on the pressure or change in pressure. In another embodiment, the sensor may detect pressure in more than one chamber and adjust the stimulation based on the relationship between the pressure waveforms of two chambers.

[0102] The controller may be configured to adjust the stimulation pattern by performing an adjustment process that includes adjusting parameters of at least a first stimulation setting of at least one stimulation pulse.

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

[0104] The parameters may include adjustment of the AV delay. For example, the natural AV delay may occur naturally (i.e., without stimulation of the heart) or may be set to time the delivery of stimulation to one or more of the atrium and ventricle, and may be in the range of 120 - 200 ms from the start of atrial excitation to the start of ventricular excitation. Optionally, adjusting the AV delay means adjusting it from a normal AV delay (e.g., 120 ms) to a shorter AV delay (e.g., 0 - 70 ms from the start of atrial excitation to the start of ventricular excitation, or an AV delay of 0 - -50 ms where ventricular excitation occurs before atrial excitation). In one embodiment, -50 ms Stimulation settings having an AV delay between ~70 ms, preferably -40 ms to 60 ms, more preferably -50 ms to 0 ms, or 0 to 70 ms, preferably >0 to 70 ms, are selected to reduce or prevent atrial stimulation. Selected.

[0105] Stimulation patterns configured to reduce atrial stimulation cause a decrease in blood pressure of at least a predetermined amount within about 3 seconds from the application of electricity to the heart and may be configured to maintain the decrease in blood pressure for at least a period of 1 minute. For example, the stimulation pattern may be selected and / or adjusted based on feedback related to one or more detected BP parameters. The time interval may be at least 5 minutes.

[0106] The predetermined amount of blood pressure reduction may be 8 mmHg or less.

[0107] The predetermined amount of blood pressure reduction may be at least 4% of the patient's pre-treatment blood pressure.

[0108] The patient's blood pressure may not exceed a predetermined average value by more than a predetermined degree during the time interval. The predetermined degree may be a difference of about 8 mmHg or less. In some embodiments,

[0109] the patient's blood pressure may exceed the predetermined average value for some beats, but the patient's average blood pressure may not exceed the predetermined average value. The controller may be configured to apply a plurality of stimulation patterns and receive corresponding input data related to the patient's blood pressure during stimulation for each stimulation pattern. The controller may be configured to calculate at least one blood pressure variation parameter related to the input data for each of the plurality of stimulation patterns. The controller may be configured to adjust the stimulation pattern according to the blood pressure variation parameter.

[0110] ​​

[0111] The controller may be configured to adjust the stimulation pattern to have the best blood pressure fluctuation parameters.

[0112] The best blood pressure fluctuation parameters may indicate the lowest degree of baroreflex or the lowest degree or extent of adaptation as detailed herein.

[0113] The best blood pressure fluctuation parameters may indicate 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 atrial pressure and / or dilation. They may be. At least two of the stimulation patterns may differ in the number or length of time that at least one stimulation pulse is continuously supplied.

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

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

[0117] The plurality of stimulation patterns may include a first stimulation setting and a second stimulation setting applied after the first stimulation setting. The second stimulation setting may have at least one stimulation setting set based on an algorithm that uses blood pressure fluctuation parameters related to the input data of the first stimulation setting. It may have settings.

[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 the 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 the patient's heart with stimulation pulses. The system may include a controller. The controller may be configured to provide a first stimulation pattern having at least one stimulation setting configured to reduce or prevent an 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 variation parameter related to the first input data. The controller may be configured to adjust at least one parameter of a second stimulation pattern having a second stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle. The second stimulation setting may be based on at least one blood pressure variation parameter. The controller may be configured to supply the second stimulation pattern during a second time interval. 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 the patient's heart with stimulation pulses. The system may include at least one controller configured to apply a stimulation pattern having at least one stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle. The stimulation pattern may initially

[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 the patient's heart with stimulation pulses. The system may include at least one stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle. The system may include at least one controller configured to apply the stimulation pattern. from the pressure value to a reduced pressure value, causing an immediate reduction in blood pressure and being selected to maintain the patient's average blood pressure at rest at least 8 mmHg lower than the initial pressure may also be.

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

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

[0125] In another aspect, one embodiment provides a system for lowering blood pressure. The system may comprise at least one stimulation electrode for stimulating at least one chamber of the patient's heart. The system comprises at least one controller configured to execute a stimulation pattern comprising at least one stimulation pulse having at least one stimulation setting configured to reduce or prevent atrial stimulation in at least one ventricle. The at least one stimulation setting may be configured such that the maximum atrial dilation is approximately equal to, or lower than, the maximum atrial dilation of the same heart when not being stimulated.

[0126] In any of the embodiments described herein, atrial dilation may be measured, calculated, and / or estimated as known in the art. Atrial contraction is known to affect intra-atrial pressure and atrial dilation. The intra-atrial pressure and dilation of the atria depend on the atrial volume. The atrial volume depends on the amount of blood within the atria and the active forces generated by muscular contraction. In a healthy heart, when the atria contract, the intra-atrial pressure rises. The intra-atrial pressure drops when atrial contraction ceases, blood flows out of the atria, and the ventricles are filled. Next, when the ventricles contract, the AV valves close and the atria begin to fill again because there are no valves to prevent the flow of blood from the venous system into the atria. The intra-ventricular pressure generated further raises the intra-atrial pressure through various mechanisms, one of which is related to the bulging of the AV valves into the atria. The increase in intra-atrial pressure that occurs against the closed AV valves also increases the atrial dilation related to atrial volume and intra-atrial pressure. When the atria contract while the AV valves are closed, the intra-atrial pressure rises and the atrial dilation increases because the closed valves prevent a reduction in volume. The increase in atrial dilation stimulates the baroreceptors (also known as stretch receptors) present in the atrial walls. These baroreceptors are related to the decrease in blood pressure by hormones and / or neurons.

[0127] Accordingly, in some embodiments, the measurement of atrial dilation may include measuring the intra-atrial pressure. In some embodiments, the atrial dilation measurement may include measuring or estimating the size (e.g., diameter, size, or circumference) of the atria. In some cases, when a single atrial contraction occurs per cardiac cycle, the amount of blood in the atria is predicted to be greater than when the atria contract twice during a single cardiac cycle. Thus, the atria contract once per cardiac cycle, and when the atrial contraction fully resists against the closed valves, the intra-atrial pressure and / or atrial dilation will be greater than when the atria contract twice per cardiac cycle. This may be the case. However, when the atrium contracts only against a closed valve, there is no atrial stimulation, and in some embodiments, a balance may be taken between the atrial pressure (and atrial dilation) and the set value for atrial stimulation (per cardiac cycle and / or per pacing pattern).

[0128] At least one stimulation setting may be configured to cause the atrium to contract maximally when the AV valve is open. to be so configured.

[0129] At least one stimulation setting may be configured to change at least one mechanism of atrial contraction such that at least one mechanism of atrial contraction is different from that of a preceding natural atrial contraction. The mechanism of atrial contraction may be evaluated using known techniques including, for example, ultrasound (such as echocardiography or cardiac echo).

[0130] At least one stimulation setting may be configured to reduce the force of at least one atrial contraction. The force of atrial contraction may be reduced, for example, by temporarily generating atrial spasm or atrial flutter. One example is to transmit a burst of rapid stimulation pulses to the atrium for a short period of a predetermined time. The force of atrial contraction can be calculated by detecting its derivatives such as atrial pressure and / or wall motion or wall flow using known means. Such detection may be used as a closed-loop feedback and / or occasionally (e.g., during implantation and / or examination). by detecting its derivatives such as atrial pressure and / or wall motion or wall flow using known means. Such detection may be used as a closed-loop feedback and / or occasionally (e.g., during implantation and / or examination). Thereof, it can be calculated. Such detection may be used as a closed-loop feedback and / or occasionally (e.g., during implantation and / or examination).

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

[0132] In another aspect, an embodiment of a system for reducing blood pressure is provided. The system may comprise at least one stimulation electrode for stimulating at least one chamber of a patient's heart. At least one controller may be configured to apply a stimulation pattern of stimulation pulses to the patient's heart. At least one controller may be configured to receive an input related to the state of the patient's AV valve. This input may be provided by wired or wireless communication from an implanted or external acoustic or blood flow sensor and / or via a user interface. At least one controller may be configured to adjust at least one stimulation pattern based on the valve state. The input related to the state of the patient's AV valve may be configured to suggest the timing of closure of the AV valve. The input related to the state of the patient's AV valve may be provided based on a heart sound sensor. The input related to the state of the patient's AV valve may be provided based on a blood flow sensor. The blood flow sensor may comprise an implanted sensor.

[0133] The blood flow sensor may comprise an ultrasonic sensor for detecting blood flow through the AV valve.

[0134] The blood flow sensor and the controller may be configured to operate at least partially as a closed loop.

[0135] The stimulation pattern may comprise at least one stimulation pulse configured to reduce or prevent an atrial kick in at least one ventricle.

[0136]

[0137]

[0138]

[0139]

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

[0141] In another aspect, embodiments of a system for reducing ventricular filling volume in a patient having a pre-treatment ventricular filling volume are provided. The system may comprise a stimulation circuit configured to deliver stimulation pulses to at least one heart chamber. The system may comprise at least one controller configured to effect delivery of one or more stimulation patterns of stimulation pulses to 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 be configured to reduce or prevent an atrial kick, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume.

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

[0143] The first stimulation setting may have an AV delay 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 in a one-hour period.

[0145] The at least one controller may be configured to continuously effect one or more stimulation patterns during time intervals lasting 10 minutes or more. The first stimulation setting may be configured to reduce or prevent an atrial kick in at least one ventricle during at least 50% of the time interval.

[0146]

[0147] ​​​​The second stimulation setting has an AV delay that is longer than the first stimulation setting.

[0148] 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 in length. The time interval may be at least 1 hour in length.

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

[0151] One or more consecutive stimulation patterns may have a third stimulation setting that is different from the first and second stimulation settings and may comprise at least one stimulation pulse configured to reduce or prevent an atrial kick in at least one ventricle.

[0152] One or more consecutive stimulation patterns may have a third stimulation setting that is different from the first and second stimulation settings and may comprise at least one stimulation pulse configured not to reduce or prevent an atrial kick in at least one ventricle for less than about 50% of the time interval.

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

[0154] ​​​One or more consecutive stimulation patterns may comprise a sequence of 10 to 60 stimulation pulses having a first stimulation setting. The first stimulation setting may be configured to reduce or prevent 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 an AV delay that is longer 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] The sequence of 1 to 10 beats may include at least one stimulation pulse having a second stimulation setting and may include it.

[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 may be configured to limit an increase in blood pressure value occurring between stimulation pulses to a predetermined value and to reduce an atrial kick in at least one ventricle, and the second stimulation setting may be configured to reduce an adaptation to a baroreflex response or a reduction in atrial kick. and may be configured to allow an increase in blood pressure between about one beat and five beats.

[0160] The second stimulation setting may be configured to allow an increase in blood pressure between about one beat and five beats. and may be configured to allow it.

[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 second stimulation setting may be provided between approximately 1% and approximately 40% of the plurality of stimulation pulses of the stimulation pattern.

[0164] The stimulation pattern may include a ratio of the stimulation pulses having a first stimulation setting to the stimulation pulses having a second stimulation setting corresponding to the ratio of the time constants of the responses to increases and decreases in blood pressure. The stimulation pattern may include a ratio of the stimulation pulses having a first stimulation setting to the stimulation pulses having a second stimulation setting corresponding to the ratio of the time constants of the responses to increases and decreases in blood pressure. It may be included.

[0165] 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 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 second stimulation setting may be provided between approximately 1% and approximately 40% of the plurality of stimulation pulses of the stimulation pattern.

[0169] The stimulation pattern may include a ratio of the stimulation pulses having a first stimulation setting to the stimulation pulses having a second stimulation setting corresponding to the ratio of the time constants of the responses to increases and decreases in blood pressure. The stimulation pattern may include a ratio of the stimulation pulses having a first stimulation setting to the stimulation pulses having a second stimulation setting corresponding to the ratio of the time constants of the responses to increases and decreases in blood pressure. It may be included.

[0170] The stimulation pattern may include a ratio of approximately 8 to approximately 13 stimulation pulses having a first stimulation setting to approximately 2 to approximately 5 stimulation pulses having a 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 is provided for reducing the ventricular filling volume of a patient having a pre-treatment ventricular filling volume. The system may comprise a stimulation circuit configured to deliver stimulation pulses to at least one heart chamber. The system may comprise at least one controller configured to effect delivery of one or more stimulation patterns of stimulation pulses to at least one heart chamber. At least one of the stimulation pulses may include a setting configured such that ventricular excitation is initiated about 0 ms to about 70 ms after the initiation of atrial excitation, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume. For example, the processor circuit may be configured to operate in an operating mode in which one or more excitatory pulses are delivered to the ventricles between about 0 ms and about 70 ms after the initiation of ventricular excitation 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. In some embodiments, the timing of the detected atrial excitation may be determined by taking into account the delay between the actual onset of the excitation and the setting. For example, if the detection delay is estimated to be 20 to 40 ms and the stimulation pulse is to be delivered 0 to 70 ms after the onset of atrial excitation, the system may be set to deliver the 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 detection event. Similarly, if the stimulation pulse is to be delivered to the ventricles 0 to 50 ms before the onset of atrial excitation and the same 20 to 40 ms detection delay is assumed, the system may be set to deliver the pulse between 40

[0173] ms before the next expected detection event and 90 ms before the next expected detection event. The detection delay may be due to one or more of the distance between the location of the onset of excitation and the detection electrode, the level of the electrical signal, the characteristics of the detection circuit, and the threshold set of the detection event. The delay may be, for example such that, if the stimulation pulse is to be delivered to the ventricles 0 to 50 ms before the onset of atrial excitation and the same 20 to 40 ms detection delay is assumed, the system may be set to deliver the pulse between 40 ms before the next expected detection event and 90 ms before the next expected detection event. The detection delay may be due to one or more of the distance between the location of the onset of excitation and the detection electrode, the level of the electrical signal, the characteristics of the detection circuit, and the threshold set of the detection event. The delay may be, for example such that, if the stimulation pulse is to be delivered to the ventricles 0 to 50 ms before the onset of atrial excitation and the same 20 to 40 ms detection delay is assumed, the system may be set to deliver the pulse between 40 If so, it may include the duration of signal propagation from the origin of excitation to the electrode position, the duration related to the frequency response of the detection circuit, and / or the duration required for the signal propagation energy to reach a level detectable by the detection circuit. The delay may be significant, for example, in the range between about 5 ms and about 100 ms. One method of estimating the delay is to use the time difference between the AV delay measured when both the atrium and ventricle are detected and the AV delay when the atrium is paced and the ventricle is detected. In other methods, the calculation of the amplifier response time based on the set threshold, signal strength, and frequency components may be used. Other methods may include modifying the delay used with atrial detection until the effect on blood pressure is the same as the effect obtained by pacing both the atrium and ventricle at 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 may include a stimulation circuit configured to deliver stimulation pulses to at least one heart chamber. At least one controller may be configured to deliver one or more stimulation patterns of stimulation pulses to at least one heart chamber during a time interval that lasts for 10 minutes or more. At least one of the stimulation pulses may have a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle for at least 5 minutes of the time interval, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume. At least one of the stimulation pulses may have a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle for at least 5 minutes of the time interval, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume. At least one of the stimulation pulses may have a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle for at least 5 minutes of the time interval, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume.

[0175] In another aspect, a method for reducing ventricular filling in a patient having a pre-treatment ventricular filling volume is provided. The method may include delivering one or more stimulation patterns of stimulation pulses to at least one heart chamber during a time interval that lasts for 10 minutes or more. At least one of the stimulation pulses may have a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle for at least 5 minutes of the time interval, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume. At least one of the pulses is configured to reduce or prevent an atrial kick in at least one ventricle for at least five minutes of the time interval and may have a first stimulation setting configured to reduce or prevent an atrial kick in an atrium, wherein at least one of the stimulation pulses has a second stimulation setting different from the first stimulation setting.

[0176] Other systems, methods, features and advantages of the present invention will be apparent to or will become apparent to those of ordinary skill in the art upon examination of the following drawings and detailed description. Such additional systems, methods, features and advantages are all included within this description and this summary, are within the scope of the present invention, and are intended to be protected by the following claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0177]

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Mode for Carrying Out the Invention

[0178] The present invention can be better understood by referring to the following drawings and description. The components in the drawings are not necessarily drawn to scale and emphasis is placed on illustrating the principles of the present invention. Further, in the drawings, like reference numerals indicate corresponding components throughout different figures.

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

[0180] The mechanical process of cardiac contraction is controlled by the conduction of electricity in the heart. During each heartbeat, a wave of depolarization is induced by cells in the sinoatrial node. Depolarization propagates within 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 start of atrial excitation and the start of ventricular excitation, is usually between 120 milliseconds (ms) and 200 ms. The relative timing of atrial and ventricular contractions depends especially on the relative timing of excitation of each chamber and on the time required for the chamber to generate mechanical contraction as a result of electrical activation (depending on differences in size, propagation speed, myocyte characteristics, etc.).

[0181] Before contraction, the myocardium relaxes and blood flows freely from the atria into the ventricles through the valves between them. This period can be divided into a rapid filling phase and a slow filling phase. The rapid filling phase begins immediately after ventricular relaxation, when blood from the venous system and atria rapidly fills the ventricles. The rapid filling phase lasts for about 110 ms and is followed by a slow filling phase that continues until the start of atrial contraction. The duration of the slow filling phase depends on the heart rate. Then, when the atria contract, the 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 typically accounts for about 10% - 30% of ventricular filling.

[0182] Figure 17 shows the changes in ventricular volume, intraventricular pressure, atrial pressure, and cardiac electrical activity during a certain period within a single cardiac cycle. As used herein, a cardiac cycle is the period between two relaxations of the ventricles, during which atrial contraction occurs only once while the ventricles relax twice. The duration of the cardiac cycle is inversely proportional to the heart rate, so when the heart rate decreases, the cardiac cycle duration increases, and when the heart rate increases, the cardiac cycle duration decreases. At a typical human heart rate of 75 beats per minute, one cardiac cycle is approximately 0.8 seconds in length.

[0183] Referring to Figure 17, the cardiac cycle can be said to begin at the start of atrial excitation when the P wave is observed on the ECG. Then, approximately 50 - 70 ms later, the atria begin to contract for about 70 - 110 ms. As the atria contract, the atrial pressure rises to its maximum value. Then, the atria begin to relax and the pressure decreases. The maximum value is represented by point 1701 in Figure 17. On the other hand, the electrical stimulus propagates to the ventricles, and ventricular excitation begins with an AV delay of about 120 - 200 ms (the AV delay can be about 250 ms or more in some unhealthy individuals). This ventricular excitation appears as the QRS complex on the ECG. As the ventricles contract, the intraventricular pressure rises and corresponds to each atrium ​​The valve (AV valve) between the atrium and the ventricle is closed passively, thereby stopping the blood flow from the atrium into the ventricle and preventing backflow.

[0184] During the next period of ventricular contraction, i.e., during the isovolumetric contraction period, which lasts about 50 ms and is also known as the isovolumetric phase, as shown in FIG. 17 by the intraventricular pressure line and the ventricular volume line within vertical lines 1703 and 1704 that demarcate the isovolumetric phase, all the valves of the ventricle are closed and the volume remains significantly unchanged while the intraventricular pressure rises rapidly.

[0185] When the intraventricular pressure further rises, at the point indicated by line 1704 in FIG. 17, the valve between the ventricle and the artery opens and blood is ejected from the ventricle and away from the heart. This ventricular contraction period is divided into a rapid ejection period and a slow ejection period. The rapid ejection period lasts about 90 - 110 ms, during which about 2 / 3 of the stroke volume is ejected. The rapid ejection period is represented in FIG. 17 as the period between line 1704 and line 1705. is represented.

[0186] During the isovolumetric phase and at the beginning of the rapid ejection period, ventricular contraction typically causes a passive increase in atrial pressure. This increase in atrial pressure is thought to be due to the mechanical effect of ventricular contraction on the associated atrium. For example, this increase in atrial pressure may be due to the fact that the atrium is closely related to a much larger ventricle. When the large ventricular muscle contracts, it affects the connected atrium. The increase in atrial pressure may also be due to the valve bulging backward into the atrium, but this bulging of the valve may be due to the increase in internal pressure in the ventricle. The passive filling of the atrium continues throughout the cardiac cycle (including between point 1701 and point 1702) because there is no valve between the atrium and the vasculature. This continuous passive filling in conjunction with the increase in internal pressure due to the mechanical effect of ventricular contraction may contribute to the increase in atrial pressure.

[0187] Accordingly, as represented by point 1702 in FIG. 17, passive atrial pressure increase reaches a peak at some point between the second half of the isovolumic period (i.e., about 25 to 35 ms after the start of the isovolumic period) and the start of the rapid ejection period (e.g., within the first about 10 ms of the rapid ejection period). In FIG. 17, as indicated by the high atrial pressure at point 1702 relative to the low atrial pressure at point 1701, the passive atrial pressure rise may be higher than the maximum atrial pressure due to atrial contraction.

[0188] After the rapid ejection period, a slow ejection period that lasts about 130 to 140 ms follows. Thereafter, all valves close again, and the ventricle relaxes in an isovolumic relaxation state for about 60 to 80 ms, during which the pressure inside the ventricle decreases. At this time, the valve between the ventricle and the atrium may open again to allow blood to freely flow into the ventricle, and then a new cardiac cycle may start.

[0189] <Control of Atrial Pressure and Atrial Dilation> In the present disclosure, cardiac stimulation can be used to increase atrial pressure and dilation, thereby reducing blood pressure (BP). By cardiac stimulation, the atrial pressure generated by atrial contraction of the atrium overlaps in time with the passive pressure rise of the atrium, so that the atrial pressure generated by the stimulation is a combination of the atrial pressure generated by atrial contraction and the passive pressure rise, and the heart is stimulated so that it is higher than the atrial pressure of the atrium without stimulation, thereby achieving an increase in atrial pressure.

[0190] In an embodiment, the maximum atrial pressure may be reached by causing maximum atrial contraction during a period in which the maximum passive increase in atrial pressure overlaps. For example, using cardiac stimulation, the maximum atrial pressure caused by atrial contraction may be reached between about 25 to 35 ms after the start of the isovolumic period and about 10 ms after the end of the isovolumic period. The increase in atrial pressure (due to the atrial pressure caused by atrial contraction overlapping with the passive increase in atrial pressure) increases atrial dilation, which is known to affect blood pressure through the hormonal pathway and / or the neuronal pathway. For example, an increase in atrial dilation may cause the secretion of atrial natriuretic hormone or atrial natriuretic peptide, which may thereby lower blood pressure.

[0191] In an embodiment, cardiac stimulation may be applied long-term or temporarily to increase atrial pressure and atrial dilation and to cause the secretion of atrial natriuretic hormone or atrial natriuretic peptide. Long-term application of cardiac stimulation is not necessary, and a temporary stimulation may be sufficient to increase atrial pressure and atrial dilation, cause hormone secretion, and lower blood pressure. This may be the case. The change in atrial dilation may be temporary as observed in the pressure plot, and the temporary dilation may be even more effective than long-term dilation in causing the release of atrial natriuretic hormone or atrial natriuretic peptide and lowering blood pressure. In an embodiment, beneficially, a temporary increase in atrial pressure may not result in a long-term increase in atrial pressure.

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

[0193] In some embodiments, the maximum atrial pressure means the highest portion of the systolic or passive pressure increase and has a pressure value that is at least about 25% higher than the remaining atrial pressure values. Optionally, if only one peak is observed in the pressure from atrial contraction and passive pressure increase, and if two peaks are observed, the maximum atrial pressure caused by atrial contraction is considered to occur during the period overlapping the maximum passive increase in atrial pressure, and the maximum atrial pressure caused by atrial contraction and the maximum passive increase in atrial pressure are separated by no more than about 30 ms. Optionally, the temporal overlap is mathematically detectable by analyzing the measured values and / or visually, for example, by plotting the atrial pressure over a period or the change in atrial pressure over a period.

[0194] BP or a change in BP may be measured as systolic BP (SysBP), diastolic BP, mean arterial BP, BP in one or more chambers, and / or any other relevant BP parameter. In some embodiments, an electrical stimulation device, such as a pacemaker or other type of device having a pulse generator, may be used to stimulate the patient's heart to lower blood pressure. Electrodes electrically connected to the electrical stimulation device by a wired or wireless connection may be disposed adjacent to the heart chamber. The electrical stimulation device may be operative to transmit a pulse 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 intra-atrial pressure increase 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 may include delivering at least one stimulation pulse to at least one chamber of the heart so that the atrium reaches a maximum intra-atrial pressure caused by atrial contraction in a period from the latter half of the isovolumic phase to about the first 10 ms of the rapid ejection phase. Such stimulation pulses are referred to herein as "AC stimulation pulses" or "AC pulses".

[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 is such that the atrial intracardiac pressure caused by the stimulation is higher than the atrial intracardiac pressure of the atrium without stimulation, by a combination of the atrial intracardiac pressure caused by atrial contraction and the passive pressure increase, and the AC pulse may be transmitted at a timing such that it overlaps with the passive pressure increase of the atrium and has the atrial intracardiac pressure caused by atrial contraction of the atrium with respect to the cardiac cycle. Preferably, the AC pulse may be transmitted so as to reach the maximum atrial intracardiac pressure caused by atrial contraction at a point in time that overlaps with the maximum passive pressure increase of the atrium with respect to the cardiac cycle. Optionally, the timing of transmission of this AC pulse is set according to one or more detected events, such as events related to the cardiac cycle.

[0198] For example, atrial and / or ventricular excitation may be detected, and the AC pulse may be transmitted to the atrium and / or ventricle accordingly. For example, the pacing pulse may be transmitted to the atrium at a timing predicted to be within about -20 to 30 ms from ventricular detection or pacing, and at least about 20 milliseconds within the end of the atrial refractory period. Optionally, the heart rate and ventricular excitation or contraction may be detected, the timing of the next ventricular contraction or excitation may be estimated, and the AC pulse may be transmitted such that the atrial intracardiac pressure caused by atrial contraction in a subsequent beat overlaps with the passive pressure increase of the atrium. Optionally, the AC pulse may be transmitted such that atrial contraction in a subsequent beat reaches the maximum atrial intracardiac pressure caused by atrial contraction at a point in time that overlaps with the maximum passive pressure increase of the atrium. For example, the AC pulse may include a stimulation transmitted to the atrium about 30 to 0 ms before the predicted ventricular excitation, or about 50 to 120 ms before the start of the predicted ventricular contraction.

[0199] In some embodiments, the stimulation pulse is the first atrial excitation that is detected or paced, the electrical pulse transmitted to the corresponding ventricle, and the atrial refractory period associated with the first excitation It may include another electrical pulse that is transmitted to the atrium after finishing. For example, the period from the first atrial excitation (e.g., transmission of the first excitatory pulse to the atrium) to the transmission of another excitatory pulse to the atrium may be about 150 - 250 ms. The period from the first atrial excitation (e.g., transmission of the first excitatory pulse to the atrium) to the transmission of another excitatory pulse to the atrium may be about 150 - 250 ms. The period from the first atrial excitation (e.g., transmission of the first excitatory pulse to the atrium) to the transmission of another excitatory pulse to the atrium may be about 150 - 250 ms.

[0200] In some embodiments, the AC pulse includes a first electrical pulse transmitted to the atrium and a second electrical pulse transmitted to the corresponding ventricle. Control the relative timing of the first electrical pulse and the second electrical pulse to cause the atrium to contract at a certain point within the period from the latter half of the isovolumetric phase of the heart to the initial stage of the rapid ejection phase in that heartbeat. Since the time from the transmission of the excitatory pulse to the start of contraction is longer for the ventricle than for the atrium, the delay in the transmission of the first pulse and the second pulse may have a negative value such as about -20 - 0 ms. The period from the first atrial excitation (e.g., transmission of the first excitatory pulse to the atrium) to the transmission of another excitatory pulse to the atrium may be about 150 - 250 ms. The period from the first atrial excitation (e.g., transmission of the first excitatory pulse to the atrium) to the transmission of another excitatory pulse to the atrium may be about 150 - 250 ms.

[0201] This exact timing may vary depending on different patients and different conditions (e.g., different arrangements of one or more electrodes to the chambers). Therefore, in some embodiments, the settings of the AC pulse may be adjusted, for example, at the time of implanting the device and / or periodically, for example, during regular inspections or during use (e.g., based on feedback from one or more relevant sensors). This exact timing may vary depending on different patients and different conditions (e.g., different arrangements of one or more electrodes to the chambers). Therefore, in some embodiments, the settings of the AC pulse may be adjusted, for example, at the time of implanting the device and / or periodically, for example, during regular inspections or during use (e.g., based on feedback from one or more relevant sensors). This exact timing may vary depending on different patients and different conditions (e.g., different arrangements of one or more electrodes to the chambers). Therefore, in some embodiments, the settings of the AC pulse may be adjusted, for example, at the time of implanting the device and / or periodically, for example, during regular inspections or during use (e.g., based on feedback from one or more relevant sensors).

[0202] For example, until the desired atrial internal pressure generated by atrial contraction that overlaps with the passive increase in atrial internal pressure is detected, AC pulses with different settings may be transmitted to the patient and the atrial internal pressure may be detected. In some embodiments, the desired atrial internal pressure may be any internal pressure that exceeds the atrial internal pressure that the atrium would reach without stimulation. Optionally, the desired atrial internal pressure may be selected as the highest (or one of the highest) atrial internal pressures generated by a plurality of AC pulses with different settings. For example, the AC pulse For example, until the desired atrial internal pressure generated by atrial contraction that overlaps with the passive increase in atrial internal pressure is detected, AC pulses with different settings may be transmitted to the patient and the atrial internal pressure may be detected. In some embodiments, the desired atrial internal pressure may be any internal pressure that exceeds the atrial internal pressure that the atrium would reach without stimulation. Optionally, the desired atrial internal pressure may be selected as the highest (or one of the highest) atrial internal pressures generated by a plurality of AC pulses with different settings. For example, the AC pulse S may vary by having different AV delays between the sensed or paced atrial contractions and the paced or sensed ventricular contractions. As a result, one or more AV pulse settings for use for a period of time for a given patient may be selected.

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

[0204] Optionally, the AC pulse may be delivered as part of a pacing pattern where the settings of the different pulses within the pattern are different, and one or more patterns are selected for repeated use based on pulse selection configured to reduce or prevent atrial stimulation and one or more parameters related to the aforementioned overlap of the internal pressures. Optionally, it may be selected for repeated use based on one or more parameters related to the overlap of the internal pressures.

[0205] Stimulation settings mean one or more parameters of one or more stimulation pulses transmitted in a single cardiac cycle. For example, these parameters may include output, the time interval between electrical pulses included in a single stimulation pulse (e.g., AV delay or the delay between two atrial pulses), the transmission cycle relative to the natural rhythm of the heart, the length of the stimulation pulse or a part thereof, and the transmission site between two or more chambers and / or within a single chamber. The AC stimulation settings, i.e., the "AC settings", may include the settings of one or more AC pulses.

[0206] In some embodiments, detecting may include detecting the electrical activity of one or more chambers of the heart, e.g., one or more of atrial excitation and / or ventricular excitation. In some embodiments, detecting may include detecting cardiac activity using the sounds of the cardiac cycle. For example, the closure of the AV valve results in the first sound of the heartbeat. This closure further signifies the start of the isovolumic phase. Optionally, based on the timing of the closure of the AV valve and the heartbeat, the pulse settings may be selected for subsequent AC pulses. For example, the stimulation pulse may be provided to the atrium approximately 80 - 10 milliseconds before the next predicted closure of the AV valve. Optionally, the refractory period of a cardiac chamber (e.g., the atrium) may be estimated as is known in the art. The AC pulse may include delivering a stimulation pulse to the atrium that induces atrial contraction. For example, the stimulation pulse may be timed for delivery after the end of the refractory period, or if delivered during the associated refractory period, the stimulation pulse may have electrical properties such that it induces contraction despite a relatively fast timing.

[0207] In some embodiments, the heartbeat is detected based on, e.g., electrical activity, sound, pressure, and / or any other means, as is known in the art.

[0208] In some embodiments, one or more AC pulses may be provided as part of a sequence of pulses or as a pacing pattern that includes multiple heartbeats. The pacing pattern may include multiple pacing pulses with different settings. Optionally, the pulses may all be AC pulses, or some may have different pulse settings. Optionally, only a portion of the pulses of a given pattern may be configured to cause an increased or peak atrial intracardiac pressure that occurs due to atrial contraction in the atrium during the period from the latter half of the isovolumic phase to the beginning of the rapid ejection phase.

[0209] In some embodiments, one or more AC pulses may be provided as part of a sequence of pulses or as a pacing pattern that includes multiple heartbeats. The pacing pattern may include multiple pacing pulses with different settings. Optionally, the pulses may all be AC pulses, or some may have different pulse settings. Optionally, only a portion of the pulses of a given pattern may be configured to cause an increased or peak atrial intracardiac pressure that occurs due to atrial contraction in the atrium during the period from the latter half of the isovolumic phase to the beginning of the rapid ejection phase.

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

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

[0212] For example, using the aortic pressure and / or sound associated with the opening of one or both heart valves, the timing of the start and / or end of the isovolumic phase and / or the start of the rapid ejection phase can be accurately targeted. Such timing may be compared to the time at which the pulse is transmitted and / or the cardiac event is detected so that the desired contraction timing is achieved more accurately and / or more repeatedly.

[0213] In another embodiment, the timing from the transmission or detection of an excitatory stimulus (to the atrium and / or ventricle) to the time when the peak pressure (due to contraction or passive pressure increase) is detected in the atrium may be measured.

[0214] Other options may be to adjust the AC pulse settings according to one or more of heart rate, patient activity, posture, and / or respiratory rate. Thus, it may be to adjust the AC pulse settings.

[0215] In fact, the combinations described above may be used for adjustment and / or optimization. For example, the timing between atrial excitation and the highest intra-atrial pressure caused by atrial contraction, ventricular excitation, the highest atrial passive pressure, and the timing of the isovolumic phase and / or rapid ejection phase, one or more of Alternatively, a plurality may be measured. Optionally, the atrial pressure generated by the transmission of the stimulation pulse may be measured, and the adjustment may include selecting a stimulation setting according to the measured generated internal pressure. These measured values may further be related to the patient's heart rate under various conditions. Specific measured values of the patient may be used to adjust or optimize the pulse settings.

[0216] Optimization and / or adjustment as described above may be performed, for example, in some cases as a closed loop where the sensor is associated with an implantable 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, for example, when the sensor is implanted according to the heart rate), and / or may be performed during implantation when the patient has the device, and / or when needed. Finally, the optimization and / or adjustment may be automated and / or may involve a physician.

[0217] Embodiments may implement different pacing techniques to achieve AC stimulation and a desired overlap between the atrial pressure generated by atrial contraction and the passive increase in atrial pressure. 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 higher than the intrinsic ventricular rate. Additionally, different pacing techniques may be implemented to achieve a desired AC stimulation where the atrium contracts once or the atrium contracts twice.

[0218] For one contraction of the atrium, the pacing technique to achieve the desired AC stimulation may include, for example, the following. may include the following.

[0219] a. Detection of the atrium (optionally including anticipating atrial activation) and ventricular pacing ing, b. It may be necessary to perform atrial pacing before the expected time of ventricular sensing. , ventricular sensing and atrial pacing, or c. Atrial pacing and ventricular pacing.

[0220] For two atrial contractions, pacing techniques to achieve the desired AC stimulation may include, for example, the following.

[0221] a. First, detect atrial activation, sense the ventricle, and pace the atrium in the same cardiac cycle to cause a second contraction. b. Sense the atrium, pace the ventricle, and pace the atrium in the same cardiac cycle to cause a second contraction. c. Pace the atrium, sense the ventricle, and pace the atrium again, or d. Pace the atrium, pace the ventricle, and pace the atrium again.

[0222] Other pacing techniques may be utilized to achieve the desired AC stimulation and the overlap between the atrial pressure generated by atrial contraction and the passive increase in atrial pressure. Thus, despite the specific merits associated with the pacing techniques described herein, this embodiment should be considered widely applicable to any pacing technique that provides the desired AC stimulation and overlap.

[0223] Figures 18 - 19 show two different stimulation patterns transmitted to the heart of an anesthetized healthy dog 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 the change from sinus rhythm stimulation to atrial and ventricular pacing with an AV delay of 2 ms, which pacing results in an overlap between the pressure due to atrial contraction and the atrial pressure due to passive pressure increase. In this example, pacing with an AV delay of 2 ms caused a temporal overlap between the maximum pressure due to atrial contraction and the maximum atrial pressure due to passive pressure increase, and a measurable increase in atrial pressure, thus also causing atrial dilation. For comparison purposes, FIG. 19 shows an AV delay of 40 ms, which had a small degree of overlap and did not result in a significant increase in atrial pressure. Optionally, a greater degree of overlap may be defined as a function of the proximity of the maxima, i.e., the closer the maxima are to each other, the greater the degree of overlap, and eventually the maxima completely overlap and a single maximum pressure is observed. Optionally, the degree of overlap is a function of the detected maximum atrial pressure, characterized by a greater degree of overlap as the maximum pressure value increases.

[0224] In the experiments related to FIGS. 18-19, a pacemaker configured with an algorithm enabling pacing at a specific AV delay was attached to the heart of a healthy dog. The pacemaker was connected to the heart via two pacing electrodes, one in the right atrial appendage and the other in the right ventricular apex. Four solid-state pressure sensors were inserted into the right atrium, right ventricle, left ventricle, and aorta. Additionally, a unipolar-derived ECG was also connected to the animal. The sensors were connected to an amplifier and a data acquisition system (DAQ system), and the signals were sampled at a rate of 1 kHz to provide the graphs shown in FIGS. 18-19. As shown, the graph includes plots of ECG, RV pressure, RA pressure, Ao pressure, and LV pressure from bottom to top.

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

[0226] Referring to each of FIGS. 18-19, during the period of sinus rhythm 1802, two separate increases in atrial pressure are seen. The first increase in atrial pressure 1804 occurs following atrial electrical activity (P wave 1806) and corresponds to atrial contraction. The second increase in atrial pressure 1808 occurs during ventricular isovolumic contraction (characterized by a rapid increase in intraventricular pressure) and persists for a short initial period of the rapid ejection phase (which begins when aortic pressure starts to rise). The second increase in atrial pressure 1808 is caused by the effect of ventricular contraction on atrial pressure. As shown in the RA pressure plots of FIGS. 18-19, the maximum atrial pressure reached during isovolumic contraction is slightly higher than the maximum atrial pressure reached during atrial contraction. As described above, an embodiment may include preparing to maximize atrial pressure and thus maximize atrial dilation. More specifically, the stimulation may be delivered to the atrium at a timing such that, for the cardiac cycle, it reaches the atrium at a point that overlaps with the maximum passive increase in atrial pressure and causes the atrium to reach the maximum atrial pressure produced by atrial contraction. FIG. 18 shows an example of the timing at which the atrium and ventricle are paced with a 2 ms AV delay, represented by ventricular pacing 1812 following atrial pacing 1810 by 2 ms. FIG. 18 shows three examples of this pacing. Referring to the plot portion of the right atrial pressure (RA pressure) in FIG. 18, three examples of this pacing

[0227]

[0228] In this case, a significant increase in atrial pressure can be seen at points 1814, 1816, and 1818. These significant increases in internal pressure are caused by simultaneous or nearly simultaneous increases in atrial pressure due to atrial contraction and ventricular contraction. That is, when comparing the sinus rhythm portion 1802 of the right atrial pressure plot with the AV delay pacing portion 1803 of the right atrial pressure plot, the first increase in atrial pressure 1804 and the second increase in atrial pressure 1808 in the sinus rhythm portion 1802 are essentially superimposed on the AV delay pacing portion 1803 such that the increases in atrial pressure 1804 and 1808 are combined to result in higher increases in atrial pressure 1814, 1816, and 1818. The first increase in atrial pressure 1804 and the second increase in atrial pressure 1808 are combined to result in higher increases in atrial pressure 1814, 1816, and 1818, and are essentially superimposed on the AV delay pacing portion 1803.

[0229] Optionally, the AC pulse may have a setting that includes a predefined AV delay between the atrial excitation that is sensed or paced and the ventricular excitation that is paced or sensed. The AV delay may be selected such that the atrial pressure caused by atrial contraction and the passive increase in atrial pressure essentially overlap as described above, and such that the atrial pressure of the atrium, which is a combination of the atrial pressure caused by atrial contraction and the passive pressure increase, is higher than the atrial pressure of the atrium in the absence of stimulation (or when receiving a different stimulation). The AV delay may be selected such that the maximum atrial pressure and the maximum passive increase in atrial pressure caused by atrial contraction essentially overlap as described above. This setting may vary by patient and may even vary over time for a given patient. Nevertheless, in most cases, an AV delay of about 30 ms to about 0 ms is expected to be effective. For some patients (such as in the example shown by the heart of a healthy dog shown in FIG. 18), the AV delay between atrial excitation and ventricular excitation may be about 30 ms to about 0 ms, or about 20 ms to about 0 ms.

[0230] When using sensing to detect cardiac events and an AV delay is set for them, the following may optionally be taken into account, that is, first, when an electrical excitation is sensed, the actual It should be noted that there is a delay between the actual excitation and its detection. This may be due to the location of the sensing electrode and the limitations of the sensing system. Thus, for example, the period from the detected atrial excitation to the delivery of the 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 the actual excitation and the occurrence of the mechanical event must also be taken into account. Some examples of the relative timing of the detected event and the delivery of the pacing pulse are disclosed herein. In addition, as described in detail in this application, the settings may be adjusted to match the patient's specific timing at implantation and / or periodically.

[0231] In contrast to the surprising beneficial results achieved by pacing using an AV delay that causes the atrial contraction of the atrium to overlap in time with the passive increase in atrial pressure, such that the combination of the atrial pressure generated by the atrial contraction and the passive increase in pressure results in an atrial pressure that is higher than the atrial pressure of the atrium in the absence of stimulation (as in the example of FIG. 18), FIG. 19 shows that a short AV delay compared to a normal AV delay (e.g., 140 ms in a dog heart) does not result in a significant increase in atrial pressure. As shown in FIG. 19, during the AV delay pacing portion 1803, the heart was paced with a 40 ms AV delay, as represented by the ventricle pace 1912 following 40 ms after the atrial pace 1910 after the sinus rhythm portion 1802. FIG. 19 shows two examples of this pacing. Referring to the trace portion of the atrial pressure (RA pressure) after a short time after pacing, the 40 ms AV delay did not result in a significant increase in atrial pressure relative to the atrial pressure increases 1804 and 1808 during the sinus rhythm portion 1802, despite 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, which were approximately equal to the previous atrial pressure increases 1804 and 1808.

[0232] ​​Therefore, by comparing FIGS. 18 and 19, it is shown that the significantly increased atrial pressure occurs when atrial contraction and the latter half of ventricular isovolumic contraction or the initial stage of the rapid ejection phase occur simultaneously or almost simultaneously, as shown in FIG. 18. This significant increase in atrial pressure may result in the release of desired stress-related hormones to lower blood pressure. Accordingly, embodiments pace the atrium and ventricle with an AV delay of about 2 ms.

[0233] FIGS. 20A-20C illustrate some theoretical examples for combining the atrial pressure due to atrial contraction and the passive increase in atrial pressure. In these examples, different degrees of overlap are shown, as detailed below, and the pressures due to atrial contraction and passive pressure increase are summed. First, for example, as shown during the atrial rhythm 1802 period in FIGS. 18 and 19, the atrial pressure was traced during a natural cardiac cycle. From this trace, the atrial pressures due to atrial contraction 1804 and passive pressure increase 1804 were extracted. In FIG. 20A, assuming a 60 ms delay from the start of atrial contraction to the start of the passive pressure increase, the two pressure curves (corresponding to 1802 and 1804 in FIG. 18) were summed. As can be seen, atrial contraction lasted approximately 60 ms and reached a peak pressure of approximately 1.5 mmHg, while the passive pressure increase lasted approximately 50 ms and reached a peak pressure slightly higher than 2 mmHg. Since atrial contraction lasted approximately 60 ms (which is approximately the same as the assumed delay), two increases in pressure were observed as separate portions in this trace, having two different peaks, and the observed peak pressure is the peak pressure of the passive pressure increase 1804.

[0234] FIG. 20B shows in more detail the theoretical combination of the atrial pressure due to atrial contraction and the passive increase in atrial pressure. In this trace, the start of the passive pressure increase 1804 (dashed line) is assumed to occur 30 ms after the start of atrial contraction 1802 (dotted line), as shown. The two traces 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 pressure rise due to the atrial contraction are combined such that the peaks are closely overlapping (there is a 0 ms delay between the onset of the two changes in pressure, which may not coincide exactly due to different durations), i.e. it is assumed that both the atrial pressure and the passive pressure rise due to the atrial contraction started at approximately the same time. As can be seen, in this case trace 207 shows the sum of the pressures reaching a single peak of about 3.5 mmHg. Similarly, with a delay of 10 ms (trace 206), a single peak was observed that was slightly delayed from trace 207 and had a lower peak than the peak of trace 207. With increasing time delay, in trace 205 (20 ms delay), the traces start to separate but still result in a single peak (between 2.5 mmHg and 3 mmHg). Trace 204 (30 ms delay identical to the trace shown in FIG. 20B) clearly shows two maxima, but there is still sufficient overlap, and the total atrial pressure is somewhat higher than the maxima in trace 201. Finally, even with a smaller degree of overlap, trace 203 (40 ms delay) and trace 202 (50 ms delay) show some overlap between the atrial contraction and the passive pressure rise, whereas in each trace the two maxima are more than 30 ms apart, and the peak pressure is nearly 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 lowered by intermittently applying exclusively a stimulation pattern that includes or consists of AC pulses. For example, by applying intermittent AC pulses, natural pulsations may occur between pulses configured such that the intracardiac pressure due to the AC pulse and / or atrial contraction does not overlap (or their respective peaks do not overlap) with the intracardiac pressure due to passive pressure rise, thereby providing an intracardiac pressure of the atrium that is higher than the intracardiac pressure of the atrium in the absence of stimulation by a combination of the intracardiac pressure generated by atrial contraction and passive pressure rise. Optionally, the time during which the AC pulse is applied may be selected according to the time constant of the secretion and / or absorption of natriuretic peptide such that sufficient stimulation is transmitted to provide essentially the desired effect without causing excessive stimulation. This may have the advantage of reducing the power used by an implantable device and / or reducing the degree of cardiac operation.

[0239] An exemplary method 230 for controlling intracardiac pressure is schematically illustrated in FIG. 23. Method 230 may be implemented by an implantable device as described herein. Thus, the device may be configured to perform any or all steps of method 230. Similarly , method 230 may include any steps configured to be performed by the device. . For example, method 230 may include any of the functions discussed below with respect to device 50 of FIG. 14. It may be included.

[0240] In some embodiments, method 230 may include detecting a cardiac event, as shown in step 231. This event(s) may include electrical and / or mechanical events and may be detected as is known in the art and as described in more detail herein. For example, the detection Known events may include detecting the excitation of the atria and / or ventricles, and / or the mechanical activity of the heart, such as the timing of the opening and / or closing steps of one or more heart valves. It may include detecting the timing. The detected events may include inferring the relative timing between cardiac events. In some embodiments, step 231 may include triggering one or more cardiac events, such as atrial excitation or ventricular excitation. Optionally, step 231 may include detecting the intrinsic heart rate or setting the heart rate. For example, step 231 may include defining the start of the isovolumic phase by detecting the closure of the AV valve, and / or defining the point in time when the rapid ejection phase begins by detecting the opening of the aortic valve. Step 231 may further include determining the time difference between the detection of ventricular activation or ventricular stimulation and the closure of the AV valve that defines the start of the isovolumic phase. For example, step 231 may include detecting the closure of the AV valve. It may include defining the start of the isovolumic phase and / or defining the point in time when the rapid ejection phase begins. Step 231 may further include determining the time difference between the detection of ventricular activation or ventricular stimulation and the closure of the AV valve that defines the start of the isovolumic phase.

[0241] Method 230 may include step 232 where a pulse setting is selected. Selecting may include setting the time interval between atrial excitation and ventricular excitation, or may include selecting the ratio of atrial excitation to ventricular excitation for a given stimulation pulse. Selecting may include a power setting based on the timing of the detected or inferred excitatory pulse transmission in the 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 be set in step 232 if desired, and this pulse setting may be selected based on the timing of the event detected in step 231. In some embodiments, an excitatory current may be applied to both ventricles, simultaneously or in sequence. In some embodiments where both ventricles are paced in sequence, the time interval from the onset of excitation of at least one atrium (e.g., the right atrium) to the onset of excitation of the corresponding ventricle (e.g., the right ventricle) being paced may be measured. In some embodiments where the time interval is set to be zero or negative, step 233 may be performed before or simultaneously with step 231. In some embodiments, the time interval may be measured in milliseconds.

[0243] The pulse setting selected in step 232 may be selected based on feedback. If so, method 230 may include detecting the atrial pressure as shown in step 234. For example, the feedback information may be obtained during and / or periodically, e.g., during implantation and / or during periodic inspections, by using an implantable sensor for pulse setting feedback and adjustment. Method 230 may include step 235 of estimating the time overlap between the atrial pressure generated by atrial contraction (preferably, the maximum atrial pressure) and the passive atrial pressure rise (preferably, the maximum passive pressure rise). For example, estimating in step 235 may involve the number of peaks of the atrial pressure and their times Detecting a length and / or a time distance between peaks, and / or detecting a number of peaks and troughs of the atrial pressure, and estimating a contraction duration or a change in the internal pressure based on the time between the peaks and troughs, and / or detecting a peak value of the atrial pressure compared to the atrial pressure of the same heart without stimulation. This comparison may be performed using a stored value corresponding to the internal pressure measured before the start of treatment, and / or may include the step of detecting the atrial pressure of at least one beat without transmitting a stimulation pulse according to method 230.

[0244] Method 230 may include step 236 of adjusting the selected pulse setting based on the detected overlap estimated in step 235. For example, step 236 may include adjusting the time interval to provide the greatest degree of overlap observed among a plurality of settings. Optionally, a greater degree of overlap may be defined as a function of the proximity of the maximum atrial pressures, i.e., the closer the peaks are to each other, the greater the degree of overlap, until finally the peaks completely overlap and a single maximum internal pressure is observed. Optionally, the degree of overlap is a function of the detected maximum atrial pressure, and is characterized by a greater degree of overlap as the internal pressure increases. As indicated by the arrow from step 236 to step 231 in FIG. 23, steps 231, step 232, step 233, step 234, and / or step 235 may be repeated after step 236 is executed. In some embodiments, the time pulse setting may first be set to a first value in step 231, and based on the feedback detection performed between 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).

[0245] This may also be done (for example, by reducing or increasing the time interval).

[0246] The steps of method 230 may be performed in any order. For example, the steps may be performed in the order shown by the arrows shown in FIG. 23. In another embodiment, step 232 may be performed before step 231.

[0247] The timing of atrial contraction, atrial excitation, ventricular contraction, closing and / or opening of the AV valve, 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 excitation may be used as a trigger for the delivery of excitatory stimuli to one or more heart chambers (e.g., one or two ventricles, or atria and ventricles). The detected information may be used additionally or instead in adjusting the timing intervals of the device.

[0248] Embodiments may provide a method of adjusting the pulse settings of a system for controlling blood pressure. The method may include receiving intracardiac pressure data associated with the atria of a patient's heart during at least one cardiac cycle. The intracardiac pressure data may result from the system delivering a stimulus pulse having a first pulse setting to the heart. The method may further include analyzing the intracardiac pressure data and providing a second pulse setting different from the first pulse setting adjusted according to this analysis. Analyzing may include analyzing the intracardiac pressure data to estimate the temporal overlap between the intracardiac pressure caused by atrial contraction and the passive increase in atrial pressure. Analyzing may further include plotting the intracardiac pressure data and / or mathematically analyzing the intracardiac pressure data.

[0249] ​​ Embodiments may provide a system for lowering blood pressure. The system may comprise components such as those shown in FIG. 14. The system may include means for providing information about the intracardiac pressure fluctuations in the atrium during at least one cardiac cycle of the heart, means for generating stimulation pulses, and means for applying the stimulation pulses to at least one cardiac chamber. The means for generating stimulation pulses may be configured to generate stimulation pulses so as to control the timing of atrial contraction relative to the timing of ventricular contraction during a single cardiac cycle according to the information about the intracardiac pressure fluctuations in the atrium. In one embodiment, the means for providing information may first detect information (e.g., intracardiac pressure and the time during which the intracardiac pressure changes), and the means for generating stimulation pulses may then determine the timing of the stimulation based on this information. The information about the intracardiac pressure fluctuations in the atrium may include information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction. The information may include information about the relative timing between the maximum intracardiac pressure generated by atrial contraction and the maximum passive intracardiac pressure rise in the atrium. The information may include information related to the occurrence and / or timing of one or more cardiac events as described herein, including, for example, one or more of atrial contraction, ventricular contraction, opening of the atrioventricular valve, closing of the atrioventricular valve, electrical activity of the atrium, electrical activity of the ventricle, blood flow, refractory period of the atrium, and heart rate.

[0250] The means for generating stimulation pulses may cause atrial contraction for at least one cardiac cycle. and / or timing.

[0251] 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 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 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 an atrial contraction may include information about the occurrence of a P-wave pattern in a natural stimulation pattern of a cardiac cycle. The information about the occurrence of a ventricular contraction may include information about the occurrence of a QRS complex in a natural stimulation pattern of a 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 may be configured to generate a stimulation pulse to provide stimulation to the ventricle and / or to provide an excitatory stimulation to the atrium and then provide an excitatory stimulation to the ventricle within a range of about 30 ms to about 0 ms.

[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. Means for providing information about the timing of a vent, means for generating a stimulation pulse, and means for applying the stimulation pulse to at least one heart chamber may be provided. Information about the timing of one or more cardiac activity events may include at least one of the occurrence of atrial contraction in the atrium, the occurrence of ventricular contraction in the ventricle, the opening of the atrioventricular valve, the closing of the atrioventricular valve, the electrical activity of the atrium, the electrical activity of the ventricle, blood flow, the intracardiac pressure in the atrium, the change in intracardiac pressure in the atrium, the refractory period of the atrium, and the heart rate. The means for generating a stimulation pulse may be configured to generate a stimulation pulse so as to set the timing of atrial contraction relative to ventricular contraction based on the information. The timing of atrial contraction relative to ventricular contraction may correspond to an AV delay within the range of about 30 ms to about 0 ms.

[0254] The means for generating a stimulation pulse may be configured to provide an excitatory stimulus to the atrium within the range of about 30 ms to about 0 ms before ventricular excitation occurs, provide an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms after atrial excitation occurs, and / or provide an excitatory stimulus to the atrium and then provide an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms thereafter. The timing of atrial contraction relative to ventricular contraction may correspond to an AV delay within the range of about 30 ms to about 0 ms. The means for generating a stimulation pulse may be configured to provide an excitatory stimulus to the atrium within the range of about 30 ms to about 0 ms before ventricular excitation occurs, provide an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms after atrial excitation occurs, and / or provide an excitatory stimulus to the atrium and then provide an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms thereafter. The means for generating a stimulation pulse may be configured to provide an excitatory stimulus to the atrium within the range of about 30 ms to about 0 ms before ventricular excitation occurs, provide an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms after atrial excitation occurs, and / or provide an excitatory stimulus to the atrium and then provide an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms thereafter.

[0255] Information about the timing of one or more cardiac activity events may include information about the timing between two or more cardiac activity events in a single cardiac cycle. Information about the timing of one or more cardiac activity events may include information about the timing between two or more cardiac activity events in a single cardiac cycle. Information about the timing of one or more cardiac activity events may include information about the timing between two or more cardiac activity events in a single cardiac cycle.

[0256] The means for generating a stimulation pulse may, for at least one cardiac cycle, generate at least one atrial stimulation pulse that causes atrial contraction and / or at least one ventricular stimulation pulse that causes ventricular contraction. It may be configured to generate ventricular stimulation pulses. The means for generating the stimulation pulses is in a relationship such that it synchronizes with the occurrence of atrial contraction and / or the occurrence of ventricular contraction, and generates at least one atrial stimulation pulse based on information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction, and / or is configured to generate at least one ventricular stimulation pulse based on information about the occurrence of ventricular contraction and / or information about the occurrence of atrial contraction in a relationship such that it synchronizes with the occurrence of ventricular contraction and / or the occurrence of atrial contraction. The information about the occurrence of atrial contraction may include information about the occurrence of the P-wave pattern in the natural stimulation pattern of the cardiac cycle. The information about the occurrence of ventricular contraction may include information about the occurrence of the QRS complex in the natural stimulation pattern of the cardiac cycle.

[0257] 〈Control of atrial stimulation〉 In some embodiments, by stimulating the heart such that the contribution of atrial contraction (atrial stimulation) to ventricular filling is reduced or even prevented, cardiac filling is reduced at the end of diastole, and as a result, blood pressure decreases. For the sake of simplicity, in the following description, such stimulation is referred to as "BPR (Blood Pressure Reducing) stimulation". BPR stimulation is atrial stimulation that is reduced or even prevented by transmitting at least one stimulation pulse to at least one chamber of the heart. Such pulses are described in this specification and may include transmitting at least one stimulation pulse to at least one chamber of the heart. It is referred to as "BPR stimulation pulse" or "BPR pulse" in the literature. As described above, a "stimulation pulse" may include a sequence of one or more electrical pulses that are transmitted to one or more chambers of the heart within a single beat or the time frame of the cardiac cycle. For example, in some embodiments, the stimulation pulse may include one or more electrical pulses transmitted to one or more locations of the ventricle and / or one or more electrical pulses transmitted to one or more locations of the atrium. Thus, in some embodiments, the stimulation pulse may include a first electrical pulse transmitted to the atrium and a second electrical pulse transmitted to the corresponding ventricle. In some embodiments, the stimulation pulse may include a single pulse that is transmitted to multiple locations of one or more chambers of the heart.

[0258] A "stimulation setting" means one or more parameters of one or more stimulation pulses transmitted in a single cardiac cycle. For example, these parameters may include power (power), the time interval between electrical pulses included in a single stimulation pulse (e.g., AV delay ), the period of transmission relative to the natural rhythm of the heart, the length of the stimulation pulse or a part thereof, and / or one or more of the locations of transmission between two or more chambers and / or within a single chamber. A BPR stimulation setting, i.e., a "BPR setting", may include the setting 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 a plurality of 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 different from the first setting. When a stimulation pattern has a certain setting it means that the stimulation pattern has at least one stimulation pa It is understood to mean that it may include a pause. In some embodiments, it is also understood that one or more cardiac cycles in which a stimulation pulse is not transmitted may be included in the stimulation pattern. , in which case the pulse can be considered to be transmitted at zero power. The stimulation pattern may include a plurality of identical pulses or a sequence of pulses including two or more different settings. Two stimulation sequences in one pattern may differ in the order of pulses provided within one setting. Two or more stimulation sequences Preferably, they may differ in their length (in the time and / or number of beats). In some embodiments, the stimulation pattern may include pulses having a BPR setting. In some embodiments, the stimulation pattern may include pulses not having a BPR setting.

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

[0261] a. Transmitting one or more stimulation pulses to the patient's ventricle 0 - 50 ms before excitation begins in the patient's atrium. Preferably, this delay is set based on the setting of atrial excitation. Preferably, this includes transmitting one or more stimulation pulses to the atrium 0 - 50 ms after transmission of the stimulation pulse to the ventricle. Preferably, this is done at a number slightly higher than the patient's natural heart rate.

[0262] b. Initiate one or more stimulation pulses to the patient's ventricles 0 to 70 ms after excitation begins in the patient's atrium. Preferably, this delay is set based on detection of atrial excitation. Preferably, this includes transmitting one or more stimulation pulses to the atrium 0 to 70 ms prior to transmission of the stimulation pulse to the ventricle. Preferably, this is done at a number slightly higher than the patient's natural heart rate. Ventricular transmission. Preferably, this delay is set based on detection of atrial excitation. Preferably, this includes transmitting one or more stimulation pulses to the atrium 0 to 70 ms prior to transmission of the stimulation pulse to the ventricle. Preferably, this is done at a number slightly higher than the patient's natural heart rate.

[0263] Some embodiments may provide a system for reducing blood pressure configured to deliver stimulation at a number higher than the natural heart rate based on the detected natural heart rate or natural excitation. For example, the system may be configured to detect natural excitation during delivery of the stimulation pulse, and if natural activity is detected, the system may be configured to inhibit delivery of the stimulation pulse to the chamber. If the amount of detected activation within a given time frame exceeds a threshold, the natural heart rate may be considered higher than the number of stimulation pulses delivered, in which case the number of deliveries may be increased to accommodate, for example, the patient's increased heart rate. On the other hand, if the amount of detected activation within a given time frame is lower than a threshold (which may be zero), the natural beating may be considered lower than the number of stimulation pulses delivered, in which case the number of deliveries may be reduced to avoid, for example, excessive excitation of the patient's heart. Activation is detected, and if it is lower than a threshold (which may be zero), the natural beating may be considered lower than the number of stimulation pulses delivered, in which case the number of deliveries may be reduced to avoid, for example, excessive excitation of the patient's heart. Activation is detected, and if it is lower than a threshold (which may be zero), the natural beating may be considered lower than the number of stimulation pulses delivered, 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 detects the excitation rate of at least one of the atrium and ventricle of the patient's heart. It may include a sensor for doing so, a stimulation circuit configured to transmit stimulation pulses to the atrium and ventricle, and a processor circuit coupled to the stimulation circuit. Preferably, the sensor for detecting the excitation rate of at least one of the atrium and ventricle may include an electrode for detecting atrial excitation. The processor circuit may be configured to detect the patient's heart rate based on the detection and operate in an operating mode in which stimulation pulses are supplied to at least one of the atrium and ventricle respectively. The stimulation pulses may be transmitted at a rate higher than the detected excitation rate and may be configured to stimulate the ventricle during a time between about 50 ms before and about 70 ms after the stimulation of the atrium.

[0265] Reducing the atrial kick may have an immediate effect on blood pressure, but the hormone mediated mechanism may take a longer period. 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 the atrial kick without a significant increase in atrial dilation. For example, when the AV valve closes at or after the time of peak pressure of atrial contraction, atrial dilation does not increase due to premature closure of the valve.

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

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

[0268] In some embodiments, only one or more ventricles may be stimulated, and the stimulation pulses may be time - adjusted to have an abnormal AV delay (e.g., 50 ms before to 120 ms after atrial excitation). In some embodiments, the BPR stimulation setting may include the delivery of at least one electrical pulse or stimulation to one or more atria. In some embodiments, this at least one atrial stimulation may cause atrial contraction. In some embodiments, the at least one atrial stimulation may interfere with atrial contraction. In some embodiments, the at least one atrial pulse may cause atrial fibrillation or other types of inefficient atrial contraction.

[0269] The reduction in blood pressure from BPR stimulation may be observed substantially immediately upon application of the stimulation signal (e.g., within 1 or 3 seconds or within 1, 3, or 5 beats), and may reach a minimum blood pressure value within less than 5 beats from the start of the stimulation.

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

[0271] By controlling the BPR stimulation setting, the degree to which the BP drops may be controlled. This degree​​​​ The degree is sometimes patient-specific and / or related to the exact placement of one or more stimulating electrodes and / or sensing electrodes within or to the heart. Since the degree to which BP changes can be, for example, a function of the AV delay, 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 will be described in more detail later.

[0272] <Adaptation> a. The inventors of the present application have found that while the stimulation is maintained, the blood pressure may show an adaptation pattern (some of which often occur within a short time of less than 5 minutes, or even less than 1 minute) in which the blood pressure increases after a certain time and reaches near or even higher than the blood pressure value before the stimulation (possibly due to at least the baroreflex). The adaptation may be at least partly due to changes in the characteristics of the cardiovascular system, such as an increase in total peripheral resistance. The inventors have further found that upon termination of the stimulation, the blood pressure rapidly returns to the value before the stimulation or even to a higher value, and thereafter the heart responds to the blood pressure reducing stimulation signal to a similar extent as a heart that has not been so stimulated. In addition, it has been found that different stimulation patterns with multiple BPR stimulation settings lead to different blood pressure adaptation patterns.

[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, and the first stimulation setting and the second stimulation setting are configured to reduce or prevent atrial kick and / or to control either or both of the atrial pressure and atrial dilation. The stimulation pattern may have more than two different stimulation settings It may even be provided with. The second setting in some embodiments has an AV delay (e.g., about 80 ms to about 160 ms) longer than the first setting. The second setting in some embodiments may not be configured to reduce the atrial kick and / or control either or both of the atrial pressure and atrial dilation.

[0274] In FIG. 1, the systolic blood pressure of a hypertensive patient receiving a stimulation signal is plotted against time There is. The crosses along the plotted line indicate the peak systolic blood Pressure. During approximately the first two minutes of plotting, no stimulation signal was transmitted As can be seen, the patient's initial blood pressure exceeded 150 mmHg on average. The amplitude of the blood pressure (about ±10 mmHg) is due to the respiratory cycle, as is known in the art.

[0275] Next, a first stimulation pattern was applied during the time interval a-a', a second stimulation pattern was applied during the time Interval b-b', and a third stimulation pattern was applied during the time interval c-c'. Between the middle of the stimulation pattern and after the third stimulation pattern, the heart was not stimulated.

[0276] Here, referring to FIG. 2, which shows an enlarged portion of the portion of FIG. 1 indicated by the dashed rectangle A. During the time indicated by the dashed rectangle in FIG. 2 corresponding to the time interval a-a' in FIG. 1, the stimulation began and was transmitted to the patient's right atrium and right ventricle, and as a result, the atrium received a BPR stimulation signal (pulse) 2 ms before the ventricle. The stimulation ended at the time indicated by a' in FIGS. 1 and 2. During the time interval a-a', the patient's systolic pressure first decreased to a minimum value of less than 110 mmHg and then gradually increased to an intermediate value between the initial blood pressure and the realized minimum value. At point a', the stimulation stopped and an immediate overshoot of the blood pressure to a value exceeding 170 mmHg was observed. Within about a dozen beats, the blood pressure returned to its initial range.

[0277] ​The blood pressure changes shown in FIGS. 1 and 2 indicate, at least in part, the cardiovascular response to blood pressure changes known as the baroreflex. The baroreflex works to restore blood pressure to its pre-stimulus level by changing cardiovascular characteristics (e.g., peripheral resistance and / or myocardial contractility). It may be assumed that a decrease in blood pressure resulting from a reduction in ventricular filling induced a baroreflex response directed toward 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 was withdrawn, and the blood pressure immediately exceeded the pre-stimulus blood pressure. This may be regarded as indicating a baroreflex change in the cardiovascular system (e.g., increased peripheral resistance and increased contractility). At point a' where the stimulus ceased and the blood pressure peaked, in this case, the baroreflex responded to the increase in blood pressure by changing one or more characteristics of the cardiovascular system again in order to lower the blood pressure back to the pre-change level. As can be clearly understood, the baroreflex feedback response to increases and decreases in blood pressure is asymmetric in that the response to an increase in blood pressure is much faster than the response to a decrease in blood pressure. In some embodiments, this asymmetry of the baroreflex may be utilized, for example, by controlling the stimulation pattern accordingly to reduce or even prevent the adaptation of the blood pressure reduction due to reduced filling as detailed herein. The baroreflex works to restore blood pressure to its pre-stimulus level by changing cardiovascular characteristics (e.g., peripheral resistance and / or myocardial contractility). It may be assumed that a decrease in blood pressure resulting from a reduction in ventricular filling induced a baroreflex response directed toward 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 was withdrawn, and the blood pressure immediately exceeded the pre-stimulus blood pressure. This may be regarded as indicating a baroreflex change in the cardiovascular system (e.g., increased peripheral resistance and increased contractility). At point a' where the stimulus ceased and the blood pressure peaked, in this case, the baroreflex responded to the increase in blood pressure by changing one or more characteristics of the cardiovascular system again in order to lower the blood pressure back to the pre-change level. As can be clearly understood, the baroreflex feedback response to increases and decreases in blood pressure is asymmetric in that the response to an increase in blood pressure is much faster than the response to a decrease in blood pressure. In some embodiments, this asymmetry of the baroreflex may be utilized, for example, by controlling the stimulation pattern accordingly to reduce or even prevent the adaptation of the blood pressure reduction due to reduced filling as detailed herein.

[0278] FIG. 3A shows an enlarged view of the curve of FIG. 1 between time points a and a'. In FIG. 3A, an exponential function was fitted to the plotted curve showing the adaptation response. The function describes the relationship between time and SysBP and has the following equation. The function describes the relationship between time and SysBP and has the following equation. The function describes the relationship between time and SysBP and has the following equation.

[0279] P = Pi+DP(1 - e -t / k ) where P (in mmHg) represents systolic blood pressure, Pi (mmHg) is the first mean reduced blood pressure at the start of the BPR stimulation, and DP (mmHg) is the initial drop to the new steady-state level where P0 is a constant representing the amount of increase in pressure, k (seconds) is the response time constant, e is the mathematical constant that is the base of the natural logarithm, and t (seconds) is time.

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

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

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

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

[0284] P = 190 - 35(1 - e -t / 4.946 ) wherein it was found that Pi was 190 mmHg. DP was -35 mmHg. K was 4.946 seconds.

[0285] As described 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 above-described time constant k (from about 15 seconds to about 5 seconds) to a much faster response to an increase in blood pressure. This asymmetry in the speed of the baroreflex response may provide a means of designing a stimulus pattern that produces a reduction in mean blood pressure and a reduction or even prevention of adaptation. For example, in a preferred embodiment, the weighted response may cause the stimulus pattern to alternate between two stimulus settings in a manner that is advantageous for the cardiovascular changes caused by an increase in blood pressure. In this embodiment, ventricular filling is reduced A first setting designed to reduce blood pressure, and a second setting designed to have normal ventricular filling or a ventricular filling higher than that of the first setting, at least Two stimulation patterns, and the heart may be stimulated using these two stimulation patterns. This stimulation pattern may include pulses having a first setting (BPR) that is transmitted 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 apparent, and the blood pressure may increase from the reduced level, but may not reach the level before the stimulation. The stimulation pattern may also include pulses having a second setting (e.g., natural AV delay) that is transmitted for a period longer than the time constant of the baroreflex response to an increase in blood pressure. In this case

[0286] The reduction in blood pressure caused by the baroreflex may be fully utilized, and the blood pressure may even return to its level before the stimulation pattern switched to this second setting. In such A weighted response of the baroreflex in such a pattern may reduce or prevent adaptation, but the average pressure may be lower than the level before the stimulation. The relationship between the time constant and the period assigned to the transmission of pulses with different settings may determine the level of the baroreflex response that takes effect during the entire stimulation pattern. For a given stimulation setting, if the transmission period is selected to be shorter than the time constant of the response, the baroreflex may not be able to change the cardiovascular system to return to the level before the stimulation, and if the selected period is larger than the time constant, the baroreflex effect may become more prominent. As can be seen from FIG. 1, the second stimulation pattern was transmitted at the interval between point b and point b'.

[0287] As can be seen from FIG. 1, the second stimulation pattern was transmitted at the interval between point b and point b'. FIG. 4 shows an enlarged version of this part of FIG. 1 (indicated by the dashed rectangle B in FIG. 1). In the second stimulation pattern, a sequence of 12 BPR pulses is transmitted to the atrium and the pair with a 2 ms AV delay It was transmitted to both ventricles in response, and then three beats followed in which only atrial stimulation was artificially transmitted and ventricular stimulation was not transmitted. During these last three beats, ventricular excitation occurred through the natural conductance through the AV node, resulting in an AV delay of ~180 ms. This second stimulation pattern was repeated while the previously established time intervals persisted. In Figure 4, it was found that the exponential function that fit the curve was as follows.

[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 Figure 3A). However, k for the second pattern was nearly twice the time constant of the first stimulation pattern. At this time interval, adaptation occurred at a slower rate than in Figure 3A, but when the pattern switched between stimulation pulses, blood pressure increased more abruptly than in Figure 3A. This result demonstrates that the use of stimulation patterns with alternating stimulation settings reduces adaptation.

[0289] The third stimulation pattern was similarly transmitted between points c and c' as seen in Figure 1. Figure 5A shows an enlarged view of the portion of Figure 1 indicated by the dashed rectangle C, which includes the portion of the curve between points c and c'. In the third stimulation pattern, a sequence of 12 BPR pulses was transmitted with a 2 ms AV delay, followed by three BPR pulses each having a 120 ms AV delay. This was repeated while the previously established time intervals persisted.

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

[0291] In Figure 5B, the exponential function was as follows.

[0292] P = 109.7 + 22.3(1 - e -t / 45.4 ) Wherein, it was found that Pi is 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 much higher (45.4 seconds vs. 15.5 seconds). This means that low blood pressure was maintained for a period approximately three times longer than that in Figure 3A. As can be seen, in this case, the adaptation rate was very low and hardly detectable within the assigned time interval. The exponential formula could not be fitted,

[0293] Now, look at Figure 6. In Figure 6, the heart of a hypertensive patient was stimulated with a stimulation pattern having a sequence of 12 BPR pulses transmitted with a 2 ms AV delay, followed by three BPR pulses each having an 80 ms AV delay.

[0294] As can be seen, in this case, the adaptation rate was very low and hardly detectable within the assigned time interval. The exponential formula could not be fitted, suggesting that the adaptation was extremely slow or non-existent.

[0295] In Figure 7, the heart of a hypertensive patient was stimulated with a stimulation pattern having a sequence of 12 BPR pulses transmitted with a 2 ms AV delay, followed by three BPR pulses each having a 40 ms AV delay. The stimulation started at point t1 and ended at point t2. There was no measured adaptation response, and the curve that fits is actually a straight line, with a fixed mean reduced blood pressure of approximately 112 mmHg, which is about 31 mmHg lower than the blood pressure immediately before and after the time interval t1 - t2. As is clear from the different stimulation patterns described above, a stimulation pattern with at least one BPR stimulation can be set to approach at least one target. For example

[0296] ​​For example, in some embodiments, the stimulation pattern is set to cause an initial reduction in blood pressure (systolic and / or diastolic) that will exceed a predetermined threshold or will be within a predetermined range. In more specific embodiments, the blood pressure may be reduced by at least a given percentage or by at least a given measure (e.g., 10 or even 20 mmHg or 30 mmHg), or the blood pressure may be reduced to be within a given range (e.g., 90 - 130 mmHg SysBP) or below a given target (e.g., SysBP below 130 mmHg). In some embodiments, the target may include maintaining the reduced blood pressure within a reduced average range for an extended period. For example, a given blood pressure may be reduced to a given average blood pressure over a period or a number of beats.

[0297] In another embodiment, the target may include bringing a given percentage of the beats to a reduced range / threshold state. In some embodiments, the target may include reducing the blood pressure while also reducing the level of the sharp increase during the stimulation pulse. For example, the stimulation pattern may be used to lower the blood pressure to a constant blood pressure over a given time interval. In some embodiments, the stimulation pattern may be used to lower the blood pressure without significantly affecting the cardiac output. For example, by applying intermittent BPR pulses, pulses with a higher (or even sufficient) atrial kick may occur during the BPR pulses. Pulses with a higher (or even sufficient) atrial kick can prevent the BPR pulses from significantly reducing the cardiac output.

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

[0299] When setting the stimulation pattern to approach one or more targets, providing different values of blood pressure reduction may include adjusting the stimulation parameters that affect the AV delay. For example, stimulation parameters that provide a shorter AV delay can reduce blood pressure to a greater extent than stimulation parameters that provide a longer AV delay. In an embodiment, the stimulation settings that reduce atrial stimulation may provide an AV delay that varies from about 5 ms to about 30 ms (e.g., between day and night, or between intense activity and light activity), and the shorter the AV delay, the greater the reduction in blood pressure.

[0300] Providing different values of blood pressure reduction may also include changing stimulation parameters other than the short AV delay period. For example, in one embodiment, the ratio of the short AV delay to the longer AV delay may be adjusted. As another example, in other embodiments where pulses with a short AV delay are transmitted while comparing with the heart rate having a longer AV delay, the heart rate may be adjusted.

[0301] In some embodiments, the time constant of the change in blood pressure of a given pattern may be calculated, and the stimulation pattern may be set to have one or more BPR stimulation parameters for the amount of the time or number of pulsations set as a specific 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 the transmission of the BPR pulse and about 4.9 seconds for the rate of adaptation to the end of the transmission of the BPR pulse. In some embodiments, it may be desirable to prevent the blood pressure from increasing beyond a given value, in which case the duration of the transmission of the BPR pulse is selected to be significantly smaller than k (e.g., 30% to 6 0%). In this embodiment, the interval may be selected to be less than 15 seconds . Such an interval may include about 6 to 10 seconds or 8 to 14 pulsations for a heart rate of about 80 pulsations per minute.

[0302] Preferably, it is desirable to utilize the adaptive response to the withdrawal of the BPR pulse. In such a case, a larger portion of k may be applied. For example, based on FIG. 3B, a period of 3 to 5 pulsations may be selected (wherein k is about 4.9 seconds). In this way, for example, based on FIGS. 3A and 3B, the inventors of the present application applied the stimulation pattern of FIG. 4. The stimulation pattern may be set, for example, to be the best of a plurality of stimulation patterns (i.e., the one closest to the set target parameters), and / or selected as the first tested stimulation pattern that matches the set target

[0303] . Embodiments Based on Slow Baroreflex Response

[0304] ​In experiments using dogs, the inventor has found that when treatment is terminated after several days of treatment, it can take a relatively long time for blood pressure to return to its pre-treatment value. This slow baroreflex response can be utilized. In particular, in an embodiment, treatment over a long period (e.g., normal pacing or no pacing at all) can be interrupted, thereby enabling conservation of the battery power of the stimulation device and a longer service life.

[0305] As an example of the slow baroreflex response, refer to FIG. 27. This figure is a graph showing the effect of the blood pressure lowering treatment of the dogs disclosed herein, and plots the change over time (days) of the systolic blood pressure (mmHg). As shown in the graph, the pre-treatment blood pressure value is indicated by the baseline ("BL") marked with diamond data points, the values during the treatment period are indicated by the treatment line marked with square data points, and the post-treatment values are indicated by the device off ("Dev Off") line marked with triangular data points. In this experiment, The systolic blood pressure was continuously measured over 24 hours using an implantable sensor that transmits the systolic blood pressure to the receiver. Each data point on the graph represents the average value of the measured values over 24 hours.

[0306] The dog subject showed a blood pressure of about 210 mmHg, as indicated by the baseline of FIG. 27. Immediately upon applying the blood pressure lowering treatment disclosed throughout this disclosure, the blood pressure of the dog decreased to about 170 mmHg, as shown by the treatment line in FIG. 27. During the treatment period, the blood pressure of the dog varied between about 150 mmHg and about 175 mmHg (i.e., about 35 - 60 mmHg lower than the pre-treatment value). This treatment was applied for 30 days.

[0307] When the treatment was stopped (pacing was no longer applied to the dog's heart), the blood pressure of the dog slightly increased to about 180 mmHg, as shown by the device off line in FIG. 27. This value It was significantly lower by about 30 mmHg than the blood pressure before treatment. The blood pressure of the dog remained near that level for about 20 days and then gradually increased and began to return to nearly the pre-treatment value.

[0308] Considering the mechanism of the slow baroreflex response, such as the response illustrated in FIG. 27, embodiments provide a method for treating hypertension that includes alternating between a first stimulation pattern (i.e., the treatment stimulation pattern) configured to lower blood pressure and a second stimulation pattern (i.e., the "rest" stimulation pattern) configured such that the degree of blood pressure reduction is smaller, and the two patterns are each applied over a period of several days, several weeks, or more. In embodiments, the two patterns may each be applied for at least one week and may provide treatment over a weekly time scale. The rest stimulation pattern may or may not involve stimulation. That is, the "rest" stimulation pattern), and the two patterns are each applied over a period of several days, several weeks, or more. In embodiments, the two patterns may each be applied for at least one week and may provide treatment over a weekly time scale. The rest stimulation pattern may or may not involve stimulation. In embodiments, the two patterns may each be applied for at least one week and may provide treatment over a weekly time scale. The rest stimulation pattern may or may not involve stimulation.

[0309] In embodiments, the durations of the first and second stimulation patterns may be the same or different.

[0310] For example, the duration of the rest stimulation pattern may be shorter than the duration of the treatment stimulation pattern, e.g., 25% - 90% thereof, or in some cases 50% - 80%. In one embodiment, the duration of the rest stimulation pattern may be about 2 / 3 of the duration of the treatment stimulation pattern.

[0311] The duration of the rest stimulation pattern may depend on or be proportional to the degree of blood pressure reduction by the treatment stimulation pattern. For example, if the treatment stimulation pattern is configured to lower blood pressure by at least 50 mmHg, the rest stimulation pattern may last longer than if the treatment stimulation pattern is configured to lower blood pressure by only 30 mmHg.

[0312] Optionally, the duration of the rest stimulation period may be 2 weeks to 1 month (e.g., 14 to 31 days) or less, regardless of the duration of the treatment stimulation pattern.

[0313] Each stimulation pattern may include a plurality of stimulation patterns, and at least some of the plurality of stimulation patterns may include one or more atrial stimulation reduction pulse settings, for example, according to one or more of the patterns described in the present disclosure. For example, during the treatment stimulation pattern period, the treatment may include variations as needed (e.g., alternating between daytime and nighttime settings).

[0314] In an embodiment, the rest stimulation pattern may be selected from (1) no application of pacing, (2) pacing without atrial stimulation reduction, and (3) overall and / or average Pacing with a small reduction in atrial stimulation. Optionally, the rest stimulation pattern may include a switch from one rest stimulation pattern to another. The rest stimulation pattern may not necessarily completely stop the blood pressure reduction. For example, it may include the application of atrial stimulation reduction pulses at a very low frequency (e.g., 10 pulses or less during a 20-minute period), or alternating between one degree of blood pressure reduction and another different degree of blood pressure reduction.

[0315] In other embodiments, three or more stimulation patterns may be used in one or more of the treatment stimulation period and the rest period. For example, a first stimulation pattern providing a 2 ms AV delay is applied in the first week followed by no pacing for one week, and then a stimulation pattern providing an AV delay of about 0 to 20 ms for one month (alternating the stimulation patterns), and then for 3 weeks or 6 weeks, a stimulation pattern providing an AV delay of about 140 ms may be applied, provided that a stimulation period with an AV delay of about 30 ms is provided once a day during those 3 weeks or 6 weeks.

[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, 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 features described below for system 700. Additionally, method 600 may be performed by apparatus 50, described below with reference to FIG. 14. Method 600 may include steps that apparatus 50 is configured to perform.

[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. It may be a value. This target blood pressure value may be set before, during, and / or after other method steps, and may be corrected, for example, if it cannot be reached by a tested stimulation pattern. It may be set, and may be corrected, for example, if it cannot be reached by a tested stimulation pattern.

[0319] Step 602 may include transmitting one or more stimulation patterns including a 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 already be selected to be suitable for a given patient (e.g., when an implantable device is implanted). The first stimulation pattern may include at least one stimulation pattern configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation during a first time interval. It may already be selected to be suitable for a given patient (e.g., when an implantable device is implanted). The first stimulation pattern may include at least one stimulation pattern configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation during a first time interval.

[0320] Step 603 may include detecting one or more parameters before, during, and / or after the transmission of each of the one or more stimulation patterns (step 602). before, during, and / or after the transmission of each of the one or more stimulation patterns (step 602), and may include detecting one or more parameters. Yes. The detected parameter may include detecting the intracardiac pressure to evaluate the overlap between the maximum value of the intracardiac pressure due to atrial contraction and the maximum value of the intracardiac pressure due to ventricular contraction. The detected parameter may include detecting the intracardiac pressure as a result of the transmission of each of one or more stimulation patterns (step 602), evaluating the intracardiac pressure obtained by the stimulation, and optionally comparing this intracardiac pressure with one or more of the intracardiac pressures obtained by different stimulations or without 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 detected parameter may include information related to the timing and / or degree of closure and / or opening of the AV valve. In some embodiments, the detected parameter may include information related to the timing and / or flow rate of blood flow between the atria and ventricles of the heart. In some embodiments, the detected parameter may include detecting the intracardiac pressure of a heart chamber (e.g., atria and / or ventricles). In some embodiments, detecting the state or position of the patient's AV valve (i.e., open or closed) may include detecting heart sounds, for example, using a voice sensor. In some embodiments, detecting the state of the patient's AV valve may include Doppler detection and / or imaging of the movement of the heart. In some embodiments, the state of the patient's AV valve may be detected by a blood flow sensor.

[0321] In some embodiments, the detection of blood flow may be performed by one or more implanted sensors within one or more heart chambers. For example, one or more pressure sensors may be placed in the right ventricle. Yes. In some embodiments, a plurality of pressure sensors may be placed in a plurality of chambers. Preferably, the measurements of the plurality of sensors may be combined. Preferably, pressure changes, trends in pressure changes, and / or pressure change patterns may be used to provide information related to blood flow. In some embodiments, it may be used to compare the relative changes between two or more sensors in different chambers.

[0322] When the stimulation pattern is transmitted to the heart (step 602), during the transmission of the stimulation pattern, at least once, or multiple times, or even continuously, one or more parameters may be measured. Each stimulation pattern may be transmitted more than once.

[0323] Step 604 may include analyzing the detected parameters. In some embodiments, when at least one stimulation pattern is transmitted and the corresponding parameters are detected, analysis may be performed (604). In embodiments where multiple parameters are detected, step 604 may include comparing the detected parameter values with a target, comparing the detected parameters between two or more stimulation patterns, comparing calculated values (e.g., k constant) associated with two or more stimulation patterns, and comparing additional detected parameters between two or more stimulation patterns. In some embodiments, this last function may be executed to determine and select which stimulation pattern produces a higher ejection rate, stroke volume, cardiac output, and / or a lower battery usage.

[0324] Step 605 may include setting a pacing (stimulation) pattern. When more than one parameter is detected, the stimulation pattern used in step 605 may be selected based on multiple parameters, multiple target values, and / or multiple target ranges.

[0325]

[0325] In some embodiments, the steps shown in FIG. 8 may be performed in the order indicated by the arrows in FIG. 8. In another embodiment, 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 ambiguously. In some embodiments, the stimulation pattern may be set to be performed for a predetermined period. For example, in some embodiments, the stimulation pattern set during step 605 may be performed for a predetermined period, and then steps 602, 603, and 604 may be repeated to determine how another stimulation pattern affects the patient's blood pressure. Then, based on the analysis performed in step 604, step 605 may also be repeated.

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

[0327] In some embodiments, step 605 may include adjusting the stimulation pattern to be a stimulation pattern configured to cause an immediate reduction in blood pressure by at least a predetermined amount. For example, in some embodiments, step 605 may adjust the stimulation pattern to be a stimulation pattern configured to cause a reduction in blood pressure by at least a predetermined amount within about 3 seconds from the application of current to the heart. That's fine. For example, in some embodiments, step 605 may include adjusting the stimulation pattern to be a stimulation pattern configured to cause a reduction in blood pressure by at least a predetermined amount within at least five beats of the applied current. That's fine. In some embodiments, step 605 may include adjusting the stimulation pattern to be a stimulation pattern configured to cause a reduction in blood pressure by at least a predetermined amount within at least five beats of the applied current. In some embodiments, the reduction in blood pressure resulting from the stimulation pattern set during step 605 may occur within 1 to 3 seconds of the application of current to the heart, or within one, three, or five beats of the application of current to the heart. That's fine. In some embodiments, the reduction in blood pressure resulting from the stimulation pattern set during step 605 may occur within 1 to 3 seconds of the application of current to the heart, or within one, three, or five beats of the application of current to the heart. That's fine. In some embodiments, the reduction in blood pressure resulting from the stimulation pattern set during step 605 may occur within 1 to 3 seconds of the application of current to the heart, or within one, three, or five beats of the application of current to the heart. In some embodiments, the reduction in blood pressure resulting from the stimulation pattern set during step 605 may be such that the average blood pressure of the patient at rest is at least 8 mmHg lower than the patient's initial blood pressure at rest. That's fine. In some embodiments, the reduction in blood pressure resulting from the stimulation pattern set during step 605 may be maintained for at least 1 minute. In some embodiments, the reduction in blood pressure resulting from the stimulation pattern set during step 605 may be maintained for at least 5 minutes. In some embodiments, the blood pressure may reach a minimum blood pressure value within less than five beats from the start of the stimulation. For example, step 605 may adjust the first stimulation pattern to be a second stimulation pattern configured to cause a reduction in blood pressure.

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

[0329] In some embodiments, the second stimulation pattern may be configured to maintain blood pressure such that it does not exceed a predetermined average value by more than a predetermined degree during a predetermined interval. For example, this predetermined degree may be a difference of about 20 mmHg or less. In some embodiments, this predetermined degree 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 average blood pressure may not exceed the predetermined average value.

[0330] In some embodiments, the second stimulation pattern may include a second stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation. The second stimulation setting may be based on at least one blood pressure variation parameter calculated from input data detected during application of the first stimulation pattern.

[0331] In some embodiments, the second stimulation pattern may be configured to reduce or limit the magnitude of a rapid increase in blood pressure between stimulation patterns. In some embodiments, the rapid increase in blood pressure between stimulation pulses may be reduced to a percentage of a baseline 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 rapidly increasing by more than about 80% between pulses. In some embodiments ​​​In this case, the second stimulation pattern may be configured to prevent an increase of more than about 40% in blood pressure between pulses. In some embodiments, the second stimulation pattern may be configured to prevent a rapid increase in blood pressure of more than about 10 mmHg to about 30 mmHg between pulses. For example, in some embodiments, the second stimulation pattern may be configured to prevent a rapid increase in blood pressure of more than about 20 mmHg between pulses. In some embodiments, the second stimulation pattern may include 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 the atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation. At least one stimulation pulse of the plurality of stimulation pulses may have a second stimulation setting configured to reduce the baroreflex response to the reduction of the atrial kick or the control of the atrial dilation such that an increase in the blood pressure value occurring between the stimulation pulses is limited to a predetermined value. In some embodiments, the second stimulation pattern may be configured to increase the blood pressure between about one beat and five beats to trigger a baroreflex response. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In some embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In such embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern.

[0332] In some embodiments, the second stimulation pattern may include 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 the atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation. At least one stimulation pulse of the plurality of stimulation pulses may have a second stimulation setting configured to reduce the baroreflex response to the reduction of the atrial kick or the control of the atrial dilation such that an increase in the blood pressure value occurring between the stimulation pulses is limited to a predetermined value. In some embodiments, the second stimulation pattern may be configured to increase the blood pressure between about one beat and five beats to trigger a baroreflex response. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In some embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In such embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation pattern may be configured to increase the blood pressure between about one beat and five beats to trigger a baroreflex response. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In some embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In such embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In some embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In such embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In such embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having the first stimulation setting and a plurality of stimulation pulses having the second stimulation setting. In such embodiments, the second stimulation pattern may have the second stimulation setting between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern.

[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 the time constants of the responses to increases and decreases in blood pressure. For example, the ratio of stimulation pulses having a first stimulation setting to stimulation pulses having a second stimulation setting may be based on the ratio of the time constants of the resulting blood pressure changes for each of the first and second settings. In some embodiments, the first stimulation setting may include a first AV delay, the second stimulation setting may include a second AV delay, and the first AV delay may be shorter than the second AV delay. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting and one or more stimulation pulses having a second stimulation setting. In some embodiments, the ratio of stimulation pulses having a first stimulation setting to stimulation pulses having a second stimulation setting may be based on the ratio of the time constants of the resulting blood pressure changes for each of the first and second settings. In some embodiments, the first stimulation setting may include a first AV delay, the second stimulation setting may include a second AV delay, and the first AV delay may be shorter than the second AV delay. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting and one or more stimulation pulses having a second stimulation setting. In some embodiments, the first stimulation setting may include a first AV delay, the second stimulation setting may include a second AV delay, and the first AV delay may be shorter than the second AV delay. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting and one or more stimulation pulses having a second stimulation setting. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting and one or more stimulation pulses having a second stimulation setting. In some embodiments, the second stimulation pattern may include a ratio of about 8 to about 13 stimulation pulses having a first setting to about 2 to about 5 stimulation pulses having a second setting. In some embodiments, the second stimulation pattern may include a ratio of about 8 to about 13 stimulation pulses having a first setting to about 2 to about 5 stimulation pulses having a second setting. In some embodiments, the second stimulation pattern may include at least one stimulation pulse having a stimulation setting configured to cause a hormonal response from the patient's body. In some embodiments, the second stimulation pattern may include at least one stimulation pulse having a stimulation setting configured to cause a hormonal response from the patient's body. In some embodiments, the first stimulation pattern may include at least one stimulation pulse having a stimulation setting configured not to cause a hormonal response from the patient's body. In some embodiments, the first stimulation pattern may include at least one stimulation pulse having a stimulation setting configured not to cause a hormonal response from the patient's body. In some embodiments, a second stimulation pattern may be applied prior to the first stimulation pattern in a given sequence of stimulation patterns.

[0334] In some embodiments, method 600 may include alternating between two or more stimulation patterns. For example, method 600 may include alternating between 2 and 10 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. In some embodiments, 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 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. It may include a controller that adjusts the stimulation pattern so as to be a stimulation pattern. For example, the best blood pressure fluctuation parameter may include a blood pressure fluctuation parameter that exhibits the lowest degree of baroreflex. The best blood pressure fluctuation parameter may include a blood pressure fluctuation parameter that exhibits a baroreflex within a predetermined range.

[0338] In some embodiments, the second stimulation pattern may include at least one stimulation pulse having a stimulation setting configured to elicit a hormonal response from the patient's body However, in some embodiments, the first stimulation pattern may include at least one stimulation pulse having a stimulation setting configured not to elicit a hormonal response from the patient's body In some embodiments, the first stimulation pattern may include at least one stimulation pulse having a stimulation setting configured not to elicit a hormonal response from the patient's body However, in some embodiments, the second stimulation pattern may include at least one stimulation pulse having a stimulation setting configured to elicit a hormonal response from the patient's body It may be.

[0339] In some embodiments, the plurality of stimulation patterns may include a first stimulation pattern and a second stimulation pattern applied after the first stimulation pattern. The second stimulation pattern may have at least one stimulation setting set based on an algorithm that uses a blood pressure fluctuation parameter related to the input data of the first stimulation setting.

[0340] 〈System for reducing blood pressure〉 FIG. 9 schematically shows a system 700 for reducing blood pressure according to some embodiments. The system 700 may be a single device, or preferably may include a plurality of devices associated by wired or wireless communication. The device may have a plurality of components disposed within the housing and / or electrically and / or wired to the housing. As shown in FIG. 9, the heart 701 is connected to the system 700 by one or more stimulation electrodes 702. The stimulation electrode 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 plurality of electrodes 702 is disposed in a different chamber of the heart This may be the case. For example, one electrode may be disposed in the atrium, and another electrode may be disposed in the ventricle This may be the case. In some embodiments, a plurality of electrodes 702 may be disposed in a single chamber This may be the case. For example, two electrodes may be disposed in the atrium, and / or two electrodes may be disposed in the ventricle. In some embodiments, one electrode may be disposed in a first chamber, and a plurality of electrodes may be disposed in a second chamber.

[0342] In this embodiment, the electrode 702 may include a common cardiac pacemaker lead, such as a Medtronic Capsure® pacing lead. These leads are used to connect the heart 701 to the system 700. The pacing lead may be composed of an industry standard IS-1 B1 connector (reference standard ISO 5148-3:2013) at one end, an electrode at the other end, and an insulated conductor system therebetween. In some embodiments, the IS-1 B1 connector is composed of using stainless steel for two electrode contacts and using silicon as an insulating material. Some embodiments may use polyurethane as the insulating material.

[0343] Stimulation of one or more heart 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 vary a capacitor to a specific programmable voltage, such as 2.0 V, and then controls the connection to the electrodes for a programmable time period of a fixed duration, such as 0.5 ms. The same network may also manage the discharge of any residual charge that may accumulate on the electrodes after the stimulation is complete. The same network may control the type of stimulation applied, such as bipolar (between two electrodes) or unipolar (between one electrode and the stimulation device housing). This may be the case. For example, one electrode may be disposed in the atrium, and another electrode may be disposed in the ventricle This may be the case. In some embodiments, a plurality of electrodes 702 may be disposed in a single chamber This may be the case. For example, two electrodes may be disposed in the atrium, and / or two electrodes may be disposed in the ventricle. In some embodiments, one electrode may be disposed in a first chamber, and a plurality of electrodes may be disposed in a second chamber.

[0344] As is known in the art, one or more electrodes may be disposed in contact with one or both ventricles and / or one or both atria. Such electrodes may be used to sense each heart chamber and / or to deliver stimulation to each heart chamber, and it may be possible. For example, one electrode is implanted in the right ventricle, and additional electrodes are placed in the left ventricle through the coronary sinus. In order to reduce the asynchrony caused by ventricular stimulation, when the system 700 includes means for generating bi-ventricular stimulation of both ventricles, pacing electrodes can be introduced into both ventricles. The system 700 includes a controller 703. The system 700 may be an electrical stimulation device including a power source 704 (e.g., a battery known in the field of electrical stimulation devices). The controller 703 and / or

[0345] the electrode 702 may draw power from the power source 704. Preferably, the electrical stimulation device of the system 700 may be composed of a sealed housing and a header. The housing may be formed of titanium or other biocompatible materials and may include the power source 704, electronics, and a telemetry coil or communication module 707 for communication with an external device. The power source 704 may be an implantable tilted-sealed primary battery. The battery chemistry may be lithium-iodine. 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 in some embodiments may be composed of standard off-the-shelf electronics (e.g., transistors and diodes) and / or custom electronics (e.g., ASICs).

[0346] Preferably, the electrical stimulation device of the system 700 may be composed of a sealed housing and a header. The housing may be formed of titanium or other biocompatible materials and may include the power source 704, electronics, and a telemetry coil or communication module 707 for communication with an external device. The power source 704 may be an implantable tilted-sealed primary battery. The battery chemistry may be lithium-iodine. 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 in some embodiments may be composed of standard off-the-shelf electronics (e.g., transistors and diodes) and / or custom electronics (e.g., ASICs). Preferably, the electrical stimulation device of the system 700 may be composed of a sealed housing and a header. The housing may be formed of titanium or other biocompatible materials and may include the power source 704, electronics, and a telemetry coil or communication module 707 for communication with an external device. The power source 704 may be an implantable tilted-sealed primary battery. The battery chemistry may be lithium-iodine. 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 in some embodiments may be composed of standard off-the-shelf electronics (e.g., transistors and diodes) and / or custom electronics (e.g., ASICs).

[0347] To detect the onset of atrial excitation and / or ventricular excitation, one or more sensing electrodes may be implanted at or near a target location within 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 passed through a bandpass filter to remove unwanted noise with a programmable cut-off frequency and may comply with the international standard for cardiac pacemakers (see EN45502-2-1:2003). An electrical circuit may be used to amplify the electrical signals generated by the propagating activation of the cardiac chamber and to determine the onset of activation when the electrical signal meets a specific criterion, such as crossing a predetermined threshold. The signal may be amplified, for example, with a programmable gain and then passed to a comparator with programmable detection thresholds in steps of 0.2 mV (atrium) and 0.4 mV (ventricle) for threshold detection. These means for detecting excitation may introduce a delay between the actual onset of activation in the chamber and its detection. This is because the sensing electrodes may be away from the origin of the excitation and the time it takes for the signal to meet the detection criteria may be non-negligible, ranging from 5 to 50 ms or more. In such a case, the timing of the onset of excitation may be estimated based on the timing of the detected excitation and the delivery of the stimulation pulses may be calculated to compensate for this delay. In this way, the onset of excitation may be estimated based on the timing of the detected excitation and the delivery of the stimulation pulses may be calculated to compensate for this delay. These means for detecting excitation may introduce a delay between the actual onset of activation in the chamber and its detection. This is because the sensing electrodes may be away from the origin of the excitation and the time it takes for the signal to meet the detection criteria may be non-negligible, ranging from 5 to 50 ms or more. In such a case, the timing of the onset of excitation may be estimated based on the timing of the detected excitation and the delivery of the stimulation pulses may be calculated to compensate for this delay.

[0348] Preferably, the controller 703 is associated with an accelerometer to measure the activity level of the patient. This activity level of the patient may be used to adjust the pacing rate and / or BPR setting and / or stimulation pattern based on the patient's needs. The activity level may also be used to control the effect of a desired level on blood pressure. For example, reducing blood pressure at a high activity level may allow for better performance when an increase in blood pressure is required. Preferably This activity level of the patient may be used to adjust the pacing rate and / or BPR setting and / or stimulation pattern based on the patient's needs. The activity level may also be used to control the effect of a desired level on blood pressure. For example, reducing blood pressure at a high activity level may allow for better performance when an increase in blood pressure is required. Alternatively, when the patient is not active (e.g., when sleeping), the blood pressure may naturally decrease. In this case, pacing may be adjusted to avoid reducing the blood pressure below the desired threshold. The activity level may also be used to adjust the settings based on the baroreflex to allow for a better response, if necessary. 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 transmit an electric current to the heart 701 via one or more electrodes 702. The controller 703 may be a stimulation pulse according to any embodiment of the present disclosure It may be configured to execute the stimulation pattern. In some embodiments, the stimulation pulse may be transmitted to at least the ventricles 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, and the first stimulation setting and the second stimulation setting are configured to reduce or prevent atrial stimulation and / or control the atrial internal pressure and / or dilation of the atrium. In some embodiments, the first stimulation setting has an AV delay different from that of the second stimulation setting. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured such that the atrial internal pressure caused by atrial contraction of the atrium overlaps in time with the passive increase in atrial internal pressure, whereby the combination of the atrial internal pressure caused by atrial contraction and the passive increase in internal pressure provides an atrial internal pressure of the atrium that is higher than the atrial internal pressure of the atrium without stimulation. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured such that the maximum atrial dilation is approximately equal to or lower than the maximum atrial dilation of the same heart when not receiving stimulation. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured such that the atrial contractility is maximized when the AV valve is open. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured to change the mechanism of at least one atrial contraction such that the mechanism of at least one atrial contraction is different from that of the preceding natural atrial contraction. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured to reduce the force of at least one atrial contraction. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured to prevent at least one atrial contraction.

[0350] In some embodiments, the controller 703 may be configured to transmit various different AV delays It may be. The controller 703 (as described herein) causes atrial contraction or excitation to occur 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 consecutive stimulation patterns during a predetermined time interval. For example, in some embodiments, the time interval may be 10 minutes or more. In another embodiment, 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 between months, such as 1 month to 1 year. In some embodiments, the time interval may be 1 year or more.

[0353] In some embodiments, one or more consecutive stimulation patterns may be during a portion of the time interval to reduce or prevent atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation. It may include a first stimulation setting configured as such. For example, one or more consecutive stimulation patterns may include a first stimulation setting configured to reduce or prevent atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation during about 50% to about 100% of the time interval. In another embodiment, one or more consecutive stimulation patterns may include a first stimulation setting configured to reduce or prevent atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation during about 50% to about 85% of the time interval. In some embodiments, one or more consecutive stimulation patterns may include a second stimulation setting having a longer AV delay than the first stimulation setting during at least one beat during the time interval. In another embodiment, one or more consecutive stimulation patterns may include the second stimulation setting and / or

[0354] ​​The third stimulation setting may be included. Each of the second stimulation setting and / or the third stimulation setting may be different from the first stimulation setting. In some embodiments, each of the second stimulation setting and / or the third stimulation setting is configured to reduce or prevent atrial kick in at least one ventricle and / or to control either or both of atrial pressure and atrial dilation. In some embodiments, each of the second stimulation setting and / or the third stimulation setting is configured not to reduce or prevent atrial kick in at least one ventricle and / or not to control either or both of atrial pressure and atrial dilation. In some embodiments, the second stimulation setting and / or the third stimulation setting may include from about 0% to about 50% of the time interval. In some embodiments, the second stimulation setting and / or the third stimulation setting may include from about 0% to about 30% of the time interval. In some embodiments, the second stimulation setting and / or the third stimulation setting may include from about 0% to about 20% of the time interval. In some embodiments, the second stimulation setting and / or the third stimulation setting may include from about 5% to about 20% of the time interval.

[0355] Blood pressure is known to vary over a 24-hour period, and in some cases, abnormally high blood pressure is present only during a portion (e.g., at night or during the day or a portion thereof) of the 24 hours, or is predominant for most of the 24 hours. In addition, blood pressure is known to vary with physical activity, and a person during activity has a 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 treatment parameters to lower blood pressure, or even by not delivering cardiac stimulation at all. In other words, at different times of the day and / or when the patient is active or at rest, the cardiac stimulation may be varied, the parameters of the stimulation may be adjusted, or simply turned on / off. Optionally, such delivery of stimulation may be controlled according to time, or adjusted to match the patient's 24-hour cycle BP rhythm.

[0356] Example 1 Figure 21 shows the systolic BP of an untreated patient monitored over 24 hours. The time average is represented as shown. As shown, the patient's BP was abnormally high during the day (approximately from 10 am to 6 pm) . In such a type of case, it may be preferable to deliver pulses configured to reduce atrial stimulation only during the time period (i.e., when needed or when need is anticipated) during which the BP is expected to be abnormally high, and / or to set the device to provide AC stimulation.

[0357] Example 2 Another example is shown in Figure 22. Here, the untreated blood pressure of the patient (in Figure 22, the data of "x") The (represented by the line with a point "タ") was found to be abnormally high at night (from 2:00 PM to 7:00 AM). The increase in BP during the day is within the normal range and may be due to the increased activity of the patient. If desired, this patient may be assumed to need treatment only at night, and the device may be set to deliver stimulation accordingly. If desired, this patient may be assumed to not need treatment 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 induce the delivery of treatment to lower the blood pressure. If desired, the device may be set to not measure the blood pressure during the day.

[0358] In the embodiment shown in FIG. 22, the patient was then paced both the atrium and ventricle with an AV delay of 15 ms for 10 beats, and then paced the atrium and ventricle with an AV delay of 40 ms for 3 beats using a blood pressure reducing pulse having a setting of pacing. The delivery of treatment starts at 3:00 PM every day and continues for 13 hours. The resulting BP was plotted (represented by the line with round data points in FIG. 22), and as can be seen, the BP is essentially within the normal range throughout the day and shows much smaller fluctuations than before treatment (under treatment, the BP fluctuated by only about 30 mmHg or less, while the untreated BP range fluctuated by more than 40 mmHg).

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

[0360] As discussed with respect to the exemplary approaches of Example 1 and Example 2 of FIGS. 21 and 22, rather than alternating between a cardiac stimulation period and a period without cardiac stimulation, in other approaches, the stimulation parameters may be adjusted to result in different values of blood pressure reduction in each of two or more periods of a time interval. These periods may be for several minutes or hours over a 24-hour time interval. The different values of blood pressure reduction in each period may be based on, for example, blood pressure detection feedback, time, patient activity, or needs such as a specific patient-specific blood pressure pattern. The stimulation parameters for each period may be selected to achieve different degrees of blood pressure reduction based on the needs during that specific period.

[0361] For example, a first stimulation setting may achieve a higher degree of blood pressure reduction during the day, followed by a second stimulation setting at night that can achieve a lower degree of blood pressure reduction than the first stimulation setting, and further reduce the blood pressure from the blood pressure level when no stimulation is applied. As another example, a first stimulation setting may achieve a higher degree of blood pressure reduction during low patient activity, followed by a second stimulation setting during high patient activity that can achieve a lower degree of blood pressure reduction than the first stimulation setting, and further reduce the blood pressure from the blood pressure level when no stimulation is applied.

[0362] When alternating between periods of different stimulation settings, in an embodiment, the degree of blood pressure change may be gradually adjusted by a temporary incremental adjustment or a continuous adjustment to a parameter that affects the degree of blood pressure change. For example, if a first stimulation setting uses an AV delay of 30 ms and a second stimulation When using an AV delay of 60 ms for the setting, when switching from the first stimulation setting to the second stimulation setting, the AV delay may be gradually adjusted in 5 ms increments (e.g., up to 35 ms, then up to 40 ms, etc.) from the first stimulation setting with an AV delay of 30 ms to the second stimulation setting with an AV delay of 60 ms. A similar incremental adjustment may be used for the switch back from the second stimulation setting to the first stimulation setting. In other embodiments, this adjustment may be continuous in that the rate of change of the parameter (e.g., AV delay) that affects blood pressure when switching from the first stimulation setting to the second stimulation setting is constant.

[0363] As described above, providing different values of blood pressure reduction may include adjusting the stimulation parameter that affects the AV delay, and this adjustment may be used to switch the stimulation setting. For example, a stimulation parameter that provides a shorter AV delay may reduce blood pressure to a greater extent than a stimulation parameter that provides a longer AV delay. In an embodiment, a stimulation setting that reduces atrial stimulation may provide an AV delay that varies from about 5 ms to about 30 ms (e.g., between day and night, or between strenuous activity and light activity), and the shorter the AV delay, the greater the reduction in blood pressure.

[0364] FIG. 24 is a graph showing an embodiment of the relationship between the AV delay (less than 100 ms in this example) of a specific patient and the reduction in systolic blood pressure. As shown, a stimulation parameter that achieves an AV delay that results in the desired reduction in systolic blood pressure may be selected. Thus, based on the relationship between the AV delay and the blood pressure reduction, the blood pressure reduction therapy may be adjusted to achieve the desired blood pressure reduction based on the patient's needs during a specific period of a certain time interval (e.g., a period of several minutes or several hours over a one-day time interval), as shown in the following two examples. specific period (e.g., a period of several minutes or several hours over a one-day time interval) within a certain time interval.

[0365] Example 3 Figure 25 is a graph of systolic blood pressure over 24 hours for a particular outpatient. As shown, the patient in Figure 25 has very high blood pressure at the beginning of the day (about 140 - 160 mmHg from approximately 6 am to approximately 2 pm), very low blood pressure in the second half of the night (less than 100 mmHg from approximately midnight to approximately 2 am), and intermediate blood pressure values in between (about 120 - 140 mmHg from approximately 3 pm to approximately 11 pm).

[0366] Regarding the type of patient in Figure 25, it may be useful to apply therapies using different sets of stimulation parameters throughout the day. For example, in one embodiment, a first set of stimulation parameters that significantly reduces blood pressure may be applied from approximately 6 am to approximately 2 pm (with a relatively very short AV delay), a second set of stimulation parameters that still slightly reduces blood pressure may be applied from approximately 2 pm to approximately midnight, and a third set of stimulation parameters that provides a longer AV delay (e.g., no stimulation or stimulation that provides a normal AV delay may be applied from approximately midnight to approximately 6 am. In this way the different stimulation parameters reduce or prevent atrial stimulation, lower blood pressure, and provide a more normalized and controlled blood pressure for the patient overall, according to the patient's needs during different periods within this time interval.

[0367] Example 4 Figure 26 is a graph of systolic blood pressure over 24 hours for another particular outpatient, different from the patient in Figure 25. The patient in Figure 26 has high blood pressure at night (over 140 mmHg from approximately midnight to approximately 7 am) and shows unstable blood pressure during the day.

[0368] The patient type of FIG. 26 may enjoy the benefits of a different set of stimulation parameters than the patient type of FIG. 25. For example, a long AV delay may be applied at night. Subsequently, the AV delay may be increased periodically and reach a normal value from approximately 9:00 a.m. to approximately 2:00 p.m. (when the blood pressure is within the approximate normal range of 120 mmHg or less ). Thereafter, from approximately 9:00 p.m. to approximately midnight a further increase (or set of increases) in the AV delay may result in a longer AV delay (the same as or slightly shorter than that applied at night) being applied.

[0369] All of the stimulation patterns of the above embodiments may include a feedback loop and / or may be pre-programmed based on the known 24-hour blood pressure variations of the patient.

[0370] In some embodiments, the controller 703 has a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation, and applies one or more continuous stimulation patterns including a sequence of 10 to 60 stimulation pulses. In some embodiments In one form, the controller 703 may be configured to apply one or more continuous stimulation patterns including one to ten sequences of pulsations embedded within ten to sixty stimulation pulses, and the one to ten sequences of pulsations may have an AV delay longer than the first stimulation setting. For example, the ten to sixty stimulation pulses may include five stimulation pulses having a first stimulation setting, followed by one pulsation having an AV delay longer than the first stimulation setting, followed by fifty stimulation pulses having the first stimulation setting. The one to ten sequences of pulsations 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 and / or to control either or both of atrial pressure and atrial dilation. The one to ten sequences of pulsations may include a natural AV delay. The one to ten sequences of pulsations may occur without stimulation.

[0371] System 700 may further include one or more sensors 705. In some embodiments such sensors 705 may include one or more sensing electrodes for detecting the 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, sensor 705 may include one or more sensors (implanted or external). In some embodiments, the one or more sen sors 705 may include one or more pressure sensors implanted in the heart (e.g., in the atrium and / or ventricle) In some embodiments, sensor 705 may include one or more blood flow sensors (implanted or external). For example, the one or more sensors 705 may include ultrasonic detection of blood flow through the AV valve. In some embodiments, sensor 705 may include one or more sensors configured to monitor the timing of closure of the AV valve. One or more of these sensors may be configured to operate as a closed loop with the controller In some embodiments, sensor 705 may include one or more blood flow sensors (implanted or external). For example, the one or more sensors 705 may include ultrasonic detection of blood flow through the AV valve. In some embodiments, sensor 705 may include one or more sensors configured to monitor the timing of closure of the AV valve. One or more of these sensors may be configured to operate as a closed loop with the controller In some embodiments, sensor 705 may include one or more sensors configured to monitor the timing of closure of the AV valve. One or more of these sensors may be configured to operate as a closed loop with the controller One or more of these sensors are configured to operate as a closed loop with the controller It may also be good.

[0372] Information from the sensor 705 may be supplied to the controller 703 by some form of communication including wired communication and / or wireless communication. Preferably, the system 700 may include 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, the input data related to the patient's blood pressure may include data indicating the BP measured at one or more time points, or the variation of the BP (e.g., a function representing the degree of change and / or the ratio of change or the change in blood pressure over time), and / or statistical data related to the BP or the variation of the BP, the maximum and / or minimum BP values.

[0373] Preferably, the system 700 may include one or more user interfaces 708 for providing information and / or enabling input of information. Providing information may include, for example, displaying operation information related to the system, and / or displaying data recorded by and / or received by the system during operation. This may also include the detected parameters, and / or the relationship between the detected parameters and the operation information (such as the stimulation pattern setting, and / or the relative timing between a given pace and the detected information, etc.). This may include the relationship between the detected parameters and the operation information (such as the stimulation pattern setting, and / or the relative timing between a given pace and the detected information). This may include the relationship between the detected parameters and the operation information (such as the stimulation pattern setting, and / or the relative timing between a given pace and the detected information, etc.).

[0374] Preferably, the user interface 708 is a commercially available laptop computer (e.g., a Windows (registered trademark)-based computer) that runs a software application that runs a software application It may also include. The software application may function to generate instructions that are transmitted to an interface connected to a handheld wand (rod) that includes a telemetry circuit for communication with an implantable stimulation device. The instructions sent to the wand may be used to set stimulation parameters and / or to retrieve diagnostic messages of the device, device data, heart data, and real-time heart sensing. The interface may also enable connection of a 3-lead ECG, and this data is displayed on a laptop computer screen by the software application. In other embodiments, a 3-lead ECG electronic circuit may not be included, or a 12-lead ECG electronic circuit may be included. In other embodiments, the functionality of the wand, interface, and laptop computer may be incorporated into a dedicated hardware component that performs all three functions. In other embodiments, printing capabilities may also be added to the user interface 708. In some embodiments, the interface 708 may be configured to allow a user (e.g., a physician) to supply a set of control instructions to the system (e.g., target values and / or ranges, and / or other restrictions or instructions). Preferably, the interface 708 may allow the user to input data from one or more sensors 705 (e.g., the results of a manual blood pressure measurement and / or the results of an ultrasound monitoring). Preferably, one or more user interfaces 708 may allow the user to select a stimulation pattern (e.g., from a set of stimulation patterns stored in the system 700), or to impose constraints on the setting and / or selection of the stimulation pattern. It may also be included. The software application may function to generate instructions that are transmitted to an interface connected to a handheld wand (rod) that includes a telemetry circuit for communication with an implantable stimulation device. The instructions sent to the wand may be used to set stimulation parameters and / or to retrieve diagnostic messages of the device, device data, heart data, and real-time heart sensing. The interface may also enable connection of a 3-lead ECG, and this data is displayed on a laptop computer screen by the software application. In other embodiments, a 3-lead ECG electronic circuit may not be included, or a 12-lead ECG electronic circuit may be included. In other embodiments, the functionality of the wand, interface, and laptop computer may be incorporated into a dedicated hardware component that performs all three functions. In other embodiments, printing capabilities may also be added to the user interface 708. In some embodiments, the interface 708 may be configured to allow a user (e.g., a physician) to supply a set of control instructions to the system (e.g., target values and / or ranges, and / or other restrictions or instructions). Preferably, the interface 708 may allow the user to input data from one or more sensors 705 (e.g., the results of a manual blood pressure measurement and / or the results of an ultrasound monitoring).

[0375] In some embodiments, the interface 708 may be configured to allow a user (e.g., a physician) to supply a set of control instructions to the system (e.g., target values and / or ranges, and / or other restrictions or instructions). Preferably, the interface 708 may allow the user to input data from one or more sensors 705 (e.g., the results of a manual blood pressure measurement and / or the results of an ultrasound monitoring). Preferably, one or more user interfaces 708 may allow the user to select a stimulation pattern (e.g., from a set of stimulation patterns stored in the system 700), or to impose constraints on the setting and / or selection of the stimulation pattern. It may also be included. The software application may function to generate instructions that are transmitted to an interface connected to a handheld wand (rod) that includes a telemetry circuit for communication with an implantable stimulation device. The instructions sent to the wand may be used to set stimulation parameters and / or to retrieve diagnostic messages of the device, device data, heart data, and real-time heart sensing. The interface may also enable connection of a 3-lead ECG, and this data is displayed on a laptop computer screen by the software application. In other embodiments, a 3-lead ECG electronic circuit may not be included, or a 12-lead ECG electronic circuit may be included. In other embodiments, the functionality of the wand, interface, and laptop computer may be incorporated into a dedicated hardware component that performs all three functions. In other embodiments, printing capabilities may also be added to the user interface 708.

[0376] Preferably, one or more user interfaces 708 may allow the user to select a stimulation pattern (e.g., from a set of stimulation patterns stored in the system 700), or to impose constraints on the setting and / or selection of the stimulation pattern. It may also be included. The software application may function to generate instructions that are transmitted to an interface connected to a handheld wand (rod) that includes a telemetry circuit for communication with an implantable stimulation device. The instructions sent to the wand may be used to set stimulation parameters and / or to retrieve diagnostic messages of the device, device data, heart data, and real-time heart sensing. The interface may also enable connection of a 3-lead ECG, and this data is displayed on a laptop computer screen by the software application. In other embodiments, a 3-lead ECG electronic circuit may not be included, or a 12-lead ECG electronic circuit may be included. In other embodiments, the functionality of the wand, interface, and laptop computer may be incorporated into a dedicated hardware component that performs all three functions. In other embodiments, printing capabilities may also be added to the user interface 708.

[0377] Preferably, system 700 may comprise one or more processors 706. The processor is configured to process the sensed parameters from sensor 705 and / or the input force data from interface 708 to select a stimulation pattern for transmission by system 700. Preferably, processor 706 is configured to analyze the sensed parameters and extract information and / or formula constants that will be used in the selection and / or evaluation of the stimulation pattern.

[0378] One or more components of system 700, or a portion of such components, may be implanted in the patient, although some components of system 700, or a portion of such components, may be external to the patient. When some components (or portions thereof) are implanted and others are not, communication between the components may be effected by wired and / or wireless means known per se in the art. For example, some or all of the functions of both controller 703 and / or processor 706 may be performed outside the body. Placing some components of system 700 outside the patient's body may assist in reducing the size and / or energy requirements of the implant device and / or in increasing the computational power of the system.

[0379] System 700 may have additional functions related to the function of the heart and the overall ability of the cardiovascular system. It may also be included. For example, the system 700 may include one or more algorithms and / or electrodes that enable biventricular pacing or resynchronization therapy to reduce the asynchrony that may be caused by ventricular stimulation. In some embodiments, the system 700 may include one or more algorithms to counteract a possible reduction in cardiac output. Such algorithms may vary the heart rate ...

Claims

1. A system for reducing a patient's blood pressure, comprising: a stimulation circuit configured to supply stimulation pulses to at least one heart chamber of the patient; a sensor configured to sense a parameter indicative of the patient's blood pressure; and at least one controller configured to execute delivery of stimulation pulses of a plurality of stimulation patterns to at least one heart chamber over a certain time interval, wherein a first stimulation pattern of the plurality of stimulation patterns reduces the patient's blood pressure by a first reduction amount, a second stimulation pattern of the plurality of stimulation patterns reduces the patient's blood pressure by a second reduction amount, the first reduction amount is greater than the second reduction amount, and the second reduction amount is greater than zero, wherein the at least one controller is configured to continuously receive parameter information indicative of the patient's blood pressure from the sensor during operation, analyze the parameter information indicative of the patient's blood pressure, and adjust the plurality of stimulation patterns according to the analysis.

2. The system according to claim 1, wherein the sensor includes a blood pressure sensor, and the parameter information includes a blood pressure value.

3. The system according to claim 1, wherein the parameter information includes an atrial pressure, and the analyzing includes at least one of: (1) evaluating an overlap between a maximum value of the atrial pressure due to contraction and a maximum value of the atrial pressure due to ventricular contraction; or (2) comparing the atrial pressure obtained by stimulation with one or more atrial pressures obtained without stimulation or with different stimulations.

4. The system according to claim 1, wherein the parameter information includes at least one of information regarding the timing and / or degree of closure and / or opening of the atrioventricular valve, or information regarding the timing and / or velocity of blood flow between the atrium and ventricle of the heart.

5. Analyzing the parameter information indicative of the patient's blood pressure comprises comparing the blood pressure of the sensed atrial-pace-ventricular stimulation with the desired blood pressure change of the pace-atrial-pace-ventricular stimulation, and adjusting the stimulation pattern according to the analysis comprises adjusting the timing of the sensed atrial-pace-ventricular stimulation until the sensed atrial-pace-ventricular stimulation achieves a blood pressure change substantially equal to the desired blood pressure change of the sensed atrial-pace-ventricular stimulation. The system according to claim 1.

6. The system of claim 5, wherein adjusting the stimulation pattern according to the analysis includes adjusting the time interval of the first stimulation pattern. **Claim 7** The system of claim 1, wherein adjusting the stimulation pattern according to the analysis includes causing an immediate decrease in blood pressure. **Claim 8** The system of claim 1, wherein adjusting the stimulation pattern according to the analysis includes causing a decrease in blood pressure at a predetermined time interval. **Claim 9** The system of claim 1, wherein adjusting the stimulation pattern includes changing a shorter atrioventricular delay of the first stimulation pattern and a longer atrioventricular delay of the second stimulation pattern between day and night or between intense exercise and light exercise. **Claim 10** The system of claim 1, wherein the at least one controller is configured to alternate the plurality of stimulation patterns. **Claim 11** A system for reducing a patient's blood pressure, comprising a stimulation circuit configured to supply stimulation pulses to at least one heart chamber of the patient's heart, a sensor configured to sense a parameter indicative of the patient's blood pressure, an initial stimulation pattern of stimulation pulses that reduces the patient's blood pressure by a first reduction amount, and a subsequent stimulation pattern of stimulation pulses that reduces the patient's blood pressure by a second reduction amount, and at least one controller configured to perform delivery to at least one heart chamber over a time interval. To adjust the first reduction amount of the initial stimulation pattern and / or the second reduction amount of the subsequent stimulation pattern, the at least one controller is configured as follows: Receive a first value of the parameter from the sensor, deliver a first stimulation pattern to at least one chamber of the heart to reduce blood pressure, receive a second value of the parameter from the sensor during delivery of the first stimulation pattern, determine a first blood pressure change value based on the second value of the parameter and the first value of the parameter, deliver a second stimulation pattern to at least one chamber of the heart to reduce blood pressure, receive a third value of the parameter from the sensor during delivery of the second stimulation pattern, determine a second blood pressure change value based on the third value of the parameter and the first value of the parameter, compare the second blood pressure change value with the first blood pressure change value, and based on the comparison, adjust the second stimulation pattern to provide an adjusted blood pressure change value. **Claim 12** The system according to claim 11, wherein the at least one controller is configured to adjust the second stimulation pattern based on the comparison to provide an adjusted blood pressure change value close to the first blood pressure change value.

13. The system according to claim 11, wherein the at least one controller is configured to repeat the following until the adjusted blood pressure change value equals the first blood pressure change value: Deliver an adjusted second stimulation pattern, receive an adjusted value of a parameter from a sensor during delivery of the adjusted second stimulation pattern, determine an adjusted blood pressure change value based on the adjusted value of the parameter and a first value of the parameter, compare the adjusted blood pressure change value with the first blood pressure change value, and adjust the adjusted second stimulation pattern based on the comparison between the adjusted blood pressure change value and the first blood pressure change value to provide a next adjusted blood pressure change value.

14. The system according to claim 11, wherein the sensor comprises a blood pressure sensor configured to sense a patient's blood pressure.

15. The system according to claim 14, wherein the first value consists of a first blood pressure of the patient sensed by the blood pressure sensor, the second value consists of a second blood pressure of the patient sensed by the blood pressure sensor, and the third value consists of a third blood pressure of the patient sensed by the blood pressure sensor.

16. The system according to claim 11, wherein the at least one controller is configured to adjust the second stimulation pattern by adjusting an atrioventricular delay of the second stimulation pattern.

17. The system according to claim 11, wherein the at least one controller is configured to adjust the second stimulation pattern by adjusting a timing of the sensed atrial - pace - ventricular stimulation until the sensed atrial - pace - ventricular stimulation provides an adjusted blood pressure change value equal to the first blood pressure change value.

18. The system according to claim 17, wherein the first blood pressure change value consists of a first blood pressure change value of a pace - atrial - pace - ventricular stimulation.

19. The system according to claim 11, wherein the parameter indicating the patient's blood pressure includes at least one of information related to the timing and / or extent of the closure / opening of the atrioventricular valve, or information related to the timing and / or velocity of the blood flow between the atrium and ventricle of the heart.

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