Method and system for controlling blood pressure

Abstract

Methods and systems for controlling blood pressure by electrically stimulating the heart are disclosed. Embodiments may include delivering a first stimulation pattern to at least one lumen of a patient's heart, the first stimulation pattern reducing both systolic and diastolic pressures of the patient (e.g., for treating hypertension), and delivering a second stimulation pattern to the at least one lumen of the patient's heart, the second stimulation pattern reducing both systolic and diastolic pressures of the patient (e.g., for treating hypertension). The second stimulation pattern reduces the systolic pressure of the patient while controlling the diastolic pressure (e.g., producing minimal or no effect on the diastolic pressure, or increasing the diastolic pressure) in order to reduce the difference between the systolic pressure and the diastolic pressure. In an embodiment, a target blood pressure reduction for the second stimulation pattern may be achieved by a physiological response that modulates the heart rate to cause a reduction in pulse pressure. This pulse pressure reduction (RPP) can reduce systolic pressure while having no significant effect on diastolic pressure, thereby providing an effective treatment of simple systolic hypertension (ISH).

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 365,668, filed on June 1, 2022, which is incorporated herein by reference in its entirety.

[0002] This application is related to the following applications, all of which are incorporated herein by reference in their entirety: (1) U.S. application Ser. No. 17 / 205,114, filed on March 18, 2021 (U.S. publication No. US2021 / 0346702, published on November 11, 2021), which is a continuation of U.S. application Ser. No. 16 / 276,958, filed on February 15, 2019 (now U.S. Patent No. 10,967,188, issued on April 6, 2021), which is a continuation of U.S. application Ser. No. 15 / 851,787, filed on December 22, 2017 U.S. Application No. 10,252,061, issued April 9, 2019, which is a continuation of U.S. Application No. 15 / 851,787, filed December 8, 2016, which is a continuation of U.S. Application No. 9,878,162, issued January 30, 2018, which is a continuation of U.S. Application No. 14 / 667,931, filed March 25, 2015 ...5 / 851,787, filed December 8, 2016, which is a continuation of U.S. Application No. 9,878,162, issued January 30, 2018, which is a continuation of U.S. Application No. 14 / 667,931, filed March 25, 2015, which is a continuation of U.S. Application No. 1 No. 9,526,900, filed on March 11, 2015, which is a divisional application of U.S. Application No. 14 / 427,478, filed on March 11, 2015 (now U.S. Application No. 9,370,662, issued on June 21, 2016), which is a national phase application of International Application No. PCT / US2014 / 042777, filed on June 17, 2014, and National Phase Application No. PCT / US2014 / 042777 PCT / US2013 / 076600, filed December 19, 2013, which claims priority to U.S. Application No. 13 / 826,215, filed March 14, 2013 (now U.S. Patent No. 9,008,769, issued April 14, 2015), the first two of which claim the benefit of U.S. Provisional Application No. 61 / 740,977, filed December 21, 2012; and (2) U.S. application No. 16 / 663,573, filed on October 25, 2019 (U.S. publication No. US2020 / 0121451, published on April 23, 2020), which is a continuation of U.S. application No. 15 / 492,802, filed on April 20, 2017 (now U.S. Patent No. 10,485,658, issued on November 26, 2019), which claims the benefit of U.S. Provisional Application No. 62 / 326,215, filed on April 22, 2016. background

[0003] 1. Field Embodiments relate to the field of treating hypertension by controlling cardiac function including filling and contraction. In general, embodiments may allow for changes (increases or decreases) in systolic and / or diastolic blood pressure, but as a treatment for hypertension only, embodiments that allow for a reduction in systolic blood pressure while having the effect of reducing, increasing, or not changing diastolic blood pressure may have therapeutic value. For example, in certain cases of diastolic hypotension, an increase in diastolic blood pressure may also have therapeutic value. Specific embodiments may include applying focal electrical stimulation to the heart, controlling cardiac activity to reduce systolic blood pressure while controlling diastolic blood pressure (e.g., producing minimal or no effect on diastolic blood pressure, or increasing diastolic blood pressure). Targeted reductions in systolic blood pressure may be particularly helpful for patients with isolated systolic hypertension (ISH).

[0004] 2. Description of Related Technology For example, it is known that changes in blood pressure usually occur due to increased activity (which usually increases blood pressure) or large amounts of blood loss (which tends to cause a decrease in blood pressure). However, blood pressure is usually maintained within a limited range, for example, due to the body's baroreflex, whereby increased or decreased blood pressure affects cardiac function and the characteristics of the cardiovascular system through a feedback loop. Such feedback control is regulated by the nervous system as well as the endocrine system (e.g., by natriuretic peptides). In individuals with hypertension, blood pressure is maintained at an elevated level despite the baroreflex's duties. Other factors or conditions, such as impaired cardiac filling, ventricular hypertrophy, and arteriosclerosis, can also reduce the effectiveness of the feedback control system, thereby affecting blood pressure levels and / or changes therein.

[0005] High blood pressure, or hypertension (e.g., blood pressure of 130 / 80 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 suffer from hypertension. High blood pressure can lead to life-threatening conditions such as stroke, heart attack, and / or congestive heart failure. Approximately 44.1% of people with hypertension and on existing treatment have satisfactory control of their high blood pressure. Accordingly, 55.9% of the same people have poor control.

[0006] Isolated systolic hypertension (ISH) is a type of hypertension in which the systolic (high) blood pressure is 130 mmHg or higher (as defined by hypertension), but the diastolic (low) blood pressure is 80 mmHg or lower. Therefore, patients with ISH are characterized by higher pulse pressure (PP) values ​​(the difference between systolic and diastolic blood pressure) than non-ISH hypertensive patients. ISH is the most common form of hypertension in people over 65 years of age. A high pulse pressure (e.g., 70 mmHg) is an independent risk factor for cardiovascular disease; therefore, it is desirable to maintain pulse pressure at a level that will reduce this risk. Currently, there are no options for lowering pulse pressure because existing hypertension therapies lower both systolic and diastolic blood pressure and therefore have limited effects on pulse pressure.

[0007] Isolated systolic hypotension refers to a condition in which the diastolic blood pressure is less than 60 mmHg and the systolic blood pressure is greater than 100 mmHg. When the diastolic blood pressure is low, cardiac perfusion is impaired, which is an independent risk factor for heart failure.

[0008] Traditionally, treatment for hypertension includes medication and lifestyle changes. Both types of treatment are only partially effective for all patients and are even less effective for ISH patients. Most hypertension treatments reduce both systolic and diastolic blood pressure, but for ISH patients, a reduction in diastolic blood pressure is undesirable and may even be dangerous. Therefore, a blood pressure lowering treatment that reduces systolic blood pressure while controlling the effect on diastolic blood pressure is needed. Overview

[0009] Embodiments provide systems and methods for controlling blood pressure, which have different effects on systolic and diastolic pressures, particularly for reducing systolic pressure while having minimal or no effect on diastolic pressure, or even reducing systolic pressure while increasing diastolic pressure. Embodiments can achieve this target blood pressure reduction by adjusting both the interbeat and intrabeat intervals to cause a physiological response of pulse pressure reduction. This pulse pressure reduction (RPP) can reduce systolic pressure while having no significant effect on diastolic pressure, thereby providing effective treatment for isolated systolic hypertension (ISH). As used herein, the "minimal" effect on diastolic pressure means an effect at a level that does not prevent the achievement of a therapeutically effective reduced pulse pressure. In some cases, diastolic pressure may already be below the target pressure, and a combination of a reduction in systolic pressure and an increase in diastolic pressure to above the minimum recommended level may be desirable. In other cases, it may be desirable to significantly reduce systolic pressure and avoid diastolic pressure from being reduced to an optimal level (e.g., 70 mmHg) below diastolic pressure. In other cases, the diastolic pressure may be below a threshold (e.g., 60 mmHg), and an increase in the diastolic pressure may be necessary to reduce the risk of heart failure. In other cases, the pulse pressure may be above a specified threshold, and a combination of changes in the systolic and diastolic pressures may be required to reduce the pulse pressure below the threshold.

[0010] To regulate the inter- and intra-beat intervals and provide RPP therapy, embodiments may achieve a target blood pressure reduction by electrically stimulating the heart, for example, using a pacemaker device. Thus, embodiments may include provision for both RPP therapy (for treating isolated systolic hypertension) and hypertension therapy (for treating both systolic and diastolic blood pressure).

[0011] This overview discusses embodiments of isolated systolic hypertension treatment, associated pulse pressure lowering therapies, and systems, devices, and methods for combining isolated systolic hypertension treatment with other forms of hypertension treatment in Section I below. Section II below describes other forms of hypertension treatment and embodiments of systems, devices, and methods that can be used for isolated systolic hypertension treatment and / or other forms of hypertension treatment.

[0012] I. Examples of Treatment for Isolated Systolic Hypertension (ISH) An embodiment provides a system for controlling blood pressure, comprising a stimulation circuit and at least one controller. The stimulation circuit can be configured to deliver stimulation pulses to at least one cardiac chamber of a patient's heart. The at least one controller can be configured to perform delivery of stimulation pulses of one or more stimulation modes to the at least one cardiac chamber. In a first operating mode, a first stimulation mode of the one or more stimulation modes can reduce both the systolic and diastolic blood pressures of the patient. In a second operating mode, a second stimulation mode of the one or more stimulation modes can reduce the systolic blood pressure of the patient while controlling the diastolic blood pressure so as to reduce the difference between the systolic and diastolic blood pressures.

[0013] In one aspect, the second stimulation mode can reduce systolic blood pressure while having minimal or no effect on diastolic blood pressure.

[0014] In one aspect, the second stimulation mode can reduce systolic blood pressure while limiting the effect on diastolic blood pressure to a level that does not prevent achieving a therapeutically effective lowered pulse pressure.

[0015] In one aspect, the second stimulation mode can reduce the patient's systolic blood pressure while implementing an increase in diastolic blood pressure, which may be useful if the patient's diastolic blood pressure level is believed to be too low.

[0016] In one aspect, at least one controller can be configured to treat hypertension in the patient using a first stimulation pattern, or to treat isolated systolic hypertension in the patient using a second stimulation pattern.

[0017] On the other hand, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while having minimal or no effect on diastolic blood pressure.

[0018] In another aspect, the second stimulation pattern may combine a blood pressure lowering stimulation pattern with a heart rate increasing stimulation to lower systolic blood pressure while limiting the effect on diastolic blood pressure to a level that does not prevent achieving a therapeutically effective lowered pulse pressure.

[0019] On the other hand, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure with stimulation that increases heart rate to simultaneously lower systolic blood pressure while increasing diastolic blood pressure.

[0020] In yet another aspect, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while controlling diastolic blood pressure so that it is between a lower allowed value and an upper allowed value.

[0021] On the other hand, the second stimulation mode can combine a stimulation mode that lowers blood pressure with a stimulation that increases heart rate to control systolic and diastolic blood pressure so that the resulting pulse pressure is between a lower allowed value and an upper allowed value, and / or is lower than the initial (e.g., intrinsic) pulse pressure by a predetermined amount and / or a predetermined percentage.

[0022] On the other hand, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while maintaining diastolic blood pressure above a specified minimum value.

[0023] In another aspect, the at least one controller can be configured to obtain an indication of the patient's intrinsic heart rate, and wherein the second stimulation pattern increases the heart rate above the intrinsic heart rate.

[0024] On the other hand, at least one controller can be configured to obtain an indication of intrinsic heart rate from at least one of a heart rate sensor, a fixed value based on an average heart rate for a group, a table representing average heart rate values ​​for different groups, or a value based on previous heart rate measurements performed in the patient.

[0025] In another aspect, the at least one controller can be configured to obtain an indication of intrinsic heart rate prior to and / or during delivery of the second stimulation pattern.

[0026] In another aspect, the system may further include an activity sensor that may be configured to detect an activity level of the patient. The at least one controller may be configured to derive the indication of intrinsic heart rate from the estimate of intrinsic heart rate based on an activity level signal received from the activity sensor.

[0027] On the other hand, at least one controller can be configured to calibrate the first stimulation mode with the second stimulation mode by determining a decrease in diastolic blood pressure and / or a decrease in systolic blood pressure attributable to the first stimulation mode; determine increases in systolic and diastolic blood pressure at different heart rates by actively stimulating the patient at different heart rates; and set the second stimulation mode to provide a desired increase in heart rate based on the determined decrease in diastolic blood pressure and / or decrease in systolic blood pressure and increases in systolic and diastolic blood pressure at different heart rates.

[0028] In another aspect, at least one controller can be configured to determine the desired heart rate increase by first finding the heart rate at which the increase in diastolic pressure above the intrinsic heart rate is equal to the decrease in diastolic pressure caused by the first stimulation pattern, and then subtracting the intrinsic heart rate.

[0029] On the other hand, at least one controller can be configured to determine the expected heart rate increase by calculating the expected overall effect on systolic blood pressure using the patient's existing systolic blood pressure data in the following manner: subtracting the expected increase in systolic blood pressure due to the expected increase in heart rate from the decrease in systolic blood pressure produced by the first stimulation mode; determining whether the expected overall effect on systolic blood pressure is sufficient; and if the expected overall effect on systolic blood pressure is not sufficient, selecting a lower heart rate increase to obtain the desired heart rate increase.

[0030] In another aspect, the system may further include a tachyarrythmia sensor that may be configured to monitor the patient's heart for tachycardia during the second stimulation mode and send a signal to the at least one controller when tachycardia is detected. The at least one controller may be configured to interrupt the second stimulation mode upon receiving the signal.

[0031] In another aspect, at least one controller can be configured to receive data associated with a heart rate condition during delivery of the second stimulation pattern to interrupt delivery of the second stimulation pattern, and interrupt delivery of the second stimulation pattern when the heart rate condition is met.

[0032] In another aspect, at least one controller can be configured to automatically receive data associated with the heart rate condition based on the measured parameter value.

[0033] In another aspect, the data associated with the heart rate condition may include a cutoff heart rate determined based on at least one of time of day, patient activity level, or blood pressure.

[0034] In another aspect, the heart rate conditions may include different levels of the second stimulation pattern at different heart rates.

[0035] Another embodiment provides a method for controlling a patient's blood pressure performed with an implanted myocardial stimulator associated with the patient's heart. The method may include delivering a first stimulation pattern to at least one chamber of the patient's heart that reduces both the patient's systolic and diastolic blood pressures, and delivering a second stimulation pattern to at least one chamber of the patient's heart that reduces the patient's systolic blood pressure while controlling the patient's diastolic blood pressure to reduce a difference between the systolic and diastolic blood pressures.

[0036] On the other hand, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure with stimulation that increases heart rate to lower the patient's systolic blood pressure while having minimal or no effect on diastolic blood pressure.

[0037] In another aspect, the second stimulation pattern may combine a blood pressure lowering stimulation pattern with a heart rate increasing stimulation to lower systolic blood pressure while limiting the effect on diastolic blood pressure to a level that does not prevent achieving a therapeutically effective lowered pulse pressure.

[0038] On the other hand, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while increasing diastolic blood pressure.

[0039] II. Examples of Hypertension Treatment Embodiments apply focal, electrical stimulation to the heart, the stimulation comprising at least two different stimulation modes, each mode configured to lower blood pressure to a different degree. The cardiac stimulation can alternate between stimulation modes based on the needs of the patient, for example, alternating between one degree of blood pressure reduction during a portion of a 24-hour cycle (e.g., daytime or a portion thereof) and another different degree of blood pressure reduction during another portion of the 24-hour cycle (e.g., nighttime or a portion thereof). As another example, the cardiac stimulation can alternate between a first stimulation mode that provides a first degree of blood pressure reduction during periods of vigorous activity of the patient and a second stimulation mode that provides a second different degree of blood pressure reduction during periods of light activity of the patient.

[0040] Instead of or in addition to treating hypertension pharmaceutically, certain embodiments treat hypertension mechanically. In some embodiments, an electrical stimulator, such as a pacemaker or other type of device with a pulse generator can be used to stimulate the patient's heart to lower blood pressure. When the heart is stimulated in a consistent manner to lower blood pressure, over time, the cardiovascular system can adapt to the stimulation and return to a higher blood pressure. Therefore, in some embodiments, the stimulation pattern can be configured to modulate the baroreceptor reflex, thus reducing or even avoiding the adaptive response of the cardiovascular system.

[0041] Some embodiments may take advantage of the slow baroreceptor reflex response that occurs after treatment is stopped or reduced. In such cases, it may take a long time for blood pressure levels to return to pre-treatment values, allowing embodiments in which treatment may be paused or reduced for an extended period of time and then resumed at the treatment level that was applied before the extended period of pause or reduction of treatment, before blood pressure levels reach pre-treatment values.

[0042] In some embodiments, an electrical stimulator can be used to stimulate the patient's heart to induce at least partial atrial contraction while the atrioventricular valve is closed. Such atrial contraction can cause less blood to be pumped into the corresponding ventricle than when the atrioventricular valve is opened during atrial contraction, which can cause an almost immediate drop in blood pressure.

[0043] In some embodiments, an electrical stimulator may be used to stimulate the patient's heart so that the atrial pressure due to atrial contraction of the atrium overlaps in time with the passive pressure increase of the atrium, thereby providing an atrial pressure of the atrium that is a combination of the atrial pressure due to atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium when there is no stimulation. This may cause an increase in atrial stretch, thereby lowering blood pressure through hormonal and / or neuronal pathways. This reduction in blood pressure may take some time to appear, and its timeline will depend on hormonal and / or neuronal pathways. The atrial pressure due to atrial contraction may reach the maximum atrial pressure due to atrial contraction. The passive pressure increase of the atrium may reach the maximum passive pressure increase of the atrium. Alternatively or in addition, the overlap in time between the atrial pressure due to atrial contraction of the atrium and the passive pressure increase of the atrium may include the overlap in time between the maximum atrial pressure due to atrial contraction and the maximum passive pressure increase. In some embodiments, the overlap of the above maxima may result in a combined atrial pressure (atrial pressure and passive pressure increase due to atrial contraction) that is higher than the atrial pressure of the atrium in the absence of stimulation.

[0044] In some embodiments, the electrical stimulator can be used to stimulate the patient's heart to induce at least partial atrial contraction while the atrioventricular valve is closed during a single cardiac cycle, and / or to stimulate the patient's heart so that the atrial pressure due to atrial contraction of the atria overlaps in time with the passive pressure increase of the atria, thereby providing an atrial pressure of the atria that is a combination of the atrial pressure due to atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atria in the absence of stimulation.

[0045] In treating hypertension, some embodiments may utilize artificial valves. In certain medical conditions, in the event of malfunction of one or more of the atrioventricular (AV) valves, the valves may be replaced by the implantation of artificial (prosthetic) valves. These artificial valves may generally be configured to passively open and close based on the pressure difference between the atria and ventricles, like natural valves. Passive artificial valves are generally divided into three types based on their mechanical structure: cage-ball valves, tilted disc valves, and bileaflet valves. As an alternative, some embodiments may utilize active artificial valves that are configured to actively open and close.

[0046] In one aspect, an embodiment provides a system for reducing blood pressure in a patient having pre-treatment blood pressure. 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 perform 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 atrial drive and / or configured to control atrial pressure and / or stretch.

[0047] In one aspect, an embodiment provides a system for reducing blood pressure. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart. The system may include at least one controller configured to execute a stimulation pattern including a plurality of stimulation pulses. At least one stimulation pulse of the plurality of stimulation pulses may have a first stimulation setting configured to reduce atrial drive in at least one ventricle. At least one stimulation pulse of the plurality of stimulation pulses may have a second stimulation setting configured to reduce a baroreceptor reflex response to a reduction in atrial drive such that an increase in blood pressure values ​​occurring between stimulation pulses is limited to a predetermined value or range of values.

[0048] In another aspect, an embodiment provides an apparatus for reducing blood pressure in a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume. The apparatus may include a stimulation circuit configured to deliver stimulation pulses to at least one of the atria and the ventricles. The apparatus may include a processor circuit coupled to the stimulation circuit and optionally also coupled to the sensing circuit.

[0049] In some embodiments, the processor circuit of the device can be configured to operate in an operating mode in which the device controls AV delay, which, as used herein, can be understood as the delay that occurs between ventricular excitation and / or contraction and atrial excitation and / or contraction in a single heartbeat. Additionally, as used herein, AV delay in a system or method can be understood as, within a heartbeat, the time delay between at least one excitatory stimulus delivered to the ventricles and one of: sensing of the initiation of atrial excitation; timing of the expected initiation of atrial excitation; and delivery of at least one excitatory stimulus to the atria.

[0050] Such AV delay may be set by delivering at least one stimulation pulse to both at least one atrium and at least one ventricle. Optionally, such stimulation is performed at a higher rate than the natural activity of the heart. For example, such a rate may be set by sensing the natural activity in the heart (e.g., in the right atrium when no stimulation is delivered) using at least one sensing electrode and adjusting the stimulation pulse delivery rate accordingly.

[0051] Optionally, when ventricular excitation begins prior to one or more stimulation pulses being delivered to the atria, the timing of delivery of stimulation pulses to the heart is set so that one or more excitatory pulses are delivered to the atria earlier than the next expected natural initiation of atrial excitation.

[0052] In some embodiments, AV delay may be set by delivering at least one stimulation pulse to one or more ventricles instead of to the atria. In such a case, the natural activity of one or more of the atria may be sensed and the timing of ventricular excitation and / or contraction may be set ahead of its natural expected timing based on the sensed rate of atrial activity.

[0053] In some embodiments, the processor circuit may be configured to operate in an operating mode in which the ventricles are stimulated so as to cause ventricular excitation to begin between about 0 milliseconds (ms) and about 50 ms before the initiation 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 sensed so as to determine the initiation of atrial excitation. 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 50 ms before the next atrial excitation is expected to occur. The time interval between the initiation of atrial excitation and the moment when atrial excitation is sensed may be known or estimated, and the time interval is used to calculate the timing of the initiation of atrial excitation. For example, if it is known or estimated that atrial excitation is sensed 5 ms after the initiation of atrial excitation, and the ventricles are stimulated 20 ms before the initiation of atrial excitation, then the ventricles will be stimulated 25 ms before the sensing of the next expected atrial excitation. In other embodiments, the processor circuit may be configured to operate in an operating mode in which the atria are stimulated so as to cause atrial excitation to begin between about 0 ms and 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 circuit may be configured to operate in an operating mode in which one or more excitatory pulses are delivered to the atria between about 0 ms and about 50 ms after one or more excitatory pulses are provided to the patient's ventricles. In such an embodiment, the timing of pacing can be set without relying on sensing atrial excitation. Optionally, in such an embodiment, atrial excitation is sensed to confirm that one or more excitatory pulses are delivered to the atria before natural excitation occurs. Optionally, when the intrinsic atrial excitation rate is lower than the intrinsic ventricular excitation rate, atrial excitation is set to begin between about 0 ms and about 50 ms after the initiation of ventricular excitation.

[0054] In some embodiments, the timing of mechanical contraction with respect to electrical excitation of a patient's chambers can be determined, for example, by sensing changes in atrial and ventricular pressure, sensing wall motion using ultrasound (e.g., echocardiography or cardiac echo), detecting impedance changes using implanted and / or external sensors known in the art, or the opening and / or closing of a heart valve. Examples of such sensors include pressure sensors, impedance sensors, ultrasound sensors, and / or one or more audio sensors and / or one or more blood flow sensors.

[0055] The timing of mechanical contraction with respect to electrical excitation of the patient's chambers can be considered, and the processor circuit can be configured accordingly so that one or more excitatory pulses are delivered to the heart at a timing that will generate the desired contraction pattern. Such delivery can be performed in a closed loop mode using one or more implanted sensors, and / or, for example, occasionally (e.g., at the time of implantation of the device and / or during an examination) using an interface with an external measurement device.

[0056] The mode of operation may include stimulating the ventricle to cause the ventricle to begin contracting prior to initiation of contraction of at least one atrium.

[0057] The mode of operation may include stimulating the ventricle to cause the ventricle to begin contracting prior to the end of contraction of the at least one atrium, thereby causing the AV valve to close during at least a portion of the contraction of the at least one atrium.

[0058] The mode of operation may include stimulating the ventricle to cause the ventricle to begin contracting less than 100 ms after initiation of contraction of at least one atrium.

[0059] Optionally, care should be taken to ensure that atrial contraction will start before ventricular contraction reaches peak pressure. This is possible even in the case where ventricular contraction will start before the onset of atrial contraction, since atrial contraction is generally faster than ventricular contraction. Therefore, one of the following settings may be selected:

[0060] a. The mode of operation may include stimulating the ventricle to cause the ventricle to begin contracting at any time during atrial contraction but before the atrium reaches its maximum pressure due to atrial contraction.

[0061] b. The mode of operation may include stimulating the ventricle to cause the ventricle to begin contracting at any time during atrial contraction but after the atrium has reached its maximum pressure due to atrial contraction.

[0062] c. The mode of operation may include stimulating the ventricles with a timing such that contractions in the atria and ventricles will begin at substantially the same time (eg, within 5 ms of each other).

[0063] d. The mode of operation may include stimulating the ventricles to cause the ventricles to begin contracting with a timing such that a peak atrial contraction will occur when the ventricles are near or at maximum stretch, thereby causing an increase in atrial wall stretch, as described in more detail below with respect to the isovolumetric and rapid ejection phases of the ventricles.

[0064] The mode of operation may include stimulating the ventricle to cause the ventricle to at least partially contract prior to initiation of contraction of the at least one atrium, thereby causing the AV valve to close during initiation of contraction of the at least one atrium.

[0065] Optionally, the processor circuit may be configured to operate in an operating mode in which the one or more excitatory pulses are delivered to the atria between about 0 ms and about 50 ms after the one or more excitatory pulses are delivered to the ventricles of the patient.

[0066] In another aspect, an embodiment provides a method for reducing the blood pressure of a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume. The method may include delivering a stimulation pulse from a stimulation circuit to at least one of the atria and the ventricles, and operating a processor circuit coupled to the stimulation circuit to operate in an operating mode in which the ventricles are stimulated to cause ventricular excitation to begin between about 0 ms and about 50 ms before the initiation 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 can be sensed to determine the initiation of atrial excitation. For example, the method may include delivering one or more excitatory pulses to the ventricles between about 0 ms and about 50 ms before the next atrial excitation is expected to occur. The time interval between the initiation of atrial excitation and the moment when atrial excitation is sensed can be known and can be used to calculate the timing of the initiation of atrial excitation. For example, if it is known or estimated that atrial excitation is sensed 5 ms after the initiation of atrial excitation, and the ventricles are stimulated 20 ms before the initiation of atrial excitation, then the ventricles will be stimulated 25 ms before the sensing of the next expected atrial excitation. In other embodiments, the method may include operating a processor circuit coupled to the stimulation circuit to operate in an operating mode in which the atria are stimulated to cause atrial excitation to begin between approximately 0 ms and approximately 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 method may include delivering one or more excitatory pulses to the atria between approximately 0 ms and approximately 50 ms after delivering the one or more excitatory pulses to the patient's ventricles. In such an embodiment, the timing of pacing can be set without relying on sensing atrial excitation. Optionally, such an embodiment includes sensing atrial excitation to confirm that one or more excitatory pulses are delivered to the atria before natural excitation occurs. Optionally, when the intrinsic atrial excitation rate is lower than the intrinsic ventricular excitation rate, atrial excitation is configured to begin between about 0 ms and about 50 ms after initiation of ventricular excitation.

[0067] In some embodiments, the timing of mechanical contractions with respect to electrical excitation of the patient's chambers can be assessed using, for example, ultrasound (e.g., echocardiography or cardiac echo) or other known means. The timing of mechanical contractions with respect to electrical excitation of the patient's chambers can be considered, and the timing of delivery of one or more excitatory pulses to the heart can be selected so as to generate a desired contraction pattern.

[0068] The mode of operation may include stimulating the ventricle to cause contraction of the ventricle prior to initiation of contraction of at least one atrium.

[0069] The mode of operation may include stimulating the ventricle to cause the ventricle to contract prior to initiation of contraction of the at least one atrium, thereby causing the AV valve to close during at least a portion of the contraction of the at least one atrium.

[0070] The mode of operation may include stimulating the ventricle to cause the ventricle to contract prior to the end of contraction of the at least one atrium, thereby causing the AV valve to close during the initiation of contraction of the at least one atrium.

[0071] Optionally, the method includes delivering one or more excitatory pulses to the atria between about 0 ms and about 50 ms after delivering one or more excitatory pulses to the patient's ventricles.

[0072] In another aspect, an embodiment provides a device for reducing the blood pressure of a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume. The device may include a stimulation circuit configured to deliver stimulation pulses to at least one chamber of the patient's heart. The device may include a processor circuit coupled to the stimulation circuit. The processor circuit may be configured to operate in an operating mode in which the at least one chamber is stimulated to cause atrial contraction that occurs between about 40% of atrial contraction and about 100% of atrial contraction at a time when an 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. For example, this may be achieved by causing the atria to begin contracting approximately 60 ms or less prior to the closure of the AV valve. Optionally, this timing may be set periodically (e.g., at the time of implantation) based on data from an external sensor and / or as a closed loop using one or more implanted sensors.

[0073] In another aspect, an embodiment provides an apparatus for reducing blood pressure of a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume. The apparatus may include a stimulation circuit configured to deliver stimulation pulses to at least one cardiac chamber. The apparatus may include a processor circuit coupled to the stimulation circuit. The processor circuit may be configured to operate in an operating mode in which at least one cardiac chamber is paced so as to cause atrial contraction to occur by about 50% to about 95% during ventricular contraction, 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, this may be achieved by causing the atrial contraction to begin about 50 ms to 5 ms before the start of ventricular contraction. Optionally, the timing of the start of ventricular contraction may be set based on the timing of the closing of the AV valve. Optionally, this timing may be set periodically (e.g., at the time of implantation) based on data from an external sensor and / or as a closed loop using one or more implanted sensors.

[0074] In another aspect, an embodiment provides a method implemented using an implantable myocardial stimulator associated with a patient's heart, the method being used to treat a blood pressure disorder in the patient, the patient having a pre-treatment blood pressure. The method may include stimulating the heart so as to cause its atria to contract while the heart valves associated with the atria are closed, such that the contraction causes the atria to dilate, and the dilated atria results in a reduction in the patient's blood pressure from the pre-treatment blood pressure. For example, this may be achieved by causing the atria to contract at a time point when the pressure in the ventricles is maximum so that the force of the atrial contraction will increase the atrial pressure and atrial stretch above the maximum passive pressure and stretch caused by the contraction of the associated ventricles. In this case, the timing of the maximum contraction of the atria should coincide with the end of the isovolumetric period of the ventricles or during the rapid ejection period. Optionally, this timing may be set periodically (e.g., at the time of implantation) based on data from an external sensor and / or as a closed loop using one or more implanted sensors.

[0075] In another aspect, an embodiment provides a system for reducing a patient's blood pressure by controlling atrial pressure and atrial stretch. The system may include a stimulation circuit configured to deliver stimulation pulses to at least one chamber of the patient's heart, and at least one controller configured to perform delivery of one or more stimulation patterns of stimulation pulses to the at least one chamber. At least one of the stimulation pulses may stimulate the heart such that an atrial pressure resulting from atrial contraction of the atrium overlaps temporally with a passive pressure increase of the atrium, such that an atrial pressure of the atrium resulting from stimulation is a combination of an atrial pressure resulting from atrial contraction and a passive pressure increase and is higher than an atrial pressure of the atrium in the absence of stimulation, and in this way, the patient's blood pressure is reduced.

[0076] Atrial pressure resulting from the stimulation of the atria may cause increased atrial stretch of the atria, which lowers blood pressure via hormonal and / or neural pathways.

[0077] The atrial pressure due to atrial contraction may reach a maximum atrial pressure due to atrial contraction. The passive pressure increase of the atrium may reach a maximum passive pressure increase of the atrium. Alternatively or in addition, the temporal overlap of the atrial pressure due to atrial contraction of the atrium and the passive pressure increase of the atrium may include the temporal overlap of the maximum atrial pressure due to atrial contraction and the maximum passive pressure increase. In some embodiments, the overlap of the above-mentioned maximum values ​​can result in a combined atrial pressure (of the atrial pressure due to atrial contraction and the passive pressure increase) that is higher than the atrial pressure of the atrium when there is no stimulation.

[0078] At least one of the stimulation pulses may include stimulating the atria of the heart. At least one of the stimulation pulses may include stimulating the ventricles of the heart. At least one of the stimulation pulses may also include pacing the atria and ventricles, optionally at substantially equal rates, or pacing the atria at a rate that is higher than the rate of ventricular pacing.

[0079] At least one of the stimulation pulses may include stimulating the atria, for example, either by stimulating the atria twice during a single cardiac cycle or by stimulating the atria once during a single cardiac cycle, so that the atria contract twice during a single cardiac cycle.

[0080] Optionally, at least one of the stimulation pulses may include stimulating the atria such that the atria contract only once during a single cardiac cycle.

[0081] At least one of the stimulation pulses may further include stimulating the heart such that atrial drive is reduced or prevented.

[0082] One or more stimulation modes may further include stimulating the heart such that atrial drive is reduced or prevented. At least one of the stimulation modes may include stimulating the heart for a plurality of heartbeats, wherein at least some of the stimulation pulses stimulate the heart such that atrial pressure resulting from atrial contraction of the atria overlaps temporally with a passive pressure increase of the atria, such that atrial pressure resulting from the stimulation of the atria is a combination of atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than atrial pressure of the atria in the absence of stimulation, and wherein at least some of the stimulation pulses are configured to reduce or prevent atrial drive.

[0083] A stimulation pulse can be provided so that in a single heartbeat atrial drive is reduced or prevented and the atrial pressure resulting from atrial contraction of the atrium overlaps in time with the passive pressure increase of the atrium, such that the atrial pressure of the atrium resulting from stimulation is a combination of the atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation.

[0084] At least one stimulation pattern may include at least one stimulation pulse configured to cause a first atrial contraction to begin when the atrioventricular valve opens and to end after the atrioventricular valve closes in a single heartbeat, and configured to cause a second atrial contraction, wherein an atrial pressure resulting from the atrial contraction of the atrium overlaps in time with a passive pressure increase of the atrium, such that the atrial pressure of the atrium resulting from the stimulation is a combination of the atrial pressure resulting from the atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation. The first atrial contraction may be sensed and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0085] Alternatively, at least one stimulation pattern may include at least one stimulation pulse configured to cause a first atrial contraction to begin when the atrioventricular valve opens and to end before the atrioventricular valve closes in a single heartbeat, and to cause a second atrial contraction, wherein the atrial pressure resulting from the atrial contraction of the atrium overlaps in time with a passive pressure increase of the atrium, such that the atrial pressure of the atrium resulting from the stimulation is a combination of the atrial pressure resulting from the atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation. The first atrial contraction may be sensed and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0086] One or more stimulation modes may include alternating between a plurality of stimulation modes having different ratios of: (1) a first stimulation pulse that stimulates the heart such that atrial pressure resulting from atrial contraction of the atrium overlaps in time with a passive pressure increase of the atrium, such that atrial pressure of the atrium resulting from stimulation is a combination of atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than atrial pressure of the atrium in the absence of stimulation; and (2) a second stimulation pulse that stimulates the heart such that atrial drive is reduced or prevented. Optionally, one or more stimulation modes may include at least one stimulation pulse configured to reduce or prevent atrial drive and stimulate the heart such that atrial pressure resulting from atrial contraction of the atrium overlaps in time with a passive pressure increase of the atrium, such that atrial pressure of the atrium resulting from stimulation is a combination of atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than atrial pressure of the atrium in the absence of stimulation, both within a single cardiac cycle.

[0087] One or more stimulation modes may include alternating between multiple stimulation modes having different ratios of: (1) a first stimulation pulse that stimulates the heart so that an atrial pressure resulting from atrial contraction of the atrium overlaps in time with a passive pressure increase of the atrium, such that an atrial pressure resulting from the stimulation of the atrium is a combination of the atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation; and (2) a second stimulation pulse that does not provide an atrial pressure resulting from atrial contraction of the atrium that overlaps in time with the passive pressure increase of the atrium.

[0088] At least one stimulation pulse may include pacing at least one of an atrium of the heart and a ventricle of the heart such that the relative timing of stimulation corresponds to an atrioventricular delay of approximately 2 ms.

[0089] At least one stimulation pulse may include pacing at least one of an atrium of the heart and a ventricle of the heart such that the relative timing of stimulation corresponds to an atrioventricular delay of between about 30 ms and about 0 ms, or even between 10 ms and 0 ms.

[0090] In another aspect, an embodiment provides a method for reducing a patient's blood pressure by controlling atrial pressure and atrial stretch. The method may be implemented using an implantable myocardial stimulator associated with a patient's heart. The method may include stimulating the heart to provide an atrial pressure resulting from atrial contraction that temporally overlaps a passive pressure increase in the atrium, such that the overlap of the atrial pressure resulting from atrial contraction and the passive pressure increase causes an atrial pressure that is a combination of the atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium that would not be stimulated, and in this way, reducing the patient's blood pressure.

[0091] Atrial pressure resulting from the stimulation of the atria may cause increased atrial stretch of the atria, which lowers blood pressure via hormonal or neuronal pathways.

[0092] The atrial pressure due to atrial contraction may reach a maximum atrial pressure due to atrial contraction. The passive pressure increase of the atrium may reach a maximum passive pressure increase of the atrium. Alternatively or in addition, the temporal overlap of the atrial pressure due to atrial contraction of the atrium and the passive pressure increase of the atrium may include the temporal overlap of the maximum atrial pressure due to atrial contraction and the maximum passive pressure increase. In some embodiments, the overlap of the above-mentioned maximum values ​​may result in a combined atrial pressure (of the atrial pressure due to atrial contraction and the passive pressure increase) that is higher than the atrial pressure of the atrium in the absence of stimulation. Therefore, the method may include stimulating the heart so that the maximum value of the atrial pressure due to atrial contraction of the atrium overlaps in time with the maximum passive pressure increase of the atrium.

[0093] The method may include stimulating the atria of the heart. Additionally or alternatively, the method may include stimulating the ventricles of the heart. The method may also include pacing the atria and ventricles at substantially equal rates, or pacing the atria at a rate that is higher than the rate at which the ventricles are paced or contracted.

[0094] The method may further comprise stimulating the atria, such as by stimulating the atria twice during a single cardiac cycle or by stimulating the atria once during a single cardiac cycle, so that the atria contract twice during a single cardiac cycle.

[0095] Optionally, the method may include stimulating the atria such that the atria contract only once during a single cardiac cycle.

[0096] The method may also include stimulating the heart such that atrial drive is reduced or prevented. Stimulating the heart may include delivering a stimulation pattern to the heart at a plurality of heartbeats, wherein at least some of the stimulation pulses in the stimulation pattern stimulate the heart such that atrial pressure resulting from atrial contraction of the atrium temporally overlaps with a passive pressure increase of the atrium, such that the atrial pressure of the atrium resulting from the stimulation is a combination of the atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation, and wherein at least some of the stimulation pulses are configured to reduce or prevent atrial drive. A stimulation pulse may be provided such that atrial drive is reduced or prevented in a single heartbeat and the atrial pressure resulting from atrial contraction of the atrium temporally overlaps with a passive pressure increase of the atrium, such that the atrial pressure of the atrium resulting from the stimulation is a combination of the atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation.

[0097] Stimulating the heart may include delivering at least one stimulation pulse configured to cause a first atrial contraction to begin when the atrioventricular valve opens and to end after the atrioventricular valve closes within a single heartbeat, and configured to cause a second atrial contraction, wherein an atrial pressure resulting from the atrial contraction of the atrium overlaps in time with a passive pressure increase of the atrium, such that the atrial pressure of the atrium resulting from the stimulation is a combination of the atrial pressure resulting from the atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation. The first atrial contraction may be sensed and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0098] Alternatively, stimulating the heart may include delivering at least one stimulation pulse configured to cause a first atrial contraction to begin when the atrioventricular valve opens and to end before the atrioventricular valve closes within a single heartbeat, and configured to cause a second atrial contraction, wherein the atrial pressure resulting from the atrial contraction of the atrium overlaps in time with a passive pressure increase of the atrium, such that the atrial pressure of the atrium resulting from the stimulation is a combination of the atrial pressure resulting from the atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation. The first atrial contraction may be sensed and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0099] The method may also include alternating between a plurality of stimulation patterns having different ratios of: (1) a first stimulation pulse that stimulates the heart such that atrial pressure resulting from atrial contraction of the atrium overlaps temporally with a passive pressure increase of the atrium, such that atrial pressure of the atrium resulting from stimulation is a combination of atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than atrial pressure of the atrium in the absence of stimulation; and (2) a second stimulation pulse that stimulates the heart such that atrial drive is reduced or prevented. Optionally, one or more stimulation patterns may include at least one stimulation pulse configured to reduce or prevent atrial drive and stimulate the heart such that atrial pressure resulting from atrial contraction of the atrium overlaps temporally with a passive pressure increase of the atrium, such that atrial pressure of the atrium resulting from stimulation is a combination of atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than atrial pressure of the atrium in the absence of stimulation, both within a single cardiac cycle.

[0100] The method may also include alternating between multiple stimulation modes having different ratios of the following items: (1) a first stimulation pulse that stimulates the heart so that an atrial pressure due to atrial contraction of the atrium overlaps in time with a passive pressure increase of the atrium, so that the atrial pressure of the atrium due to stimulation is a combination of the atrial pressure due to atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation; and (2) a second stimulation pulse that does not provide an atrial pressure due to atrial contraction of the atrium that overlaps in time with the passive pressure increase of the atrium.

[0101] The method may also include pacing at least one of an atrium of the heart and a ventricle of the heart such that the relative timing of stimulation corresponds to an atrioventricular delay of approximately 2 ms.

[0102] The method may also include pacing at least one of an atrium of the heart and a ventricle of the heart such that the relative timing of stimulation corresponds to an atrioventricular delay between approximately 30 ms and approximately 0 ms.

[0103] In another aspect, an embodiment provides a method for reducing blood pressure in a patient, which can be implemented using an implantable myocardial stimulator associated with a heart of the patient. The method can include delivering one or more stimulation patterns of stimulation pulses to at least one chamber of the heart of the patient. At least one of the stimulation pulses can have a first stimulation setting, and at least one of the stimulation pulses can have a second stimulation setting that is different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting can be configured to reduce or prevent atrial drive. Stimulation pulses having a stimulation setting configured to reduce or prevent atrial drive can be delivered based on need.

[0104] The delivery of stimulation pulses on an as-needed basis may include one or more of the following: a. Limiting therapy to times when needed, e.g., limiting delivery of stimulation settings configured to reduce or prevent atrial drive to times when the patient's known or expected blood pressure is abnormally high. This can include utilizing real-time feedback measurements of one or more blood pressure-related parameters or desired patterns of need based on previous measurements taken from the same patient. For example, in some patients, BP may be high 24 hours a day, whereas other patients may experience high BP only during a portion of a 24-hour cycle (e.g., day or night).

[0105] b. Preventing therapy when high BP is desired, e.g., preventing delivery of stimulation settings configured to reduce or prevent atrial drive, during periods when an increase in BP may be healthy and therefore desirable. For example, it is known that BP increases when a person is active and decreases again when activity is reduced (e.g., when exercising or performing physical tasks that are naturally associated with an increase in BP).

[0106] Stimulation pulses having stimulation settings configured to reduce or prevent atrial drive may be provided only during a portion of a 24-hour cycle, which may be nighttime or a portion thereof, or may be daytime or a portion thereof.

[0107] Stimulation pulses having stimulation settings configured to reduce or prevent atrial drive can be provided only when the heart rate is below a predefined threshold. The predefined threshold can be an absolute value such as 90 bpm. The predefined threshold can be set at a numerical value relative to the patient's average heart rate. For example, the predefined threshold can be at least one of 30 heart beats above the average heart rate and above the 80th percentile of heart rate.

[0108] Stimulation pulses having stimulation settings configured to reduce or prevent atrial drive may be provided only when the patient is at rest or at an activity level below a predefined threshold. The method may also include determining whether the patient is at rest or at an activity level below a predefined threshold by sensing at least one of motion, posture, respiration rate, and heart rate.

[0109] Optionally, a patient may be considered to be "at rest" or "at a low activity level" when the patient's activity is low. For example, a patient may be considered to be "at rest" or "at a low activity level" as long as the heart rate does not exceed a predefined threshold or only low activity is sensed (e.g., characterized by slight and / or slow motions and / or a low rate of postural changes and / or no noticeable increase in breathing, etc.). For example, sitting activities such as while reading or talking or exercise around the home or office may be considered to be a sufficiently low activity level to allow delivery of stimulation pulses with stimulation settings configured to reduce or prevent atrial drive.

[0110] One or more stimulation patterns may be selected based on the measured blood pressure parameters.The method may further include changing one or more stimulation patterns when a baroreceptor reflex is sensed.

[0111] In another aspect, an embodiment provides a system for reducing blood pressure in a patient, the system comprising a stimulation circuit configured to deliver one or more stimulation patterns of stimulation pulses to at least one chamber of the patient's heart, and at least one controller configured to perform delivery of the one or more stimulation patterns of stimulation pulses to the at least one chamber of the 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 that is different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting may be configured to reduce or prevent atrial drive. Stimulation pulses having a stimulation setting configured to reduce or prevent atrial drive may be delivered based on need.

[0112] At least one controller may be configured to deliver stimulation pulses having stimulation settings configured to reduce or prevent atrial drive only during a portion of a 24-hour cycle. The portion of a 24-hour cycle may be night or a portion thereof, or may be day or a portion thereof.

[0113] At least one controller may be configured to deliver stimulation pulses having stimulation settings configured to reduce or prevent atrial drive only when the heart rate is below a predefined threshold. The predefined threshold may be an absolute value such as 90 bpm. The predefined threshold may be set at a value relative to the patient's average heart rate. For example, the predefined threshold may be at least one of 30 beats above the average heart rate and above the 80th percentile of heart rate.

[0114] At least one controller may be configured to deliver stimulation pulses having stimulation settings configured to reduce or prevent atrial drive 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 sensing at least one of motion, posture, respiration rate, and heart rate.

[0115] The at least one controller may be configured to select one or more stimulation patterns based on the measured blood pressure parameters. The at least one controller may be configured to change one or more stimulation patterns when a baroreceptor reflex is sensed.

[0116] In another aspect, an embodiment may provide a method for adjusting pulse settings in a system for controlling blood pressure. The method may include receiving atrial pressure data related to the atria of the heart of the patient during at least one cardiac cycle. The atrial pressure data may result from a stimulation pulse having a first pulse setting delivered to the heart by the system. The method may also include analyzing the atrial pressure data and providing an adjusted second pulse setting based on the analysis, the adjusted second pulse setting being different from the first pulse setting. The analysis may include analyzing the atrial pressure data to estimate the temporal overlap between the atrial pressure resulting from atrial contraction and the passive pressure increase of the atria. The analysis may also include analyzing the atrial pressure data to estimate the temporal overlap between the maximum atrial pressure resulting from atrial contraction and the maximum passive pressure increase of the atria. The analysis may include analyzing the atrial pressure data to compare the first atrial pressure (or maximum atrial pressure) reached in the cardiac cycle in which the stimulation pulse is delivered with the second atrial pressure of the atria without stimulation. The analysis may also include plotting the atrial pressure data and / or mathematically analyzing the atrial pressure data.

[0117] In another aspect, an embodiment may provide a system for reducing blood pressure. The system may include means for providing information about pressure changes in the atria 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 arranged to generate the stimulation pulses so as to control the timing of atrial contraction relative to the timing of ventricular contraction in a single cardiac cycle based on the information about pressure changes in the atria.

[0118] The information about the pressure changes in the atria may include information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction. The means for generating stimulation pulses may be arranged to generate for at least one cardiac cycle: at least one atrial stimulation pulse for generating atrial contraction; and / or at least one ventricular stimulation pulse for generating ventricular contraction. The means for generating stimulation pulses may be arranged to generate, on the basis of information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction, at least one atrial stimulation pulse in a timed relationship with the occurrence of atrial contraction and / or the occurrence of ventricular contraction; and / or to generate, on the basis of information about the occurrence of ventricular contraction and / or information about the occurrence of atrial contraction, at least one ventricular stimulation pulse in a timed relationship 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 a 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 a QRS complex in the natural stimulation pattern of the cardiac cycle.

[0119] In another aspect, an embodiment may provide a system for reducing blood pressure. The system may include a device for providing information about the timing of one or more cardiac activity events, a device for generating stimulation pulses, and a device for applying the stimulation pulses to at least one cardiac chamber. The information about the timing of one or more cardiac activity events may include at least one of the following items: 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, atrial pressure of the atrium, changes in atrial pressure of the atrium, and heart rate. The device for generating the stimulation pulse may be arranged to generate the stimulation pulse so as to set the timing of atrial contraction relative to ventricular contraction based on the information.

[0120] The timing of atrial contraction relative to ventricular contraction may correspond to an AV delay in the range of about 30 ms to about 0 ms. The means for generating the stimulation pulse may be arranged to generate the stimulation pulse so as to: provide excitatory stimulation to the atria in the range of about 30 ms to about 0 ms before the onset of ventricular excitation; provide excitatory stimulation to the ventricles in the range of about 30 ms to about 0 ms after the onset of atrial excitation; and / or provide excitatory stimulation to the atria and then provide excitatory stimulation to the ventricles in the range of about 30 ms to about 0 ms thereafter.

[0121] 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.

[0122] The device for generating stimulation pulses may be arranged to generate for at least one cardiac cycle: at least one atrial stimulation pulse for generating atrial contraction; and / or at least one ventricular stimulation pulse for generating ventricular contraction. The device for generating stimulation pulses may be arranged to generate at least one atrial stimulation pulse in a timed relationship with the occurrence of atrial contraction and / or the occurrence of ventricular contraction on the basis of information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction; and / or to generate at least one ventricular stimulation pulse in a timed relationship with the occurrence of ventricular contraction and / or the occurrence of atrial contraction on the basis of 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 a 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 a QRS complex in the natural stimulation pattern of the cardiac cycle.

[0123] In another aspect, an embodiment provides another method for reducing blood pressure in a patient by controlling atrial pressure and atrial stretch. The method may be implemented using an implantable myocardial stimulator associated with a heart of the patient. The method may include delivering one or more stimulation patterns of stimulation pulses to at least one cardiac 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 cause the atria to contract so that an atrial pressure resulting from atrial contraction of the atria overlaps temporally with a passive pressure increase of the atria; and providing an atrial pressure of the atria by overlapping the atrial pressure resulting from atrial contraction and the passive pressure increase, which is a combination of the atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atria in the absence of stimulation, thereby causing increased atrial stretch of the atria, which lowers blood pressure through hormonal or neuronal pathways. Optionally, at least one of the first stimulation setting and the second stimulation setting can be configured to cause the atria to contract so that the maximum atrial pressure resulting from the atrial contraction overlaps in time with the maximum passive pressure increase of the atria, and the method may include providing an atrial pressure of the atria that is higher than the atrial pressure of the atria in the absence of stimulation by the overlap of the maximum atrial pressure resulting from the atrial contraction and the maximum passive pressure increase, thereby causing increased atrial stretch of the atria, which reduces blood pressure via hormonal or neuronal pathways.

[0124] In another aspect, an embodiment provides a system for reducing blood pressure in a patient by controlling atrial pressure and atrial stretch. The system may include a stimulation circuit configured to deliver one or more stimulation patterns of stimulation pulses to at least one cardiac chamber, and at least one controller configured to perform the delivery of the one or more stimulation patterns of stimulation pulses to at least one cardiac chamber. At least one of the stimulation pulses may have a first stimulation setting, and at least one of the stimulation pulses may have a second stimulation setting that is different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting may be configured to cause the atria of the heart to contract so that the atrial pressure resulting from the atrial contraction of the atria overlaps in time with the passive pressure increase of the atria, thereby providing an atrial pressure of the atria that is a combination of the atrial pressure resulting from the atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atria in the absence of stimulation, thereby causing increased atrial stretch of the atria that lowers blood pressure through hormonal or neuronal pathways. Optionally, at least one of the first stimulation setting and the second stimulation setting can be configured to cause the atria of the heart to contract such that the maximum atrial pressure resulting from the atrial contraction overlaps in time with the maximum passive pressure increase in the atria, thereby providing an atrial pressure in the atria that is higher than the atrial pressure in the atria in the absence of stimulation and causing increased atrial stretch of the atria that lowers blood pressure via hormonal or neuronal pathways.

[0125] In another aspect, an embodiment provides a method for treating a patient's blood pressure disorder by controlling atrial pressure and atrial stretch. The method can be implemented using an implantable myocardial stimulator associated with the patient's heart, the patient having a pre-treatment blood pressure. The method can include stimulating the heart so that its atria contract while the heart valves associated with the atria are closed, such that the contraction causes the atria to dilate, and the dilated atria causes a decrease in the patient's blood pressure from the pre-treatment blood pressure, preferably by causing the atrial contraction at a time point when the pressure in the ventricles is maximum, so that the force of the atrial contraction increases the atrial pressure and stretch to above the maximum passive pressure and stretch caused by the contraction of the ventricles.

[0126] In another aspect, an embodiment provides a system for reducing blood pressure. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart using a stimulation pattern including at least one stimulation pulse. The system may include at least one controller configured to receive input related to the patient's blood pressure and 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 provided by a user. For example, during implantation and / or periodic examination, the user may provide data about the measured blood pressure. Optionally, the system includes an input port for receiving such input from a measurement sensor and / or a user interface via wired and / or wireless communication. The input may include data related to blood pressure (BP) or changes in BP, which may be measured as systolic BP (SysBP), diastolic BP, mean arterial BP, and / or any other relevant BP parameter. For example, at least one sensor may sense pressure or pressure changes in one or more cardiac chambers and adjust the stimulation pattern based on the pressure or pressure changes. In another embodiment, the sensor may sense pressure in more than one chamber and adjust the stimulation based on the relationship between the pressure waveforms of the two chambers.

[0127] The controller may be configured to adjust the stimulation pattern by performing an adjustment process comprising adjusting a parameter of the first stimulation setting of at least one of the at least one stimulation pulse.

[0128] The first stimulation setting may be configured to reduce or prevent atrial drive in at least one ventricle.

[0129] Parameters may include adjustment of AV delay. For example, a natural AV delay may be in the range of 120 to 200 ms between the initiation of atrial excitation and the initiation of ventricular excitation, whether occurring naturally (i.e., without delivery to the heart) or by setting the timing of delivery of stimulation to one or more of the atria and ventricles. 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 to 70 ms from the initiation of atrial excitation to the initiation of ventricular excitation; or an AV delay of 0 to -50 ms in which ventricular excitation occurs before atrial excitation). In an embodiment, a stimulation setting having an AV delay between -50 ms and 70 ms, preferably -40 ms to 60 ms, more preferably -50 ms to 0 or 0 to 70 ms, preferably greater than 0 to 70 ms, is selected to reduce or prevent atrial drive.

[0130] A stimulation mode configured to reduce atrial drive can be configured to cause a reduction in blood pressure of at least a predetermined amount within approximately 3 seconds from application of the current to the heart, and to maintain the reduction in blood pressure for a time interval of at least 1 minute. For example, a stimulation mode can be selected and / or adjusted based on feedback related to one or more sensed BP parameters.

[0131] The time interval may be at least 5 minutes.

[0132] The predetermined amount of blood pressure reduction may be 8 mmHg or more.

[0133] The predetermined amount of blood pressure reduction may be at least 4% of the patient's pre-treatment blood pressure.

[0134] During the time interval, the patient's blood pressure may not exceed a predetermined average value by more than a predetermined degree. The predetermined degree may be a difference of about 8 mmHg or less. In some embodiments, the patient's blood pressure may exceed the predetermined average value for some heartbeats, but the patient's average blood pressure may not exceed the predetermined average value.

[0135] The controller may be configured to execute a plurality of stimulation modes and, for each stimulation mode, receive corresponding input data related to the patient's blood pressure during stimulation. The controller may be configured to calculate, for each of the plurality of stimulation modes, at least one blood pressure change parameter related to the input data. The controller may be configured to adjust the stimulation mode based on the blood pressure change parameter.

[0136] The controller may be configured to adjust the stimulation pattern to a stimulation pattern having the best blood pressure variation parameter.

[0137] As detailed herein, the best blood pressure variation parameter may be the blood pressure variation parameter that exhibits the lowest degree of baroreceptor reflex, or the lowest degree or rate of adaptation.

[0138] As detailed herein, the best blood pressure variation parameter may be one that demonstrates a degree of baroreceptor reflex or adaptability within a predetermined range.

[0139] At least two stimulation modes of the plurality of stimulation modes may each include at least one stimulation pulse having a stimulation setting configured to reduce or prevent atrial drive in at least one ventricle and / or for controlling atrial pressure and / or stretch. The at least two stimulation modes may differ from each other by the number of times or the length of time that at least one stimulation pulse is provided in sequence.

[0140] The multiple stimulation patterns may differ by the number or length of time the system is configured to induce a predetermined AV delay in the sequence.

[0141] At least two stimulation patterns of the plurality of stimulation patterns may differ from each other by one or more stimulation settings included in each of the at least two stimulation patterns.

[0142] The plurality of stimulation modes may include a first stimulation mode and a second stimulation mode performed after the first stimulation mode. The second stimulation mode may have at least one stimulation setting that is set based on an algorithm using a blood pressure variation parameter associated with input data of the first stimulation mode.

[0143] The system may include a blood pressure sensor for providing input data related to the patient's blood pressure.

[0144] The blood pressure sensor may be implantable.

[0145] The blood pressure sensor and controller may be configured to operate at least partially as a closed loop.

[0146] In another aspect, an embodiment provides a system for reducing blood pressure. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart with stimulation pulses. The system may include a controller. The controller may be configured to provide a first stimulation mode including at least one stimulation setting configured to reduce or prevent atrial drive of at least one ventricle within a first time interval, and 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 change parameter related to the first input data. The controller may be configured to adjust at least one parameter of a second stimulation mode, which includes a second stimulation setting configured to reduce or prevent atrial drive in at least one ventricle. The second stimulation setting may be based on the at least one blood pressure change parameter. The controller may be configured to provide a second stimulation mode within a second time interval.

[0147] In another aspect, an embodiment may provide a system for reducing blood pressure. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart with stimulation pulses. The system may include at least one controller configured to execute a stimulation mode, the stimulation mode including at least one stimulation setting configured to reduce or prevent atrial drive in at least one ventricle. The stimulation mode may be selected so as to cause an immediate reduction in blood pressure from an initial pressure value to a reduced pressure value and to maintain the patient's average blood pressure at rest at least 8 mmHg below the initial pressure.

[0148] The lowered blood pressure value may be maintained for a time interval of at least 1 minute.

[0149] In another aspect, an embodiment provides a kit for reducing blood pressure. The kit may include at least one device for setting a stimulation pattern for reducing blood pressure. The device may include at least one stimulation electrode. The device may include a controller for setting an adjustable stimulation pattern and a set of instructions for adjusting the stimulation pattern based on input related to the patient's blood pressure.

[0150] In another aspect, an embodiment provides a system for reducing blood pressure. The system may include at least one stimulation electrode for stimulating at least one chamber of a patient's heart. The system may include at least one controller configured to execute a stimulation pattern, the stimulation pattern including at least one stimulation pulse having at least one stimulation setting configured to reduce or prevent atrial drive in at least one ventricle. The at least one stimulation setting may be configured such that maximum atrial stretch is at a value approximately equal to or below the maximum atrial stretch of the same heart when not receiving stimulation.

[0151] In any of the embodiments described herein, atrial stretch may be measured, calculated, and / or estimated as known in the art. It is known that atrial contraction affects atrial pressure and atrial stretch. Atrial pressure and stretch depend on the volume of the atria, which depends on the amount of blood in the atria and the forces generated by the muscle contraction. In a healthy heart, as the atria contract, atrial pressure increases. When atrial contraction stops, atrial pressure drops and blood flows out of the atria to fill the ventricles. Then, when the ventricles contract, the AV valves close and the atria begin to fill again because there is no valve to prevent blood flow from the venous system to the atria. The pressure generated in the ventricles also increases atrial pressure by various mechanisms, one of which involves expansion of the AV valve into the atria. The increase in atrial pressure that occurs in response to a closed AV valve will also increase atrial stretch, which involves atrial volume and atrial pressure. When the AV valve is closed, the contraction of the atria increases both atrial pressure and atrial stretch because the closed valve prevents the reduction in volume. The increase in stretch in the atria stimulates pressure receptors (also referred to as stretch receptors) present in the atrial wall chamber. These pressure receptors are involved in hormonal and / or neuronal reductions in blood pressure. Therefore, in some embodiments, atrial stretch determination may include measuring atrial pressure. In some embodiments, atrial stretch determination 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 expected to be greater than the amount of blood when the atria contract twice during a single cardiac cycle. Therefore, if atrial contraction is performed once per cardiac cycle and the atrial contraction is entirely against a closed valve, the atrial pressure and / or atrial stretch may be higher than the atrial pressure and / or atrial stretch in the case when the atria contract twice per cycle. However, when the atria contract only against a closed valve, there is also no atrial drive, and in some embodiments, a balance may be achieved between the values ​​set for atrial pressure (and atrial stretch) and atrial drive (per cardiac cycle and / or per pacing mode).

[0152] At least one stimulation setting may be configured to induce maximal contraction of the atrium when the AV valve is open.

[0153] At least one stimulation setting can be configured to change the mechanism of at least one atrium contraction such that the mechanism of at least one atrium contraction is different from a previous natural mechanism of atrium contraction. The mechanism of atrium contraction can be assessed using any known technique, including, for example, ultrasound (e.g., echocardiography or cardiac echo).

[0154] At least one stimulation setting can be configured to reduce the force of at least one atrium contraction. For example, the force of the atrium contraction can be reduced by temporarily generating atrial spasm or atrial flutter. An example is to deliver a burst of rapid stimulation pulses to the atrium for a short predefined time. The force of the atrium contraction can be calculated from sensing of atrial pressure and / or its derivatives such as wall motion or flow using any known means. Such sensing can be used as feedback for a closed loop and / or used occasionally (e.g., at implantation and / or during examination).

[0155] At least one stimulation setting may be configured to prevent at least one atrium from contracting. For example, contraction of an atrium may be prevented by temporarily creating atrial spasm or atrial flutter. An example is delivering a burst of rapid stimulation pulses to the atrium over a short predefined time.

[0156] In another aspect, an embodiment provides a system for reducing blood pressure. The system may include at least one stimulation electrode for stimulating at least one chamber of the patient's heart. At least one controller may be configured to execute a stimulation pattern of stimulation pulses to the patient's heart. At least one controller may be configured to receive input related to the patient's AV valve state. Such input may be provided by wired or wireless communication from an implanted or external acoustic sensor 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.

[0157] Input related to the patient's AV valve status may indicate the timing of closure of the AV valve.

[0158] A heart sound sensor may be used as a basis to provide input regarding the patient's AV valve status.

[0159] Blood flow sensors may be used to provide input related to the patient's AV valve status.

[0160] The blood flow sensor may include an implanted sensor.

[0161] The blood flow sensor may include an ultrasonic sensor for sensing blood flow through the AV valve.

[0162] The blood flow sensor and controller may be configured to operate at least partially as a closed loop.

[0163] The stimulation pattern may include at least one stimulation pulse configured to reduce or prevent atrial drive of at least one ventricle.

[0164] The step of adjusting at least one stimulation pattern may include adjusting an AV delay of at least one stimulation pulse.

[0165] In another aspect, an embodiment provides a system for reducing a ventricular filling volume in a patient having a pre-treatment ventricular filling volume. The system may include a stimulation circuit configured to deliver stimulation pulses to at least one cardiac chamber. The system may include at least one controller configured to perform delivery of stimulation pulses to at least one cardiac chamber of one or more stimulation patterns. At least one of the stimulation pulses may have a first stimulation setting, and at least one of the stimulation pulses may have a second stimulation setting that is different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting may be configured to reduce or prevent atrial drive, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume.

[0166] The first stimulation setting and the second stimulation setting may be configured to reduce or prevent atrial drive.

[0167] The first stimulation setup may have an AV delay that is different from the AV delay of the second stimulation setup.

[0168] At least one of the one or more stimulation patterns may be repeated at least twice within a one hour period.

[0169] The at least one controller may be configured to continuously perform one or more stimulation patterns over a time interval lasting 10 minutes or longer.The first stimulation setting may be configured to reduce or prevent atrial drive in the at least one ventricle for at least 50% of the time interval.

[0170] The second stimulation setting may have a longer AV delay than the first stimulation setting.

[0171] The second stimulation setup has a longer AV delay than the first stimulation setup.

[0172] The one or more consecutive stimulation patterns may include at least one stimulation pulse having the first stimulation setting for at least about 85% of the time intervals.

[0173] The interval may be at least 30 minutes long.

[0174] The time interval may be at least an hour long.

[0175] The time interval may be at least 24 hours long.

[0176] The one or more consecutive stimulation patterns may include at least one stimulation pulse having a third stimulation setting that is different from the first stimulation setting and the second stimulation setting and is configured to reduce or prevent atrial drive in at least one ventricle.

[0177] One or more consecutive stimulation patterns may include at least one stimulation pulse having a third stimulation setting that is different from the first stimulation setting and the second stimulation setting and is configured to not reduce or prevent atrial drive in at least one ventricle for less than about 50% of the time interval.

[0178] One or more consecutive stimulation patterns may include a third stimulation configured to not reduce or prevent atrial drive in at least one ventricle for about 20% or less of the time interval.

[0179] One or more stimulation patterns may include a sequence of 10-60 stimulation pulses with a first stimulation setting. The first stimulation setting may be configured to reduce or prevent atrial drive in at least one ventricle and include a sequence of 1-10 heartbeats within the 10-60 stimulation pulses. The sequence of 1-10 heartbeats may have a longer AV delay than the first stimulation setting.

[0180] The sequence of 1-10 heartbeats may include at least one stimulation pulse having a first stimulation setting configured to reduce or prevent atrial drive in at least one ventricle.

[0181] The sequence of 1-10 heart beats may include at least one stimulation pulse having a second stimulation setting.

[0182] Sequences of 1-10 heartbeats may include natural AV delays.

[0183] At least one heartbeat in the sequence of 1-10 heartbeats may occur without stimulation.

[0184] The first stimulation setting can be configured to reduce atrial drive in at least one ventricle and the second stimulation setting can be configured to reduce the baroreceptor reflex response or adaptation to the reduction in atrial drive such that increases in blood pressure values ​​occurring between stimulation pulses are limited to predetermined values.

[0185] The second stimulation setting may be configured to allow an increase in blood pressure about 1 to 5 heartbeats.

[0186] The stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting.

[0187] The stimulation pattern may include a plurality of stimulation pulses having a second stimulation setting.

[0188] The second stimulation setting may be present between approximately 1% of the plurality of stimulation pulses and 40% of the plurality of stimulation pulses of the stimulation pattern.

[0189] The stimulation pattern may comprise a ratio of stimulation pulses having a first stimulation setting to stimulation pulses having a second stimulation setting that corresponds to a ratio of time constants of responses to increases and decreases in blood pressure.

[0190] The first stimulation setup may include a first AV delay and the second stimulation setup may include a second AV delay. The first AV delay may be shorter than the second AV delay.

[0191] The stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting.

[0192] The stimulation pattern may include a plurality of stimulation pulses having a second stimulation setting.

[0193] The second stimulation setting may be present between approximately 1% of the plurality of stimulation pulses and 40% of the plurality of stimulation pulses of the stimulation pattern.

[0194] The stimulation pattern may comprise a ratio of stimulation pulses having a first stimulation setting to stimulation pulses having a second stimulation setting that corresponds to a ratio of time constants of responses to increases and decreases in blood pressure.

[0195] The stimulation pattern may include a ratio of about 8 to about 13 stimulation pulses having the first stimulation setup to about 2 to about 5 stimulation pulses having the second stimulation setup.

[0196] One of the first stimulation setting and the second stimulation setting may be configured to evoke a hormonal response from the patient's body.

[0197] In another aspect, an embodiment provides a system for reducing the ventricular filling volume of a patient having a pre-treatment ventricular filling volume. The system may include a stimulation circuit configured to deliver a stimulation pulse to at least one cardiac chamber. The system may include at least one controller configured to deliver a stimulation pulse to at least one cardiac chamber in one or more stimulation modes. At least one of the stimulation pulses may include a setting that is configured to cause ventricular excitation to begin between about 0 ms and 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 atrial excitation in at least one atrium occurs, or between about 0 ms and about 70 ms after one or more excitatory pulses are delivered to the atria.

[0198] In some embodiments, the timing of sensed atrial excitement can be determined by considering the delay between the actual start of excitement and sensing it. For example, if the estimated sensing delay is 20 ms-40 ms, and the stimulation pulse is to be delivered 0 ms-70 ms after the start of atrial excitement, then the system can be set to deliver the pulse between 40 ms before the next expected sensing event to 30 ms after the next expected sensing event or 30 ms after the next sensing event. Similarly, if the stimulation pulse is to be delivered to the ventricle 0 ms-50 ms before the start of atrial excitement, assuming the same 20 ms-40 ms sensing delay, the system can be set to deliver the pulse between 40 ms before the next expected sensing event to 90 ms before the next expected sensing event. The sensing delay may be caused by one or more of the distance between the location of the start of excitement and the sensing electrode, the level of the electrical signal, the characteristics of the sensing circuit, and the threshold setting of the sensing event. The delay may include, for example, the duration of signal propagation from the origin of excitement to the electrode position, the duration related to the frequency response of the sensing circuit, and / or the duration necessary for the signal propagation energy to reach a level that can be detected by the sensing circuit. The delay may be significant, for example, and may range between about 5 ms to about 100 ms. One method for estimating the delay is to use the time difference between the sensed AV delay when sensing the atria and ventricles and the AV delay when pacing the atria and sensing the ventricles. Other methods may use calculations of amplifier response times based on set thresholds, signal strength, and frequency content. Other methods may include modifying the delay used for atrial sensing until the effect on blood pressure is the same as that obtained by pacing the atria and ventricles with the desired AV delay.

[0199] In another aspect, a system for reducing a 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 cardiac chamber. At least one controller may be configured to perform delivery of stimulation pulses of one or more stimulation patterns to the at least one cardiac chamber over a time interval lasting 10 minutes or longer. At least one of the stimulation pulses may have a first stimulation setting configured to reduce or prevent atrial drive 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.

[0200] 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 the step of delivering stimulation pulses of one or more stimulation patterns to at least one cardiac chamber over a time interval lasting 10 minutes or longer. At least one of the stimulation pulses may have a first stimulation setting configured to reduce or prevent atrial drive 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.

[0201] Other systems, methods, features and advantages of the present embodiments will be or will become apparent to one of ordinary skill in the art upon review of the following drawings and detailed description. It is intended that all such additional systems, methods, features and advantages be included in this description and this overview, be within the scope of the present embodiments, and be protected by the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0202] The present embodiment may be better understood with reference to the following drawings and descriptions. The components in the drawings are not necessarily drawn to scale, but emphasis is placed on illustrating the principles of the present embodiment. In addition, in the drawings, similar reference numerals throughout the different figures indicate corresponding parts.

[0203] Figure 1 showing systolic blood pressure of a hypertensive patient receiving a stimulation signal plotted against time; Figure 2 Show Figure 1 an enlarged view of the portion indicated by the dotted rectangle A; Figure 3A Depiction Figure 2 An enlarged view of a portion between time point a and time point a'; Figure 3B Depiction Figure 1 an enlarged view of the portion indicated by the dotted rectangle A'; Figure 4 Depiction Figure 1 an enlarged view of the portion indicated by a dotted rectangle B; Figure 5A Depiction Figure 1 an enlarged view of the portion indicated by a dotted rectangle C; Figure 5B Depiction Figure 5A An enlarged view of the portion between time point c and point c'; Figure 6 showing systolic blood pressure of a hypertensive patient receiving a stimulation signal plotted against time; Figure 7 showing systolic blood pressure of a hypertensive patient receiving a stimulation signal plotted against time; Figure 8is a flow chart illustrating an exemplary method for setting and / or selecting a stimulation mode; Fig. 9 is a schematic diagram illustrating an exemplary system for reducing blood pressure; Fig. 10A Time graphs showing a healthy canine heart, including: electrocardiogram, aortic pressure, and left ventricular pressure; Fig. 10B Time graphs showing a healthy canine heart, including: electrocardiogram, aortic pressure, and left ventricular pressure; Fig.11A A time plot of a hypertensive canine heart is shown, including right atrial pressure, an enlarged diastolic portion of right ventricular pressure, right ventricular pressure, and an electrocardiogram; Fig. 11B A time plot of a hypertensive canine heart is shown, including right atrial pressure, an enlarged diastolic portion of right ventricular pressure, right ventricular pressure, and an electrocardiogram; Fig.12 Shown is the right atrial pressure, the enlarged diastolic portion of the right ventricular pressure, the right ventricular pressure, the left ventricular pressure and the aortic pressure and electrocardiogram in the same graph of a hypertensive canine heart; Fig.13 is a flow chart illustrating an exemplary method for reducing blood pressure; Fig.14 is a flow chart illustrating an exemplary apparatus for reducing blood pressure, which can perform one or more of the methods described herein, such as Fig.13 and Fig.23 Methods; Fig.15 is a schematic diagram showing an artificial valve according to an embodiment; Fig.16 showing systolic blood pressure of a hypertensive patient receiving a stimulation signal plotted against time; Fig.17 is a graph showing ventricular volume, ventricular pressure, atrial pressure, and an electrocardiogram (ECG) plotted against time, highlighting the isovolumetric and rapid ejection phases of a single cardiac cycle; Fig.18 is a set of graphs showing an electrocardiogram (ECG), right ventricular pressure (RVPress), right atrial pressure (RA Press), aortic pressure (Ao Press), and left ventricular pressure (LV Press) tracked over a period of time, showing a significant increase in atrial pressure, during which time stimulation was changed from sinus rhythm to atrial and ventricular pacing with an AV delay of 2 ms, in accordance with an embodiment; Fig.19is a set of graphs showing electrocardiogram (ECG), right ventricular pressure (RV Press), right atrial pressure (RA Press), aortic pressure (Ao Press), and left ventricular pressure (LV Press) traced over a period of time, showing no significant increase in atrial pressure, during which the stimulus was changed from sinus rhythm to atrial and ventricular pacing with an AV delay of 40 ms; Figure 20A-20C is a graph of atrial pressure versus time showing varying degrees of overlap between atrial pressure resulting from atrial contractions and passive pressure increases occurring in the atria at different time intervals between atrial contractions, wherein Fig. 20A shows an example of no overlap between atrial pressure due to atrial contraction and passive pressure increase in the atrium, Fig. 20B shows an example of combining atrial pressure resulting from atrial contraction and a passive pressure increase in the atrium with a 30 ms delay between the initiation of atrial contraction, and Fig. 20C Different degrees of overlap due to delays of 0 ms, 10 ms, 20 ms, 30 ms, 40 ms, 50 ms, and 60 ms are comparatively shown; Fig.21 is a graph that plots a patient's average blood pressure over a 24-hour period; Fig. 22 is a graph plotting the average blood pressure of a patient during a 24 hour period when not treated and when treated according to an embodiment; Fig.23 is a flow chart illustrating an exemplary method for controlling atrial pressure and atrial stretch according to an embodiment; Fig.24 is a graph illustrating an example of the relationship between AV delay and systolic blood pressure reduction for a particular patient; Fig.25 It is a graph of systolic blood pressure obtained over a 24-hour period for a specific outpatient; Fig.26 It is for different Fig.25 a line graph of systolic blood pressure obtained during a 24-hour period for another specific outpatient of a patient; Fig. 27 is a graph showing the effect of antihypertensive treatment as disclosed herein on dogs, plotting systolic blood pressure (in mmHg) versus time (in days); Fig.28A Contains graphs A and B showing the effect of heart rate on peripheral and central blood pressure according to an embodiment; Fig.28B is a diagram plotting A waves and R waves over time and showing AA and RR intervals according to an embodiment; Fig.29 is a schematic diagram illustrating an embodiment of a cardiac stimulation system for controlling blood pressure and delivering both hypertension therapy and isolated systolic hypertension therapy; Fig. 30A and Fig. 30B It shows that Fig.29 A flowchart of an embodiment of a method for controlling blood pressure implemented by a system of FIG. Fig.31 is a table of blood pressure measurement data obtained by conducting an experiment on a hypertensive patient according to an embodiment, the experiment applying hypertension treatment using a short atrioventricular delay value and increasing the heart rate.

[0204] Detailed Description Embodiments provide systems and methods for controlling blood pressure, particularly for reducing systolic pressure while having minimal or no effect on diastolic pressure. Other embodiments may provide systems and methods for reducing systolic pressure while increasing diastolic pressure to further reduce pulse pressure. Other embodiments may provide systems and methods for reducing systolic pressure while maintaining or increasing diastolic pressure above a predefined threshold. Other embodiments may provide systems and methods for increasing diastolic pressure above a specified threshold. Embodiments may achieve such a target blood pressure reduction by adjusting the inter-beat and intra-beat intervals to induce a physiological response of pulse pressure reduction. As used herein, an "inter-beat interval" is a time interval between different events occurring within the same heartbeat, such as the time interval between atrial electrical activation and ventricular electrical activation within the same heartbeat. As used herein, an "intra-beat interval" is a time interval between similar events occurring in different consecutive heartbeats, such as the time interval between atrial electrical activation and the next atrial electrical activation. Reducing systolic pressure without a significant effect on diastolic pressure may provide an effective treatment for isolated systolic hypertension (ISH). Maintaining diastolic pressure above a specified threshold may prevent the risk of reduced cardiac perfusion or isolated diastolic hypotension.

[0205] To regulate the inter- and intra-beat intervals and provide RPP therapy while also facilitating other hypertension treatments, embodiments may achieve target blood pressure reduction by electrically stimulating the heart, for example, using a pacemaker device. Thus, embodiments include provisions for both RPP therapy (for treating isolated systolic hypertension) and hypertension therapy (for treatments affecting both systolic and diastolic blood pressure).

[0206] The detailed description discusses embodiments of isolated systolic hypertension treatment, associated pulse pressure lowering therapies, and systems, devices, and methods for combining isolated systolic hypertension treatment with other forms of hypertension treatment in Section I below. Section II below describes other forms of hypertension treatment and embodiments of systems, devices, and methods that can be used for isolated systolic hypertension treatment and / or other forms of hypertension treatment.

[0207] I. Examples of Treatment for Isolated Systolic Hypertension (ISH) Fig.28A An experimental example of the effect of heart rate on peripheral blood pressure and central blood pressure according to an embodiment is shown. Fig.28A Graph A in the figure shows the change in systolic blood pressure with increasing heart rate, while Graph B shows the change in diastolic blood pressure with increasing heart rate. Both Graphs A and B depict the peripheral (brachial) arterial pressure (denoted by the rectangular symbol ) and central (ascending aorta) arterial pressure (denoted by a triangle symbol These experiments are described in detail in Wilkinson, Ian B. et al. (2000), "The influence of heart rate on augmentation index and central arterial pressure in humans," Journal of Physiology, 525.1, pp. 263-270, which is incorporated herein by reference, a copy of which is attached as Annex A to U.S. Provisional Application No. 63 / 365,668, filed June 1, 2022, to which this application claims priority. As explained in the Wilkinson article (cited in that paragraph Figure 3A and Figure 3B In this application Fig.28A :

[0208] There were no significant differences in peripheral and central diastolic blood pressure responses to pacing ( ), but the effect on systolic blood pressure was significantly different ( ), such as in Figure 3A and Figure 3B During pacing, arterial pressure amplification from the aorta to the brachial artery increased, as defined by the ratio of peripheral to central pulse pressure (Table 2). However, when the ratio of peripheral to non-augmented central pulse pressure (P1-central diastolic pressure) was calculated, there was no significant change.

[0209] like Fig.28A As shown, an increase in heart rate results in a consistent increase in both central (measured in the aorta) and peripheral (measured in the brachial artery) diastolic blood pressure. An increase in heart rate also results in an increase in central and peripheral systolic blood pressure. A decrease in heart rate results in a decrease in both systolic and diastolic blood pressure.

[0210] The inventors have found a way to combine hypertension treatment (reducing both systolic and diastolic blood pressure) with a certain heart rate effect manipulation, which itself increases both systolic and diastolic blood pressure, such that the combined effect of the hypertension treatment and the manipulation of the effect of heart rate on blood pressure is a reduction in systolic blood pressure and minimal or no reduction in diastolic blood pressure. In other words, the inventors have found a way to combine hypertension treatment with a certain heart rate manipulation to reduce pulse pressure (PP). Based on this physiological interaction, embodiments may provide systems and methods for treating isolated systolic hypertension by reducing pulse pressure, referred to herein as reduced pulse pressure (RPP) therapy.

[0211] Fig.28A The data in were obtained using a pacemaker to increase heart rate. Therefore, the device can be used to treat RPP in hypertensive patients who are receiving other forms of hypertension treatment that affect both systolic and diastolic blood pressure, as described further below.

[0212] There are many ways to increase your heart rate. Ways to increase your heart rate include physical exercise, inducing emotional responses, and using drugs or hormones (such as adrenaline). However, these methods affect many other functions in the body and are therefore not known to have a significant effect on your heart rate. Fig.28A Another problem is that these methods affect the timing of atrial contraction and the AA interval, which usually translates into a very similar change in the RR interval, but as discussed further below, this translation may not occur if AV delay is altered in parallel as part of the treatment.

[0213] Unless it occurs naturally, an increase in heart rate may result in undesirable side effects, such as an increased risk of life-threatening tachycardia. Therefore, increasing heart rate for therapeutic purposes may require precise control of the increased heart rate, assessment of whether the condition requires pausing the setting of the increased heart rate, and immediate cessation of the setting of the increased heart rate if necessary.

[0214] Therefore, the use of a device capable of providing cardiac stimulation pulses is a preferred embodiment. A cardiac stimulation pulse is an energy pulse, typically electrical, that triggers depolarization in cardiac tissue. In a preferred embodiment, the device may be implantable to conveniently provide chronic isolated systolic hypertension treatment. In a most preferred embodiment, the device may include at least one cardiac lead to achieve cardiac stimulation.

[0215] Specifically, as explained below, the use of such a device allows precise manipulation of the intra-beat intervals, thereby setting the inter-beat intervals and heart rate. By definition, the heart rate (expressed in beats per minute) is calculated by dividing the number of heartbeats by the time they occur, which averages the inter-beat durations of those beats. The inter-beat duration, or the time between identical cardiac events in consecutive beats, is constantly changing. Two types of inter-beat durations are often used: the AA interval, which is the duration between two consecutive atrial electrical activations (as seen by the "P" wave on an ECG graph); and the RR interval, which is the duration between two consecutive ventricular electrical activations (as seen by the "R" wave of the QRS complex on an ECG graph).

[0216] Hemodynamically, ventricular contraction affects systemic blood pressure. Once the previous ventricular contraction is over, systemic blood pressure continues to fall as arterial blood flows into the organs and, through the tissues, into the veins. It is the opening of the aortic valve, which connects the ventricles to the arterial system, that allows the increased pressure in the contracting ventricles to propagate from the heart into the arterial system. The timing of these events is contained in the RR interval.

[0217] However, AA intervals and RR intervals are not unrelated. Fig.28B , using the AV interval (the delay between atrial and ventricular activation), these two intervals can be expressed using another interval and the AV delay as: RR(t) = AA(t) - AV(t) + AV(t+1).

[0218] The use of the hypertension therapy described below requires the manipulation of AV delay on a beat-by-beat basis. Therefore, the combination of heart rate increase and this therapy into RPP is not obvious because when AV delay is manipulated to be different from the natural delay, the RR interval, the AA interval, or both are affected.

[0219] Fig.29 An embodiment of a cardiac stimulation system 2900 for controlling blood pressure and delivering RPP and isolated systolic hypertension therapy is shown. As shown, system 2900 may include device 2950, ​​multiple ventricular and / or atrial electrodes 2956, and multiple sensors 2958. Sensors 2958 may include atrial sensors, heart rate sensors, activity sensors (e.g., accelerometers), and / or ECG sensors. As shown, device 2950 may include a controller, power supply, clock, memory, and telemetry or communication unit. Device 2950 may be constructed and have components similar to a cardiac pacemaker, and may be configured to communicate with the following references. Fig.14 The device 50 described above is substantially the same as described above. In addition, the device 2950 may include any component of the system 700 (see the following description). Fig. 9 ), and system 700 may include any components of device 2950.

[0220] like Fig.29 As shown, the system 2900 may also include a data source 2990 with which the device 2950 can communicate. In embodiments, the data source may include a database, a data table, and / or a computer user interface through which a user enters data. The data types provided by the data source 2990 may include, for example, intrinsic cardiac data and / or pressure data (diastolic and / or systolic pressure as a function of heart rate).

[0221] In a preferred embodiment, a cardiac stimulation device (such as device 2950) may include a provision for obtaining an indication of the intrinsic heart rate (most preferably obtaining such an indication during the delivery of RPP therapy), while the actual heart rate produced may be higher than the intrinsic heart rate. Fig.29 As shown, in an embodiment, an indication of intrinsic heart rate along with other data may be provided by data source 2990 and transmitted to device 2950 via a telemetry or communication unit and stored in a memory of device 2950 .

[0222] To provide effective heart rate sensing, in some embodiments, a single value may be used as an indication of intrinsic heart rate. The value may be a fixed value based on the average heart rate in a population. Other embodiments may use a table of values, such as representing average heart rate values ​​for different populations (e.g., based on age and / or gender). In other embodiments, the value may be based on previous heart rate measurements performed in patients who are about to be treated for isolated systolic hypertension. In some embodiments, the table may be further divided into different times of the day.

[0223] In some embodiments, an indication of heart rate may also be obtained before and while an increase in heart rate is caused to implement a reduction in pulse pressure and the increase in heart rate masks a slower (intrinsic) heart rate. Implantable embodiments of the device may include an activity sensor (e.g., Fig.29 ), which generates an estimate of intrinsic heart rate based on activity level, regardless of the actual heart rate at the time of the estimate. In other embodiments, the device may include an ECG sensor or cardiac sensing leads (e.g., as shown in Fig.29 ), which is used to achieve atrial overdrive pacing, a method of pacing the heart at rates close to and above the intrinsic rate that was originally developed in attempts to treat atrial arrhythmias.

[0224] In embodiments, system 2900 including device 2950 and its controller may operate according to any embodiment of the methods described herein.

[0225] In another aspect, the present disclosure provides a non-transitory computer-readable medium storing software, which may include instructions executable by one or more computers that, when executed, cause the one or more computers to perform any of the methods described herein.

[0226] In an embodiment, the device 2950 may generally be any computing device including a processor and a machine-readable medium including instructions that can be executed by the processor. Broadly speaking, any type of computing system having one or more central processing units (CPUs) and / or graphics processing units (GPUs) may be used to implement the processes and methods of the embodiments described in the detailed description and shown in the accompanying drawings. Special circuits such as application-specific integrated circuits (ASICs) may also be used to implement the processes and methods of the embodiments. The processes and methods of the embodiments may also be implemented on a computing system including a read-only memory (ROM) and / or a random access memory (RAM), which may be connected to one or more processing units. Embodiments of computing systems and devices include, but are not limited to, servers, cellular phones, smart phones, tablet computers, notebook computers, laptop computers or desktop computers, all-in-one computers.

[0227] The processes and methods of the embodiments may be stored as instructions and / or data on a non-transitory computer-readable medium. The non-transitory computer-readable medium may include any suitable computer-readable medium, such as a memory, such as RAM, ROM, flash memory, or any other type of memory known in the art. In some embodiments, the non-transitory computer-readable medium may include, for example, an electronic storage device, a magnetic storage device, an optical storage device, an electromagnetic storage device, a semiconductor storage device, or any suitable combination of such devices. More specific examples of non-transitory computer-readable media may include a portable computer disk, a floppy disk, a hard disk, a disk or a tape, a read-only memory (ROM), a random access memory (RAM), a static random access memory (SRAM), a portable compact disc read-only memory (CD-ROM), an erasable programmable read-only memory (EPROM or flash memory), an electrically erasable programmable read-only memory (EEPROM), a digital versatile disk (DVD and DVD-ROM), a memory stick, other kinds of solid-state drives, and any suitable combination of these exemplary media. As used herein, non-transitory computer readable media should not be construed as transient signals such as radio waves or other freely propagating electromagnetic waves, electromagnetic waves propagating through a waveguide or other transmission medium (e.g., light pulses passing through a fiber optic cable), or electrical signals transmitted through wires.

[0228] The instructions stored on the non-transitory computer-readable medium for performing operations of the present embodiment may be instruction set architecture (ISA) instructions, assembly instructions, machine instructions, machine-dependent instructions, microcode, firmware instructions, configuration data for an integrated circuit, state setting data, or source code or object code written in any of one or more programming languages, including an object-oriented programming language such as Smalltalk, C++ or a suitable language, and a procedural programming language such as the "C" programming language or a similar programming language.

[0229] In one or more embodiments, the functions described may be implemented in hardware, software, firmware, or any combination thereof. If implemented in software or firmware, the functions may be stored as one or more instructions or codes on a computer-readable medium and executed by a hardware-based processing unit. A computer-readable medium may include a computer-readable storage medium, which corresponds to a tangible medium such as a data storage medium (e.g., RAM, ROM, EEPROM, flash memory, or any other medium that can be used to store desired program code in the form of instructions or data structures and can be accessed by a computer).

[0230] Instructions may be executed by one or more processors, such as one or more digital signal processors (DSPs), general-purpose microprocessors, application-specific integrated circuits (ASICs), field programmable logic arrays (FPGAs), or other equivalent integrated or discrete logic circuits. Therefore, the term "processor" as used herein may refer to any of the aforementioned structures or any other structure suitable for implementing the techniques described herein. Likewise, these techniques may be fully implemented in one or more circuits or logic elements.

[0231] Embodiments may also include settings for calibrating hypertension therapy and RPP therapy in order to achieve a desired therapeutic effect in a patient.

[0232] In some embodiments, a value may represent a decrease in diastolic blood pressure resulting from the application of a hypertension therapy. A table of diastolic blood pressure at different heart rates may be used to calculate the expected increase in diastolic blood pressure given a certain basal (intrinsic) heart rate and a potential increased heart rate, using extrapolated values ​​to make the table values ​​more complete (if necessary). In embodiments, a value representing the effect of a hypertension therapy on systolic blood pressure and a table of systolic blood pressure at different heart rates may also be provided. In embodiments, as Fig.29 As shown, these tables and values ​​can be provided by data source 2990.

[0233] In some embodiments, several values ​​may represent the reduction in diastolic blood pressure (and optionally systolic blood pressure) resulting from the application of a hypertension treatment according to different known or measurable parameters (e.g., patient age, treatment titration / dose, heart rate, and / or activity level). Fig.29 A data source 2990) provides or generates a corresponding table of diastolic pressure at different heart rates. In an embodiment, some of these values ​​can be obtained by applying hypertension therapy and / or RPP therapy to the patient. In other embodiments, these values ​​can be updated throughout the process of delivering the treatment to the patient.

[0234] In an embodiment, the expected heart rate increase can be calculated by first finding the heart rate at which the increase in diastolic pressure (above the intrinsic rate) is equal to the decrease in diastolic pressure caused by the hypertension therapy, and then subtracting the intrinsic rate. The potential heart rate increase can then be risk assessed (i.e., the risk of undesirable effects). In some embodiments, the heart rate increase can be compared to a predetermined feasible heart rate increase (e.g., 10 beats per minute). In other embodiments, a health care professional can determine whether the amount of the heart rate increase is an appropriate risk. If not, in some embodiments, a predetermined increase can be used to provide a partial increase in diastolic pressure. Other embodiments can use a specified heart rate increase, for example, a heart rate increase determined to be appropriate by a health care professional. When updates to values ​​are available throughout the delivery of therapy, optimally, risk assessments are performed at some or all time points at which updated values ​​are available.

[0235] In some embodiments where there is data about systolic blood pressure, the expected overall effect on systolic blood pressure can be calculated by subtracting the expected increase (caused by the expected increase in heart rate) from the systolic blood pressure reduction implemented by the hypertension therapy. This potential systolic blood pressure reduction can then undergo an efficacy assessment to determine whether the potential systolic blood pressure is sufficient. In some embodiments, the potential systolic blood pressure reduction can be compared with a predetermined minimum effective reduction (e.g., 5 mmHg). In other embodiments, a health care professional can determine whether the amount of potential systolic blood pressure is sufficient. If insufficient, in some embodiments, a lower increase in heart rate can be selected so that the reduction is sufficient; although the reduction in diastolic blood pressure may be smaller, there is no need to assess the risk of an increase in heart rate because the increase is lower than the increase determined to be an appropriate risk. When updates to values ​​are available throughout the course of therapy delivery, optimally, efficacy assessments are performed at some or all time points where updated values ​​are available.

[0236] In embodiments, the predetermined or professionally determined increase in heart rate may depend on heart rate and blood pressure data previously obtained from the patient. In some embodiments, the appropriate increase in risk may be updated using heart rate and blood pressure data obtained from the patient while hypertension therapy and / or RPP therapy, respectively, are being used on the patient. In embodiments, the appropriate increase in risk may be updated based on data obtained when hypertension therapy and RPP therapy are applied to the patient using one or several different settings and / or doses. In embodiments, the appropriate increase in risk may then be continuously updated, and risk assessments may then be performed at different time points during the long-term application of therapy to the patient.

[0237] When RPP therapy is combined with a hypertension therapy that uses short atrioventricular (AV) delay values ​​(see, e.g., those described in Section II below), embodiments of the RPP therapy may include modifying the VA interval such that the AV delay selected for the hypertension therapy plus the VA delay selected for the RPP therapy includes an AA interval appropriate for the desired increased heart rate because the AA interval (in milliseconds) is equal to 60,000 divided by the heart rate (in arbitrary units).

[0238] In some embodiments, an AA interval suitable for a desired heart rate increase refers to an AA interval that is shorter than a natural AA interval by a certain duration. In some embodiments, it means that the AA interval is shorter than the natural AA interval by a certain percentage. In some embodiments, the shortening of the AA interval can be a function of the natural AA interval, or a function of the natural AA interval and input from other sensors (e.g., an activity sensor).

[0239] In some embodiments, a cutoff heart rate can be defined so that RPP therapy is not delivered even if hypertension therapy is delivered. This cutoff may be required for several different reasons, including preventing an increased risk of tachycardia at high heart rates and preventing increased myocardial oxygen consumption that occurs at higher rates (and is particularly troublesome in heart failure patients). The cutoff rate can be a single preset number, or selected from a table of values ​​that depend on different patient characteristics or medical history (e.g., age, gender, and / or susceptibility to tachycardia). The cutoff rate can be updated (automatically or manually) throughout the delivery of RPP therapy. The cutoff heart rate can be different depending on different parameters (such as time of day, patient activity level, or blood pressure), and can be manually changed or automatically updated based on measured parameter values ​​(if available for the device). In an embodiment, the cutoff can be a "soft cutoff" that defines different levels of RPP therapy delivery at different heart rates. For example: (1) for beats over 90 beats per minute, RPP therapy may be delivered for no more than 10 minutes unless the heart rate drops below 90; (2) for beats over 100 beats per minute, RPP therapy may be delivered for only 2 minutes unless the heart rate drops below 100; and (3) for beats over 110 beats per minute, RPP therapy may not be delivered at all.

[0240] Fig. 30A An embodiment of a method 3000 for controlling blood pressure is shown, which may be used Fig.29. As shown, method 3000 may include the main steps of providing hypertension therapy, providing isolated systolic hypertension therapy, and repeating therapy as needed to achieve treatment goals. Specifically, as represented by a solid rectangle, method 3000 may start in step 3002 by delivering a first stimulation mode that reduces both systolic and diastolic pressures (e.g., to treat hypertension). Then, the method may continue in step 3008 by delivering a second stimulation mode that reduces systolic pressure while controlling diastolic pressure (e.g., causing minimal effect or no effect, or increasing) so as to reduce the difference between systolic and diastolic pressures, for example, to treat isolated systolic hypertension. Then, in step 3014, method 3000 may repeat steps 3002, 3008 as needed to achieve hypertension and ISH treatment. The adequacy of treatment of hypertension or ISH treatment may be achieved by comparing the systolic and diastolic pressure data of the patient when the treatment is applied with the systolic and diastolic pressure data when the treatment is not applied. For example, a blood pressure reading may be obtained before the start of the therapy, and the value may be compared with a similar measurement obtained when the therapy is effective. Optionally, further measurements can be taken over time during the application of therapy to determine adequacy over time. Additionally, optionally, at various times during the application of therapy, therapy can be temporarily suspended to allow blood pressure to be measured without therapy application, and this measurement compared to the value obtained when therapy was effective. Optimally, such blood pressure measurements are repeated several times at different times of the day. If a greater than expected decrease in diastolic blood pressure is observed when assessing the adequacy of therapy, further shortening of the AA interval should be performed.

[0241] In an embodiment, method 3000 may include an optional step for implementing ISH therapy by Fig. 30A . As shown, before delivering the second stimulation mode, method 3000 can obtain an indication of the intrinsic heart rate at step 3004 and set the increased heart rate for ISH therapy to be above the intrinsic heart rate as described above. As described above, method 3000 can also calibrate the first stimulation mode with the second stimulation mode at step 3006. Although shown after step 3002, steps 3004 and 3006 can be completed at other times, such as before step 3002.

[0242] Fig. 30B Shown include Fig. 30A An embodiment of method 3020 of steps 3004 and 3006 of the present invention, which determines for a second stimulation mode a heart rate suitable for controlling an increase in diastolic pressure while reducing systolic pressure. As shown, method 3020 can be performed at step 3022 by measuring the heart rate during the use of a hypertension therapy (e.g., Fig. 30AIn other words, step 3022 may determine a diastolic reduction and / or a systolic reduction attributable to the first stimulation pattern. Then, in step 3024, method 3020 may continue by applying different increased heart rates and measuring the increases in systolic and diastolic pressure that occur at the different increased heart rates. The systolic and diastolic pressure increases at different heart rates may be determined by actively stimulating the patient at different heart rates and then determining a diastolic reduction and / or a systolic reduction and a systolic and diastolic pressure increase at the different heart rates. Then, in step 3026, method 3020 may continue by determining an appropriate heart rate to achieve a desired pulse pressure given the previously measured data. Then, in step 3028, method 3020 may continue by applying ISH therapy using the determined heart rate. In other words, step 3028 may use the determined increased heart rate to deliver a second stimulation pattern ( Fig. 30A Step 3008) to control diastolic pressure as needed. Therefore, in implementing this control, the second mode can combine a stimulation mode that lowers blood pressure with a stimulation that increases heart rate. The control provided by this combination of a stimulation mode that lowers blood pressure and a stimulation that increases heart rate can include: (1) lowering systolic pressure while having minimal or no effect on diastolic pressure; (2) lowering systolic pressure while increasing diastolic pressure; (3) lowering systolic pressure while controlling diastolic pressure so that diastolic pressure is between a lower allowable value and a higher allowable value; (4) controlling systolic and diastolic pressure so that the resulting pulse pressure is between a lower allowable value and a higher allowable value and / or is a predetermined amount and / or a predetermined percentage lower than the initial pulse pressure; and / or (5) lowering systolic pressure while maintaining diastolic pressure above a specified minimum value.

[0243] Reference again Fig. 30A , embodiments may also include control settings during delivery of the second stimulation mode. Specifically, as shown, as described above, method 3000 may include, at step 3010, monitoring the heart for condition limits, and, as described above, interrupting the second stimulation mode if the limits are reached.

[0244] For purposes of illustration, the following is an example of method 3000. A patient with a measured blood pressure of 145 / 75 mmHg requires therapy. These blood pressure values ​​are indicative of ISH. A natural resting heart rate is measured and is 66 bpm. Hypertension therapy is applied ( Fig. 30A 3002), and the resulting blood pressure is 135 / 70 mmHg. The diastolic blood pressure value is 5 mmHg lower than its original level. Fig.28A, Graph B does not show a diastolic pressure of 70 mmHg, but at a heart rate of 66 bpm, the peripheral diastolic pressure is about 82 mmHg; at a heart rate of about 76 bpm, a value 5 mmHg higher (87 mmHg) is obtained, and the heart rate has increased by 10 bpm. Then, Fig. 30A Step 3004 of will constitute calculating a new AA interval for therapy that contains an increase of approximately 10 beats / minute that is expected to cause the diastolic pressure value to return to its value prior to application of therapy. An additional portion of step 3004 will constitute calculating the expected effect on systolic pressure. Fig.28A In graph A, at a heart rate of 66 bpm, the peripheral systolic blood pressure value is about 137 mmHg, while at 76 bpm it is about 139 mmHg, so an increase of 2 mmHg in systolic blood pressure is expected. Therefore, the overall expected effect of the change (increase of 10 bpm) would be an increase in blood pressure value from 135 / 70 mmHg to 137 / 75 mmHg, which means (compared to the original 145 / 75 mmHg value) an effect of only a decrease in systolic blood pressure of 8 mmHg, which means a decrease in pulse pressure of 8 mmHg. Fig. 30A The modified stimulation pattern is applied in step 3008 of the present invention, and blood pressure measurements should be used to determine the diastolic and systolic blood pressure levels. If the diastolic blood pressure level still has not returned to the initial value, it is recommended to further increase the heart rate, using the same process as described previously for calculation. If the diastolic blood pressure value is too high, it is recommended to reduce the heart rate and observe Fig.28A The effect of a lower heart rate on diastolic blood pressure is shown in graph B. If the systolic blood pressure value is too high, it is recommended to reduce the heart rate moderately to reduce the systolic blood pressure value while minimizing the reduction in diastolic blood pressure.

[0245] Thus, in this embodiment, a first stimulation that lowers both systolic and diastolic blood pressure is combined with a second stimulation that increases heart rate to increase both diastolic and systolic blood pressure to return the diastolic blood pressure to its original value (no increase or decrease) while providing a systolic blood pressure reduced from its original value.

[0246] As one of ordinary skill in the art will recognize, using the above and Fig.28A Other embodiments of method 3000 may achieve different effects on systolic and diastolic pressures, based on the relationship described in . For example, another embodiment of method 3000 may provide an overall effect of lowering systolic pressure while increasing diastolic pressure, rather than simply preventing a decrease in diastolic pressure. In this embodiment, the patient may have an original measured blood pressure of 145 / 75 mmHg. As in the previous embodiment, a hypertension therapy ( Fig. 30A 3002), resulting in a blood pressure of 135 / 70 mmHg, where the diastolic blood pressure value is 5 mmHg lower than its original level. Fig.28AIn graph B, the heart rate increases from a starting rate of 66 bpm by about 14 bpm to about 80 bpm, achieving a peripheral diastolic pressure of about 90 mmHg, which represents an increase of about 8 mmHg in peripheral diastolic pressure of about 82 mmHg at a heart rate of 66 bpm. Then, Fig. 30A Step 3004 of may constitute calculating a new AA interval for therapy that includes an increase of approximately 14 beats / minute, which is expected to result in an increase in diastolic blood pressure value of approximately 8 mmHg over its value prior to application of therapy. An additional portion of step 3004 would constitute calculating the expected effect on systolic blood pressure. Fig.28A In graph A, when the heart rate is 66 bpm, the peripheral systolic blood pressure value is about 137 mmHg, while at 80 bpm it is about 140 mmHg, so the expected systolic pressure increase is 3 mmHg. Therefore, in this example, the overall expected effect of the change (increase of 14 bpm) will be an increase in blood pressure value from 135 / 70 mmHg to 138 / 78 mmHg, which means (compared to the original 145 / 75 mmHg value) a decrease in systolic blood pressure of 7 mmHg (which means a decrease in pulse pressure of 7 mmHg) and an increase in diastolic blood pressure of 3 mmHg. Fig. 30A The modified stimulation pattern is applied in step 3008 of , and the blood pressure measurement should be used to determine the diastolic and systolic blood pressure levels. Thus, in this embodiment, a first stimulation that reduces both systolic and diastolic blood pressure is combined with a second stimulation that increases the heart rate to increase both diastolic and systolic blood pressure to provide a diastolic blood pressure that is increased from its original value and a systolic blood pressure that is decreased from its original value.

[0247] Fig.31 is a table listing data collected from actual hypertensive patients, as is apparent from the baseline data on the left side of the table: the initial systolic pressure was approximately 178 mmHg, the diastolic pressure was approximately 85 mmHg, and the resulting pulse pressure was 93. Hypertension therapy using short atrioventricular (AV) delay values ​​(see, for example, those described in Section II below) was applied to the patient, and the patient's heart rate was caused to increase (60, 70, 80, and 90 beats / minute) using a pacemaker. The amount of systolic pressure reduction was approximately 10 mmHg at each heart rate. The amount of this reduction did not seem to have any relationship to heart rate. However, diastolic pressure seemed to increase significantly with increasing heart rate. Therefore, it is clear that the application of a similar therapy that causes a reduction in diastolic pressure at an initial heart rate can offset this reduction by increasing the patient's heart rate by a certain amount (e.g., by applying cardiac pacing), which increases the heart rate by an amount that causes an increase in diastolic pressure, thereby offsetting the reduction in diastolic pressure caused by the therapy. Note that pulse pressure is reduced by the presence of therapy and also by the increase in heart rate.

[0248] This embodiment involves the following items: Item 1: A system for controlling blood pressure, comprising a stimulation circuit configured to deliver stimulation pulses to at least one cardiac chamber of a patient's heart; and at least one controller configured to perform delivery of stimulation pulses of one or more stimulation modes to at least one cardiac chamber, wherein, in a first operating mode, a first stimulation mode of the one or more stimulation modes lowers both the systolic and diastolic blood pressures of the patient, and wherein, in a second operating mode, a second stimulation mode of the one or more stimulation modes lowers the systolic blood pressure of the patient while controlling the diastolic blood pressure so as to reduce the difference between the systolic and diastolic blood pressures.

[0249] Item 2: In the system described in Item 1, the second stimulation mode can reduce systolic blood pressure while having minimal or no effect on diastolic blood pressure.

[0250] Item 3: In the system of Item 1, the second stimulation mode can reduce systolic blood pressure while limiting the effect on diastolic blood pressure to a level that does not prevent achieving a therapeutically effective reduced pulse pressure.

[0251] Item 4: In the system described in Item 1, the second stimulation mode can reduce the patient's systolic blood pressure while increasing the diastolic blood pressure.

[0252] Item 5: In the system of any of Items 1 to 4, at least one controller can be configured to treat hypertension in the patient using the first stimulation pattern, or to treat isolated systolic hypertension in the patient using the second stimulation pattern.

[0253] Item 6: In the system described in Item 1 or Item 2, the second stimulation mode can combine a stimulation mode that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while having minimal or no effect on diastolic blood pressure.

[0254] Item 7: In the system described in Item 1 or Item 3, the second stimulation mode can combine a stimulation mode that lowers blood pressure with stimulation that increases heart rate to lower systolic blood pressure while limiting the effect on diastolic blood pressure to a level that does not prevent a therapeutically effective lowered pulse pressure from being achieved.

[0255] Item 8: In the system described in Item 1 or Item 4, the second stimulation mode can combine a stimulation mode that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while increasing diastolic blood pressure.

[0256] Item 9: In the system of any one of Items 1 to 8, the second stimulation mode can combine a stimulation mode that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while controlling diastolic blood pressure so that the diastolic blood pressure is between a lower allowable value and an upper allowable value.

[0257] Item 10: In the system described in any one of Items 1 to 9, the second stimulation mode can combine a stimulation mode for lowering blood pressure with a stimulation for increasing heart rate to control systolic and diastolic blood pressure so that the resulting pulse pressure is between a lower allowable value and an upper allowable value and / or is lower than the initial pulse pressure by a predetermined amount and / or a predetermined percentage.

[0258] Item 11: In the system of any of items 1 to 10, the second stimulation mode can combine a stimulation mode that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while maintaining diastolic blood pressure above a specified minimum value.

[0259] Item 12: In the system of any of items 1 to 11, the at least one controller can be configured to obtain an indication of the patient's intrinsic heart rate, and the second stimulation pattern can increase the heart rate above the intrinsic heart rate.

[0260] Item 13: In the system described in Item 12, at least one controller can be configured to obtain an indication of intrinsic heart rate from at least one of a heart rate sensor, a fixed value based on an average heart rate for a group, a table representing average heart rate values ​​for different groups, or a value based on previous heart rate measurements performed in the patient.

[0261] Item 14: In the system of item 12 or item 13, at least one controller can be configured to obtain an indication of intrinsic heart rate before and / or during delivery of the second stimulation pattern.

[0262] Item 15: In the system described in any of Items 12 to 14, the system may also include an activity sensor configured to detect the patient's activity level, and at least one controller may be configured to obtain an indication of the intrinsic heart rate from an estimate of the intrinsic heart rate based on an activity level signal received from the activity sensor.

[0263] Item 16: In the system described in any of Items 1 to 11, at least one controller can be configured to: calibrate the first stimulation mode with the second stimulation mode by determining a decrease in diastolic blood pressure and / or a decrease in systolic blood pressure attributable to the first stimulation mode; determine an increase in systolic and diastolic blood pressure at different heart rates by actively stimulating the patient at different heart rates; and set the second stimulation mode to provide a desired increase in heart rate based on the determined decrease in diastolic blood pressure and / or decrease in systolic blood pressure and an increase in systolic and diastolic blood pressure at different heart rates.

[0264] Item 17: In the system of Item 16, at least one controller can be configured to determine the desired heart rate increase by first finding the heart rate at which the increase in diastolic pressure above the intrinsic heart rate is equal to the decrease in diastolic pressure caused by the first stimulation pattern, and then subtracting the intrinsic heart rate.

[0265] Item 18: In the system described in Item 16 or Item 17, at least one controller can be configured to determine the expected heart rate increase by calculating the expected overall effect on systolic blood pressure using the patient's existing systolic blood pressure data in the following manner: subtracting the expected increase in systolic blood pressure due to the expected heart rate increase from the decrease in systolic blood pressure produced by the first stimulation mode; determining whether the expected overall effect on systolic blood pressure is sufficient; and if the expected overall effect on systolic blood pressure is not sufficient, selecting a lower heart rate increase to obtain the desired heart rate increase.

[0266] Item 19: In the system described in any of Items 1 to 18, the system may also include a tachycardia sensor, which is configured to monitor the patient's heart for tachycardia during the second stimulation mode and send a signal to at least one controller when tachycardia is detected, and the at least one controller may be configured to interrupt the second stimulation mode after receiving the signal.

[0267] Item 20: In the system of any one of Items 1 to 11, at least one controller can be configured to receive data associated with a heart rate condition for interrupting delivery of the second stimulation mode during delivery of the second stimulation mode, and interrupt delivery of the second stimulation mode when the heart rate condition is met.

[0268] Item 21: In the system of Item 20, at least one controller can be configured to automatically receive data associated with the heart rate condition based on the measured parameter value.

[0269] Item 22: In the system of Item 20 or Item 21, the data associated with the heart rate condition may include a cutoff heart rate determined based on at least one of time of day, patient activity level, or blood pressure.

[0270] Item 23: In the system of any one of Items 20 to 22, the heart rate condition may include different levels of the second stimulation mode at different heart rates.

[0271] II. Examples of Hypertension Treatment The human heart consists of two atria and two ventricles. In a normal cardiac cycle, cardiac contraction begins with atrial contraction, followed by ventricular contraction. The mechanical process of cardiac contraction is controlled by the conduction of electrical currents in the heart. During each heartbeat, a wave of depolarization is triggered by cells in the sinoatrial node. The depolarization propagates in the atria to the atrioventricular (AV) node and then to the ventricles. In a healthy heart, the atrioventricular delay (AV delay) - that is, the delay time between the onset of atrial excitation and the onset of ventricular excitation - is typically between 120 milliseconds (ms) and 200 ms. The relative timing of atrial and ventricular contractions is affected, among other things, by the relative timing of the excitation of each chamber and the time required for the chamber to form a mechanical contraction due to electrical activation (which depends on size, speed of propagation, differences in muscle cell properties, etc.).

[0272] Before contraction, the myocardium relaxes and blood flows freely from the atria to the ventricles through the valves between the ventricles and atria. This cycle can be divided into a rapid filling phase and a slow filling phase. The rapid filling phase begins just after the ventricular diastole, during which blood from the venous system and the atria rapidly fills the ventricles. The rapid filling phase lasts for about 110 ms and is followed by a slow filling phase, which lasts until the beginning of the contraction of the atria. The duration of the slow filling phase depends on the heart rate. Afterwards, as the atria contract, the increased pressure in the atria causes blood to flow more rapidly to the ventricles. This contribution of atrial contraction to ventricular filling is called "atrial drive". Atrial drive is usually responsible for about 10%-30% of ventricular filling. Fig.17 The changes in ventricular volume, ventricular pressure, atrial pressure and cardiac electrical activity over time through a single cardiac cycle are shown. As used herein, a cardiac cycle is a period of time between two diastole of the ventricles, between which only the contraction of a single ventricle occurs. The duration of a cardiac cycle is inversely proportional to the heart rate, such that as the heart rate decreases the duration of the cardiac cycle increases and as the heart rate increases the duration of the cardiac cycle decreases. At a typical human heart rate of 75 beats per minute, a cardiac cycle lasts about 0.8 seconds.

[0273] Reference Fig.17 , when a P wave is observed in the ECG, the cardiac cycle can be said to begin with the onset of atrial excitation. Then, about 50 ms-70 ms later, the atria begin to contract, which lasts for a period of about 70 ms-110 ms. As the atria contract, the pressure within the atria increases and reaches a maximum, after which the atria begin to relax and the pressure decreases. The maximum is at Fig.171701 in FIG. 17A . At the same time, the electrical stimulus is propagated to the ventricles and subsequent initiation of ventricular excitation occurs at an AV delay of approximately 120 ms-200 ms (in some unhealthy individuals the AV delay may be approximately 250 ms or even more). This ventricular excitation is displayed on the ECG as a QRS complex. As the ventricles contract, the pressure within the ventricles increases and passively closes the valves between each atrium and the respective ventricle (AV valves), thereby blocking blood flow from the atria into the ventricles and preventing backflow.

[0274] During the next cycle of ventricular contraction—a cycle lasting about 50 ms called isovolumetric contraction or isovolumetric period—all ventricular valves close and pressure in the ventricles rises rapidly without significant changes in volume, as Fig.17 This is shown by the ventricular pressure line and ventricular volume line within vertical lines 1703 and 1704 that define the isovolumetric period.

[0275] As ventricular pressure increases further, Fig.17 At the time indicated by line 1704 in FIG. 1 , the valve between the ventricle and the artery opens and blood is ejected from the ventricle and leaves the heart. The phase of ventricular contraction is divided into a rapid ejection phase and a slow ejection phase. The rapid ejection phase lasts approximately 90 ms -110 ms, during which approximately 2 / 3 of the stroke volume is ejected. The rapid ejection phase is Fig.17 It is represented as the period between lines 1704 and 1705.

[0276] During the isovolumetric period and at the beginning of the rapid ejection phase, the contraction of the ventricles typically causes a passive increase in atrial pressure. This increase in atrial pressure is believed to be due to the mechanical effect of the contraction of the ventricles on the associated atria. For example, this increase in atrial pressure may be due to the close connection of the atria to the larger ventricles; as the large ventricle muscle contracts, it affects the connected atria. Increased atrial pressure may also result from the backward expansion of the valves into the atria, which may be due to the increasing pressure in the ventricles. Passive filling of the atria continues throughout the entire cardiac cycle (including between points 1701 and 1702) because there are no valves between the atria and the vascular system. This continued passive filling combined with the increased pressure due to the mechanical effect of ventricular contraction can help to increase atrial pressure. Therefore, the passive atrial pressure increase reaches a maximum value at some time between the second half of the isovolumetric period (i.e., approximately 25 ms-35 ms after the beginning of the isovolumetric period) and the beginning of the rapid ejection phase (e.g., within the first approximately 10 ms of the rapid ejection phase), such as at Fig.17 As a result of atrial contraction, the passive atrial pressure increase may be higher than the maximum atrial pressure, such as Fig.17 This is shown by the higher atrial pressure at point 1702 relative to the lower atrial pressure at point 1701.

[0277] The rapid ejection phase is followed by a slow ejection phase, which lasts about 130 ms -140 ms. Afterwards, all valves close again and the ventricles relax, in an isovolumetric relaxation lasting about 60 ms -80 ms, during which the pressure in the ventricles decreases. At this time, the valves between the ventricles and atria open again, allowing blood to flow freely into the ventricles, after which a new cardiac cycle can begin.

[0278] 1. Control atrial pressure and atrial stretch In the present disclosure, cardiac stimulation can be used to increase atrial pressure and stretch, and thereby reduce blood pressure (BP). Cardiac stimulation can achieve increased atrial pressure by stimulating the heart so that atrial pressure resulting from atrial contraction of the atrium overlaps in time with a passive pressure increase of the atrium, such that the atrial pressure of the atrium resulting from the stimulation is a combination of the atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation. An embodiment can achieve maximum atrial pressure by causing maximum atrial contraction during a time period of overlapping maximum passive increase in atrial pressure. For example, cardiac stimulation can be used to achieve maximum atrial pressure resulting from atrial contraction during a time period between approximately 25 ms-35 ms after the start of the isovolumetric period and approximately 10 ms after the end of the isovolumetric period. Increased atrial pressure (by temporally overlapping atrial pressure resulting from atrial contraction with a passive increase in atrial pressure) increases atrial stretch, which is known to affect blood pressure through hormonal and / or neuronal pathways. For example, an increase in atrial stretch can cause secretion of atrial natriuretic hormone or atrial natriuretic peptide, which in turn can lower blood pressure.

[0279] Embodiments may apply cardiac stimulation chronically or transiently to increase atrial pressure and stretch and induce secretion of atrial natriuretic hormone or atrial natriuretic peptide. Chronic application of cardiac stimulation is not required, and transient stimulation may be sufficient to increase atrial pressure and stretch, induce hormone secretion, and lower blood pressure. As observed in the pressure graph, changes in atrial stretch may be transient, and transient stretch may be more effective than chronic stretch in inducing release of atrial natriuretic hormone or atrial natriuretic peptide and lowering blood pressure. In embodiments, advantageously, transient increases in atrial pressure may not result in chronic increases in atrial pressure.

[0280] In some embodiments, if the maximum atrial pressure due to atrial contraction coincides completely or at least partially with the maximum passive increase in atrial pressure, then the maximum atrial pressure due to atrial contraction is considered to have occurred at a time period overlapping the maximum passive increase in atrial pressure. For example, if the maximum atrial contraction is expected to occur within about 20 ms before or after the expected maximum passive increase in atrial pressure, then the maximum atrial pressure due to atrial contraction is considered to have occurred at a time period overlapping the maximum passive increase in atrial pressure. In some embodiments, the maximum atrial pressure means the highest part of the contraction or passive pressure increase, having a pressure value that is at least about 25% higher than the pressure value of the atrium at rest. Optionally, if only one pressure peak is observed from the atrial contraction and the passive pressure increase, the maximum atrial pressure due to atrial contraction is considered to have occurred at a time period overlapping the maximum passive increase in atrial pressure, or if two peaks are observed, the maximum atrial pressure due to atrial contraction and the maximum passive increase in atrial pressure are separated by no more than about 30 ms. Alternatively, overlap in time may be detected mathematically by analyzing measured values ​​and / or visually, for example, by plotting atrial pressure over time or atrial pressure changes over time.

[0281] BP or changes 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 stimulator, such as a pacemaker or other type of device with a pulse generator may be used to stimulate the patient's heart to lower blood pressure. Electrodes electrically connected to the electrical stimulator using a wired or wireless connection may be placed adjacent to the heart chamber. The electrical stimulator may be operated so that pulses are delivered to the heart chambers through the electrodes.

[0282] In some embodiments, stimulating the heart so that the atria reach an increased (and preferably maximum) atrial pressure due to atrial contraction at a period overlapping with a (preferably maximum) passive pressure increase in atrial pressure can thereby reduce blood pressure. For simplicity, in the following description, such stimulation is referred to as "AC (atrial contraction) stimulation". AC stimulation can include delivering at least one stimulation pulse to at least one chamber of the heart so that the atria reach a maximum atrial pressure due to atrial contraction during a period between the second half of the isovolumetric period and the first approximately 10 ms of the rapid ejection period. In this article, such stimulation pulses are referred to as "AC stimulation pulses" or "AC pulses".

[0283] As used herein, a "stimulation pulse" 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 single heartbeat time period (when a single heartbeat is defined as a period of time between two diastole of the ventricle, between which only a single contraction of the ventricle occurs). Optionally, such excitatory electrical pulses (or stimulation pulses) are also referred to as pacing pulses. For example, in some embodiments, the stimulation pulse may include one or more electrical pulses delivered to one or more locations in the ventricle and / or one or more electrical pulses delivered to one or more locations in the atrium. Thus, in some embodiments, the stimulation pulse may include a first electrical pulse delivered to the atrium and a second electrical pulse delivered to the corresponding ventricle. In some embodiments, the stimulation pulse may include a first electrical pulse delivered to the atrium, a second electrical pulse delivered to the corresponding ventricle, and a third electrical pulse delivered to the atrium after it has exited the refractory period associated with the first pulse. In some embodiments, the stimulation pulse may include a single pulse delivered to multiple locations on one or more chambers of the heart.

[0284] In some embodiments, the AC pulses may be delivered at such timing relative to the cardiac cycle so that the atrial pressure resulting from atrial contraction of the atria overlaps in time with the passive pressure increase of the atria, such that the atrial pressure of the atria resulting from stimulation is a combination of the atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atria in the absence of stimulation. Preferably, the AC pulses may be delivered at such timing relative to the cardiac cycle so that the atria reaches a maximum atrial pressure resulting from atrial contraction at a time that overlaps with the maximum passive pressure increase of the atria. Optionally, such timing of delivery of the AC pulses is set based on one or more sensed events, such as events related to the cardiac cycle.

[0285] For example, the atrial and / or ventricular excitement can be sensed and the AC pulse can be delivered to the atrium and / or ventricle accordingly. For example, the pacing pulse can be delivered to the atrium at such a timing that is expected to be within about -20 ms to 30 ms from the sensing or pacing of the ventricle and at least about 20 milliseconds from the end of the refractory period of the atrium. Alternatively, the heart rate and ventricular excitement or contraction can be sensed and the timing of the next ventricular contraction or excitement can be estimated, and the AC pulse can be delivered so that the atrial pressure caused by the atrial contraction overlaps with the passive pressure increase of the atrium in time in the future heartbeat. Alternatively, the AC pulse can be delivered so that the atrial contraction reaches the maximum atrial pressure caused by the atrial contraction at the time of the maximum passive pressure increase of the atrium in the future heartbeat. For example, the AC pulse can include a stimulus that is delivered to the atrium at about 30 ms to 0 ms before the desired ventricular excitement or at about 50 ms-120 ms before the start of the desired ventricular contraction.

[0286] In some embodiments, the stimulation pulse may include a sensed or paced first atrial excitation, an electrical pulse delivered to the corresponding ventricle, and another electrical pulse delivered to the atrium after the atrium has exited a refractory period associated with the first excitation. For example, the time period between the first atrial excitation (such as the delivery of the first excitatory pulse to the atrium) and the delivery of another excitatory pulse to the atrium may be between approximately 150 ms and 250 ms.

[0287] In some embodiments, the AC pulses include a first electrical pulse delivered to the atria and a second electrical pulse delivered to the corresponding ventricles. The relative timing of the first electrical pulse and the second electrical pulse is controlled to cause the atria to contract at a time within a period between the second half of the isovolumetric period and the early part of the rapid ejection phase of the heart at that heartbeat. Because the time between the delivery of the excitatory pulse and the initiation of contraction is longer for the ventricles than for the atria, the delay between the delivery of the first pulse and the second pulse can have a negative value, for example, between about -20 ms and 0 ms.

[0288] This precise timing can vary between different patients and between different situations (e.g., different placement of one or more electrodes on the chamber). Thus, in some embodiments, the settings of the AC pulses can be adjusted, for example, upon device implantation and / or periodically, for example, upon periodic inspection or during use (e.g., based on feedback from one or more associated sensors).

[0289] For example, AC pulses with different settings may be delivered to a patient and atrial pressure may be sensed until a desired atrial pressure resulting from atrial contraction of the atria is sensed that overlaps in time with a passive pressure increase in the atria. In certain embodiments, the desired atrial pressure may be any pressure that exceeds the atrial pressure that the atria would reach without stimulation. Optionally, the desired atrial pressure may be selected as the highest value (or one of the highest values) among multiple atrial pressures resulting from multiple AC pulses with different settings. For example, the AC pulses may differ due to having different AV delays between a sensed or paced atrial contraction and a paced or sensed ventricular contraction. As a result, one or more AV pulse settings may be selected for use during a time period for a given patient.

[0290] For example, AC pulses with different settings can be delivered to a patient and atrial pressure can be sensed until a desired degree of overlap is observed between the maximum atrial pressure resulting from atrial contraction and the maximum value of the passive pressure increase of the atria. For example, the AC pulses may differ in having different AV delays between the sensed or paced atrial contraction and the paced or sensed ventricular contraction. As a result, one or more AV pulse settings can be selected for use during a time period for a given patient. Optionally, AC pulses can be delivered as part of a pacing mode that differs in the settings of different pulses within the mode, and one or more modes can be selected for repeated use based on one or more parameters related to the selection of pulses configured to reduce or prevent atrial drive and the pressure overlap described above.

[0291] Stimulation settings mean one or more parameters of one or more stimulation pulses delivered in a single cardiac cycle. For example, these parameters may include one or more of the following: power, time intervals between electrical pulses included in a single stimulation pulse (e.g., AV delay or delay between two atrial pulses), delivery period with respect to the natural rhythm of the heart, length of the stimulation pulse or its portion, and site of delivery between two or more chambers and / or within a single chamber. AC stimulation settings, or "AC settings" may include settings for one or more AC pulses.

[0292] In some embodiments, sensing can include sensing electrical activity of one or more chambers of the heart, such as one or more atrial excitation and / or ventricular excitation. In some embodiments, sensing includes using the sounds of the cardiac cycle to detect cardiac activity. For example, the closing of the AV valve causes the first sound of a heartbeat. This closing also signifies the beginning of an isovolumetric period. Optionally, based on the timing of the closing of the AV valve and the heart rate, pulse settings for future AC pulses can be selected. For example, a stimulatory pulse can be provided to the atria approximately 80-10 milliseconds before the next expected closure of the AV valve.

[0293] Alternatively, the refractory period of a cardiac chamber (e.g., atrium) may be estimated as known in the art. The AC pulses may include a stimulation pulse delivered to the atrium that causes atrial contraction. For example, the stimulation pulse may be timed for delivery after the end of the refractory period, or if delivered during a relative refractory period, the stimulation pulse has such electrical properties as to cause contraction regardless of relatively early timing.

[0294] In some embodiments, heart rate is sensed based on electrical activity, sound, pressure, and / or any other means, for example, as known in the art.

[0295] In some embodiments, one or more AC pulses may be provided as part of a pulse sequence or pacing pattern, comprising multiple heartbeats. A pacing pattern may include multiple pacing pulses with different settings. Optionally, all pulses may be AC ​​pulses but some may have different pulse settings than others. Optionally, only some of the pulses in a given pattern may be configured to cause the atria to reach an increased or maximum atrial pressure resulting from atrial contraction during the period between the second half of the isovolumetric period and the early stages of the rapid ejection phase.

[0296] It should also be noted that one or more pulse settings (eg, timing between events, sensed and / or delivered) may be optimized and / or adjusted to suit a particular patient and / or variations in a patient's cardiac function.

[0297] For example, a patient's heart rate may vary for many reasons, including activity and time of day. Changes in heart rate may cause changes in the relative timing of cardiac events. Therefore, one or more of the following parameters may be sensed and used to optimize and / or adjust pulse settings.

[0298] For example, aortic pressure and / or sounds associated with the opening of one or both heart valves can be used to confirm the timing of the beginning and / or end of the isovolumetric period and / or the beginning of the rapid ejection period. Such timing can be compared with the time of delivering pulses and / or sensing cardiac events so that the desired timing of contraction can be achieved more accurately and / or more repeatedly.

[0299] In another example, the timing from the delivery or sensing of an excitatory stimulus (to the atria and / or ventricles) to when peak pressure is sensed in the atria (due to contraction or passive pressure increase) can be measured.

[0300] Another option may be to adjust the AC pulse settings based on one or more of heart rate, patient activity, posture, and / or breathing rate.

[0301] In practice, the above combination can be used to adjust and / or optimize. For example, one or more of the timing between atrial excitation and maximum atrial pressure due to atrial contraction, ventricular excitation, maximum atrial passive pressure, and the timing of the isovolumetric period and / or rapid ejection period can be measured. Optionally, the atrial pressure due to the transmission of the stimulation pulse can be measured, and the adjustment can include selecting the stimulation settings based on the measured pressure. These measurements can also be related to the patient's heart rate in different situations. Using the specific measurements obtained from the patient, the pulse settings can be adjusted or optimized.

[0302] Optimization and / or adjustment as described above can be performed as a closed loop in certain situations, such as when a sensor is associated with an implanted stimulation device. Alternatively, optimization and / or adjustment can be performed as an open loop. Optimization and / or adjustment can be a continuous process (e.g., particularly when the sensor is implanted based on heart rate) and / or can be performed during implantation when the patient is provided with the device, occasionally, and / or when needed. Finally, optimization and / or adjustment can be automatic and / or require a medical professional.

[0303] Embodiments may implement different pacing techniques to achieve the desired overlap of AC stimulation and atrial pressure and passive increase in atrial pressure resulting from atrial contraction. In certain embodiments, AC stimulation may include pacing the atria at an atrial rate substantially equal to the intrinsic ventricular rate or pacing the atria at an atrial rate greater than the intrinsic ventricular rate. Furthermore, different pacing techniques may be implemented to achieve the desired AC stimulation with a single contraction of the atria or a double contraction of the atria.

[0304] For a single contraction of the atria, pacing techniques to achieve the desired AC stimulation may include, for example: a. Sensing the atria (optionally involving predicted atrial activation) and pacing the ventricles; b. Sense the ventricles and pace the atrials, which may require that atrial pacing be performed before the predicted time of ventricular sensing; or c. Pace the atria and pace the ventricles.

[0305] For atrial bisystole, pacing techniques to achieve the desired AC stimulation may include, for example: a. sensing a first atrial activation, sensing a ventricle, and pacing the atrium to produce a second contraction in the same cardiac cycle; b. Sensing the atria, pacing the ventricles, and pacing the atria to produce a second contraction in the same cardiac cycle; c. pace the atria, sense the ventricles, and pace the atria again; or d. Pace the atria, pace the ventricles, and pace the atria again.

[0306] Other pacing techniques may be utilized to achieve the desired AC stimulation and overlap of atrial pressure and passive increase in atrial pressure resulting from atrial contraction. Thus, while there are specific benefits associated with the pacing techniques described herein, the present embodiments should be considered broadly applicable to any pacing technique that provides the desired AC stimulation and overlap.

[0307] Figure 18 to Figure 19is a graph showing two different stimulation patterns delivered to a healthy anesthetized canine heart, showing an electrocardiogram (ECG), right ventricular pressure (RV Press), right atrial pressure (RA Press), aortic pressure (Ao Press), and left ventricular pressure (LV Press) tracked over a period of time. According to one embodiment, Fig.18 The change from sinus rhythm to stimulation of the atria and ventricles paced at an AV delay of 2 ms is shown, which results in an overlap of the pressure due to atrial contraction and the atrial pressure due to passive pressure increase. In this example, pacing at an AV delay of 2 ms causes an overlap in time of the maximum pressure due to atrial contraction and the maximum atrial pressure due to passive pressure increase, as well as a measurable increase in atrial pressure, and therefore also an increase in atrial stretch. For comparison purposes, Fig.19 An AV delay of 40 ms is shown, which shows a small degree of overlap and does not produce a significant increase in atrial pressure. Alternatively, a higher degree of overlap can be defined based on the approximation of the atrial pressure maximum, with the closer to the maximum, the higher the degree of overlap, until the maxima completely overlap and a single maximum pressure is observed. Optionally, the degree of overlap is a function of the maximum sensed atrial pressure, with higher pressure maximums characterizing a higher degree of overlap.

[0308] In with Figure 18-Figure 19 In a related experiment, a healthy canine heart was equipped with a pacemaker configured with an algorithm that allowed pacing at specific AV delays. The pacemaker was connected to the heart via two pacing electrodes, one in the right atrial appendage and one in the right ventricular apex. Four solid-state pressure sensors were inserted into the right atrium, right ventricle, left ventricle, and aorta. A single-lead 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 and plotted at a rate of 1 kHz to provide Figure 18-Figure 19 As shown in the figure, the graph includes the following plots from bottom to top: ECG, RV pressure, RA pressure, Ao pressure and LV pressure.

[0309] In each experiment, the heart was allowed to contract with natural sinus rhythm for several beats and then paced at the atria and ventricles with the indicated AV delays.

[0310] Reference Figure 18-Figure 19In each of the above, two distinct increases in atrial pressure can be seen during periods of sinus rhythm 1802. The first atrial pressure increase 1804 follows atrial electrical activity (P wave 1806) and corresponds to contraction of the atria. The second atrial pressure increase 1808 occurs during isovolumetric contraction of the ventricles (characterized by a rapid increase in ventricular pressure) and continues through a brief initial period of the rapid ejection phase (beginning when aortic pressure begins to increase). The effect of ventricular contraction on atrial pressure causes the second atrial pressure increase 1808. Figure 18-Figure 19 As shown in the RA Press plot of Figure 1, the maximum atrial pressure reached during isovolumetric contraction is slightly higher than the maximum atrial pressure reached during atrial systole.

[0311] As described above, embodiments may include arrangements to maximize atrial pressure and, therefore, atrial stretch. In particular, stimulation may be delivered to the atria at such a timing relative to the cardiac cycle as to cause the atria to reach a maximum atrial pressure resulting from atrial contraction at a time that overlaps with a maximum passive pressure increase in the atria. Fig.18 An example of such timing is shown where the atrial and ventricular pacers are paced with an AV delay of 2 ms, as represented by atrial pacing 1810 followed by ventricular pacing 1812 2 ms later. Fig.18 Three examples of such pacing are shown.

[0312] Reference Fig.18 1802 , with three instances of pacing, significant increases in atrial pressure at points 1814, 1816, and 1818 can be seen. These significant pressure increases result from simultaneous or nearly simultaneous atrial pressure increases due to atrial contraction and ventricular contraction. In other words, comparing the sinus rhythm portion 1802 of the right atrial pressure plot with the AV delayed paced portion 1803 of the right atrial pressure plot, the first atrial pressure increase 1804 and the second atrial pressure increase 1808 of the sinus rhythm portion 1802 are substantially superimposed on the AV delayed paced portion 1803, such that the atrial pressure increases 1804 and 1808 are combined to provide higher atrial pressure increases 1814, 1816, and 1818.

[0313] Optionally, the AC pulses can have a setting that includes a predefined AV delay between sensed or paced atrial excitation and paced or sensed ventricular excitation. The AV delay can be selected substantially as described above so that the atrial pressure due to atrial contraction and the passive atrial pressure increase overlap, and so that the atrial pressure of the atrium resulting from the combination of atrial pressure due to atrial contraction and the passive pressure increase is higher than the atrial pressure of the atrium that would not be stimulated (or would have a different stimulation). The AV delay can be selected substantially as described above so that the maximum values ​​of the atrial pressure due to atrial contraction and the passive atrial pressure increase overlap. Such a setting can vary between patients and can even vary in time for a given patient. Nevertheless, in most cases, it is expected that an AV delay of between about 30 ms and about 0 ms will be effective. In some patients (such as in Fig.18 ), the AV delay between atrial excitation and ventricular excitation can be between about 30 ms and about 0 ms or between about 20 ms and about 0 ms. It should be noted that when sensing is used to detect cardiac events when setting the AV delay, the following items are optionally considered: First, when electrical excitation is sensed, there is a delay between the actual excitation and its detection. This may be due to the location of the sensing electrodes and limitations of the sensing system. Thus, for example, the time period between sensed atrial excitation and the delivery of the pacing pulse to the ventricles will be shorter than the expected AV delay. When sensing is based on a mechanical event (such as contraction or valve closure), the time between the actual excitation and the occurrence of the mechanical event also needs to be considered. Some examples of the relative timing of sensed events and the delivery of pacing pulses are disclosed herein. In addition, as detailed in this application, the settings can be adjusted to suit the specific time of the patient at the time of implantation and / or periodically.

[0314] In contrast to the surprisingly beneficial results achieved by pacing with an AV delay, the AV delay causes an atrial contraction of the atrium to overlap in time with a passive pressure increase in the atrium, thereby providing an atrial pressure in the atrium that is a combination of the atrial pressure due to atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium in the absence of stimulation (e.g., Fig.18 ), as in the example above. Fig.19 A short AV delay relative to conventional AV delay (e.g., 140 ms in canine hearts) was demonstrated, but did not provide a significant increase in atrial pressure. Fig.19 As shown, after the sinus rhythm portion 1802, the heart is paced with an AV delay of 40 ms during an AV delay pacing portion 1803, as represented by atrial pacing 1910 followed by ventricular pacing 1912 40 ms later. Fig.19Two examples of such pacing are shown. Referring to the portion of the trace of atrial pressure (RA Press) shortly after pacing, despite the short 40 ms AV delay relative to the conventional 140 ms AV delay, the 40 ms AV delay does not result in a significant increase in atrial pressure compared to the atrial pressure increases 1804 and 1808 during the sinus rhythm portion 1802. In contrast, Fig.19 As shown, the 40 ms AV delay results in two separate atrial pressure increases 1904 and 1908 that are roughly equivalent to the previous atrial pressure increases 1804 and 1808.

[0315] Will Fig.18 and Fig.19 For comparison, it is shown that when the second half of the atrium's contraction and isovolumetric contraction or the early part of the ventricular rapid ejection phase is as Fig.18 When the AV delay of about 2 ms occurs simultaneously or nearly simultaneously, a significant increase in atrial pressure occurs. This significant increase in atrial pressure can provide a desired release of stress hormones for lowering blood pressure. Therefore, an embodiment paces the atria and ventricles with an AV delay of about 2 ms.

[0316] Figure 20A-20C Some theoretical examples for combining the atrial pressure due to atrial contraction and the passive pressure increase in the atria are depicted. In these examples, as detailed below, different degrees of overlap are shown, and the pressure due to atrial contraction and the passive pressure increase are added. Initially, the atrial pressure is tracked during a natural cardiac cycle, such as at Fig.18 and Fig.19 The period of sinus rhythm 1802 shown in FIG. From this trace, the atrial pressure 1804 and the passive pressure increase 1804 due to atrial contraction are extracted. Fig. 20A In the present study, a 60 ms delay was assumed between the onset of atrial contraction and the onset of passive pressure increase, and the two pressure curves (corresponding to Fig.18 1802 and 1804). As can be seen, the atrial contraction lasts for about 60 ms and reaches a maximum pressure close to 1.5 mmHg, while the passive pressure increase lasts for about 50 ms and reaches a maximum pressure slightly above 2 mmHg. Because the atrial contraction lasts for about 60 ms (which is roughly the same as the assumed delay), the two pressure increases are observed as different parts of the trace with two different maxima and the maximum pressure observed is the maximum pressure of the passive pressure increase 1804.

[0317] Fig. 20BThe theoretical merging of atrial pressure and passive pressure increase in the atrium due to atrial contraction is illustrated in more detail. In this trace, as shown, it is assumed that the initiation of passive pressure increase 1804 (dashed line) occurs 30 ms after the initiation of atrial contraction 1802 (dotted line). The two traces are added and the sum is tracked as pressure trace 204 (solid line). As can be seen in this example, due to some degree of overlap, the merged pressure line 204 has a maximum pressure that is slightly higher than the maximum pressure observed in the passive pressure increase 1804 (dashed line) without overlap, while two maxima are still visible, one corresponding to each of the merged traces 1802 and 1804.

[0318] Although the timing of the maximum atrial pressure due to atrial contraction is set to occur simultaneously with the maximum passive pressure increase so that the maximum occurs as a single event, the maximum achievable atrial pressure can be produced, but the embodiments can provide a significant beneficial increase in atrial pressure over a time range that exceeds that single event. In other words, in order to stimulate the heart so as to obtain an atrial pressure that is a combination of the atrial pressure and the passive pressure increase caused by atrial contraction and is higher than the atrial pressure of the atrium when there is no stimulation, the timing of the stimulation only needs to provide that the combination (e.g., and) of the atrial pressure and the passive pressure increase caused by atrial contraction is higher than the maximum pressure produced in the atrium without stimulation. If the maximum atrial pressure due to atrial contraction occurs simultaneously with the maximum passive pressure increase of the atrium, the combination (e.g., and) of these pressures may be higher than each of the individual pressures. However, providing a combined atrial pressure that is higher than the two individual pressures is not limited to a single event of the maximum points occurring simultaneously, and as discussed in more detail below, it will be correct for the time range where the pressures overlap each other.

[0319] exist Fig. 20C In FIG. 1 , the pressure due to atrial contraction and the passive pressure increase are combined at various assumed degrees of overlap between the pressure due to atrial contraction and the passive pressure increase, thereby illustrating how controlling the relative timing of atrial and ventricular contraction may affect the combined atrial pressure. In this example, a pressure similar to Fig. 20B In , a time delay between the onset of atrial contraction and the onset of passive pressure increase is assumed, so that at each point in time, the atrial pressure due to atrial contraction is added to the passive pressure increase at the same point in time to provide a combined pressure. Different examples of combined (e.g., added) pressures are shown in FIG. Fig. 20C being tracked.

[0320] Fig. 20C The trace 201 and Fig. 20A, with a delay of 60 ms between the onset of the pressure due to atrial contraction and the onset of the passive pressure increase. In trace 207, on the other hand, the atrial pressure due to atrial contraction and the passive pressure increase are combined at a point close to the maximum overlap (a delay of 0 ms between the onset of the two changes in pressure, which cannot be completely consistent due to the different durations), i.e., assuming that they both start at approximately the same time. As can be seen, in this case, trace 207 shows the sum of the pressures reaching a single maximum of approximately 3.5 mmHg. Similarly, a single maximum is observed at a delay of 10 ms (trace 206), slightly later than in trace 207 and with a lower maximum than that of trace 207. As the delay increases, in trace 205 (20 ms delay), the traces begin to separate but still produce a single maximum (between 2.5 mmHg and 3 mmHg). Trace 204 (30 ms delay; which is identical to Fig. 20B 201. Finally, even at a lower degree of overlap, in traces 203 and 202 (40 ms and 50 ms delays, respectively), although there is some overlap between the pressure due to atrial contraction and the passive pressure increase, in each trace the two maxima are separated by more than 30 ms and the maximum pressures are about the same as in trace 201, where no overlap is shown.

[0321] In some embodiments, a stimulation pattern may be used to lower blood pressure by applying a stimulation pattern comprising or consisting of one or more AC pulses only intermittently. For example, applying intermittent AC pulses may allow a natural heartbeat to occur between the AC pulses and / or between the pulses, the pulses being configured to not cause overlap between atrial pressure due to atrial contraction and atrial pressure due to passive pressure increase (or not cause overlap of respective maxima), thereby providing an atrial pressure in the atrium that is a combination of atrial pressure due to atrial contraction and passive pressure increase and is higher than the atrial pressure in the atrium in the absence of stimulation. Optionally, the period between the application of the AC pulses may be selected based on the time constant of secretion and / or absorption of the natriuretic peptide, such that sufficient stimulation will be delivered to substantially provide the desired effect without excessive stimulation. This may have the benefit of reducing the power used by the implanted device and / or may reduce the extent of cardiac manipulation.

[0322] exist Fig.23An exemplary method 230 for controlling atrial pressure is schematically depicted in FIG. As described herein, method 230 may be performed by an implanted device. Thus, the device may be configured to perform any or all of the steps of method 230. Likewise, method 230 may include any steps that the device is configured to perform. For example, method 230 may include the steps described below with respect to Fig.14 Any one of the functions discussed for device 50.

[0323] In some embodiments, as shown in step 231, method 230 may include sensing a cardiac event. This event or events may include one or more electrical events and / or mechanical events, and this event or events may be sensed as known in the art and as described in further detail herein. For example, the sensed event may include sensing of atrial and / or ventricular excitation and / or the timing of steps in cardiac mechanical activity such as the opening and / or closing of one or more cardiac valves. The sensed event may include inferences of relative timing between cardiac events. In some embodiments, step 231 may include triggering one or more cardiac events, such as atrial or ventricular excitation. Optionally, step 231 may include sensing an intrinsic heart rate or setting a heart rate. For example, step 231 may include sensing the closing of the AV valve, thereby defining the beginning of the isovolumetric period, and / or sensing the opening of the aortic valve, thereby defining the time point at which the rapid ejection period begins. Step 231 may also include determining the time difference between sensing ventricular activation or ventricular stimulation and the closing of the AV valve (which defines the beginning of the isovolumetric period).

[0324] Method 230 may include a step 232 of selecting pulse settings. The settings may include or include setting the time interval between atrial and ventricular excitation. The settings may include selecting the ratio between atrial excitation and ventricular excitation for a given stimulation pulse. The settings may include power settings based on sensed or estimated timing of the delivery of excitatory pulses during the relative refractory period of the target chamber.

[0325] Method 230 may include a step 233 of delivering at least one stimulation pulse using a pulse setting optionally set in step 232, the pulse setting of step 232 may be selected based on the timing of the event sensed in step 231. In some embodiments, the excitatory current may be applied to both ventricles simultaneously or sequentially. In some embodiments, where both ventricles are paced sequentially, the time interval between the initiation of excitation of at least one atrium (e.g., the right atrium) and the initiation of excitation of the corresponding ventricle to be paced (e.g., the right ventricle) may be measured. In some embodiments where the time interval is set to zero or a negative number, step 233 may be performed before step 231 or at the same time as step 231. In some embodiments, the time interval may be measured in milliseconds.

[0326] The pulse setting selected in step 232 may be selected based on feedback. In such a case, method 230 may include sensing atrial pressure, as shown in step 234. For example, feedback information may be obtained on a continuous basis and / or on a periodic basis, such as during implantation and / or periodic inspection using an implanted sensor for feedback and adjustment of pulse settings. Method 230 may include a step 235 of estimating the overlap in time between atrial pressure (preferably, maximum atrial pressure) and passive pressure increase of the atrium (preferably maximum passive pressure increase) resulting from atrial contraction. For example, the estimation of step 235 may include detecting the magnitude of the maximum values ​​in atrial pressure and their temporal length and / or the temporal distance between the maximum values, and / or detecting the magnitude of the maximum and minimum values ​​in atrial pressure and estimating the duration of contraction or the change in pressure based on the time between the maximum and minimum values, and / or detecting the maximum value of atrial pressure compared to atrial pressure of the same heart without stimulation. According to method 230, such comparison may be performed using stored values ​​corresponding to pressure measured before treatment begins, and / or may include the step of sensing atrial pressure in at least one heartbeat without the delivery of a stimulation pulse.

[0327] The method 230 may include a step 236 of adjusting the pulse settings selected in step 232 based on the sensed overlap estimated in step 235. For example, step 236 may include adjusting the time intervals to provide the highest degree of overlap observed between the plurality of settings. Alternatively, a higher degree of overlap may be defined based on an approximation of atrial pressure maximum, with the closer to the maximum, the higher the degree of overlap, until the maximum values ​​completely overlap and a single maximum pressure is observed. Alternatively, the degree of overlap is a function of the maximum sensed atrial pressure, with higher pressures characterizing a higher degree of overlap.

[0328] If through Fig.23 As shown by the arrow pointing from step 236 to step 231, step 231, step 232, step 233, step 234, and / or step 235 may be repeated after step 236 is performed. In some embodiments, the time pulse setting may first be set to a first value during step 231, and, based on feedback sensing performed during steps 234 and 235, the pulse setting may be adjusted (e.g., the time interval is decreased or increased) during step 236 until the overlap level is within a given range (or above or below a given value).

[0329] The steps of method 230 may be performed in any order. Fig.23 The steps are performed in the order indicated by the arrows shown. In another embodiment, step 232 may be performed before step 231.

[0330] Atrial contraction, atrial excitation, ventricular contraction, the timing of closing and / or opening of the AV valves, and / or the flow of blood from one or more atria to the respective ventricles or the lack thereof and / or blood pressure may be detected by any method known in the art and these may be used as feedback control. In some embodiments, the initiation of excitation may be used as a trigger for the delivery of excitatory stimulation to one or more cardiac chambers (e.g., one or both ventricles or both atria and ventricles). Additionally or alternatively, the sensed information may be used for adjustment of the timing intervals of the device.

[0331] Embodiments may provide a method for adjusting pulse settings in a system for controlling blood pressure. The method may include receiving atrial pressure data related to the atria of a patient's heart during at least one cardiac cycle. The atrial pressure data may result from a stimulation pulse having a first pulse setting delivered to the heart by the system. The method may also include analyzing the atrial pressure data and providing an adjusted second pulse setting based on the analysis, the adjusted second pulse setting being different from the first pulse setting. The analysis may include analyzing the atrial pressure data to estimate the temporal overlap between atrial pressure resulting from atrial contraction and a passive pressure increase in the atria. The analysis may also include plotting the atrial pressure data and / or mathematically analyzing the atrial pressure data.

[0332] Embodiments may provide a system for reducing blood pressure that may include, for example, Fig.14 . The system may include means for providing information about changes in pressure in the atria 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 arranged to generate stimulation pulses so as to control the timing of atrial contraction relative to the timing of ventricular contraction in a single cardiac cycle based on the information about changes in pressure in the atria. In one implementation, the means for providing information may first sense information (e.g., pressure and time between changes in pressure) and the means for generating stimulation pulses may then set the timing of stimulation based on the information.

[0333] Information about changes in pressure in the atria 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 atrial pressure and the maximum passive pressure increase in the atria resulting from atrial contraction. The information may include information related to the occurrence and / or timing of one or more cardiac events as described herein, for example, including one or more of atrial contraction, ventricular contraction, opening of the atrioventricular valve, closing of the atrioventricular valve, electrical activity of the atria, electrical activity of the ventricles, blood flow, atrial refractory period, and heart rate.

[0334] The device for generating stimulation pulses may be arranged to generate for at least one cardiac cycle: at least one atrial stimulation pulse for generating atrial contraction; and / or at least one ventricular stimulation pulse for generating ventricular contraction. The device for generating stimulation pulses may be arranged to generate at least one atrial stimulation pulse in a timed relationship with the occurrence of atrial contraction and / or the occurrence of ventricular contraction on the basis of information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction; and / or to generate at least one ventricular stimulation pulse in a timed relationship with the occurrence of ventricular contraction and / or the occurrence of atrial contraction on the basis of 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 a 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 a QRS complex in the natural stimulation pattern of the cardiac cycle.

[0335] The timing of atrial contraction relative to ventricular contraction may correspond to an AV delay in the range of about 30 ms to about 0 ms. The means for generating the stimulation pulse may be arranged to generate the stimulation pulse so as to: provide excitatory stimulation to the atria in the range of about 30 ms to about 0 ms before the onset of ventricular excitation; provide excitatory stimulation to the ventricles in the range of about 30 ms to about 0 ms after the onset of atrial excitation; and / or provide excitatory stimulation to the atria and then provide excitatory stimulation to the ventricles in the range of about 30 ms to about 0 ms thereafter.

[0336] Other embodiments may provide another system for reducing blood pressure, which may also include, for example, Fig.14 In those other embodiments, the system for reducing blood pressure may include means for providing information about the timing of one or more cardiac activity events, means for generating stimulation pulses, and means for applying the stimulation pulses to at least one cardiac chamber. The information about the timing of one or more cardiac activity events may include at least one of the following items: 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 of the atrium, the change in the atrial pressure of the atrium, the refractory period of the atrium, and the heart rate. The means for generating the stimulation pulses may be arranged to generate the stimulation pulses so as to set the timing of the atrial contraction relative to the ventricular contraction based on the information.

[0337] The timing of atrial contraction relative to ventricular contraction may correspond to an AV delay in the range of about 30 ms to about 0 ms. The means for generating the stimulation pulse may be arranged to generate the stimulation pulse so as to: provide excitatory stimulation to the atria in the range of about 30 ms to about 0 ms before the onset of ventricular excitation; provide excitatory stimulation to the ventricles in the range of about 30 ms to about 0 ms after the onset of atrial excitation; and / or provide excitatory stimulation to the atria and then provide excitatory stimulation to the ventricles in the range of about 30 ms to about 0 ms thereafter.

[0338] 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.

[0339] The device for generating stimulation pulses may be arranged to generate for at least one cardiac cycle: at least one atrial stimulation pulse for generating atrial contraction; and / or at least one ventricular stimulation pulse for generating ventricular contraction. The device for generating stimulation pulses may be arranged to generate at least one atrial stimulation pulse in a timed relationship with the occurrence of atrial contraction and / or the occurrence of ventricular contraction on the basis of information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction; and / or to generate at least one ventricular stimulation pulse in a timed relationship with the occurrence of ventricular contraction and / or the occurrence of atrial contraction on the basis of 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 a 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 a QRS complex in the natural stimulation pattern of the cardiac cycle.

[0340] 2. Control atrial blood expulsion In some embodiments, the heart is stimulated so that the contribution of the contraction of the atria to the filling of the ventricles (atrial drive) is reduced or even prevented, reducing cardiac filling and thereby reducing blood pressure at the end of diastole. For simplicity, in the following description, such stimulation is referred to as "BPR (blood pressure reducing) stimulation". BPR stimulation may include delivering at least one stimulation pulse to at least one chamber of the heart so that atrial drive is reduced or even prevented. Such pulses are referred to herein as "BPR stimulation pulses" or "BPR pulses". As described above, a "stimulation pulse" may include a sequence of one or more electrical pulses delivered to one or more chambers of the heart within a single heartbeat or cardiac cycle. For example, in some embodiments, the stimulation pulse may include one or more electrical pulses delivered to one or more locations in the ventricles and / or one or more electrical pulses delivered to one or more locations in the atria. Thus, in some embodiments, the stimulation pulse may include a first electrical pulse delivered to the atria and a second electrical pulse delivered to the corresponding ventricles. In some embodiments, the stimulation pulse may include a single pulse delivered to multiple locations on one or more chambers of the heart.

[0341] Stimulation settings mean one or more parameters of one or more stimulation pulses delivered in a single cardiac cycle. For example, these parameters may include one or more of the following: power, time intervals between electrical pulses included in a single stimulation pulse (e.g., AV delay), delivery period with respect to the natural rhythm of the heart, length of the stimulation pulse or its portion, and site of delivery between two or more chambers and / or within a single chamber. BPR stimulation settings, or "BPR settings" may include settings for one or more BPR pulses.

[0342] The stimulation pattern may include a series of pulses having identical stimulation settings or the stimulation pattern may include multiple stimulation pulses each having a different stimulation setting. For example, a stimulation pattern may have one or more pulses including a first setting and one or more pulses including a second setting that is different from the first setting. When a stimulation pattern is described as having a setting, it should be understood that this means that the stimulation pattern may include at least one stimulation pulse having that setting. It should also be understood that in some embodiments, the stimulation pattern may include one or more cardiac cycles in which no stimulation pulses are delivered, in which case it can be considered to be delivering pulses at zero power. The stimulation pattern may include multiple identical pulses or a sequence of pulses containing two or more different settings. Two stimulation sequences in a pattern may differ in the order of the pulses provided within the setting. Optionally, two or more stimulation sequences may differ in their length (time and / or number of heartbeats). In some embodiments, the stimulation pattern may include pulses having a BPR setting. In some embodiments, the stimulation pattern may include pulses without a BPR setting.

[0343] Examples of stimulation settings configured to reduce or prevent atrial drive in at least one ventricle can include any of the stimulation settings disclosed herein configured to cause a reduction in the patient's ventricular filling volume from a pre-treatment ventricular filling volume. Such a reduction can be caused by causing at least a portion of atrial contraction to occur with respect to a closed AV valve. Some such examples include:

[0344] a. Delivering one or more stimulation pulses to the patient's ventricles 0 ms-50 ms prior to initiation of excitation in the patient's atria. Optionally, this delay is set based on sensing of atrial excitation. Optionally, this includes delivering one or more stimulation pulses to the atria 0 ms-50 ms after the stimulation pulses are delivered to the ventricles. Optionally, this delivery is performed at a rate slightly higher than the patient's natural heart rate.

[0345] b. Delivering one or more stimulation pulses to the patient's ventricles 0 ms-70 ms after initiation of excitation in the patient's atria. Optionally, this delay is set based on sensing of atrial excitation. Optionally, this includes delivering one or more stimulation pulses to the atria 0 ms-70 ms before the stimulation pulses are delivered to the ventricles. Optionally, this delivery is performed at a rate slightly higher than the patient's natural heart rate.

[0346] Certain embodiments may provide a system for reducing blood pressure that is configured to deliver stimulation at a rate higher than the natural heart rate based on a sensed natural heart rate or natural excitement. For example, the system may be configured to sense natural excitement between the delivery of stimulation pulses, and if natural activity is sensed, the system may be configured to inhibit the delivery of stimulation pulses to the chamber. If the amount of activation sensed exceeds a threshold value within a specific time range, then the natural heart rate may be considered to be higher than the rate of delivery of stimulation pulses, in which case the rate of delivery may be increased, for example, to accommodate the patient's increased heart rate. On the other hand, if the amount of activation sensed is lower than a threshold value (which may be 0) within a specific time range, then the natural heart rate may be considered to be lower than the rate of delivery of stimulation pulses, in which case the rate of delivery may be reduced, for example, to avoid excessive excitement of the patient's heart. To achieve this effect, according to one embodiment, a system for reducing blood pressure may include a sensor for sensing the rate of excitement of at least one of the atria and ventricles of the patient's heart, a stimulation circuit configured to deliver stimulation pulses to the atria and ventricles, and a processor circuit coupled to the stimulation circuit. Optionally, the sensor for sensing the excitation rate of at least one of the atria and ventricles may include electrodes for sensing atrial excitation. The processor circuit may be configured to detect the patient's heart rate based on sensing and operate in an operating mode in which stimulation pulses are provided to each of at least one of the atria and ventricles. The stimulation pulses may be delivered at a speed higher than the sensed excitation rate and may be configured to stimulate the ventricles at a time between about 50 ms before and about 70 ms after the stimulation of the atria.

[0347] Reducing atrial drive can have an immediate effect on blood pressure, while hormonally regulated mechanisms may take longer periods of time. Although certain devices can be configured to have both immediate and hormonally regulated effects, optionally, certain of the BPR settings and / or stimulation modes can be configured to reduce or prevent atrial drive without a significant increase in atrial stretch. For example, when the AV valve closes at a time at or after atrial contraction at peak pressure, premature closure of the valve does not increase atrial stretch. Thus, in certain embodiments, the device can be configured to cause the relative timing of atrial excitation and ventricular excitation to be comparable to the AV delay, i.e., at least 40 ms long or at least 50 ms long. Atrial stretch can be measured, calculated, and / or estimated as known in the art. In certain embodiments, atrial stretch determination can include measuring atrial pressure. In some embodiments, atrial stretch determination can include measuring or estimating the size (e.g., diameter, size, or circumference) of the atrium.

[0348] In some embodiments, atrial drive can be reduced because the BPR stimulation settings can be set so that when the AV valve is open, atrial contraction of the cardiac cycle is incomplete. In some embodiments, atrial contraction can occur completely or partially with a closed AV valve. In some embodiments, atrial contraction can be prevented or reduced in pressure and / or force.

[0349] In some embodiments, only one or more ventricles may be stimulated and the timing of the stimulation pulses may be set 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, such at least one atrial stimulation may cause atrial contraction. In some embodiments, at least one atrial stimulation may interfere with atrial contraction. In some embodiments, at least one atrial pulse may cause atrial spasm or another ineffective type of atrial contraction.

[0350] In fact, the blood pressure reduction resulting from BPR stimulation can be observed immediately upon application of the stimulation signal (e.g., within 1 or 3 seconds (sec) or within 1, 3 or 5 heartbeats), and the reduction can reach a minimum blood pressure value in less than 5 heartbeats from the start of stimulation.

[0351] By controlling the settings of the BPR stimulation, the degree of BP reduction can be controlled. This degree is sometimes patient-specific and / or related to the precise positioning of one or more stimulation and / or sensing electrodes in or on the heart. The degree of BP change can be a function of, for example, the AV delay, so that this functional relationship can be used to select the AV delay that provides the desired BP change, or vice versa. As described in more detail below Fig.24 An example of this functional relationship is shown in .

[0352] 3. Adaptability a. The inventors have found that when stimulation is maintained, blood pressure may show an adaptive pattern, in which blood pressure increases after a period of time (some of which often occur in short periods of time, less than 5 minutes or even less than a minute), and may reach a blood pressure value close to the pre-stimulation value (possibly at least due to the baroreceptor reflex) or even higher. Adaptation, at least in part, may be attributed to changes in the performance of the cardiovascular system, such as an increase in total peripheral resistance. The inventors further found that the end of stimulation causes blood pressure to return quickly to pre-stimulation values ​​or even higher values, and thereafter found that the heart responds to the blood pressure reduction stimulation signal to a degree similar to that of an unstimulated heart. It was also found that different stimulation modes, including multiple BPR stimulation settings, resulted in different blood pressure adaptation patterns.

[0353] b. The stimulation pattern may include at least, for example, a first stimulation setting and a second stimulation setting different from the first stimulation setting, the first stimulation setting and the second stimulation setting being configured to reduce or prevent atrial drive and / or to control atrial pressure and / or stretch. The stimulation pattern may even include more than two different stimulation settings. In some embodiments, the second setting has a longer AV delay than the first setting (e.g., about 80 ms to about 160 ms). In some embodiments, the second setting may be configured not to reduce atrial drive and / or not to control atrial pressure and / or stretch.

[0354] exist Figure 1 , a graph of systolic blood pressure versus time for a hypertensive patient receiving a stimulation signal is depicted. The intersections along the depicted lines depict the peak systolic blood pressure for each heartbeat. During approximately the first 2 depicted minutes, no stimulation signals were delivered. As seen, the patient's initial blood pressure averaged over 150 mmHg. As is known in the art, fluctuations in blood pressure (approximately ±10 mmHg) are attributed to the respiratory cycle.

[0355] Then, the first stimulation pattern is applied during the time interval a-a', the second stimulation pattern is applied during the time interval b-b' and the third stimulation pattern is applied during the time interval c-c'. Between the stimulation patterns and after the third stimulation pattern, the heart is not stimulated.

[0356] Follow now Figure 2 , depict Figure 1 The enlarged portion of the image is indicated by the dotted rectangle A. Figure 2 The dotted rectangle in the figure indicates the time period, which is Figure 1 The stimulation begins and is delivered to the patient's right atrium and right ventricle, coinciding with the time interval a-a' in , so that the atrium receives the BPR stimulation signal (pulse) 2 ms before the ventricle. Figure 1 and Figure 2 The stimulation was terminated at the time indicated by a' in the figure. During the time interval a-a', the patient's systolic blood pressure first decreased to a minimum value below 110 mmHg, and then gradually increased to an intermediate value between the initial blood pressure and the minimum value obtained. At point a', the stimulation was terminated and the blood pressure was observed to immediately exceed a value of 170 mmHg. Within about twelve heartbeats, the blood pressure returned to its initial range.

[0357] Figure 1 and Figure 2The changes in blood pressure that occur during a stimulus represent, at least in part, a response of the cardiovascular system to changes in blood pressure, known as the baroreceptor reflex. The baroreceptor reflex acts to restore blood pressure to its pre-stimulus level by altering cardiovascular characteristics (e.g., peripheral resistance and / or myocardial contractility). It can be hypothesized that the decrease in blood pressure caused by a reduction in ventricular filling provokes a baroreceptor reflex response toward restoration of pre-stimulus blood pressure. For example, during a stimulus Figure 2 At point a' in , the effect of the baroreceptor reflex on the cardiovascular system is evident. At that point, the stimulus affecting ventricular filling is withdrawn, and the blood pressure immediately exceeds the pre-stimulus blood pressure. This may indicate a change in the baroreceptor reflex to the cardiovascular system (e.g., an increase in peripheral resistance and an increase in contractility). At point a', the stimulus is stopped and the blood pressure peaks, and the baroreceptor reflex responds to the increase in blood pressure by again changing one or more characteristics of the cardiovascular system, this time in order to reduce the blood pressure to the level before the change. As can be clearly seen, the response of the baroreceptor reflex feedback to increases and decreases in blood pressure is asymmetric, because the response to increases in blood pressure is faster than the response to decreases in blood pressure. Certain embodiments can take advantage of this asymmetry of the baroreceptor reflex, for example, in order to reduce or even prevent adaptation to a decrease in blood pressure due to reduced filling by controlling the stimulation pattern accordingly, as described in detail herein.

[0358] Figure 3A describe Figure 1 The enlarged view of the curve between time point a and point a'. Figure 3A An exponential function was fitted to the plotted curve showing the adaptive response, which describes the relationship between time and SysBP and has the following formula: .

[0359] where P (in mmHg) represents systolic blood pressure, Pi (mmHg) is the first mean decrease in blood pressure at the onset of the BPR stimulus, DP (mmHg) is a constant representing the amount of pressure increase after the initial decrease to the new steady-state level, k (seconds) is the reaction time constant, e is a mathematical constant that is the base of the natural logarithm, and t (seconds) is the time.

[0360] exist Figure 3A In , the matching function is as follows: .

[0361] Among them Pi was found to be 115 mmHg, DP to be 23 mmHg, and k to be 15.5 seconds.

[0362] Figure 3B Depiction Figure 1 An enlarged view of the portion indicated by the dotted rectangle A'. Figure 3BIn , an exponential function is fitted to the plotted curve showing the adaptive response to the end of the delivery of the BPR stimulus. As can be seen, this response, shown by the decrease in blood pressure, is faster than the response to the BPR stimulus.

[0363] exist Figure 3B In , the matching function is as follows: .

[0364] Where Pi is found to be 190 mmHg, DP is -35 mmHg, and k is 4.946 seconds.

[0365] As mentioned above, the baroreceptor reflex response to a decrease in blood pressure is much slower than the baroreceptor reflex response to an increase in blood pressure. This is indicated by the ratio of the time constant k mentioned above (about 15 seconds to about 5 seconds) to the faster response to an increase in blood pressure. This asymmetry in the speed of the baroreceptor reflex response can provide a method for designing a stimulation pattern that forms an average decrease in blood pressure and reduces or even prevents adaptation. For example, in a preferred embodiment, the stimulation pattern can alternate between two stimulation settings in the following manner: the weighted response supports the changes in the cardiovascular system evoked by the increase in blood pressure. In this embodiment, the heart can be stimulated using a stimulation pattern with two stimulation settings: a first setting, which is designed to reduce ventricular filling and thereby reduce blood pressure; and a second setting, which is designed to have normal ventricular filling, or at least higher ventricular filling than the first setting. This stimulation pattern can include a pulse (BPR) with a first setting that is delivered for a period of time shorter than the time constant of the baroreceptor reflex response to a decrease in blood pressure. In such a case, adaptation may begin to show and blood pressure may increase from a reduced level, but may not reach its pre-stimulation level. This stimulation mode may also include pulses with a second setting (e.g., a natural AV delay) that are delivered for a period of time that is longer than the time constant of the baroreceptor reflex response to an increase in blood pressure. In this case, the reduction in blood pressure caused by the baroreceptor reflex may be fully exploited, and the blood pressure may even return to the level it was before the stimulation mode was switched to this second setting. In such a mode, the weighted response of the baroreceptor reflex may reduce or prevent adaptation, while the average pressure may be lower than the pre-stimulation level. The relationship between the time constant and the period allocated to the delivery of pulses with different settings can determine the level of the baroreceptor reflex response that is active during the entire stimulation mode. With respect to a particular stimulation setting, if a delivery period that is shorter than the time constant of the response is selected, the baroreceptor reflex may not be able to change the cardiovascular system back to the pre-stimulation level, and if a period that is selected is greater than the time constant, the baroreceptor reflex effect may be more significant.

[0366] like Figure 1 It can be seen that, in the interval between points b and b', a second stimulation pattern is delivered. Figure 4 describe Figure 1 of (in Figure 1 An enlarged version of this portion (indicated by the dashed rectangle B in FIG). In the second stimulation mode, a sequence of 12 BPR pulses is delivered to both the atria and the corresponding ventricles with an AV delay of 2 ms, followed by 3 heartbeats on which only atrial stimulation is artificially delivered without ventricular stimulation. During these last 3 heartbeats, ventricular excitation occurs via natural conduction of the AV node, which results in an AV delay of ~180 ms. This second stimulation mode is repeated for the duration of the time interval shown. Figure 4 In the experiment, we find that the exponential function of the matching curve is as follows: .

[0367] As can be seen, Pi and DP are comparable to the values ​​corresponding to the first stimulation pattern ( Figure 3A However, the k of the second mode is almost twice the time constant of the first stimulation mode. Figure 3A Adaptation occurs more slowly in the , but blood pressure is higher when the mode switches between stimulation pulses than in Figure 3A This result demonstrates that the application of a stimulation pattern with alternative stimulation settings reduces adaptation.

[0368] As in Figure 1 It can be seen that the third stimulation pattern is also transmitted between points c and c'. Figure 5A describe Figure 1 1 , which includes the portion of the curve between point c and point c'. In the third stimulation pattern, a sequence of 12 BPR pulses is delivered with an AV delay of 2 ms, followed by 3 BPR pulses, each with a 120 ms AV delay. This step is repeated for the duration of the time intervals shown.

[0369] exist Figure 5B Draw in Figure 5A The portion of the curve marked by the dashed rectangle. Figure 5B An exponential function was fit to the depicted curves showing the adaptive response to a stimulation pattern of 12 BPR pulses delivered over an AV delay of 2 ms followed by 3 BPR pulses each with an AV delay of 120 ms.

[0370] exist Figure 5B In , the matching function is as follows: .

[0371] Pi was found to be 109.7 mmHg, DP was 22.3 mmHg, and k was 45.4 seconds. As can be seen, although the initial decrease in blood pressure is comparable to Figure 3A The displayed value is lower (Pi = 115 or 109.5), but the adaptation time constant (k) is much higher (45.4 seconds vs. 15.5 seconds), which means that at a value greater than Figure 3A Low blood pressure was maintained for approximately 3 times the period.

[0372] Follow now Figure 6 , in which the heart of a hypertensive patient was stimulated with a stimulation pattern having a sequence of 12 BPR pulses delivered over an AV delay of 2 ms, followed by 3 BPR pulses, each with an AV delay of 80 ms.

[0373] As can be seen, in this case, the adaptation rate is very slow and barely detectable over the allocated time interval. It may not match the exponential formula, indicating that the adaptation is very slow or non-existent.

[0374] exist Figure 7 In , the heart of a hypertensive patient was stimulated with a stimulation pattern having a sequence of 12 BPR pulses delivered over an AV delay of 2 ms, followed by 3 BPR pulses each with an AV delay of 40 ms. The stimulation started at point t1 and ended at point t2. No adaptive response was measured and the fitted curve was virtually linear with a fixed mean reduced blood pressure of approximately 112 mmHg, which was approximately 31 mmHg lower than the blood pressure immediately before and after the time interval t1-t2.

[0375] As is apparent from the different stimulation modes shown previously, a stimulation mode including at least one BPR stimulation can be set to at least approach one or more targets. For example, in some embodiments, a stimulation mode can be set so as 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 a more specific embodiment, blood pressure can be reduced by at least a specific percentage or by at least a specific measurement (e.g., 10 or 20 mmHg or even 30 mmHg), or blood pressure can be reduced to within a specific range (e.g., between 90 and 130 mmHgSysBP) or below a specific target (e.g., 130 mmHg SysBP or less). In some embodiments, the goal may include maintaining the reduced blood pressure for an extended period within a reduced average range. For example, the pre-treatment blood pressure can be reduced to a predetermined average blood pressure within a period of time or many heartbeats. In another embodiment, the goal may include causing a specific percentage of heartbeats to be on a reduced range / threshold. In some embodiments, the goal may include reducing blood pressure while also reducing the level of spikes between stimulation pulses. For example, a stimulation mode may be used to reduce blood pressure to a constant blood pressure at a predetermined time interval. In some embodiments, the stimulation mode can be used to lower blood pressure without significantly affecting cardiac output. For example, applying intermittent BPR pulses can allow pulses with higher (or even completely) atrial drive to occur between BPR pulses. Pulses with higher (or even completely) atrial drive can prevent BPR pulses from significantly reducing cardiac output. In another embodiment, the reduced adaptability associated with reducing total peripheral resistance together with the reduction in blood pressure (afterload) can positively affect cardiac output by affecting flow through the blood system. In yet another embodiment, pacing at a rate higher than the patient's natural rhythm can avoid the negative effects on cardiac output that may be associated with a lower stroke volume.

[0376] In setting a stimulation mode to approach one or more targets, providing different blood pressure reduction values ​​may involve adjusting stimulation parameters that affect AV delay. For example, stimulation parameters that provide a shorter AV delay may reduce blood pressure to a greater extent than stimulation parameters that provide a longer AV delay. In an embodiment, a stimulation setting that reduces atrial drive may provide an AV delay that varies from about 5 ms to about 30 ms (e.g., between day and night, or between vigorous activity and light activity), wherein a shorter AV delay reduces blood pressure to a greater extent.

[0377] Providing different blood pressure reduction values ​​may involve changing stimulation parameters other than the short AV delay duration. For example, an embodiment may adjust the ratio between the short AV delay and the longer AV delay. As another example, other embodiments may adjust the number of heartbeats that pulses with short AV delay are delivered compared to the number of heartbeats with longer AV delay.

[0378] In some embodiments, a time constant of change in blood pressure for a given pattern may be calculated and the stimulation pattern may be set to have one or more BPR stimulation parameters for a certain amount of time or a certain number of heartbeats that is set to a certain percentage of the calculated time constant. Figure 3A and Figure 3B , the rate k for the increase in blood pressure during the delivery of the BPR pulse was measured to be approximately 15 seconds, and the rate for the adaptation to the end of the delivery of the BPR pulse was measured to be approximately 4.9 seconds. In some embodiments, it may be desirable to prevent the blood pressure from increasing beyond a given value, in which case a period of delivery of the BPR pulse may be selected that is significantly less than k (e.g., 30% to 60% of k). In this embodiment, an interval of less than 15 seconds may be selected. Such an interval may include approximately 6-10 seconds or approximately 8-14 heartbeats, with a heart rate of approximately 80 heartbeats per minute.

[0379] Alternatively, it may be desirable to utilize an adaptive response to the withdrawal of the BPR pulse. In such a case, a larger k-fraction may be applied. For example, Figure 3B Based on , a period of 3-5 heartbeats can be selected (where k is about 4.9 seconds). Thus, for example, Figure 3A and Figure 3B Based on Figure 4 stimulation mode.

[0380] For example, the stimulation mode may be set to be the best of a plurality of stimulation modes (ie, the one closest to the set target parameters) and / or it may be selected as the first verified stimulation mode that meets the set target.

[0381] 4. Example based on slow baroreceptor reflex response In experiments with dogs, the inventors found that when treatment is terminated after a period of treatment, it may take a relatively long time for blood pressure to return to its pre-treatment value. Embodiments can take advantage of this slow baroreceptor reflex response. Specifically, embodiments can suspend treatment (e.g., pacing normally or not pacing at all) for longer periods of time, which can allow for saving battery power and extending the life of the stimulation device.

[0382] As an example of a slow baroreceptor reflex response, Fig. 27is a graph showing the effect of the antihypertensive treatment disclosed herein on dogs, plotting the change of systolic blood pressure (in mmHg) over time (in days). As shown in the figure, the blood pressure value before treatment is represented by the baseline ("BL") marked with diamond data points, the treatment period value is represented by the treatment line marked with square data points, and the post-treatment value is represented by the device off ("Dev Off") line marked with triangle data points. In this experiment, the systolic blood pressure is measured continuously for 24 hours using an implanted sensor, which transmits the systolic blood pressure to a receiver. Each data point on the graph represents the average value measured over a 24-hour period.

[0383] The blood pressure of canine subjects is approximately 210 mmHg. Fig. 27 After applying the antihypertensive treatment disclosed in the present disclosure, the dog's blood pressure dropped to about 170 mmHg, as shown in the baseline. Fig. 27 During the treatment period, the dog's blood pressure fluctuated between about 150 and about 175 mmHg (i.e., about 35 - 60 mmHg lower than the pre-treatment value). Treatment was applied for 30 days.

[0384] When treatment was stopped (the dog's heart was not being paced), the dog's blood pressure rose slightly to about 180 mmHg. Fig. 27 The device shut-off line is shown in the figure. This value is significantly lower than the blood pressure before treatment, about 30 mmHg. The dog's blood pressure remained near this pressure for about 20 days and then began to gradually increase back to essentially the value before treatment.

[0385] According to the mechanism of slow baroreceptor reflex response, e.g. Fig. 27 In an embodiment, a method of treating hypertension may be provided, comprising alternating between applying a first stimulation mode configured to reduce blood pressure (i.e., a therapeutic stimulation mode) and a second stimulation mode configured to have a lesser degree of blood pressure reduction (i.e., a "resting" stimulation mode), each of the two modes being applied for a period of time: days, weeks, or longer. In an embodiment, each of the two modes may be applied for at least one week, providing treatment at timescale intervals of several weeks. The resting stimulation mode may involve stimulation or no stimulation at all.

[0386] In an embodiment, the duration of the first stimulation pattern and the second stimulation pattern may be the same or different.

[0387] For example, the duration of the resting stimulation mode can be shorter than the duration of the therapeutic stimulation mode, for example, 25% - 90%, or in some cases 50% - 80%. In one implementation, the duration of the resting stimulation mode can be approximately two-thirds of the duration of the therapeutic stimulation mode.

[0388] The duration of the resting stimulation mode can be dependent on or proportional to the extent to which the therapeutic stimulation mode reduces blood pressure. For example, if the therapeutic stimulation mode is configured to reduce blood pressure by at least 50 mmHg, the resting stimulation mode can last longer than if the therapeutic stimulation mode is configured to reduce blood pressure by only 30 mmHg.

[0389] Optionally, the duration of the rest stimulation period may be no longer than two weeks to one month (eg, 14 - 31 days), regardless of the duration of the therapeutic stimulation mode.

[0390] Each stimulation mode may include multiple stimulation modes, and at least some of the multiple stimulation modes may include, for example, one or more atrial drive reduction pulse settings according to one or more modes described in the present disclosure. For example, during a cycle of a treatment stimulation mode, treatment may include changes based on need (e.g., alternating between a day setting and a night setting).

[0391] In embodiments, a resting stimulation mode may be selected from: (1) no pacing applied; (2) pacing without reduction of atrial drive; and (3) pacing with less overall and / or average reduction of atrial drive than a treatment stimulation mode. Optionally, a resting stimulation mode may include switching from one resting stimulation mode to another. A resting stimulation mode may not necessarily completely cease blood pressure reduction, and may include, for example, applying very few atrial drive reduction pulses (e.g., at a frequency of no more than 10 pulses in a 20 minute period), or alternating between one degree of blood pressure reduction and another different degree of blood pressure reduction.

[0392] In other embodiments, more than two stimulation modes may be used for one or more therapeutic stimulation cycles and rest cycles. For example, a first stimulation mode providing 2 ms of AV delay may be applied for the first week, followed by a week of no pacing, followed by a month of a stimulation mode providing approximately 0 - 20 ms of AV delay (alternating between stimulation modes), followed by 3 or 6 weeks of a stimulation mode providing approximately 140 ms of AV delay, except once a day during those 3 or 6 weeks of a stimulation cycle providing approximately 30 ms of AV delay.

[0393] This stimulation method can minimize the duration and extent of electrical stimulation applied to the heart while still maintaining desired long-term blood pressure levels.

[0394] 5. Embodiments of methods for setting and / or selecting stimulation modes exist Figure 8An exemplary method 600 for setting and / or selecting a stimulation mode is graphically depicted in . The method 600 may be performed during implantation of a device for performing BPR and / or AC stimulation and / or may be performed periodically to adjust device operating parameters and / or may be performed continuously during operation. The method 600 may be performed by the system 700 described below. Thus, the system 700 may be configured to perform any of the steps of the method 600. Likewise, the method 600 may include any of the steps that the system 700 is configured to perform. For example, the method 600 may include any of the functions discussed below with respect to the system 700. Additionally, the method 600 may be performed by reference to the system 700 described below. Fig.14 The depicted device 50 performs the method 600. The method 600 may include any steps that the device 50 is configured to perform.

[0395] Throughout this disclosure, the terms "first", "second", and "third" are not meant to always imply an order of events. In some cases, these terms are used to distinguish individual events from each other without regard to order.

[0396] In some embodiments, step 601 can include setting a target blood pressure value. This target can be an absolute blood pressure value (e.g., a target blood pressure range, a target threshold for spike values, and / or the number or portion of spikes in a given time period), a relative value (e.g., compared to a patient's pre-treatment blood pressure or as a comparison between multiple detected stimulation patterns), or both. The target blood pressure value can be a blood pressure value (e.g., measured in mmHg) and / or a value associated with a formula calculated to match the blood pressure measurement of the stimulation pattern, etc. This target blood pressure value can be set before, during, and / or after other method steps, and, for example, can be revised if it is not achieved by any detected stimulation pattern.

[0397] Step 602 may include delivering one or more stimulation patterns to one or more chambers of the patient's heart, including delivering a first stimulation pattern to one or more chambers of the patient's heart. The first stimulation pattern may be a general stimulation pattern or the first stimulation pattern may have been selected to match a specific patient (e.g., when implanting a replacement device). The first stimulation pattern may include at least one stimulation setting configured to reduce or prevent atrial drive in at least one ventricle for a first time interval and / or for controlling atrial pressure and / or stretch.

[0398] Step 603 may include sensing one or more parameters before, during, and / or after the delivery of each of the one or more stimulation patterns (step 602). The sensed parameters may include sensing atrial pressure to assess the overlap between the maximum value of atrial pressure due to contraction and the maximum value of atrial pressure due to ventricular contraction. The sensed parameters may include sensing atrial pressure resulting from the delivery of each of the one or more stimulation patterns (step 602) to assess the pressure obtained with stimulation and optionally compare it with one or more of the pressures obtained with different stimulation or without stimulation. Optionally, the parameters may include blood pressure values ​​or blood pressure-related parameters (e.g., blood pressure changes). In some embodiments, the sensed parameters may include information related to the timing and / or degree of closing and / or opening of the AV valve. In some embodiments, the sensed parameters may include information related to the timing and / or speed of blood flow between the atria and ventricles of the heart. In some embodiments, the sensed parameters may include sensing pressure within a heart chamber (e.g., atria and / or ventricles). In some embodiments, sensing of the patient's AV valve state, or position (i.e., open or closed) may include, for example, sensing of heart sounds using an audio sensor. In some embodiments, sensing of the patient's AV valve status may include Doppler sensing and / or imaging of cardiac activity. In some embodiments, the patient's AV valve status may be sensed by a blood flow sensor.

[0399] In some embodiments, the sensing of blood flow can be performed by one or more implanted sensors in one or more cardiac chambers. For example, one or more pressure sensors can be placed in the right ventricle. In some embodiments, multiple pressure sensors can be placed in multiple chambers. Optionally, the measurements of multiple sensors can be combined. Optionally, pressure changes, trends in pressure changes, and / or pressure change patterns can be used to provide information related to blood flow. In some embodiments, relative changes between two or more sensors in different chambers can be compared.

[0400] When a stimulation pattern is delivered to the heart (step 602), one or more parameters may be measured at least once, or at multiple times, or even continuously during the delivery of the stimulation pattern. Each stimulation pattern may be delivered more than once.

[0401] Step 604 can include analyzing the sensed parameters. In some embodiments, once at least one stimulation mode is delivered and the corresponding parameters are sensed, the analysis (604) can be performed. In embodiments where multiple parameters are sensed, step 604 can include the following: comparing sensed parameter values ​​to targets; comparing sensed parameters between two or more stimulation modes; comparing calculated values ​​(e.g., k constants) associated with the two or more stimulation modes; and comparing additional sensed parameters between the two or more stimulation modes. In some embodiments, this last function can be performed in order to determine and select which stimulation mode produces a higher ejection fraction, stroke volume, cardiac output, and / or lower battery usage.

[0402] Step 605 may include setting a pacing (stimulation) mode. When more than one parameter is sensed, the stimulation mode used in step 605 may be selected based on multiple parameters, multiple target values, and / or multiple target ranges.

[0403] In some embodiments, Figure 8 The steps shown in Figure 8 The steps may be performed in the order indicated by the arrows. In other embodiments, the steps may be performed in another order. For example, step 602 may be performed before setting the target blood pressure value according to step 601. In some embodiments, the stimulation mode may be set to be performed indefinitely. In some embodiments, the stimulation mode may be set to be performed with respect to a predetermined period of time. For example, in some embodiments, the stimulation mode setting during step 605 may be performed with respect to a predetermined period of time and then steps 602, 603, and 604 may be repeated to determine how another stimulation mode affects the patient's blood pressure. Then, step 605 may also be repeated based on the analysis performed in step 604.

[0404] In some embodiments, method 600 may include the step of adjusting the first stimulation mode, thereby changing the first stimulation mode to a second stimulation mode. In some embodiments, step 605 of setting the stimulation mode may include adjusting the stimulation mode. For example, step 605 may include adjusting a parameter of the first stimulation setting, such as the time interval from step 602. In another embodiment, step 605 may include adjusting a parameter of the first stimulation setting configured to reduce or prevent atrial drive in at least one ventricle and / or for controlling atrial pressure and / or stretch. In some embodiments, step 605 may include adjusting the first stimulation mode to a second stimulation mode, which is configured to cause a reduction in blood pressure by at least a predetermined amount. In some embodiments, the predetermined amount may include, for example, about 8 mmHg to about 30 mmHg. In some embodiments, the predetermined amount may be at least 4% of the patient's pre-treatment blood pressure. For example, the predetermined amount may be about 4% of the patient's pre-treatment blood pressure to about 30% of the patient's pre-treatment blood pressure.

[0405] In some embodiments, step 605 may include adjusting the stimulation mode to a stimulation mode configured to cause an immediate reduction in blood pressure of at least a predetermined amount. For example, in some embodiments, step 605 may include adjusting the stimulation mode to a stimulation mode configured to cause a reduction in blood pressure of at least a predetermined amount within approximately 3 seconds from the application of the current to the heart. In some embodiments, step 605 may include adjusting the stimulation mode to a stimulation mode configured to cause a reduction in blood pressure of at least a predetermined amount within at least 5 heartbeats of the applied current. In some embodiments, the reduction in blood pressure resulting from the stimulation mode set during step 605 may occur within 1-3 seconds of the application of the current to the heart or within 1, 3, or 5 heartbeats of the application of the current to the heart.

[0406] 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 initial blood pressure of the patient at rest. 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 in less than 5 heartbeats from the start of stimulation. For example, step 605 may include adjusting the first stimulation pattern to a second stimulation pattern configured to cause a reduction in blood pressure. In some embodiments, step 605 may include adjusting the first stimulation pattern to a second stimulation pattern configured to cause a reduction in blood pressure for a predetermined time interval. For example, the predetermined time interval may include at least 1 minute or at least 5 minutes.

[0407] In some embodiments, the second stimulation mode can be configured to maintain the blood pressure so that it does not exceed a predetermined average value by more than a predetermined degree during a predetermined time interval. For example, the predetermined degree may be a difference of about 20 mmHg or less. In some embodiments, the 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 heartbeats, but the patient's average blood pressure may not exceed the predetermined average value.

[0408] In some embodiments, the second stimulation mode may include a second stimulation setting configured to reduce or prevent atrial drive in at least one ventricle and / or for controlling atrial pressure and / or stretch. The second stimulation setting may be based on at least one blood pressure change parameter calculated from input data sensed during application of the first stimulation mode.

[0409] In some embodiments, the second stimulation mode can be configured to reduce or limit the size of the spike in blood pressure between stimulation pulses. In some embodiments, the spike in blood pressure between stimulation pulses can be reduced to a percentage of the baseline blood pressure value. For example, the second stimulation mode can be configured to prevent more than 80% increase in blood pressure between pulses. In other words, the second stimulation mode can be configured to prevent blood pressure from forming more than about 80% spikes between pulses. In some embodiments, the second stimulation mode can be configured to prevent more than 40% increase in blood pressure between pulses. In some embodiments, the second stimulation mode can be configured to prevent blood pressure spikes of more than about 10 mmHg to about 30 mmHg between pulses. For example, in some embodiments, the second stimulation mode can be configured to prevent blood pressure spikes of more than 20 mmHg between pulses.

[0410] In some embodiments, the second stimulation mode 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 atrial drive in at least one ventricle and / or for controlling atrial pressure and / or stretch. At least one stimulation pulse of the plurality of stimulation pulses may have a second stimulation setting configured to reduce a baroreceptor reflex response to reduced atrial drive and / or for control of atrial stretch, such that the increase in blood pressure values ​​occurring between stimulation pulses is limited to a predetermined value. In some embodiments, the second stimulation setting may be configured to increase blood pressure within approximately 1 heartbeat to 5 heartbeats in order to evoke negation of the baroreceptor reflex response. In some embodiments, the second stimulation mode may include a plurality of stimulation pulses with the first stimulation setting and a plurality of stimulation pulses with the second stimulation setting. In such embodiments, the second stimulation mode may have between approximately 1% of the plurality of stimulation pulses of the stimulation mode and 40% of the plurality of stimulation pulses. In some embodiments, the second stimulation mode may include a plurality of stimulation pulses with the first stimulation setting and a plurality of stimulation pulses with the second stimulation setting. In such embodiments, the second stimulation mode may have between approximately 1% of the plurality of stimulation pulses of the stimulation mode and 40% of the plurality of stimulation pulses. In some embodiments, the stimulation pattern may include a ratio of stimulation pulses with a first setting to stimulation pulses with a second setting based on a ratio of time constants of responses to increases and decreases in blood pressure. For example, the ratio of stimulation pulses with a first setting to stimulation pulses with a second setting may be based on a ratio of time constants of changes in blood pressure resulting from each of the first setting and the second setting. In some embodiments, the first stimulation setting may include a first AV delay and the second stimulation setting may include a second AV delay, the first AV delay being shorter than the second AV delay. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses with the first stimulation setting and one or more stimulation pulses with the second stimulation setting. In some embodiments, the second stimulation pattern may include a ratio of about 8 stimulation pulses to about 13 stimulation pulses with the first setting to about 2 stimulation pulses to about 5 stimulation pulses with the second setting. In some embodiments, the second stimulation pattern may include at least one stimulation pulse with a stimulation setting, the stimulation setting being configured to evoke a hormonal response from the patient's body. In some embodiments, the first stimulation pattern may include at least one stimulation pulse with a stimulation setting that is not configured to evoke a hormonal response from the patient's body. In some embodiments, in a given sequence of stimulation patterns, the second stimulation pattern may be applied before the first stimulation pattern.

[0411] In some embodiments, method 600 can include alternating between two or more stimulation modes. For example, method 600 can include alternating between two to ten stimulation modes.

[0412] In some embodiments, the blood pressure sensor and controller can be configured to operate at least partially as a closed loop.

[0413] In some embodiments, method 600 may include a controller that executes a plurality of stimulation modes and receives corresponding input data related to the patient's blood pressure during stimulation for each of the stimulation modes. The plurality of stimulation modes may include at least two stimulation modes, each including at least one stimulation pulse having a stimulation setting configured to reduce or prevent atrial drive of at least one ventricle and / or for controlling atrial pressure and / or stretch. The at least two stimulation modes may differ from each other by the number of times or the length of time that at least one stimulation pulse is provided in a sequence. The at least two stimulation modes may differ from each other by the number of times or the length of time that a predetermined AV delay occurs in a sequence. In some embodiments, in each of the at least two stimulation modes, the stimulation settings may be the same. In some embodiments, the stimulation settings may include the same AV delay for each of the at least two stimulation modes. In some embodiments, the at least two stimulation modes may differ from each other by one or more stimulation settings included in each of the at least two stimulation modes.

[0414] In some embodiments, the method 600 may include the controller calculating at least one blood pressure variation parameter associated with the input data for each of the plurality of stimulation modes. The method 600 may include the controller adjusting the stimulation mode according to the blood pressure variation parameter. In some embodiments, the method 600 may include the controller adjusting the stimulation mode to the stimulation mode having the best blood pressure variation parameter. For example, the best blood pressure variation parameter may include the blood pressure variation parameter showing the lowest degree of pressure receptor reflex. The best blood pressure variation parameter may include the blood pressure variation parameter showing the pressure receptor reflex within a predetermined range.

[0415] In some embodiments, the second stimulation mode may include at least one stimulation pulse having a stimulation setting configured to evoke a hormonal response from the patient's body, and in some embodiments, the first stimulation mode may include at least one stimulation pulse having a stimulation setting not configured to evoke a hormonal response from the patient's body.

[0416] In some embodiments, the plurality of stimulation modes may include a first stimulation mode and a second stimulation mode executed after the first stimulation mode. The second stimulation mode may have at least one stimulation setting that is set based on an algorithm using a blood pressure variation parameter associated with input data of the first stimulation mode.

[0417] 6. Embodiments of a system for lowering blood pressure According to some embodiments, Fig. 9An exemplary system 700 for reducing blood pressure is schematically depicted. System 700 may be one device or may include multiple devices that are optionally connected via wired or wireless communications. The device may have multiple components disposed within a housing and / or electrically and / or connected to the housing via wires. Fig. 9 As shown, a heart 701 is connected to a system 700 via one or more stimulation electrodes 702. The stimulation electrodes can be configured to stimulate at least one chamber of the patient's heart with stimulation pulses. In some embodiments, multiple electrodes 702 can each be placed in a different chamber of the heart. For example, one electrode can be placed in the atrium and another electrode can be placed in the ventricle. In some embodiments, multiple electrodes 702 can be placed in a single chamber. For example, two electrodes can be placed in the atrium and / or two electrodes can be placed in the ventricle. In some embodiments, one electrode can be placed in a first chamber and multiple electrodes can be placed in a second chamber.

[0418] In existing embodiments, electrodes 702 may include typical pacemaker leads, such as Medtronic Capsure® pacing leads. These lead wires are used to connect the heart 701 to the system 700. The pacing lead wires may be constructed of an industry standard IS-1 BI connector (reference standard ISO 5148-3:2013) on one end, an electrode on the other end, and an insulated conductor system therebetween. In some embodiments, the IS-1 BI connector is constructed using stainless steel as two electrode contacts and silicone as an insulating material. Certain embodiments may use polyurethane as an insulating material.

[0419] Stimulation of one or more cardiac chambers can be accomplished by placing a voltage between two electrodes of the atrial or ventricular cardiac pacing electrode lead described above. The stimulation circuit utilizes a transistor network (e.g., MOSFETS) to charge a capacitor to a specific programmable voltage, such as 2.0V, and then controls its connection to the electrode for a fixed programmable time period, such as 0.5 ms. The same network can also manage the discharge of any residual charge that accumulates on the electrode after stimulation is completed. The same network can control the type of stimulation applied, such as bipolar (between two electrodes) or unipolar (between one electrode and the stimulator housing).

[0420] As is known in the art, one or more electrodes may be placed in contact with one or both ventricles and / or one or both atria. Such electrodes may be used to sense stimulation and / or deliver stimulation to the respective heart chambers. For example, pacing electrodes may be introduced into both ventricles, with one electrode implanted in the right ventricle and another electrode placed in the left ventricle through the coronary sinus, and the system 700 includes means for forming biventricular stimulation of both ventricles in order to reduce asynchrony caused by ventricular stimulation.

[0421] The system 700 may include a controller 703. The system 700 may be an electrical stimulator including a power source 704 (eg, a battery as known in the art of electrical stimulators). The controller 703 and / or the electrodes 702 may draw power from the power source 704.

[0422] Optionally, the electrical stimulator of system 700 is constructed of a sealed housing and a top cover. The housing can be constructed of titanium or any other biocompatible material and can contain a power source 704, electronics, and a telemetry coil or communication module 707 for communicating with an external device. The power source 704 can be an implantable grade sealed primary battery. The battery chemistry can be lithium-iodine. Other embodiments can utilize larger or smaller batteries. Other embodiments can utilize rechargeable batteries such as Li-ion rechargeable batteries. In some embodiments, the electronics can be constructed of standard off-the-shelf electronics (e.g., transistors and diodes) and / or custom electronics (e.g., ASICs).

[0423] In order to detect the initiation of atrial and / or ventricular excitation, one or more sensing electrodes may be implanted at or near a site of interest in the heart. These sensing electrodes may be the same electrodes used to deliver pulses to the heart or dedicated sensing electrodes. The electrical activity may be bandpass filtered to remove unwanted noise and may have a programmable cutoff frequency in accordance with international standards for pacemakers (reference EN45502-2-1:2003). The circuit may be used to amplify the electrical signal formed by the activation of the propagating cardiac chamber, and once the electrical signal meets a specified condition, such as the crossing of a predetermined threshold, the initiation of activation is determined. For example, the signal may be amplified with a programmable gain and then passed to a comparator for threshold detection, wherein the programmable detection threshold is a step size of 0.2 mV (atrium) and 0.4 mV (ventricle). These means of detecting excitation may introduce a delay between the actual initiation of the activation of the chamber and its detection, because the detection electrode may be far from the origin of the excitation, and the time required for the signal to meet the detection criteria may be non-negligible and may be in the range of 5 ms to 50 ms or even greater. In such a case, the timing of the initiation of stimulation may be estimated based on the timing of the sensed stimulation, and the delivery of stimulation pulses will be calculated to compensate for this delay.

[0424] Optionally, the controller 703 interfaces with an accelerometer to measure the patient activity level. This patient activity level can be used to adjust the pacing rate and / or BPR settings and / or stimulation mode based on the patient's needs. The activity level can also be used to control the desired level of action on the blood pressure. For example, when an increase in blood pressure is desired, the reduction in blood pressure can be reduced at high activity levels to enable better performance. Optionally, when the patient is inactive (e.g., when sleeping), the blood pressure can naturally decrease, in which case the pacing can be adjusted to avoid lowering the blood pressure below a desired threshold. The activity level can also be used to adjust settings based on the baroreceptor reflex to allow for better response when needed. For example, the sensor may be a piezoelectric sensor. Other embodiments may utilize a MEMS-based accelerometer sensor. Other embodiments may utilize a minute ventilation sensor, optionally in conjunction with an accelerometer.

[0425] The controller 703 may be configured to deliver an electrical current to the heart 701 via one or more electrodes 702. According to any embodiment of the present disclosure, the controller 703 may be configured to execute a stimulation pattern of stimulation pulses. In some embodiments, stimulation pulses may be delivered to at least one ventricle of the heart. In some embodiments, the stimulation pattern may include a first stimulation setting and a second stimulation setting different from the first stimulation setting, the first stimulation setting and the second setting being configured to reduce or prevent atrial drive and / or for controlling atrial pressure and / or stretch. In some embodiments, the first stimulation setting has a different AV delay than the second stimulation setting. In some embodiments, the first stimulation setting and / or the second stimulation setting may be configured such that an atrial pressure resulting from atrial contraction of the atrium overlaps temporally with a passive pressure increase of the atrium, thereby providing an atrial pressure of the atrium that is a combination of the atrial pressure resulting from atrial contraction and the passive pressure increase and is higher than the atrial pressure of the atrium when no stimulation is received. In some embodiments, the first stimulation setting and / or the second stimulation setting may be configured such that the maximum atrial stretch is approximately equal to or lower than the maximum atrial stretch of the same heart when no stimulation is received. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured to cause the atria to contract at maximum force when the AV valve is open. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured to change the mechanics of at least one atrium contraction such that the mechanics of at least one atrium contraction is different from the mechanics of a previous natural atrium contraction. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured to reduce the force of at least one atrium contraction. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured to prevent at least one atrium from contracting.

[0426] In some embodiments, the controller 703 can be configured to deliver a variety of different AV delays. The controller 703 can be configured to sense when atrial contraction or excitation occurs (as described herein) and then deliver ventricular stimulation at a fixed interval after sensing or before a future expected atrial excitation or contraction. The interval can be programmable. The controller 703 can also be configured to stimulate the atria and then, after the stimulation, deliver ventricular stimulation at a fixed interval, which can also be programmable. For example, the programmable interval can vary between 2 ms and 70 ms to accommodate the desired therapeutic effect or even provide a negative AV delay of up to -50 ms.

[0427] In some embodiments, the controller 703 can be configured to repeat the stimulation pattern multiple times. For example, the controller 703 can repeat the stimulation pattern twice. In another embodiment, the controller 703 can be configured to repeat the stimulation pattern at least twice within a period of one hour. The stimulation pattern repeated by the controller 703 may include any type of stimulation pattern. For example, the stimulation pattern may include a stimulation setting configured to reduce or prevent atrial drive within at least one ventricle and / or for controlling atrial pressure and / or stretch. In another embodiment, the stimulation pattern may include two different stimulation settings, each configured to reduce or prevent atrial drive within at least one ventricle and / or for controlling atrial pressure and / or stretch. These two stimulation settings may differ by one or more parameters, such as AV delay.

[0428] In some embodiments, the controller 703 may be configured to perform one or more continuous stimulation patterns with respect to a predetermined time interval. For example, in some embodiments, the time interval may be 10 minutes or longer. In another embodiment, the time interval may be 30 minutes or longer, one hour or longer, or 24 hours or longer. In some embodiments, the time interval may be a period of several months, such as one month to one year. In some embodiments, the time interval may be longer than one year. In some embodiments, one or more continuous stimulation patterns may include a first stimulation setting configured to reduce or prevent atrial drive within at least one ventricle and / or control atrial pressure and / or stretch with respect to a portion of the time interval. For example, one or more continuous stimulation patterns may include a first stimulation setting configured to reduce or prevent atrial drive within at least one ventricle and / or control atrial pressure and / or stretch with respect to about 50% of the time interval to about 100% of the time interval. In another embodiment, one or more continuous stimulation patterns may include a first stimulation setting configured to reduce or prevent atrial drive within at least one ventricle and / or control atrial pressure and / or stretch with respect to about 50% of the time interval to about 85% of the time interval. In some embodiments, one or more continuous stimulation patterns may include a second stimulation setting having a longer AV delay than the first stimulation pattern with respect to at least one heartbeat during the time interval. In some embodiments, one or more continuous stimulation patterns may include a second stimulation setting and / or a third stimulation setting. The second stimulation setting and / or the third stimulation setting may each be different from the first stimulation setting. In some embodiments, the second stimulation setting and / or the third stimulation setting may each be configured to reduce or prevent atrial drive within at least one ventricle and / or for controlling atrial pressure and / or stretch. In some embodiments, the second stimulation setting and / or the third stimulation setting may each not be configured to reduce or prevent atrial drive within at least one ventricle and / or for controlling atrial pressure and / or stretch. In some embodiments, the second stimulation setting and / or the third stimulation setting may include approximately 0% of the time interval to approximately 50% of the time interval. In some embodiments, the second stimulation setting and / or the third stimulation setting may include approximately 0% of the time interval to approximately 30% of the time interval. In some embodiments, the second stimulation setting and / or the third stimulation setting may include approximately 0% of the time interval to approximately 20% of the time interval. In some embodiments, the second stimulation setting and / or the third stimulation setting may include approximately 5% of the time interval to approximately 20% of the time interval.

[0429] It is known that blood pressure varies in a diurnal manner, and in some cases, abnormally high blood pressure is prevalent only during part of a 24-hour cycle or during most of a 24-hour cycle (e.g., night or day or part thereof). In addition, it is known that blood pressure varies according to physical activity, with active people having higher blood pressure than the same people at rest. In some cases, therefore, it may be desirable to control the delivery of treatment as needed, for example, by changing treatment parameters or even suppressing the delivery of cardiac stimulation to lower blood pressure. In other words, cardiac stimulation may be varied at different times of the day and / or when the patient is active or at rest, so as to adjust the parameters of the stimulation, or may simply be turned on / off. Optionally, the delivery of such stimulation may be controlled according to the time of day and adjusted according to the patient's circadian BP rhythm, as shown in the following two examples.

[0430] Example 1 Fig.21 The systolic BP of an untreated patient during a monitored 24-hour period is shown. The hourly averages are shown. As shown, the patient's BP is abnormally high only during the day (approximately 10 a.m. to 6 p.m.). In this type of situation, it may be preferable to set the device so that pulses configured to reduce atrial drive and / or to provide AC stimulation are delivered only during moments when BP is expected to be abnormally high (i.e., when there is a need or where it is expected to be needed).

[0431] Example 2 Fig. 22 Another example is shown in . Here the patient's untreated blood pressure (at Fig. 22 The BP during the day is abnormally high (indicated by the line with "x" data points) during the night. The increase in BP during the day is within the normal range and may be attributed to the patient's increased activity. Optionally, it can be assumed that the patient will only require treatment during the night, and the device can be set to deliver stimulation accordingly. Optionally, it can be assumed that the patient does not require treatment during the day, and the device can be set so that even if an increase in blood pressure is measured during the day, such increase should not result in the delivery of treatment to lower blood pressure. Optionally, the device can be set not to measure blood pressure during the day.

[0432] exist Fig. 22 In the example shown in , the patient is then treated with a blood pressure lowering pulse with the following settings: for 10 heartbeats, both the atria and ventricles are paced with an AV delay of 15 ms, followed by 3 heartbeats with an AV delay of 40 ms. The treatment is delivered starting at 3 pm each day and lasting for 13 hours. The resulting BP (at Fig. 22), and as can be seen, BP was essentially within the normal range throughout the day and showed less variation than it did during the pre-treatment period (within treatment, BP varied by no more than approximately 30 mmHg, while the untreated range varied by no more than 40 mmHg).

[0433] In some embodiments, the intrinsic (non-stimulated) blood pressure profile of the patient is first determined, and then based on the intrinsic profile, stimulation parameters are determined accordingly to produce a desired reduction in blood pressure. Fig. 22 An example of such an approach is shown.In some embodiments, blood pressure is measured continuously or intermittently during operation of the device, and stimulation parameters that produce a desired reduction in blood pressure are then determined accordingly.

[0434] Not as referenced Fig.21 and Fig. 22 Rather than alternating between cardiac stimulation cycles and non-cardiac stimulation cycles as discussed in the exemplary methods of Examples 1 and 2, other methods may adjust stimulation parameters to provide different blood pressure reduction values ​​in each of two or more cycles in a time interval. Within a 24 hour time interval, the cycles may be minutes or hours. The different blood pressure reduction values ​​in each cycle may be based on need, such as based on blood pressure sensing feedback, time of day, patient activity, or inherent blood pressure patterns of a particular patient. Based on the needs during that particular cycle, the stimulation parameters for each cycle may be selected to achieve different degrees of blood pressure reduction.

[0435] 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 may achieve a lower degree of blood pressure reduction than the first stimulation setting, but still reduce blood pressure from the level when no stimulation is applied. As another example, a first stimulation setting may achieve a higher degree of blood pressure reduction during a period of lower patient activity, followed by a second stimulation setting during a period of higher patient activity, which may achieve a lower degree of blood pressure reduction than the first stimulation setting, but still reduce blood pressure from the level when no stimulation is applied.

[0436] When alternating between cycles of different stimulation settings, embodiments may gradually adjust the extent of the change in blood pressure to a parameter that affects the extent of the change in blood pressure by brief incremental adjustments or continuous adjustments. For example, if a first stimulation setting uses an AV delay of 30 ms and a second stimulation setting uses an AV delay of 60 ms, then 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., to 35 ms, then to 40 ms, and so on) from the 30 ms AV delay of the first stimulation setting to the 60 ms AV delay of the second stimulation setting. Similar incremental adjustments may be used to switch from the second stimulation setting back to the first stimulation setting. In other embodiments, the adjustment may be continuous in that the rate of change of the parameter that affects blood pressure (e.g., AV delay) is constant when switching from the first stimulation setting to the second stimulation setting.

[0437] As described above, providing different blood pressure lowering values ​​can include adjusting a stimulation parameter that affects the AV delay, which can be used to switch between stimulation settings. 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, a stimulation setting that reduces atrial drive can provide an AV delay that varies from about 5 ms to about 30 ms (e.g., between day and night, or between vigorous activity and light activity), wherein the shorter AV delay reduces blood pressure to a greater extent.

[0438] Fig.24 is a graph of an embodiment showing the relationship between AV delay (in this example, 100 ms or less) and systolic blood pressure reduction for a particular patient. As shown, stimulation parameters can be selected to achieve an AV delay that produces a desired systolic blood pressure reduction. Thus, based on the relationship between AV delay and blood pressure reduction, blood pressure reduction therapy can be tailored to the needs of the patient during a particular period of time (e.g., a period of minutes or hours over a time interval of a day) to achieve a desired blood pressure reduction, as shown in the following two examples.

[0439] Example 3 Fig.25 It is a graph of systolic blood pressure taken over a 24-hour period for a specific outpatient. As shown in the figure, Fig.25 Patients with BP have very high blood pressure at the beginning of the day (approximately 140 - 160 mmHg between approximately 6 AM and 2 PM), very low blood pressure late at night (less than 100 mmHg between approximately midnight and 2 AM), and intermediate blood pressure values ​​in between (approximately 120 - 140 mmHg between approximately 3 PM and 11 PM).

[0440] for Fig.25Depending on the type of patient, it may be useful to apply treatment with different sets of stimulation parameters throughout the day. For example, in one embodiment, a first set of stimulation parameters that significantly lower blood pressure may be applied between about 6 a.m. and about 2 p.m. (with a relatively very short AV delay), a second set of stimulation parameters that provide a longer AV delay but still slightly lower blood pressure may be applied between about 2 p.m. and about midnight, and a third set of stimulation parameters (e.g., no stimulation or stimulation that provides normal AV delay) may be applied between about midnight and about 6 a.m. In this way, depending on the patient's needs during different periods of the time interval, different stimulation parameters reduce or prevent atrial drive and lower blood pressure to provide the patient with a more normalized and controlled overall blood pressure.

[0441] Example 4 Fig.26 It is for different Fig.25 A graph of systolic blood pressure taken over a 24 hour period for another specific outpatient of a patient. Fig.26 Patients have nocturnal hypertension (greater than 140 mmHg between approximately midnight and 7 a.m.) and variable blood pressure during the day.

[0442] Fig.26 Types of patients may benefit from a different group of Fig.25 For example, during the night, a long AV delay may be applied. Thereafter, the AV delay may be periodically increased, reaching a normal or near-normal value (when blood pressure is substantially within normal values ​​of 120 mmHg or less) between about 9 a.m. and about 2 p.m. Thereafter, a longer AV delay (the same as or slightly shorter than the AV delay applied during the night) may be applied, with an additional increase (or set of increases) in AV delay between about 9 p.m. and about midnight.

[0443] All stimulation patterns exemplified above may include a feedback loop and / or may be pre-programmed based on the patient's known diurnal blood pressure variation.

[0444] In some embodiments, the controller 703 may be configured to perform one or more continuous stimulation patterns including a sequence of 10-60 stimulation pulses having a first stimulation setting configured to reduce or prevent atrial drive within at least one ventricle and / or for controlling atrial pressure and / or stretch. In some embodiments, the controller 703 may be configured to perform one or more continuous stimulation patterns including a sequence of 1-10 heartbeats contained within the 10-60 stimulation pulses, and the sequence of 1-10 heartbeats may have a longer AV delay than the first stimulation setting. For example, the 10-60 stimulation pulses may include 5 stimulation pulses having the first stimulation setting, followed by one heartbeat having a longer AV delay than the first stimulation setting, followed by 50 stimulation pulses having the first stimulation setting. The sequence of 1-10 heartbeats may include at least one stimulation pulse having a first stimulation setting configured to reduce or prevent atrial drive within at least one ventricle and / or for controlling atrial pressure and / or stretch. The sequence of 1-10 heartbeats may include a natural AV delay. Sequences of 1-10 heartbeats can occur without stimulation.

[0445] The system 700 may also include one or more sensors 705. In some embodiments, such sensors 705 may include one or more sensing electrodes for sensing electrical activity of the heart. In some embodiments, the one or more sensing electrodes may include one or more stimulation electrodes 702. In some embodiments, the sensors 705 may include one or more blood pressure sensors (implantable and / or external). In some embodiments, the one or more sensors 705 may include one or more pressure sensors implanted within the heart (e.g., within the atria and / or ventricles). In some embodiments, the sensors 705 may include one or more blood flow sensors (implantable and / or external). For example, the one or more sensors 705 may include ultrasonic sensing of blood flow through the AV valve. In some embodiments, the sensors 705 may include one or more sensors configured to monitor the timing of the closure of the AV valve. One or more of these sensors may be configured to operate as a closed loop with the controller.

[0446] Information from the sensor 705 can be provided to the controller 703 by any form of communication, including wired communication and / or wireless communication. Optionally, the system 700 may include one or more communication modules 707 for receiving and / or transmitting information between system components and / or transmitting information to devices external to the system. In some embodiments, the controller 703 can 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 can include data indicating BP or changes in BP measured at one or more time points (e.g., the degree of change and / or the speed of change or a function describing changes in blood pressure over time) and / or statistics related to BP or changes in BP, maximum and / or minimum BP values.

[0447] Optionally, the system 700 may include one or more user interfaces 708 for providing information and / or for allowing input of information. The information provided may include, for example, operational information related to the system and / or a display of data recorded by the system and / or received by the system during operation. This may include sensed parameters and / or relationships between sensed parameters and operational information (such as stimulation mode settings and / or the relative timing between the delivery of a particular pace and the sensed information).

[0448] Alternatively, the user interface 708 can be composed of a commercially available laptop computer (e.g., a Windows®-based computer) running a software application. The software application can be used to form commands that are passed to the interface, which in turn is connected to a handheld barcode reader (hand-held wand) that contains a telemetry circuit for communicating with an implantable stimulator. The commands sent to the barcode reader can be used to set stimulation parameters and / or retrieve device diagnostics, device data, cardiac data, and real-time cardiac sensing. The interface also allows the connection of a 3-lead ECG, and, through the software application, displays this data on the laptop screen. Other embodiments may not include a 3-lead ECG circuit or may include a 12-lead ECG circuit. Other embodiments may incorporate the functions of the barcode reader, interface, and laptop computer into a dedicated hardware part that performs all three functions. Other embodiments may also add printing capabilities to the user interface 708.

[0449] In some embodiments, the interface 708 can be configured so that a user (e.g., a physician) can provide a set of control instructions (e.g., target values ​​and / or ranges and / or other limits or instructions) to the system. Alternatively, the interface 708 can allow the user to input data from one or more sensors 705 (e.g., results of manual blood pressure measurements and / or results of an ultrasound monitor).

[0450] Optionally, one or more user interfaces 708 may allow a user to select a stimulation pattern (eg, from a set of stimulation patterns stored within system 700) or impose constraints on the setting and / or selection of a stimulation pattern.

[0451] Optionally, the system 700 may include one or more processors 706. The processor may be configured to process sensed parameters from the sensor 705 and / or input data from the user interface 708 in order to select a stimulation pattern for delivery by the system 700. Optionally, the processor 706 may be configured to analyze the sensed data and extract information and / or formula constants for use in the selection and / or evaluation of the stimulation pattern.

[0452] One or more components of the system 700 or portions of such components may be implanted within the patient's body, while certain components of the system 700 or portions of such components may be external to the patient's body. When certain components (or parts of components) are implanted and others are not, communication between the components may occur by wired and / or wireless means, substantially as known in the art. For example, some or all of the functions of the controller 703 and / or processor 706 may be performed external to the body. Having certain components of the system 700 external to the patient's body may help reduce the size and / or energy requirements of the implanted device, and / or facilitate enhancement of the computing power of the system.

[0453] The system 700 may include additional functions related to the control of cardiac function and overall cardiovascular system performance. For example, the system 700 may include one or more algorithms and / or electrodes to enable biventricular pacing or resynchronization therapy to reduce asynchrony that may be caused by ventricular stimulation. In some embodiments, the system 700 may include one or more algorithms to compensate for a possible reduction in cardiac output. Such algorithms may change the heart rate to increase cardiac output or implement other methods known in the art for controlling cardiac output. In some embodiments, the system 700 may include a rate response algorithm to affect changes in heart rate as a response to certain conditions. For example, the system 700 may include a rate response algorithm to affect changes in heart rate as a response to changes in the level of exercise, ventilation activity, and / or oxygen consumption. In some embodiments, the system 700 may include a sensor to detect activity, and, when the patient is exercising, the algorithm for stimulation may be turned off so that the patient's blood pressure is not lowered. In some embodiments, the system 700 may include a real-time clock. Such a clock may be used to control the timing of stimulation. For example, the system 700 may include an algorithm that turns stimulation on and off depending on the moment. This type of algorithm can be used to prevent nocturnal hypotension while the patient is sleeping.

[0454] In s...

Claims

1. A system for controlling blood pressure, the system comprising: a stimulation circuit configured to deliver stimulation pulses to at least one chamber of a heart of a patient; as well as at least one controller configured to execute delivery of stimulation pulses of one or more stimulation patterns to the at least one cardiac chamber; wherein, in a first operating mode, a first stimulation mode of the one or more stimulation modes reduces both systolic and diastolic blood pressure of the patient, and Wherein, in the second operation mode, a second stimulation mode of the one or more stimulation modes reduces the patient's systolic blood pressure while controlling the diastolic blood pressure so as to reduce the difference between the systolic blood pressure and the diastolic blood pressure.

2. The system according to claim 1, wherein: The second stimulation mode reduces systolic blood pressure while having minimal or no effect on diastolic blood pressure.

3. The system according to claim 1, wherein: The second stimulation mode reduces systolic blood pressure while limiting the effect on diastolic blood pressure to a level that does not prevent achieving a therapeutically effective reduced pulse pressure.

4. The system according to claim 1, wherein: The second stimulation mode reduces systolic blood pressure while simultaneously implementing an increase in diastolic blood pressure.

5. The system according to any one of claims 1 to 4, wherein: The at least one controller is configured to treat hypertension in the patient using the first stimulation pattern, or to treat isolated systolic hypertension in the patient using the second stimulation pattern.

6. A system according to claim 1 or claim 2, wherein: The second stimulation pattern combines a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while having minimal or no effect on diastolic blood pressure.

7. The system of claim 1 or claim 3, wherein: The second stimulation mode combines a stimulation mode that lowers blood pressure with stimulation that increases heart rate to lower systolic blood pressure while limiting the effect on diastolic blood pressure to a level that does not prevent achieving a therapeutically effective lowered pulse pressure.

8. The system of claim 1 or claim 4, wherein: The second stimulation mode combines a stimulation mode that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while increasing diastolic blood pressure.

9. The system according to any one of claims 1 to 8, wherein: The second stimulation mode combines a stimulation mode for lowering blood pressure with a stimulation mode for increasing heart rate to lower systolic blood pressure while controlling diastolic blood pressure so that the diastolic blood pressure is between a lower allowable value and an upper allowable value.

10. The system according to any one of claims 1 to 9, wherein: The second stimulation mode combines a stimulation mode that lowers blood pressure with a stimulation that increases heart rate to control systolic and diastolic blood pressure so that the resulting pulse pressure is between a lower allowable value and an upper allowable value and / or is a predetermined amount and / or percentage lower than the initial pulse pressure.

11. The system according to any one of claims 1 to 10, wherein: The second stimulation pattern combines a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while maintaining diastolic blood pressure above a specified minimum value.

12. The system according to any one of claims 1 to 11, wherein: The at least one controller is configured to obtain an indication of an intrinsic heart rate of the patient, and wherein the second stimulation mode increases the heart rate above the intrinsic heart rate.

13. The system according to claim 12, wherein: The at least one controller is configured to obtain the indication of the intrinsic heart rate from at least one of a heart rate sensor, a fixed value based on an average heart rate of a population, a table representing average heart rate values ​​for different populations, or a value based on previous heart rate measurements performed in the patient.

14. A system according to claim 12 or claim 13, wherein: The at least one controller is configured to obtain an indication of the intrinsic heart rate prior to and / or during delivery of the second stimulation pattern.

15. The system according to any one of claims 12 to 14, further comprising an activity sensor configured to detect an activity level of the patient, wherein The at least one controller is configured to derive the indication of the intrinsic heart rate from the estimate of the intrinsic heart rate based on the activity level signal received from the activity sensor.

16. The system according to any one of claims 1 to 11, wherein: The at least one controller is configured to: calibrating the first stimulation pattern to the second stimulation pattern by determining a diastolic blood pressure reduction and / or a systolic blood pressure reduction attributable to the first stimulation pattern; determining increases in systolic and diastolic blood pressure at different heart rates by actively stimulating the patient at said different heart rates; as well as Based on the determined diastolic blood pressure reduction and / or systolic blood pressure reduction and the systolic and diastolic blood pressure increases at the different heart rates, the second stimulation pattern is set to provide a desired heart rate increase.

17. The system of claim 16, wherein: The at least one controller is configured to determine the desired heart rate increase by first finding a heart rate at which an increase in diastolic pressure above an intrinsic heart rate is equal to the decrease in diastolic pressure caused by the first stimulation pattern, and then subtracting the intrinsic heart rate.

18. A system according to claim 16 or claim 17, wherein: The at least one controller is configured to determine the expected heart rate increase by calculating an expected overall effect on systolic blood pressure using the patient's existing systolic blood pressure data by: subtracting the expected increase in systolic blood pressure due to the expected increase in heart rate from the decrease in systolic blood pressure produced by the first stimulation pattern, Determine whether the expected overall effect on systolic blood pressure is adequate, and If the desired overall effect on systolic blood pressure is insufficient, a lower heart rate increase is selected to achieve the desired heart rate increase.

19. The system of any one of claims 1 to 18, further comprising a tachycardia sensor configured to monitor the patient's heart for tachycardia during the second stimulation mode and to send a signal to the at least one controller when tachycardia is detected, Wherein the at least one controller is configured to interrupt the second stimulation mode after receiving the signal.

20. The system according to any one of claims 1 to 11, wherein: The at least one controller is configured to receive data associated with a heart rate condition during delivery of the second stimulation mode that is to interrupt delivery of the second stimulation mode, and to interrupt delivery of the second stimulation mode when the heart rate condition is met.

21. The system of claim 20, wherein: The at least one controller is configured to automatically receive the data associated with the heart rate condition based on the measured parameter value.

22. A system according to claim 20 or claim 21, wherein: The data associated with the heart rate condition includes a cutoff heart rate determined based on at least one of time of day, patient activity level, or blood pressure.

23. A system according to any one of claims 20 to 22, wherein: The heart rate conditions include different levels of the second stimulation pattern at different heart rates.

24. A method for controlling a patient's blood pressure, the method being performed using an implanted myocardial stimulator associated with the patient's heart, the method comprising: delivering a first stimulation pattern to at least one chamber of the patient's heart, the first stimulation pattern reducing both systolic and diastolic blood pressure of the patient, and A second stimulation pattern is delivered to at least one chamber of the patient's heart, the second stimulation pattern reducing the patient's systolic blood pressure while controlling the patient's diastolic blood pressure so as to reduce a difference between the systolic and diastolic blood pressures.

25. The method according to claim 24, wherein: The second stimulation pattern combines a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower the patient's systolic blood pressure while having minimal or no effect on diastolic blood pressure.

26. The method according to claim 24, wherein: The second stimulation mode combines a stimulation mode that lowers blood pressure with stimulation that increases heart rate to lower systolic blood pressure while limiting the effect on diastolic blood pressure to a level that does not prevent achieving a therapeutically effective lowered pulse pressure.

27. The method according to claim 24, wherein: The second stimulation mode combines a stimulation mode that lowers blood pressure with a stimulation that increases heart rate to lower systolic blood pressure while increasing diastolic blood pressure.

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