Methods and systems for controlling blood pressure

Abstract

To lower systolic blood pressure while having little or no effect on diastolic blood pressure, or to lower systolic blood pressure while still increasing diastolic blood pressure, a system and method for controlling blood pressure using the difference in the effects on systolic and diastolic blood pressure are provided. **Solution**: A controller configured to perform transmission of stimulation pulses of one or more stimulation patterns to at least one heart chamber of a patient's heart is provided. In a first operating mode, both the patient's systolic and diastolic blood pressures are lowered by a first stimulation pattern. In a second operating mode, the systolic blood pressure of the patient is lowered while controlling the diastolic blood pressure so as to reduce the difference between the systolic and diastolic blood pressures by a second stimulation pattern. In particular, the second stimulation pattern can combine a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower the systolic blood pressure while limiting the effect on the diastolic blood pressure to a level that does not prevent the achievement of a therapeutically effective reduction in pulse pressure.

Description

Technical Field

[0001] The present invention relates to the field of treating hypertension by controlling cardiac functions including filling and contraction.

Background Art

[0002] Blood pressure fluctuations are typically known to occur, for example, due to an increase in activity (which usually raises blood pressure) or significant blood loss (which tends to cause a reduction in blood pressure). However, blood pressure is usually maintained within a limited range, for example, due to the body's baroreflex, whereby elevated or decreased blood pressure affects the function of the heart and the characteristics of the cardiovascular system through a feedback loop. Such feedback control is achieved by the nervous system and the endocrine system (e.g., natriuretic peptides). In people with hypertension, although the baroreflex is functioning, the blood pressure is maintained at an elevated level.

[0003] Other factors or conditions such as ventricular filling disorders, ventricular hypertrophy, and arterial stiffness can reduce the effectiveness of the feedback control system and thereby affect blood pressure levels and / or their fluctuations.

[0004] 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 years or older living in the United States have hypertension. Hypertension can lead to life-threatening conditions such as stroke, heart attack, and / or congestive heart failure. Approximately 44.1% of people with hypertension who are receiving current treatment are controlling their hypertension in a satisfactory manner. In contrast, 55.9% of the same people are not able to control it well.

[0005] Isolated systolic hypertension (ISH) is a type of hypertension in which the systolic (high) blood pressure is 130 mmHg or higher (the same as the definition of hypertension), while the diastolic (low) blood pressure is 80 mmHg or lower. Therefore, ISH patients are characterized by a larger pulse pressure (PP) value, which is the difference between the systolic blood pressure and the diastolic blood pressure, than non-ISH hypertensive patients. ISH is the most common form of hypertension seen in people over 65 years old. High pulse pressure (for example, 70 mmHg) is an independent risk factor for cardiovascular disease. Therefore, it is desirable to maintain the pulse pressure at a level that reduces this risk. Currently, existing treatments for hypertension lower both the systolic and diastolic blood pressures, and therefore the effect on pulse pressure is limited, leaving no option to lower the pulse pressure.

[0006] Isolated diastolic hypotension is a condition in which the diastolic blood pressure is less than 60 mmHg and the systolic blood pressure is over 100 mmHg. When the diastolic blood pressure is low, cardiac perfusion is inhibited, which becomes an independent risk factor for heart failure.

Prior Art Documents

Patent Documents

[0007]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0008] Traditionally, the treatment for hypertension has included medication and lifestyle changes. These two types of treatments are only partially effective for all patients, and their effectiveness is even lower when used for ISH patients. Most hypertension treatment methods lower both systolic blood pressure and diastolic blood pressure. However, for ISH patients, a decrease in diastolic blood pressure is not desirable and may even be dangerous in some cases. Therefore, there remains a need for a blood pressure lowering treatment that can lower systolic blood pressure while controlling the effect on diastolic blood pressure.

Means for Solving the Problem

[0009] The present invention provides a system and method for controlling blood pressure by using the difference in the effects on systolic blood pressure and diastolic blood pressure, in particular, to lower systolic blood pressure while having little or no effect on diastolic blood pressure, or to lower systolic blood pressure while increasing diastolic blood pressure.

[0010] In one aspect of the invention, this target blood pressure reduction may be achieved by controlling both the interbeat interval and the intrabeat interval to induce a physiological response of pulse pressure reduction. This reduction of pulse pressure (RPP) provides an effective treatment for isolated systolic hypertension (ISH) by lowering systolic blood pressure without causing a perceptible effect on diastolic blood pressure.

[0011] As used herein, the effect on "minimal" diastolic blood pressure means an effect at a level that does not prevent the achievement of a therapeutically effective pulse pressure drop. In some cases, when the diastolic blood pressure is already lower than the target blood pressure, a combination of a decrease in systolic blood pressure and an increase in diastolic blood pressure above the recommended minimal level may be desirable. In other cases, it may be desirable to significantly lower the systolic blood pressure and avoid a decrease in diastolic blood pressure below the optimal level (e.g., 70 mmHg). In other cases, the diastolic blood pressure may be lower than a threshold (e.g., 60 mmHg), and an increase in diastolic blood pressure may be desirable to reduce the risk of heart failure. In other cases, the pulse pressure may be higher than a specified threshold, and a combination of changes in systolic and diastolic blood pressures may be desirable to lower the pulse pressure below the threshold.

[0012] Generally, according to the present invention, it is possible to change (increase or decrease) the systolic blood pressure and / or diastolic blood pressure, and the present invention that enables a decrease in systolic blood pressure with the effect of no decrease, increase, or change in diastolic blood pressure as a treatment for hypertension only is considered to have therapeutic value. For example, in a specific state of diastolic hypotension, an increase in diastolic blood pressure may also have therapeutic value.

[0013] As a particular aspect of the invention, the application of local electrical stimulation to the heart is contemplated for controlling cardiac activity so as to lower the systolic blood pressure while controlling the diastolic blood pressure (e.g., while having little or no effect on the diastolic blood pressure or while increasing the diastolic blood pressure). Targeted reduction of the systolic blood pressure to the target value is particularly useful for patients with isolated systolic hypertension (ISH).

[0014] In one aspect of the invention, to provide RPP therapy by controlling the inter-beat interval and the intra-beat interval, for example, a pacemaker device may be used to electrically stimulate the heart to achieve a target blood pressure drop. Thus, aspects of the invention may include provisions for both RPP therapy (for the treatment of isolated systolic hypertension) and hypertension therapy (for treatments that affect both systolic and diastolic blood pressure).

[0015] As aspects of the invention, in Section I. below, treatments for isolated systolic hypertension, related pulse pressure reduction therapies, and systems, devices, and methods that combine isolated systolic hypertension treatment with other forms of hypertension treatment will be described. In Section II. below, other forms of hypertension treatment, and systems, devices, and methods for use in isolated systolic hypertension treatment and / or other forms of hypertension treatment will be described. I. Treatment of Isolated Systolic Hypertension (ISH) One aspect provides a system for controlling blood pressure that includes a stimulation circuit and at least one controller. The stimulation circuit may be configured to deliver stimulation pulses to at least one heart chamber of a patient's heart. The at least one controller may be configured to effect the delivery of stimulation pulses of one or more stimulation patterns to at least one heart chamber. In a first mode of operation, a first stimulation pattern of the one or more stimulation patterns may lower both the patient's systolic and diastolic blood pressures. In a second mode of operation, a second stimulation pattern of the one or more stimulation patterns may lower the patient's systolic blood pressure while controlling the diastolic blood pressure so as to reduce the difference between the systolic and diastolic blood pressures.

[0016] In one aspect, the second stimulation pattern may lower the systolic blood pressure while having little or no effect on the diastolic blood pressure.

[0017] In one aspect, the second stimulation pattern may lower the systolic blood pressure while limiting the effect on the diastolic blood pressure to a level that does not prevent the achievement of a therapeutically effective pulse pressure drop.

[0018] In one aspect, the second stimulation pattern may lower the patient's systolic blood pressure while causing an increase in the diastolic blood pressure, which may be useful when the patient's diastolic blood pressure level is considered too low.

[0019] In one aspect, at least one controller may be configured to treat the patient's hypertension using the first stimulation pattern or to treat the patient's isolated systolic hypertension using the second stimulation pattern.

[0020] In another aspect, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower the systolic blood pressure while having little or no effect on the diastolic blood pressure.

[0021] In another aspect, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower the systolic blood pressure while limiting the effect on the diastolic blood pressure to a level that does not prevent the achievement of a therapeutically effective pulse pressure drop.

[0022] In another aspect, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower the systolic blood pressure while increasing the diastolic blood pressure.

[0023] 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 the systolic blood pressure while controlling the diastolic blood pressure such that it is between a lower allowable value and an upper allowable value.

[0024] In other aspects, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure and a stimulation that increases heart rate, such that the resulting pulse pressure is between a lower tolerance value and an upper tolerance value, and / or such that the systolic blood pressure and diastolic blood pressure are controlled to be lower than the initial (e.g., intrinsic) pulse pressure by a predetermined amount and / or percentage.

[0025] In other aspects, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure and a stimulation that increases heart rate, and lower the systolic blood pressure while maintaining a diastolic blood pressure above a specified minimum value.

[0026] In other aspects, at least one controller may be configured to obtain an indicator of the patient's intrinsic heart rate, and the second stimulation pattern may be configured to increase the heart rate up to more than the intrinsic heart rate.

[0027] In other aspects, at least one controller may be configured to obtain an indicator of the intrinsic heart rate from at least one of a heart rate sensor, a fixed value based on the average heart rate of a population, a table of average heart rate values representing different populations, or a value based on previous heart rate measurements performed on the patient.

[0028] In other aspects, at least one controller may be configured to obtain an indicator of the intrinsic heart rate before and / or during transmission of the second stimulation pattern.

[0029] In other aspects, the system may also include an activity sensor configured to detect the patient's activity level. At least one controller may be configured to obtain an indicator of the intrinsic heart rate from an estimated value of the intrinsic heart rate based on the activity level signal received from the activity sensor.

[0030] On the other hand, at least one controller may be configured to calibrate a first stimulation pattern to a second stimulation pattern by determining a diastolic blood pressure drop and / or a systolic blood pressure drop resulting from the first stimulation pattern, determine an increase in systolic blood pressure and diastolic blood pressure at different heart rates by actively stimulating the patient at different heart rates, and set the second stimulation pattern based on the determined diastolic blood pressure drop and / or systolic blood pressure drop and the increase in systolic blood pressure and diastolic blood pressure at different heart rates, so as to bring about a desired heart rate increase.

[0031] On the other hand, at least one controller may be configured to determine a desired heart rate increase by first finding the heart rate at which the increase in diastolic blood pressure above the intrinsic heart rate is equal to the drop in diastolic blood pressure induced by the first stimulation pattern and then subtracting the intrinsic heart rate.

[0032] On the other hand, at least one controller may be configured to calculate the overall expected effect on systolic blood pressure using the patient's existing systolic blood pressure data to determine a desired heart rate increase by subtracting the expected increase in systolic blood pressure due to the expected increase in heart rate from the drop in systolic blood pressure caused by the first stimulation pattern, determining whether the overall expected effect on systolic blood pressure is sufficient, and selecting a lower increase in heart rate for the desired heart rate increase if the overall expected effect on systolic blood pressure is not sufficient.

[0033] On the other hand, the system may also include a tachyarrhythmia sensor configured to monitor the patient's heart for tachyarrhythmia during the second stimulation pattern and, if tachyarrhythmia is detected, transmit a signal to at least one controller. At least one controller may be configured to abort the second stimulation pattern after receiving the signal.

[0034] In other aspects, at least one controller may be configured to receive data related to a heart rate condition at which the transmission of the second stimulation pattern should be aborted during the transmission of the second stimulation pattern, and to abort the transmission of the second stimulation pattern if the heart rate condition is met.

[0035] In other aspects, at least one controller may be configured to automatically receive data related to a heart rate condition based on the measured parameter values.

[0036] In other aspects, the data related to the heart rate condition may include a cut-off heart rate determined according to at least one of time, the activity level of the patient, or blood pressure.

[0037] In other aspects, the heart rate condition may include different levels of the second stimulation pattern at different heart rates.

[0038] In another aspect, a method is provided for using an implantable myocardial stimulation device related to a patient's heart to control the patient's blood pressure. The method may include transmitting a first stimulation pattern to at least one heart chamber of the patient's heart to lower both the patient's systolic blood pressure and diastolic blood pressure, and transmitting a second stimulation pattern to at least one heart chamber of the patient's heart to lower the patient's systolic blood pressure while controlling the patient's diastolic blood pressure so as to reduce the difference between the systolic blood pressure and the diastolic blood pressure.

[0039] In other aspects, the second stimulation pattern may combine a stimulation pattern for lowering blood pressure and a stimulation for increasing heart rate to lower the patient's systolic blood pressure with little or no effect on the diastolic blood pressure.

[0040] In other aspects, the second stimulation pattern may combine a stimulation pattern for lowering blood pressure and a stimulation for increasing heart rate to lower the systolic blood pressure while limiting the effect on the diastolic blood pressure to a level that does not prevent the achievement of a therapeutically effective pulse pressure reduction.

[0041] On the other hand, the second stimulation pattern may combine a stimulation pattern that lowers blood pressure and a stimulation that increases heart rate to lower systolic blood pressure while increasing diastolic blood pressure. II. Hypertension Treatment The present invention applies focal electrical stimulation to the heart, including at least two different stimulation patterns configured to lower blood pressure to different degrees. The cardiac stimulation may alternate the stimulation patterns based on the patient's needs. For example, it may alternate between a certain degree of blood pressure reduction during a portion of a 24-hour cycle (e.g., daytime or a part thereof) and another different degree of blood pressure reduction during another part of the 24 hours (e.g., nighttime or a part thereof). As another example, the cardiac stimulation may alternate between a first stimulation pattern that provides a first degree of blood pressure reduction during a period of intense activity by the patient and a second stimulation pattern that provides a second different degree of blood pressure reduction during a period of light activity by the patient.

[0042] In some aspects of the invention, hypertension is treated mechanically instead of, or in addition to, pharmaceutically treating hypertension. In one aspect, an electrical stimulation device, such as a pacemaker or other type of device having a pulse generator, may be used to stimulate the patient's heart to reduce blood pressure. Stimulating the heart in a consistent manner may cause the cardiovascular system to eventually adapt to the stimulation and return to a higher blood pressure. Thus, in one aspect, the stimulation pattern may be configured to regulate the baroreflex so that the adaptation response of the cardiovascular system is reduced or even prevented.

[0043] Another aspect may utilize the slow baroreflex response that occurs after treatment is discontinued or reduced. In such situations, it may take a long time for the blood pressure level to return to the pre-treatment value, and treatment may be interrupted or reduced for a long period. Then, treatment may be resumed at the treatment level applied before treatment was interrupted or reduced for a long period before the blood pressure level reaches the pre-treatment value.

[0044] On the other hand, an electrical stimulation device may be used to stimulate the patient's heart such that at least a part of the atrial contraction is caused with the atrioventricular valve closed. In such atrial contractions, less blood may enter the corresponding ventricle than when the atrioventricular valve is open during atrial contraction, which achieves an immediate decrease in blood pressure.

[0045] In another aspect, the intracardiac pressure generated by atrial contraction of the atrium may overlap in time with the passive intracardiac pressure increase of the atrium, thereby providing an intracardiac pressure of the atrium that is a combination of the intracardiac pressure generated by atrial contraction and the passive intracardiac pressure increase and is higher than the intracardiac pressure of the atrium without stimulation. This may cause an increase in atrial dilation, thereby reducing blood pressure through the hormonal pathway and / or the neuronal pathway. This decrease in blood pressure may take some time to appear, and that time depends on the hormonal pathway and / or the neuronal pathway.

[0046] The intracardiac pressure generated by atrial contraction may reach the maximum intracardiac pressure generated by atrial contraction. The passive intracardiac pressure increase of the atrium may reach the maximum passive intracardiac pressure increase of the atrium. Alternatively, or in addition thereto, the time overlap between the intracardiac pressure generated by atrial contraction of the atrium and the passive intracardiac pressure increase of the atrium may include the time overlap of the maximum intracardiac pressure and the maximum passive intracardiac pressure increase generated by atrial contraction. In one aspect, the overlap of the above-mentioned maximum intracardiac pressure and the maximum passive intracardiac pressure increase may result in a combined intracardiac pressure (of the intracardiac pressure generated by atrial contraction and the passive intracardiac pressure increase) that is higher than the intracardiac pressure of the atrium without stimulation.

[0047] On the other hand, an electrical stimulation device may be used to stimulate a patient's heart to cause at least a portion of atrial contraction while keeping the atrioventricular valve closed within a single cardiac cycle, and / or the atrial pressure generated by atrial contraction of the atrium overlaps in time with the passive increase in atrial pressure of the atrium, thereby providing an atrial pressure of the atrium that is higher than the atrial pressure of the atrium without stimulation by a combination of the atrial pressure generated by atrial contraction and the passive increase in pressure. The patient's heart may be stimulated.

[0048] In other aspects, prosthetic valves may be used in the treatment of hypertension. In some medical conditions where one or more atrioventricular (AV) valves are malfunctioning, the valve may be replaced by implantation of a prosthetic (prosthetic device) valve. These prosthetic valves may typically be configured to open and close passively in response to the pressure difference between the atrium and the ventricle, similar to natural valves. Passive prosthetic valves are typically classified into three types: cage ball valves, tilting disc valves, and bileaflet valves based on their mechanical structure. Alternatively, an active prosthetic valve configured to open and close actively may be used.

[0049] In one aspect of the present invention, a system for reducing blood pressure is provided in a patient having a pre-treatment blood pressure. The system may comprise at least one stimulation electrode for stimulating at least one chamber of the patient's heart with stimulation pulses. The system may comprise at least one controller configured to apply a stimulation pattern of stimulation pulses to at least one chamber of the heart. The stimulation pattern may include a first stimulation setting and a second stimulation setting different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting may be configured to reduce or prevent an atrial kick and / or control either or both of atrial pressure and atrial dilation.

[0050] In one aspect of the present invention, a system for reducing blood pressure is provided. The system may comprise at least one stimulation electrode for stimulating at least one chamber of a patient's heart. The system may include at least one controller configured to apply a stimulation pattern comprising a plurality of stimulation pulses. At least one of the plurality of stimulation pulses may have a first stimulation setting configured to reduce an atrial kick in at least one ventricle. At least one of the plurality of stimulation pulses may have a second stimulation setting configured to reduce a baroreflex response to the reduction of the atrial kick so as to limit an increase in a blood pressure value occurring between the stimulation pulses to a predetermined value or range of values.

[0051] In another aspect, an apparatus for reducing blood pressure in a patient having a pre-treatment blood pressure and a pre-treatment ventricle filling volume is provided. The apparatus comprises a stimulation circuit configured to deliver stimulation pulses to at least one of the atrium and ventricle. The apparatus may include a processor circuit coupled to the stimulation circuit and preferably also to a sensing circuit.

[0052] In one aspect, the apparatus processor circuit may be configured to operate in an operating mode in which the apparatus controls an AV delay. As used herein, the AV delay may be understood to mean the delay that occurs during a single heartbeat between ventricle excitation and / or contraction and atrial excitation and / or contraction. Additionally, as used herein, the AV delay in a system or method may be understood to mean the time delay between the delivery of at least one excitatory stimulus to the ventricle, the detection of the onset of atrial excitation, the expected timing of the onset of atrial excitation, and the delivery of at least one excitatory stimulus to the atrium, within a single heartbeat.

[0053] This AV delay may be set by delivering at least one stimulation pulse to both at least one atrium and at least one ventricle. This stimulation is preferably carried out to a greater extent than the natural activity of the heart. Such an extent may be set, for example, by using at least one sensing electrode for sensing the natural activity in the heart (e.g., the right atrium when there is no stimulation), and adjusting the stimulation pulse delivery extent accordingly.

[0054] Preferably, if the ventricular excitation is time-regulated such that it starts prior to the delivery of one or more stimulation pulses to the atrium, the delivery of the stimulation pulses to the heart is time-regulated such that one or more excitatory pulses are delivered to the atrium at a time earlier than the expected next natural onset of the atrial excitation.

[0055] In some aspects, the AV delay may be set by delivering at least one stimulation pulse to one or more ventricles rather than to the atrium. In such a case, the natural activity of one or more atria may be sensed, and the ventricular excitation and / or contraction timing may be set to precede its natural expected timing based on the sensed atrial activity extent.

[0056] In some aspects, the processor circuit may be configured to operate in an activation mode that stimulates the ventricles such that ventricular excitation is initiated about 0 milliseconds (ms) to about 50 ms before the onset of atrial excitation in at least one atrium, whereby the ventricular filling volume is reduced from the pre-treatment ventricular filling volume and the patient's blood pressure is reduced from the pre-treatment blood pressure. In such aspects, atrial excitation may be detected and the onset of atrial excitation may be determined. For example, the processor circuit may be configured to operate in an activation mode that delivers one or more excitatory pulses to the ventricles about 0 ms to about 50 ms before the next atrial excitation is expected to occur. The time interval between the onset of atrial excitation and the moment when atrial excitation is detected may be known or estimated and may be used to calculate the timing of the onset of atrial excitation. For example, if it is known or estimated that atrial excitation is detected 5 ms after the onset of atrial excitation and the ventricles are to be stimulated 20 ms before the onset of atrial excitation, the ventricles will be stimulated 25 ms before the next expected detection of atrial excitation.

[0057] In other aspects, the processor circuit may be configured to operate in an activation mode in which the atrium is stimulated and atrial excitation is initiated about 0 ms to about 50 ms after the onset of ventricular excitation in at least one ventricle, whereby the ventricular filling volume is reduced from the pre-treatment ventricular filling volume and the patient's blood pressure is reduced from the pre-treatment blood pressure. For example, the processor circuit may be configured to operate in an activation mode in which one or more excitatory pulses are transmitted to the atrium about 0 ms to about 50 ms after one or more excitatory pulses have been supplied to the patient's ventricles. In such aspects, pacing may be time-regulated independently of detecting atrial excitation. Preferably, in such aspects, atrial excitation is detected to ensure that one or more excitatory pulses are transmitted to the atrium before a natural excitation occurs. Preferably, atrial excitation is set to begin about 0 ms to about 50 ms after the onset of ventricular excitation when the original atrial excitation rate is lower than the original ventricular excitation rate.

[0058] In some aspects, the timing of the mechanical contraction related to the electrical excitation of the chamber for the patient may be determined, for example, by detecting changes in atrial and ventricular pressures, using ultrasound to detect wall motion (such as echocardiography or cardiac echo), using impedance changes or the opening and closing of heart valves detected by embedded and / or external sensors known in the art. Such sensors may include, for example, pressure sensors, impedance, ultrasonic sensors, and / or one or more acoustic sensors and / or one or more blood flow sensors.

[0059] The timing of the mechanical contraction related to the electrical excitation of the chamber for the patient is considered such that one or more excitatory pulses are transmitted to the heart at a timing that will generate the desired pattern of contraction, and the processor circuit may be configured accordingly. This may be done in a closed-loop mode using one or more embedded sensors and / or, for example, using an interface with an external measuring device, sometimes (e.g., at the time of device implantation and / or during examination).

[0060] The operating mode may include stimulating the ventricle to initiate contraction of the ventricle before the start of contraction of at least one atrium.

[0061] The operating mode may include stimulating the ventricle to initiate contraction of the ventricle before the end of contraction of at least one atrium, thereby causing the AV valve to close during at least a portion of the contraction of at least one atrium.

[0062] The operating mode may include stimulating the ventricle to initiate contraction of the ventricle within less than 100 ms after the start of contraction of at least one atrium.

[0063] Care is taken, if desired, to ensure that atrial contraction starts reliably before ventricular contraction reaches peak internal pressure. Since atrial contraction is usually faster than ventricular contraction, this is possible even if ventricular contraction has started before the start of atrial contraction. Thus, one of the following settings may be selected.

[0064] a. The operating mode may include stimulating the ventricle to initiate contraction of the ventricle at any point during atrial contraction but before the atrium reaches its maximum internal pressure by atrial contraction.

[0065] b. The operating mode may include stimulating the ventricle to initiate contraction of the ventricle at any point during atrial contraction but after the atrium has reached its maximum internal pressure by atrial contraction.

[0066] c. The operating mode may include stimulating the ventricle at a timing such that contraction starts at essentially the same time (e.g., within 5 ms of each other) in both the atrium and the ventricle.

[0067] d. The operating mode may include stimulating the ventricle to initiate contraction of the ventricle at a timing such that peak atrial contraction occurs when the ventricle is near or at maximum dilation, thereby causing an increase in atrial wall dilation as further detailed below with respect to the isovolumetric and rapid ejection phases of the ventricle.

[0068] The operating mode may close the AV valve during the start of contraction of at least one atrium by stimulating the ventricle to contract at least partially the ventricle before at least one atrium begins to contract.

[0069] Preferably, the processor circuit may be configured to operate in an operating mode in which one or more excitatory pulses are transmitted to the atrium between about 0 ms and about 50 ms after one or more excitatory pulses are transmitted to the ventricle of the patient.

[0070] In another aspect, a method for reducing blood pressure in a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume is provided. The method includes transmitting a stimulation pulse from a stimulation circuit to at least one of the atrium and the ventricle, and stimulating the ventricle such that ventricular excitation is initiated about 0 ms to 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, and operating a processor circuit coupled to the stimulation circuit to operate in an operating mode.

[0071] In such a method, atrial excitation may be detected to determine the initiation of atrial excitation. For example, the method may include transmitting one or more excitatory pulses to the ventricle about 0 ms to about 50 ms before the next atrial excitation is expected to occur. The time interval between the initiation of atrial excitation and the moment when atrial excitation is detected may be known and may be used to calculate the timing of the initiation of atrial excitation. For example, it is known or estimated that atrial excitation is detected 5 ms after the initiation of atrial excitation, and if the ventricle is to be stimulated 20 ms before the initiation of atrial excitation, the ventricle will be stimulated 25 ms before the expected next detection of atrial excitation.

[0072] On the other hand, this method may include operating a processor circuit coupled to a stimulation circuit to operate in an operating mode that stimulates the atrium to initiate atrial excitation 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, this method may include delivering one or more excitatory pulses to the atrium between about 0 ms and about 50 ms after one or more excitatory pulses have been delivered to the patient's ventricle. In such an aspect, pacing may be time-adjusted without relying on detecting atrial excitation. Preferably, such an aspect includes detecting atrial excitation to ensure that one or more excitatory pulses are delivered to the atrium before a natural excitation occurs. Preferably, when the original atrial excitation rate is lower than the original ventricular excitation rate, atrial excitation is set to start between about 0 ms and about 50 ms after the initiation of ventricular excitation.

[0073] In one aspect, the timing of mechanical contraction related to electrical excitation of a chamber for a patient may be evaluated using, for example, ultrasound (such as echocardiography or cardiac echo) or other known means. The timing of mechanical contraction related to electrical excitation of a chamber for a patient may be considered to generate a desired pattern of contraction, and the timing at which one or more excitatory pulses are delivered to the heart may be selected.

[0074] The operating mode may include stimulating the ventricle to contract the ventricle before at least one atrium begins to contract.

[0075] The operating mode may include stimulating the ventricle to contract the ventricle before at least one atrium begins to contract, thereby causing the AV valve to close during at least a portion of the contraction of at least one atrium.

[0076] The actuation mode may include stimulating the ventricles to contract the ventricles before at least one atrium finishes contracting, thereby causing the AV valve to close during the onset of contraction of at least one atrium.

[0077] Preferably, the method may include transmitting one or more excitatory pulses to the atria between about 0 ms and about 50 ms after one or more excitatory pulses are transmitted to the ventricles of the patient.

[0078] In another aspect of the invention, an apparatus for reducing the blood pressure of a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume is provided. The apparatus may comprise a stimulation circuit configured to transmit stimulation pulses to at least one cardiac chamber of the patient's heart. The apparatus may comprise a processor circuit coupled to the stimulation circuit. The processor circuit is configured to operate in an actuation mode that stimulates at least one cardiac chamber to cause between about 40% and about 100% atrial contraction when the atrioventricular valve associated with the atria 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. This can be achieved, for example, by initiating atrial contraction up to about 60 ms or less before closure of the AV valve. Preferably, this timing may be set periodically (e.g., at implantation) based on data from an external sensor and / or as a closed loop using one or more implanted sensors.

[0079] In another aspect, an apparatus for reducing blood pressure in a patient having a pre-treatment blood pressure and a pre-treatment ventricular filling volume is provided. The apparatus may comprise a stimulation circuit configured to deliver a stimulation pulse to at least one heart chamber. The apparatus may comprise a processor circuit coupled to the stimulation circuit. The processor circuit is configured to operate in an operating mode to pace at least one heart chamber such that during ventricular systole, about 50% to about 95% of atrial contraction is induced, whereby the ventricular filling volume is reduced from the pre-treatment ventricular filling volume and the patient's blood pressure is reduced from the pre-treatment blood pressure. This can be achieved, for example, by initiating atrial contraction about 50 ms to 5 ms prior to the start of ventricular contraction. Preferably, the timing of the start of ventricular contraction may be set according to the timing of closure of the AV valve. Preferably, this timing may be set periodically (e.g., at the time of implantation) based on data from an external sensor and / or as a closed loop using one or more implanted sensors.

[0080] In another aspect, a method is provided for treating a blood pressure disorder in a patient having a pre-treatment blood pressure, the method being implemented using an implantable myocardial stimulation device associated with the patient's heart. The method may include stimulating the heart to contract the atrium while the heart valve associated with the atrium remains closed such that contraction causes the ventricle to expand and the expansion of the ventricle causes the patient's blood pressure to drop below the pre-treatment blood pressure. This can be achieved, for example, by contracting the atrium at the time when the ventricular internal pressure is at its maximum such that the active force of atrial contraction causes an increase in atrial internal pressure and atrial dilation beyond the maximum passive internal pressure and dilation caused by contraction of the associated ventricle. In such a case, the timing of the maximum contraction of the atrium must coincide with the end of the isovolumic period or must be during the rapid ejection phase of the ventricle. Optionally, this timing may be set periodically (e.g., at the time of implantation) based on data from an external sensor and / or as a closed loop using one or more implantable sensors.

[0081] In another aspect, a system is provided for reducing a patient's blood pressure by controlling atrial pressure and atrial dilation. The system may include a stimulation circuit configured to deliver stimulation pulses to at least one heart chamber of a patient's heart, and at least one controller configured to effect delivery of stimulation pulses of one or more stimulation patterns to the at least one heart chamber. At least one of the stimulation pulses may stimulate the heart such that the atrial pressure generated by the stimulation causes the atrial pressure generated by atrial contraction of the atria to overlap in time with the passive atrial pressure increase of the atria, and such that the atrial pressure generated by the stimulation is higher than the atrial pressure of the atria in the absence of stimulation and the patient's blood pressure is lowered, by a combination of the atrial pressure generated by atrial contraction and the passive pressure increase of the atria.

[0082] The atrial pressure generated by the stimulation may cause an increase in atrial dilation of the atria that lowers blood pressure through a hormonal pathway and / or a neural pathway.

[0083] The atrial pressure generated by atrial contraction may reach the maximum atrial pressure generated by atrial contraction. The passive atrial pressure increase may reach the maximum passive atrial pressure increase of the atria. Alternatively, or in addition, the time overlap between the atrial pressure generated by atrial contraction of the atria and the passive atrial pressure increase may include the time overlap of both the maximum atrial pressure generated by atrial contraction and the maximum passive pressure increase of the atria. In some aspects, the overlap of the maximum atrial pressure and the maximum passive pressure increase described above may result in a composite atrial pressure (of the atrial pressure generated by atrial contraction and the passive pressure increase) that is higher than the atrial pressure of the atria in the absence of stimulation.

[0084] At least one of the stimulation pulses may include stimulating the atrium of the heart. At least one of the stimulation pulses may include stimulating the ventricle of the heart. At least one of the stimulation pulses may further include pacing the atrium and ventricle at a substantially equal rate, or pacing the atrium at a rate faster than the rate at which the ventricle is paced, if desired.

[0085] At least one of the stimulation pulses may include stimulating the atrium such that the atrium contracts twice during a single cardiac cycle, for example, by stimulating the atrium twice during a single cardiac cycle or by stimulating the atrium once during a single cardiac cycle.

[0086] If desired, at least one of the stimulation pulses may include stimulating the atrium such that the atrium contracts only once during a single cardiac cycle.

[0087] At least one of the stimulation pulses may further include stimulating the heart to reduce or prevent atrial stimulation.

[0088] One or more stimulation patterns may further include stimulating the heart to reduce or prevent atrial stimulation. At least one of the stimulation patterns may include stimulating the heart in multiple beats, and at least some of the stimulation pulses are such that the atrial pressure generated by atrial contraction in the atrium overlaps in time with the passive atrial pressure rise in the atrium, so that the atrial pressure generated by stimulation in the atrium is higher than the atrial pressure in the atrium without stimulation due to the combination of the atrial pressure generated by atrial contraction and the passive pressure rise, and at least some of the stimulation pulses are configured to reduce or prevent atrial stimulation.

[0089] In a single beat, both atrial stimuli are reduced or prevented, and the atrial pressure generated by atrial contraction of the atrium overlaps in time with the passive atrial pressure increase, so that the atrial pressure generated by the stimulus is higher than the atrial pressure of the atrium without the stimulus by the combination of the atrial pressure generated by atrial contraction and the passive pressure increase. A stimulation pulse may be provided.

[0090] At least one stimulation pattern is such that the atrial pressure generated by the stimulus is higher than the atrial pressure of the atrium without the stimulus by the combination of the atrial pressure generated by atrial contraction and the passive pressure increase. In a single beat, it has a first atrial contraction that starts when the atrioventricular valve is open and ends after the atrioventricular valve closes, and may include at least one stimulation pulse set to induce a second atrial contraction in which the atrial pressure generated by atrial contraction of the atrium overlaps in time with the passive atrial pressure increase. The first atrial contraction may be detected, and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0091] Alternatively, at least one stimulation pattern is such that the atrial pressure generated by the stimulus is higher than the atrial pressure of the atrium without the stimulus by the combination of the atrial pressure generated by atrial contraction and the passive pressure increase. In a single beat, it has a first atrial contraction that starts when the atrioventricular valve is open and ends before the atrioventricular valve closes, and may include at least one stimulation pulse set to induce a second atrial contraction in which the atrial pressure generated by atrial contraction of the atrium overlaps in time with the passive atrial pressure increase. The first atrial contraction may be detected, and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0092] One or more stimulation patterns may include alternately performing a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that the intracardiac pressure of the atrium caused by atrial contraction of the atrium is higher than the intracardiac pressure of the atrium in the absence of stimulation by a combination of the intracardiac pressure of the atrium caused by atrial contraction and the passive pressure increase of the atrium due to overlap in time with the passive pressure increase of the atrium, and (2) a second stimulation pulse that stimulates the heart such that atrial stimulation is reduced or prevented. Optionally, one or more stimulation patterns may include at least one stimulation pulse configured to reduce or prevent atrial stimulation and to stimulate the heart such that the intracardiac pressure of the atrium caused by atrial contraction of the atrium is higher than the intracardiac pressure of the atrium in the absence of stimulation by a combination (both in a single cardiac cycle) of the intracardiac pressure of the atrium caused by atrial contraction and the passive pressure increase of the atrium due to overlap in time with the passive pressure increase of the atrium.

[0093] One or more stimulation patterns may include alternately performing a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that the intracardiac pressure of the atrium caused by atrial contraction of the atrium is higher than the intracardiac pressure of the atrium in the absence of stimulation by a combination of the intracardiac pressure of the atrium caused by atrial contraction and the passive pressure increase of the atrium, and (2) a second stimulation pulse that does not provide the intracardiac pressure of the atrium caused by atrial contraction of the atrium that overlaps in time with the passive pressure increase of the atrium.

[0094] At least one stimulation pulse may include pacing at least one of the atrium of the heart and the ventricle of the heart such that the relative timing of excitation corresponds to an atrioventricular delay of about 2 ms.

[0095] At least one stimulation pulse may include pacing at least one of the atrium of the heart and the ventricle of the heart such that the relative timing of excitation corresponds to an atrioventricular delay of about 30 ms to about 0 ms, or even 10 ms to 0 ms.

[0096] In another aspect, a method is provided for lowering a patient's blood pressure by controlling atrial pressure and atrial distension. The method may be implemented using an implantable myocardial stimulation device associated with the patient's heart. The method causes the atrial pressure generated by atrial contraction and the passive pressure increase to overlap, such that the combination of the atrial pressure generated by atrial contraction and the passive pressure increase induces an atrial pressure higher than the atrial pressure of the atrium without stimulation, and such that the patient's blood pressure is lowered, and may include stimulating the heart to provide an atrial pressure generated by atrial contraction that overlaps in time with the passive pressure increase of the atrium.

[0097] The atrial pressure of the atrium caused by stimulation may cause an increase in atrial distension of the atrium that lowers blood pressure through a hormonal pathway or a neuronal pathway.

[0098] The atrial pressure generated by atrial contraction may reach the maximum atrial pressure generated by 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 generated by atrial contraction of the atrium and the passive pressure increase of the atrium may include the overlap in time of both the maximum atrial pressure and the maximum passive pressure increase generated by atrial contraction. In some aspects, the overlap of the above-described maximum atrial pressure and maximum passive pressure increase may result in a combined atrial pressure (of the atrial pressure generated by atrial contraction and the passive pressure increase) higher than the atrial pressure of the atrium without stimulation. Thus, the method may include stimulating the heart such that the maximum value of the atrial pressure generated by atrial contraction of the atrium overlaps in time with the maximum passive pressure increase of the atrium.

[0099] The method may include stimulating the atrium of the heart. The method may additionally or alternatively include stimulating the ventricle of the heart. The method may further include pacing the atrium and ventricle at substantially equal rates, or pacing the atrium at a rate faster than the rate at which the ventricle is paced or contracts.

[0100] The method may further include stimulating the atrium such that the atrium contracts twice during a single cardiac cycle, for example, by stimulating the atrium twice during a single cardiac cycle or by stimulating the atrium once during a single cardiac cycle.

[0101] Optionally, the method may include stimulating the atrium such that the atrium contracts only once during a single cardiac cycle.

[0102] The method may further include stimulating the heart to reduce or prevent atrial stimulation. Stimulating the heart may include transmitting a stimulation pattern to the heart in a plurality of beats, and at least some of the stimulation pulses of the stimulation pattern are such that the atrial pressure generated by the atrial contraction of the atrium overlaps in time with the passive atrial pressure increase of the atrium, so that the atrial pressure of the atrium generated by the stimulation is higher than the atrial pressure of the atrium without stimulation by the combination of the atrial pressure generated by the atrial contraction and the passive pressure increase, and at least some of the stimulation pulses are configured to reduce or prevent atrial stimulation. Both atrial stimulations are reduced or prevented in a single beat, and the atrial pressure generated by the atrial contraction of the atrium overlaps in time with the passive atrial pressure increase of the atrium, so that the atrial pressure of the atrium generated by the stimulation is higher than the atrial pressure of the atrium without stimulation by the combination of the atrial pressure generated by the atrial contraction and the passive pressure increase, and stimulation pulses may be provided.

[0103] Stimulating the heart may include delivering at least one stimulation pulse that is set to have a first atrial contraction that starts when the atrioventricular valve is open and ends after the atrioventricular valve closes in a single beat, such that the atrial intracardiac pressure caused by the stimulation is higher than the atrial intracardiac pressure without stimulation by a combination of the atrial intracardiac pressure caused by atrial contraction and the passive pressure increase, and that induces a second atrial contraction in which the atrial intracardiac pressure caused by the atrial contraction of the atrium overlaps in time with the passive pressure increase of the atrium. The first atrial contraction may be detected and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0104] Alternatively, stimulating the heart may include delivering at least one stimulation pulse that is set to have a first atrial contraction that starts when the atrioventricular valve is open and ends before the atrioventricular valve closes in a single beat, such that the atrial intracardiac pressure caused by the stimulation is higher than the atrial intracardiac pressure without stimulation by a combination of the atrial intracardiac pressure caused by atrial contraction and the passive pressure increase, and that induces a second atrial contraction in which the atrial intracardiac pressure caused by the atrial contraction of the atrium overlaps in time with the passive pressure increase of the atrium. The first atrial contraction may be detected and the second atrial contraction may be paced. Alternatively, the first atrial contraction and the second atrial contraction may be paced.

[0105] This method may further include alternately performing a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that the atrial pressure generated by the atrial contraction of the atrium is higher than the atrial pressure in the absence of stimulation due to the combination of the atrial pressure generated by the atrial contraction and the passive pressure increase of the atrium overlapping in time with the passive pressure increase of the atrium, and (2) a second stimulation pulse that stimulates the heart such that atrial stimulation is reduced or prevented. Optionally, one or more of the stimulation patterns reduce or prevent atrial stimulation, and the atrial pressure generated by the atrial contraction of the atrium is higher than the atrial pressure in the absence of stimulation due to the combination of the atrial pressure generated by the atrial contraction and the passive pressure increase of the atrium (both in a single cardiac cycle) overlapping in time with the passive pressure increase of the atrium, and may include at least one stimulation pulse configured to stimulate the heart.

[0106] This method may further include alternately performing a plurality of stimulation patterns having different ratios of (1) a first stimulation pulse that stimulates the heart such that the atrial pressure generated by the atrial contraction of the atrium is higher than the atrial pressure in the absence of stimulation due to the combination of the atrial pressure generated by the atrial contraction and the passive pressure increase of the atrium, and (2) a second stimulation pulse that does not provide the atrial pressure generated by the atrial contraction of the atrium that overlaps in time with the passive pressure increase of the atrium.

[0107] This method may further include pacing at least one of the atrium of the heart and the ventricle of the heart such that the relative timing of excitation corresponds to an atrioventricular delay of about 2 ms.

[0108] This method may further include pacing at least one of the atrium of the heart and the ventricle of the heart such that the relative timing of excitation corresponds to an atrioventricular delay of about 30 ms to about 0 ms.

[0109] In another aspect, a method for lowering a patient's blood pressure is provided. The method may be implemented using an implantable myocardial stimulation device associated with the patient's heart. The method may include delivering stimulation pulses of one or more stimulation patterns to at least one heart chamber of the patient's heart. At least one of the stimulation pulses may have a first stimulation setting, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting may be configured to reduce or prevent atrial stimulation. Stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation may be delivered as needed.

[0110] Delivery of the stimulation pulses as needed may include one or more of the following.

[0111] a. Limiting treatment to times of need, for example, limiting delivery of a stimulation setting configured to reduce or prevent atrial stimulation when the patient's blood pressure is known or predicted to be abnormally high. This may include using real-time feedback measurements of one or more blood pressure-related parameters or basing the required prediction pattern on past measurements of the same patient. For example, for some patients, BP (blood pressure) can be high 24 hours a day, while for other patients, BP may be high only during a portion of the 24 hours (e.g., during the day or at night).

[0112] b. Not treating when high BP is required, for example, not delivering a stimulation setting configured to reduce or prevent atrial stimulation when the increase in BP is healthy and thus may be a desired state. For example, BP is known to increase during activity and then decrease again when activity decreases (e.g., during exercise or physical work, which is naturally associated with an increase in BP).

[0113] Stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation may be provided only for a portion of 24 hours, which may be at night or a portion thereof, or during the day or a portion thereof.

[0114] Stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation may be provided only when the heart rate is below a predetermined threshold. The predetermined threshold may be an absolute value such as 90 bpm. The predetermined threshold may be set to a value related to the average heart rate of the patient. For example, the predetermined threshold may be at least one of a heart rate exceeding the average heart rate by 30 beats and exceeding the 80th percentile of the heart rate.

[0115] Stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation may be provided only when the patient is at rest or at an activity level below a predetermined threshold. The method may further include determining whether the patient is at rest or at an activity level below a predetermined threshold by detecting at least one of movement, posture, respiratory rate, and heart rate.

[0116] Optionally, the patient may be considered to be "at rest" or "at a low activity level" when the patient's activity is low. For example, as long as the heart rate does not exceed a predetermined threshold or only low activity is detected (e.g., characterized by moderate and / or slow movements, and / or slow changes in posture, and / or no significant increase in respiration, etc.), the patient may be considered to be "at rest" or "at a low activity level". For example, sitting activities such as reading or talking, or movements around the house or in the office may be considered to be at a sufficiently low activity level to enable the delivery of stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation.

[0117] 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 baroreflex is detected.

[0118] In another aspect of the invention, there is provided a system for lowering a patient's blood pressure, comprising a stimulation circuit configured to deliver stimulation pulses of one or more stimulation patterns to at least one heart chamber of the patient's heart, and at least one controller configured to effect delivery of stimulation pulses of one or more stimulation patterns to at least one heart chamber. At least one of the stimulation pulses may have a first stimulation setting, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting may be configured to reduce or prevent atrial stimulation. Stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation may be delivered as needed.

[0119] The at least one controller may be configured to deliver stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation only during a portion of the 24 hours. The portion of the 24 hours may be at night or a portion thereof, or during the day or a portion thereof.

[0120] The at least one controller may be configured to deliver stimulation pulses having a stimulation setting configured to reduce or prevent atrial stimulation only when the heart rate is below a predetermined threshold. The predetermined threshold may be an absolute value such as 90 bpm. The predetermined threshold may be set to a value related to the patient's average heart rate. For example, the predetermined threshold may be at least one of a heart rate exceeding the average heart rate by 30 beats and above the 80th percentile of the heart rate.

[0121] At least one controller may be configured to deliver a stimulation pulse having a stimulation setting configured to reduce or prevent atrial stimulation only when the patient is at rest or at a low activity level. The system may be configured to determine whether the patient is at rest or at a low activity level by detecting at least one of motion, posture, respiratory rate, and heart rate.

[0122] At least one controller may be configured to select one or more stimulation patterns based on measured blood pressure parameters. At least one controller may be configured to change one or more stimulation patterns when a baroreflex is detected.

[0123] In another aspect, a method of adjusting a pulse setting of a system for controlling blood pressure is provided. The method may include receiving intracardiac pressure data associated with the atrium of the patient's heart during at least one cardiac cycle. The intracardiac pressure data may result from the system delivering a stimulation pulse having a first pulse setting to the heart. The method may further include analyzing the intracardiac pressure data and providing a second pulse setting different from the first pulse setting, adjusted according to this analysis. Analyzing may include analyzing the intracardiac pressure data to estimate the temporal overlap between the intracardiac pressure generated by atrial contraction and the passive intracardiac pressure rise of the atrium. Analyzing may further include analyzing the intracardiac pressure data to estimate the temporal overlap between the maximum intracardiac pressure generated by atrial contraction and the maximum passive intracardiac pressure rise of the atrium. Analyzing may include analyzing the intracardiac pressure data to compare a first intracardiac pressure (or maximum intracardiac pressure) obtained during the cardiac cycle in which the stimulation pulse was delivered with a second intracardiac pressure of the atrium in the absence of stimulation. Analyzing may further include plotting the intracardiac pressure data and / or mathematically analyzing the intracardiac pressure data.

[0124] In another aspect, a system for lowering blood pressure may be provided. The system may comprise means for providing information about the internal pressure fluctuations in the atrium during at least one cardiac cycle of the heart, means for generating a stimulation pulse, and means for applying the stimulation pulse to at least one heart chamber. The means for generating the stimulation pulse may be configured to generate the stimulation pulse so as to control the timing of atrial contraction relative to the timing of ventricular contraction during a single cardiac cycle according to the information about the internal pressure fluctuations in the atrium.

[0125] The information about the internal pressure fluctuations in the atrium may include information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction. The means for generating the stimulation pulse may be configured to generate at least one atrial stimulation pulse for causing atrial contraction and / or at least one ventricular stimulation pulse for causing ventricular contraction for at least one cardiac cycle. The means for generating the stimulation pulse may be configured to generate at least one atrial stimulation pulse based on the information about the occurrence of atrial contraction and / or the information about the occurrence of ventricular contraction in a relationship that synchronizes the occurrence of atrial contraction and / or the occurrence of ventricular contraction, and / or to generate at least one ventricular stimulation pulse based on the information about the occurrence of ventricular contraction and / or the information about the occurrence of atrial contraction in a relationship that synchronizes the occurrence of ventricular contraction and / or the occurrence of atrial contraction. The information about the occurrence of atrial contraction may include information about the occurrence of the P-wave pattern in the natural stimulation pattern of the cardiac cycle. The information about the occurrence of ventricular contraction may include information about the occurrence of the QRS complex in the natural stimulation pattern of the cardiac cycle.

[0126] In another aspect, a system for lowering blood pressure may be provided. The system may include means for providing information about the timing of one or more cardiac activity events, means for generating a stimulation pulse, and means for applying the stimulation pulse to at least one cardiac chamber. The information about the timing of one or more cardiac activity events may include at least one of the occurrence of atrial contraction of the atrium, the occurrence of ventricular contraction of the ventricle, the opening of the atrioventricular valve, the closing of the atrioventricular valve, the electrical activity of the atrium, the electrical activity of the ventricle, blood flow, the intracardiac pressure of the atrium, the change in the intracardiac pressure of the atrium, and the heart rate. The means for generating the stimulation pulse may be configured to generate the stimulation pulse so as to set the timing of atrial contraction relative to ventricular contraction based on the information.

[0127] The timing of atrial contraction relative to ventricular contraction may correspond to an AV delay within a range of about 30 ms to about 0 ms. The means for generating the stimulation pulse may provide an excitatory stimulus to the atrium within a range of about 30 ms to about 0 ms before ventricular excitation occurs, provide an excitatory stimulus to the ventricle within a range of about 30 ms to about 0 ms after atrial excitation occurs, and / or provide an excitatory stimulus to the atrium and then provide an excitatory stimulus to the ventricle within a range of about 30 ms to about 0 ms after that, and may be configured to generate the stimulation pulse accordingly.

[0128] The 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.

[0129] The means for generating stimulation pulses may be configured to generate at least one atrial stimulation pulse that causes atrial contraction and / or at least one ventricular stimulation pulse that causes ventricular contraction for at least one cardiac cycle. The means for generating stimulation pulses may be configured to generate at least one atrial stimulation pulse based on information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction in a relationship that synchronizes with the occurrence of atrial contraction and / or the occurrence of ventricular contraction, and / or to generate at least one ventricular stimulation pulse based on information about the occurrence of ventricular contraction and / or information about the occurrence of atrial contraction in a relationship that synchronizes with the occurrence of ventricular contraction and / or the occurrence of atrial contraction. The information about the occurrence of atrial contraction may include information about the occurrence of the P-wave pattern in the natural stimulation pattern of the cardiac cycle. The information about the occurrence of ventricular contraction may include information about the occurrence of the QRS complex in the natural stimulation pattern of the cardiac cycle.

[0130] Another aspect provides another method for lowering a patient's blood pressure by controlling atrial pressure and atrial dilation. The method may be implemented using an implantable myocardial stimulation device associated with the patient's heart. The method is to transmit stimulation pulses of one or more stimulation patterns to at least one heart chamber, wherein at least one of the stimulation pulses has a first stimulation setting and at least one of the stimulation pulses has a second stimulation setting different from the first stimulation setting, and at least one of the first stimulation setting and the second stimulation setting is configured to contract the atrium such that the atrial pressure generated by atrial contraction of the atrium overlaps in time with the passive atrial pressure increase of the atrium, transmitting, and by the overlap of the atrial pressure generated by atrial contraction and the passive pressure increase, providing an atrial pressure of the atrium that is higher than the atrial pressure of the atrium without stimulation by the combination of the atrial pressure generated by atrial contraction and the passive pressure increase, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through a hormonal pathway or a neuronal pathway.

[0131] Optionally, at least one of the first stimulation setting and the second stimulation setting may be configured to have an atrial contraction such that the maximum atrial pressure generated by the atrial contraction overlaps in time with the maximum passive atrial pressure rise, and the method may provide an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation due to the overlap of the maximum atrial pressure generated by the atrial contraction and the maximum passive atrial pressure rise, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through the hormonal or neuronal pathway.

[0132] In another aspect, a system is provided for lowering a patient's blood pressure by controlling atrial pressure and atrial dilation. The system may include a stimulation circuit configured to deliver stimulation pulses of one or more stimulation patterns to at least one heart chamber, and at least one controller configured to effect delivery of stimulation pulses of one or more stimulation patterns to at least one heart chamber. At least one of the stimulation pulses may have a first stimulation setting, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting is configured to contract the atrium of the heart such that the atrial pressure generated by atrial contraction of the atrium provides an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation by virtue of the atrial pressure generated by atrial contraction overlapping in time with the passive atrial pressure rise, thereby causing an increase in atrial dilation of the atrium that lowers blood pressure through the hormonal or neuronal pathway. Optionally, at least one of the first stimulation setting and the second stimulation setting is configured to contract the atrium of the heart such that the maximum atrial pressure generated by atrial contraction overlaps in time with the maximum passive atrial pressure rise of the atrium, thereby providing an atrial pressure of the atrium that is higher than the atrial pressure of the atrium in the absence of stimulation and causing an increase in atrial dilation of the atrium that lowers blood pressure through the hormonal or neuronal pathway.

[0133] In another aspect, a method is provided for treating a patient's blood pressure disorder by controlling atrial pressure and atrial dilation. The method may be carried out using an implantable myocardial stimulation device associated with the heart of a patient having a pre-treatment blood pressure. The method may include stimulating the heart to contract the atria while the heart valves associated with the atria are closed such that the atria expand upon contraction, and by expanding the atria, preferably, causing the active force of atrial contraction to increase the atrial pressure and dilation beyond the maximum passive pressure and dilation caused by ventricular contraction, by contracting the atria when the ventricular pressure is at its maximum, resulting in a decrease in the patient's blood pressure from the pre-treatment blood pressure.

[0134] In another aspect of the invention, a system for reducing blood pressure is provided. The system may comprise at least one stimulating electrode for stimulating at least one chamber of a patient's heart with a stimulation pattern comprising at least one stimulation pulse. The system may include at least one controller configured to receive an input related to the patient's blood pressure and to adjust the stimulation pattern based on the blood pressure. For example, the input may include receiving data sensed by one or more sensors (implanted or external), and / or receiving data supplied by a user. For example, during an implanted and / or periodic check, the user may supply data regarding the measured blood pressure.

[0135] Preferably, the system includes an input port for receiving this input from a measurement sensor and / or a user interface, via wired communication and / or wireless communication. The input may comprise blood pressure (BP), or data related to a change in BP, where the change in BP may be measured as systolic BP (SysBP), diastolic BP, mean arterial BP, and / or other relevant BP parameters. For example, at least one sensor may detect pressure or a change in pressure within one or more heart chambers, and adjust a stimulation pattern based on the pressure or change in pressure. In other aspects, the sensor may detect pressure within more than one chamber and adjust the stimulation based on the relationship between the pressure waveforms of two chambers.

[0136] The controller may be configured to adjust the stimulation pattern by performing an adjustment process that includes adjusting parameters of at least a first stimulation setting of at least one stimulation pulse.

[0137] The first stimulation setting may be configured to reduce or prevent an atrial kick in at least one ventricle.

[0138] The parameters may include adjustment of the AV delay. For example, the natural AV delay may range from 120 to 200 ms from the start of atrial excitation to the start of ventricular excitation, whether it occurs naturally (i.e., without stimulation of the heart) or by setting the timing of stimulation to one or more of the atrium and ventricle. 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 start of atrial excitation to the start of ventricular excitation, or an AV delay of 0 to -50 ms where ventricular excitation occurs before atrial excitation). In one aspect, a stimulation setting having an AV delay between -50 ms and 70 ms, preferably -40 ms and 60 ms, more preferably -50 ms and 0 ms, or 0 and 70 ms, preferably >0 and 70 ms, is selected to reduce or prevent atrial stimulation.

[0139] A stimulation pattern configured to reduce atrial stimulation may be configured to cause a blood pressure drop of at least a predetermined amount within about 3 seconds from the application of electricity to the heart and to maintain the blood pressure drop for at least a one-minute time interval. For example, the stimulation pattern may be selected and / or adjusted based on feedback related to one or more detected BP parameters.

[0140] The time interval may be at least 5 minutes.

[0141] The predetermined amount of blood pressure reduction may be 8 mmHg or less.

[0142] The predetermined amount of blood pressure reduction may be at least 4% of the patient's blood pressure before treatment.

[0143] The patient's blood pressure may not exceed a predetermined average value by more than a predetermined degree during the time interval. The predetermined degree may be a difference of about 8 mmHg or less. In some aspects, the patient's blood pressure may exceed the predetermined average value for some beats, but the patient's average blood pressure may not exceed the predetermined average value.

[0144] The controller may be configured to apply a plurality of stimulation patterns and to receive corresponding input data related to the patient's blood pressure for each stimulation pattern during the stimulation. The controller may be configured to calculate at least one blood pressure variation parameter related to the input data for each of the plurality of stimulation patterns. The controller may be configured to adjust the stimulation pattern according to the blood pressure variation parameter.

[0145] The controller may be configured to adjust the stimulation pattern to have the best blood pressure variation parameter.

[0146] The best blood pressure variation parameter may be one that exhibits the lowest degree of baroreflex or the lowest degree or extent of adaptation as detailed herein.

[0147] The optimal blood pressure variability parameter may indicate the degree of baroreflex or adaptation within a predetermined range detailed herein.

[0148] At least two of the plurality of stimulation patterns may each include at least one stimulation pulse having a stimulation setting configured to reduce or prevent atrial stimulation in at least one ventricle and / or control atrial pressure and / or dilation. The at least two stimulation patterns may differ from each other in the number of times or the length of time that at least one stimulation pulse is continuously supplied.

[0149] The plurality of stimulation patterns may differ by the number or length of time that the system is configured to continuously elicit a predetermined AV delay.

[0150] At least two of the plurality of stimulation patterns may differ from each other by one or more stimulation settings included within each of the at least two stimulation patterns.

[0151] The plurality of stimulation patterns may include a first stimulation setting and a second stimulation setting applied after the first stimulation setting. The second stimulation setting may have at least one stimulation setting set based on an algorithm that uses a blood pressure variability parameter related to the input data of the first stimulation setting.

[0152] The system may include a blood pressure sensor for providing input data related to the patient's blood pressure.

[0153] The blood pressure sensor may be implantable.

[0154] The blood pressure sensor and the controller may be configured to operate at least partially as a closed loop.

[0155] In another aspect, a system for reducing blood pressure is provided. The system may comprise at least one stimulation electrode for stimulating at least one chamber of a patient's heart with stimulation pulses. The system may comprise a controller. The controller may be configured to provide a first stimulation setting comprising at least one stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle during a first time interval and to receive first input data related to the patient's blood pressure during the first time interval. The controller may be configured to calculate at least one blood pressure variation parameter related to the first input data. The controller may be configured to adjust at least one parameter of a second stimulation pattern comprising a second stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle. The second stimulation setting may be based on at least one blood pressure variation parameter. The controller may be configured to deliver the second stimulation pattern during a second time interval.

[0156] In another aspect, a system for reducing blood pressure is provided. The system may comprise at least one stimulation electrode for stimulating at least one chamber of a patient's heart with stimulation pulses. The system may comprise at least one controller configured to apply a stimulation pattern comprising at least one stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle. The stimulation pattern may be selected to cause an immediate reduction in blood pressure from an initial blood pressure value to a reduced blood pressure value and to maintain the patient's average blood pressure at rest at least 8 mmHg lower than the initial blood pressure.

[0157] The reduced blood pressure value may be maintained for a time interval of at least one minute.

[0158] In another aspect, a kit for reducing blood pressure is provided. The kit comprises at least one device for setting a stimulation pattern for reducing blood pressure. The device may comprise at least one stimulation electrode. The device may comprise a controller for setting an adjustable stimulation pattern and a set of instructions for adjusting the stimulation pattern based on an input related to the patient's blood pressure.

[0159] Another aspect of the invention provides a system for lowering blood pressure. The system may comprise at least one stimulation electrode for stimulating at least one chamber of the patient's heart. The system may comprise at least one controller configured to execute a stimulation pattern comprising at least one stimulation pulse having at least one stimulation setting configured to reduce or prevent atrial stimulation in at least one ventricle. The at least one stimulation setting may be configured such that the maximum atrial dilation is approximately equal to, or lower than, the maximum atrial dilation of the same heart when not being stimulated.

[0160] In any of the aspects of the invention described herein, atrial dilation may be measured, calculated, and / or estimated as is known in the art. Atrial contraction is known to affect intra-atrial pressure and atrial dilation. The intra-atrial pressure and dilation of the atria depend on the atrial volume. The atrial volume depends on the amount of blood within the atria and the active forces generated by muscle contraction. In a healthy heart, when the atria contract, the intra-atrial pressure increases. The intra-atrial pressure decreases when atrial contraction ceases and blood flows out of the atria and the ventricles are filled. Next, when the ventricles contract, the AV valves close and the atria begin to fill again because there are no valves to prevent the flow of blood from the venous system into the atria. The intra-ventricular pressure generated further increases the intra-atrial pressure through various mechanisms, one of which is related to the bulging of the AV valves into the atria. The increase in intra-atrial pressure occurring against the closed AV valves also increases the atrial dilation related to atrial volume and intra-atrial pressure. When the atria contract while the AV valves are closed, the intra-atrial pressure increases and the atrial dilation increases because the closed valves prevent a reduction in volume. The increase in atrial dilation stimulates the pressure receptors (also known as stretch receptors) present in the atrial walls. These pressure receptors are related to the decrease in blood pressure by hormones and / or neurons.

[0161] Accordingly, in some aspects, the measurement of atrial dilation may include measuring the intra-atrial pressure. In some aspects, the atrial dilation measurement may include measuring or estimating the size of the atria (e.g., diameter, size, or circumference). In some cases, when a single atrial contraction occurs per cardiac cycle, the amount of blood in the atria is predicted to be greater than when the atria contract twice during a single cardiac cycle. Thus, if atrial contraction occurs once per cardiac cycle and the atrial contraction fully resists against the closed valves, the intra-atrial pressure and / or atrial dilation may be greater than when the atria contract twice per cardiac cycle. However, when the atria contract only against the closed valves, there is no atrial stimulation, and in some aspects, a balance may be taken between the intra-atrial pressure (and atrial dilation) and the values set for atrial stimulation (per cardiac cycle and / or per pacing pattern).

[0162] At least one stimulation setting may be configured to cause the atrium to contract maximally when the AV valve is open.

[0163] At least one stimulation setting may be configured to change at least one mechanism of atrial contraction such that at least one mechanism of atrial contraction is different from the mechanism of a preceding natural atrial contraction. The mechanism of atrial contraction may be evaluated using known techniques including, for example, ultrasound (such as echocardiography or cardiac echo).

[0164] At least one stimulation setting may be configured to reduce the force of at least one atrial contraction. The force of atrial contraction may be reduced, for example, by temporarily generating atrial spasm or atrial flutter. One example is to transmit a burst of rapid stimulation pulses to the atrium for a short period of a predetermined time. The force of atrial contraction can be calculated from the detection of atrial pressure and / or its derivatives such as wall motion or wall flow using known means. Such detection may be used as a closed-loop feedback and / or occasionally (e.g., during implantation and / or examination).

[0165] At least one stimulation setting may be configured to prevent at least one atrial contraction. Atrial contraction may be prevented, for example, by temporarily generating atrial spasm or atrial flutter. One example is to transmit a burst of rapid stimulation pulses to the atrium for a short period of a predetermined time.

[0166] In another aspect, a system for reducing blood pressure is provided. The system may comprise at least one stimulation electrode for stimulating at least one chamber of a patient's heart. At least one controller may be configured to apply a stimulation pattern of stimulation pulses to the patient's heart. At least one controller may be configured to receive an input related to the state of the patient's AV valve. This input may be supplied via wired or wireless communication from an implanted or external acoustic or blood flow sensor and / or via a user interface. At least one controller may be configured to adjust at least one stimulation pattern based on the valve state.

[0167] The input related to the state of the patient's AV valve may indicate the timing of closure of the AV valve.

[0168] The input related to the state of the patient's AV valve may be provided based on a heart sound sensor.

[0169] The input related to the state of the patient's AV valve may be provided based on a blood flow sensor.

[0170] The blood flow sensor may include an implanted sensor.

[0171] The blood flow sensor may include an ultrasonic sensor for detecting blood flow through the AV valve.

[0172] The blood flow sensor and the controller may be configured to operate at least partially as a closed loop.

[0173] The stimulation pattern may comprise at least one stimulation pulse configured to reduce or prevent an atrial kick in at least one ventricle.

[0174] The step of adjusting at least one stimulation pattern may include adjusting the AV delay of at least one stimulation pulse.

[0175] In another aspect, a system for reducing ventricular filling volume in a patient having a pre-treatment ventricular filling volume is provided. The system may comprise a stimulation circuit configured to deliver a stimulation pulse to at least one heart chamber. The system may comprise at least one controller configured to effect delivery of one or more stimulation patterns of stimulation pulses to at least one heart chamber. At least one of the stimulation pulses may have a first stimulation setting, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting. At least one of the first stimulation setting and the second stimulation setting may be configured to reduce or prevent an atrial kick, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume.

[0176] The first stimulation setting and the second stimulation setting may be configured to reduce or prevent an atrial kick.

[0177] The first stimulation setting may have an AV delay different from the AV delay of the second stimulation setting.

[0178] At least one of the one or more stimulation patterns may be repeated at least twice in a one-hour period.

[0179] The at least one controller may be configured to continuously effect one or more stimulation patterns during a time interval that lasts for 10 minutes or more. The first stimulation setting may be configured to reduce or prevent an atrial kick in at least one ventricle for at least 50% of the time interval.

[0180] The second stimulation setting may have an AV delay longer than the AV delay of the first stimulation setting.

[0181] The second stimulation setting has an AV delay longer than the AV delay of the first stimulation setting.

[0182] One or more continuous stimulation patterns may comprise at least one stimulation pulse having a first stimulation setting for at least about 85% of the time interval.

[0183] The time interval may be at least 30 minutes in length. The time interval may be at least 1 hour in length.

[0184] The time interval may be at least 24 hours in length.

[0185] One or more continuous stimulation patterns may comprise at least one stimulation pulse having a third stimulation setting different from the first and second stimulation settings and configured to reduce or prevent an atrial kick in at least one ventricle.

[0186] One or more continuous stimulation patterns may comprise at least one stimulation pulse having a third stimulation setting different from the first and second stimulation settings and configured not to reduce or prevent an atrial kick in at least one ventricle for less than about 50% of the time interval.

[0187] One or more continuous stimulation patterns may comprise a third stimulation configured not to reduce or prevent an atrial kick in at least one ventricle for about 20% or less of the time interval.

[0188] One or more continuous stimulation patterns may comprise a sequence of 10 to 60 stimulation pulses having a first stimulation setting. The first stimulation setting may be configured to reduce or prevent an atrial kick in at least one ventricle and a sequence of 1 to 10 beats embedded within the 10 to 60 stimulation pulses. The sequence of 1 to 10 beats may have an AV delay longer than the first stimulation setting.

[0189] A sequence of 1 to 10 beats may include at least one stimulation pulse having a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle.

[0190] A sequence of 1 to 10 beats may include at least one stimulation pulse having a second stimulation setting.

[0191] A sequence of 1 to 10 beats may include a natural AV delay.

[0192] At least one beat of a sequence of 1 to 10 beats may occur without stimulation.

[0193] The first stimulation setting may be configured to reduce an atrial kick in at least one ventricle such that an increase in blood pressure value occurring between stimulation pulses is limited to a predetermined value, and the second stimulation setting may be configured to reduce an adaptation to a baroreflex response or a reduction in atrial kick.

[0194] The second stimulation setting may be configured to allow an increase in blood pressure between about 1 beat and 5 beats.

[0195] The stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting.

[0196] The stimulation pattern may include a plurality of stimulation pulses having a second stimulation setting.

[0197] The second stimulation setting may be present between about 1% of the plurality of stimulation pulses and about 40% of the plurality of stimulation pulses of the stimulation pattern.

[0198] The stimulation pattern may include a ratio of stimulation pulses having a first stimulation setting to stimulation pulses having a second stimulation setting corresponding to a ratio of time constants of responses to increases and decreases in blood pressure.

[0199] The first stimulation setting may include a first AV delay, and the second stimulation setting may include a second AV delay. The first AV delay may be shorter than the second AV delay.

[0200] The stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting.

[0201] The stimulation pattern may include a plurality of stimulation pulses having a second stimulation setting.

[0202] Between about 1% of the plurality of stimulation pulses and about 40% of the plurality of stimulation pulses of the stimulation pattern, it may have a second stimulation setting.

[0203] The stimulation pattern may include the ratio of the stimulation pulses having a first stimulation setting to the stimulation pulses having a second stimulation setting corresponding to the ratio of the time constants of the responses to increases and decreases in blood pressure.

[0204] The stimulation pattern may include the ratio of about 8 to about 13 stimulation pulses having a first stimulation setting to about 2 to about 5 stimulation pulses having a second stimulation setting.

[0205] One of the first stimulation setting and the second stimulation setting may be configured to cause a hormonal response from the patient's body.

[0206] In another aspect, a system is provided for reducing the ventricular filling volume of a patient having a pre-treatment ventricular filling volume. The system may comprise a stimulation circuit configured to deliver a stimulation pulse to at least one heart chamber. The system may comprise at least one controller configured to effect delivery of one or more stimulation patterns of the stimulation pulse to at least one heart chamber. At least one of the stimulation pulses may include a setting configured such that ventricular excitation is initiated about 0 ms to about 70 ms after the onset 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 onset of ventricular excitation in at least one atrium, or between about 0 ms and about 70 ms after one or more excitatory pulses are delivered to the atria.

[0207] In some aspects, the timing of the detected atrial excitation may be determined by taking into account the delay between the actual onset of the excitation and its detection. For example, if the detection delay is estimated to be between 20 and 40 ms and the stimulation pulse is delivered between 0 and 70 ms after the onset of atrial excitation, the system may be set to deliver the pulse between 40 ms before the next expected detection event and 30 ms after the next expected detection event or 30 ms after the next detection event. Similarly, if the stimulation pulse is delivered to the ventricle between 0 and 50 ms before the onset of atrial excitation and the same 20 to 40 ms detection delay is assumed, the system may be set to deliver the pulse between 40 ms before the next expected detection event and 90 ms before the next expected detection event. The detection delay may be due to one or more of the distance between the location of the onset of the excitation and the detection electrode, the level of the electrical signal, the characteristics of the detection circuit, and the threshold set for the detection event. The delay may include, for example, the duration of signal propagation from the origin of the excitation to the electrode position, the duration associated with the frequency response of the detection circuit, and / or the duration required for the signal propagation energy to reach a level detectable by the detection circuit. The delay may be significant and may, for example, range between about 5 ms and about 100 ms. One technique for estimating the delay is to use the time difference between the AV delay measured when both the atrium and ventricle are detected and the AV delay when the atrium is paced and the ventricle is detected. In other techniques, the calculation of the amplifier response time based on the set threshold, signal strength, and frequency components may be used. Other techniques may include modifying the delay used with atrial detection until the effect on blood pressure is the same as the effect obtained by pacing both the atrium and ventricle at the desired AV delay.

[0208] In another aspect, a system for reducing ventricular filling volume in a patient having a pre-treatment ventricular filling volume is provided. The system may include a stimulation circuit configured to deliver a stimulation pulse to at least one heart chamber. At least one controller may be configured to deliver one or more stimulation patterns of stimulation pulses to at least one heart chamber during a time interval that lasts for 10 minutes or more. At least one of the stimulation pulses may have a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle for at least 5 minutes of the time interval, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting, thereby reducing the ventricular filling volume from the pre-treatment ventricular filling volume.

[0209] In other aspects, a method for reducing ventricular filling in a patient having a pre-treatment ventricular filling volume is provided. The method may include delivering one or more stimulation patterns of stimulation pulses to at least one heart chamber during a time interval that lasts for 10 minutes or more. At least one of the stimulation pulses may have a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle for at least 5 minutes of the time interval, and at least one of the stimulation pulses may have a second stimulation setting different from the first stimulation setting.

[0210] Other systems, methods, features and advantages of the present invention will be apparent or will become apparent to those of ordinary skill in the art upon examination of the following drawings and detailed description. All such additional systems, methods, features and advantages are included within this description and this summary, are within the scope of the present invention, and are intended to be protected by the following claims.

[0211] The present invention can be better understood by reference to the following drawings and description. The components in the figures are not necessarily drawn to scale and emphasis is placed on illustrating the principles of the present invention. Further, in the figures, like reference numerals indicate corresponding parts throughout the different figures. BRIEF DESCRIPTION OF THE DRAWINGS

[0212]

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Figure 3B

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Figure 5B

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Figure 10B

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Figure 20B

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Figure 28A

Figure 28B

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Figure 31

[0213] In embodiments of the present invention, systems and methods for controlling blood pressure are provided, particularly systems and methods for reducing systolic blood pressure while having little or no effect on diastolic blood pressure. In other embodiments, systems and methods for reducing pulse pressure by raising diastolic blood pressure while lowering systolic blood pressure may be provided. In other embodiments, systems and methods for reducing systolic blood pressure while maintaining diastolic blood pressure or raising it above a predetermined threshold may be provided. In other embodiments, systems and methods for raising diastolic blood pressure above a specified threshold may be provided. In an embodiment, this targeted blood pressure reduction may be achieved by controlling the interbeat interval and the intrabeat interval to induce a physiological response of pulse pressure reduction.

[0214] As used herein, "interbeat interval" is the 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, "intrabeat interval" is the 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.

[0215] A decrease in systolic blood pressure that does not have a perceptible effect on diastolic blood pressure can provide an effective treatment for isolated systolic hypertension (ISH). By maintaining a diastolic blood pressure above a specified threshold, a reduction in cardiac perfusion or the risk of isolated diastolic hypotension can be prevented.

[0216] While facilitating other hypertension treatments, in embodiments, to control the inter-beat interval and the intra-beat interval and provide RPP therapy, a target blood pressure drop may be achieved, for example, by electrically stimulating the heart using a pacemaker device. Thus, embodiments may include provisions for both RPP therapy (for the treatment of isolated systolic hypertension) and hypertension therapy (for treatments that affect both systolic and diastolic blood pressure).

[0217] In this “Detailed Description of the Invention”, in Section I below, treatments for isolated systolic hypertension, related pulse pressure drop therapies, and systems, devices, and methods combining isolated systolic hypertension treatment with other forms of hypertension treatment are described. In Section II below, other forms of hypertension treatment, and systems, devices, and methods that may use isolated systolic hypertension treatment and / or other forms of hypertension treatment are described. I. Treatment of Isolated Systolic Hypertension (ISH) FIG. 28A shows an experimental example of the influence of heart rate on peripheral blood pressure and central blood pressure according to one embodiment. Graph A in FIG. 28A shows the change in systolic blood pressure with an increase in heart rate, and graph B shows the change in diastolic blood pressure with an increase in heart rate. Both graph A and graph B represent the peripheral (upper arm) arterial pressure (represented by the rectangular symbol □) and the central (ascending aorta) arterial pressure (represented by the triangular symbol Δ). This test is described in detail in the paper "The influence of heart rate on augmentation index and central arterial pressure in humans", Wilkinson, Ian B. et al., Journal of Physiology (2000), 525.1, pages 263 - 270, which is incorporated herein by reference, and a copy of which is attached as Appendix A to U.S. Provisional Application No. 63 / 365,668, filed on June 1, 2022, for which this application claims priority. As explained in Wilkinson's paper (FIGS. 3A and 3B referred to in this section are shown in FIG. 28A of this application): there was no significant difference in the response of peripheral diastolic blood pressure and central diastolic blood pressure to pacing (P = 0.50), but as can be seen from FIGS. 3A and 3B, there was an effect on systolic blood pressure (P < 0.001). During pacing, an increase in arterial pressure amplification from the aorta to the upper arm artery, defined by the ratio of peripheral pulse pressure to central pulse pressure, was seen (Table 2). However, when calculating the ratio of peripheral pulse pressure to non-amplified central pulse pressure (P1 - central diastolic blood pressure), there was no significant change.

[0218] As shown in FIG. 28A, an increase in heart rate results in a consistent increase in diastolic blood pressure in both central blood pressure (measured in the aorta) and peripheral blood pressure (measured in the upper arm artery). An increase in heart rate also results in an increase in central systolic blood pressure and peripheral systolic blood pressure. A decrease in heart rate results in a decrease in both systolic blood pressure and diastolic blood pressure.

[0219] The inventors have found a way to combine a hypertension therapy (which lowers both systolic and diastolic blood pressure) with the effect of a specific heart rate manipulation that in itself raises both systolic and diastolic blood pressure, such that the combined effect on blood pressure caused by the hypertension therapy and the heart rate manipulation is a drop in systolic blood pressure and minimal or no drop in diastolic blood pressure. In other words, the inventors have found a way to combine a hypertension therapy with a specific heart rate manipulation for lowering pulse pressure (PP). Based on this physiological interaction, in embodiments, a system and method for treating isolated systolic hypertension by lowering pulse pressure (referred to herein as pulse pressure reduction (RPP) therapy) may be provided.

[0220] The data in FIG. 28A were obtained using a pacemaker to increase the heart rate. Thus, in hypertensive patients undergoing other forms of hypertension treatment (which affect both systolic and diastolic blood pressure), an apparatus can be used for RPP treatment, as described in more detail below.

[0221] There are many ways to increase the heart rate. Methods for increasing the heart rate include physical exercise, induction of an emotional response, and the use of drugs or hormones (such as adrenaline). However, since those methods affect many other functions in the body, they are not known to have the effect on pulse pressure shown in FIG. 28A. Another problem is that these methods affect the timing of atrial contraction and the A-A interval, which is usually converted to a similar change in the R-R interval, but this conversion may not occur if the AV delay is changed in parallel as part of the therapy, as described in more detail below.

[0222] An increase in heart rate, unless it occurs naturally, can lead to undesirable side effects such as an increased risk of life-threatening tachyarrhythmias. Therefore, increasing heart rate for therapeutic purposes may require precise control of the increased heart rate, provisions for assessing whether the state requires cessation of the increased heart rate, and provisions for immediately stopping the increased heart rate if necessary.

[0223] Therefore, the use of a device capable of supplying cardiac stimulation pulses is a preferred embodiment. A cardiac stimulation pulse is an energy pulse (usually an electrical energy pulse) that triggers depolarization in cardiac tissue. In a preferred embodiment, this device may be implantable to conveniently provide chronic isolated systolic hypertension treatment. In the most preferred embodiment, this device may include at least one cardiac lead for affecting cardiac stimulation.

[0224] Specifically, the use of such a device enables precise manipulation of the inter-beat interval, and thus enables setting of the inter-beat interval and heart rate. Heart rate, expressed in beats per minute, is defined as the number of beats divided by the time over which those beats occur, which is the average of the inter-beat durations of those beats. The inter-beat duration, i.e., the time between the same cardiac event in consecutive beats, is constantly changing. Two types of inter-beat durations are often used. The "A-A interval" is the time between two consecutive atrial electrical activations (confirmed by the "P" waves in the ECG plot), and the "R-R interval" is the time between two consecutive ventricular electrical activations (confirmed by the "R" wave of the QRS complex in the ECG plot).

[0225] Hemodynamically, it is ventricular contraction that affects systemic blood pressure. When the previous ventricular contraction ends, arterial blood flows into the organs and through the tissues into the veins, so systemic blood pressure continuously drops. By opening the aortic valve that connects the ventricle and the arterial system, the rising pressure of the contracting ventricle can be transmitted to the arterial system outside the heart. The timing of these events is included in the R-R interval.

[0226] However, the A-A interval and the R-R interval are not independent. Referring to the diagram in Figure 28B, using the AV interval (the delay between atrial activation and ventricular activation), these two intervals can be expressed as follows in terms of the other intervals and the AV delay: R-R(t)=A-A(t)-AV(t)+AV(t+1).

[0227] The use of the hypertension therapy described below requires manipulation of the AV delay for each heartbeat. Therefore, when the AV delay is manipulated to be different from normal, the R-R interval, the A-A interval, or both are affected, so it is not obvious to combine the increased heart rate with this therapy into the RPP.

[0228] Figure 29 shows one embodiment of a cardiac stimulation system 2900 for controlling blood pressure and delivering RPP and isolated systolic hypertension therapy. As shown, system 2900 includes an apparatus 2950, a plurality of ventricular and / or atrial electrodes 2956, and a plurality of sensors 2958. The sensors 2958 may include atrial sensors, heart rate sensors, activity sensors (such as accelerometers), and / or ECG sensors. As shown, the apparatus 2950 may include a controller, a power source, a clock, a memory, and a telemetry or communication unit. The apparatus 2950 may be configured similarly to a cardiac pacemaker and may have similar components, and may also be configured substantially similarly to the apparatus 50 described below with reference to Figure 14. Further, the apparatus 2950 may include any component of system 700 (see Figure 9 described below), and system 700 may include any component of the apparatus 2950.

[0229] As shown in FIG. 29, system 2900 may also include a data source 2990 to which device 2950 can communicate. In an embodiment, data source 2990 may include a database, a data table, and / or a computer user interface through which a user inputs data. The type of data provided by data source 2990 may include, for example, unique heart data and / or blood pressure data (diastolic blood pressure and / or systolic blood pressure as a function of heart rate).

[0230] In a preferred embodiment, a heart stimulation device such as device 2950 may include provisions for obtaining an indication of the intrinsic heart rate, and most preferably, may include provisions for obtaining such an indication during delivery of RPP therapy even if the measured heart rate is higher than the intrinsic heart rate. As shown in FIG. 29, in an embodiment, the indication of the intrinsic heart rate may be provided by data source 2990 along with other data, transmitted to device 2950 through a telemetry or communication unit, and stored in the memory of device 2950.

[0231] In some embodiments, a single value may be used as an indication of the intrinsic heart rate to provide effective heart rate detection. This value may be a fixed value based on the average heart rate of a population. In other embodiments, a table of values such as average heart rate values representing different populations (e.g., based on age and / or gender) may be used. In another embodiment, the value may be based on previous heart rate measurements performed in patients undergoing isolated systolic hypertension treatment. In some embodiments, this table may be further divided into different times of the day.

[0232] In some embodiments, the heart rate indicator may be obtained both before and during induction such that the increased heart rate is induced to affect the drop in pulse pressure and masks the slower (intrinsic) heart rate. An implantable embodiment of the device may include an activity sensor (such as that shown in FIG. 29) that generates an estimate of the intrinsic heart rate based on the activity level, regardless of the actual heart rate at the time of estimation. In another embodiment, the device includes an ECG sensor or cardiac sensing lead (such as that shown in FIG. 29) for use in performing atrial overdrive pacing, which is a method of cardiac pacing at a heart rate close to and above the intrinsic heart rate, originally developed to attempt to treat atrial arrhythmias.

[0233] In an embodiment, system 2900 including device 2950 and its controller may be operated in accordance with any of the embodiments of the methods described herein.

[0234] In another aspect, the present disclosure provides a non-transitory computer-readable medium storing software including one or more computer-executable instructions that, when executed thereby, cause one or more computers to execute any of the methods described herein.

[0235] In an embodiment, the apparatus 2950 may generally be any computing device including a processor and a machine-readable medium including instructions that may be executed by the processor. Generally, the processes and methods of the embodiments described in this detailed description and shown in the drawings may be implemented using any type of computing system having one or more central processing units (CPUs) and / or graphics processing units (GPUs). The processes and methods according to the embodiments may also be implemented using application-specific electronic circuits such as application-specific integrated circuits (ASICs). The processes and methods of the embodiments may also be implemented using a computing system including read-only memory (ROM) and / or random access memory (RAM) connected to one or more processing devices. Embodiments of computing systems and devices include, but are not limited to, servers, mobile phones, smartphones, tablet computers, notebook computers, laptops or desktop computers, all-in-one computers.

[0236] The processes and methods of the embodiments can 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 like 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 recording 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 diskette, a floppy disk, a hard disk, a magnetic disk or tape, a read-only memory (ROM), a random access memory (RAM), a static random access memory (SRAM), a portable compact disk 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 types of solid state drives, and any suitable combination of these exemplary media. As used herein, a non-transitory computer-readable medium should not be construed to be a transient signal such as a radio wave or other freely propagating electromagnetic wave, an electromagnetic wave propagating through a waveguide or other transmission medium (e.g., an optical pulse passing through an optical fiber cable), or an electrical signal transmitted through a wire.

[0237] The instructions stored on a non-transitory computer-readable medium to implement the operation of the present embodiment may be instruction set architecture (ISA) instructions, assembly instructions, machine instructions, machine-dependent instructions, microcode, firmware instructions, configuration data for integrated electronic circuits, state setting data, or source code or object code written in any one of one or more programming languages including object-oriented programming languages such as Smalltalk, C++, or a suitable language, and procedural programming languages such as the "C" programming language or a similar programming language.

[0238] In one or more embodiments, the described functions may be implemented by hardware, software, firmware, or any combination thereof. When implemented by software or firmware, the functions may be stored as one or more instructions or code on a computer-readable medium and executed by a hardware-based processing unit. The computer-readable medium may include a computer-readable storage medium corresponding 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 the desired program code in the form of instructions or data structures and can be accessed by a computer).

[0239] The 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 circuits or discrete logic electronic circuits. Thus, as used herein, the term "processor" may be any of the foregoing structures or any other structure suitable for implementing the embodiments of the technology described herein. Also, the present technology may be fully implemented by one or more circuits or logic elements.

[0240] In embodiments, provisions for calibrating hypertension therapy and RPP therapy may also be included to bring about the desired therapeutic effect in the patient.

[0241] In some embodiments, one value may represent the drop caused by the application of hypertension therapy to diastolic blood pressure. Using a table of diastolic blood pressure at different heart rates and using extrapolated values to complete the table values as needed, the expected increase in diastolic blood pressure may be calculated considering a specific basal (intrinsic) heart rate and a potentially increased heart rate. In embodiments, values representing the effect of hypertension therapy on systolic blood pressure and a table of systolic blood pressure at different heart rates may also be provided. In embodiments, those tables and values may be provided by data source 2990 as shown in FIG. 29.

[0242] In some embodiments, multiple values may be the drop caused by the application of hypertension treatment to diastolic blood pressure (and optionally systolic blood pressure) as a function of different known or measurable parameters such as the patient's age, therapy escalation / dosage, heart rate, and / or activity level. A corresponding table of diastolic blood pressure at different heart rates may be provided or generated for some or all of those different parameter values (e.g., by data source 2990 of FIG. 29). In embodiments, some of these tables may be obtained by the application of hypertension therapy and / or RPP therapy to the patient. In further embodiments, those values may be updated during delivery of the therapy to the patient.

[0243] In embodiments, the desired heart rate increase may be calculated by first finding the heart rate at which the diastolic blood pressure increase (above the intrinsic heart rate) and the diastolic blood pressure decrease induced by hypertension therapy are equal and then subtracting the intrinsic heart rate. This potential heart rate increase may then undergo a risk assessment (i.e., the risk of an undesirable effect). In some embodiments, the heart rate increase may be compared to a predetermined achievable heart rate increase, such as 10 beats per minute. In another embodiment, a medical professional may determine whether the amount of heart rate increase is commensurate with the risk. If it is not commensurate with the risk, in some embodiments, a predetermined increase may be used to provide a partial increase in diastolic blood pressure. Other embodiments may use a specified heart rate increase, for example, determined by a medical professional to be an appropriate heart rate increase. If value updates are available during therapy delivery, optimally, the risk assessment is performed at some or all times when updated values are available.

[0244] In some embodiments where systolic blood pressure data is present, the expected overall effect on systolic blood pressure may be calculated by subtracting the increase (caused by the expected increase in heart rate) from the decrease in systolic blood pressure affected by hypertension therapy. This potential systolic blood pressure decrease may then undergo an effectiveness assessment to determine if the potential systolic blood pressure is sufficient. In some embodiments, the potential systolic blood pressure decrease may be compared to a predetermined minimum effective decrease, such as 5 mmHg. In another embodiment, a medical professional may determine whether the amount of potential systolic blood pressure is sufficient. If it is insufficient, in some embodiments, a lower heart rate increase may then be selected such that the decrease is sufficient. Although the diastolic blood pressure decrease may be smaller, since the heart rate increase is determined to be lower than the increase commensurate with the risk, there is no need to assess the risk. If value updates are available during therapy delivery, optimally, the effectiveness assessment is performed at some or all times when updated values are available.

[0245] In embodiments, the increase in heart rate that is predefined or determined by an expert may depend on the heart rate and blood pressure data previously obtained from the patient. In some embodiments, the amount of increase corresponding to the risk may be updated using the heart rate and blood pressure data obtained from the patient if hypertension therapy and / or RPP therapy are being used individually for the patient. In embodiments, the amount of increase corresponding to the risk may be updated based on data obtained when hypertension therapy and RPP therapy are applied to the patient using one or more different settings and / or dosages. In embodiments, the amount of increase corresponding to the risk may then be continuously updated, and the risk assessment may then be performed at different times during the long-term application of the therapy to the patient.

[0246] When combining RPP therapy with hypertension therapy using a short atrioventricular (AV) delay value (see, for example, that described later in Section II), since the AA interval (in milliseconds) is equal to the value obtained by dividing 60,000 by the heart rate (in arbitrary units), embodiments of RPP therapy may include a modification of the VA interval such that the AV delay selected for hypertension therapy and the VA delay selected for RPP therapy constitute an AA interval appropriate for the desired increase in heart rate.

[0247] In some embodiments, an AA interval appropriate for the desired increase in heart rate means an AA interval that is shorter than the intrinsic AA interval by a specific period. In some embodiments, an AA interval appropriate for the desired increased heart rate means an AA interval that is shorter than the intrinsic AA interval by a specific percentage. In some embodiments, the shortening of the AA interval may be a function of the intrinsic AA interval or a function of the intrinsic AA interval and the input from other sensors (such as activity sensors).

[0248] In some embodiments, a cutoff heart rate may be defined such that the RPP therapy is not delivered even when the hypertension therapy is delivered. Such a cutoff may be necessary for several different reasons, including preventing an increased risk of tachyarrhythmia at high heart rates and preventing an increased myocardial oxygen consumption that occurs at high heart rates (which is particularly troublesome in patients with heart failure). The cutoff heart rate may be a single pre-set number or may be selected from a table of values that depend on different patient characteristics or medical histories (such as age, gender, and / or predisposition to tachyarrhythmia). The cutoff heart rate may be updated (automatically or manually) during the delivery of the RPP therapy. The cutoff heart rate may vary as a function of different parameters such as time, the patient's activity level, or blood pressure, and may be changed manually or, if the device is available, automatically updated based on the measured parameter values. In an embodiment, the cutoff may be a "soft cutoff" that defines different levels of RPP therapy delivery at different heart rates. For example, (1) if the heart rate exceeds 90 beats per minute, the RPP therapy is not delivered for more than 10 minutes unless the heart rate drops below 90, (2) if the heart rate exceeds 100 beats per minute, the RPP therapy may be delivered for only 2 minutes unless the heart rate drops below 100, (3) if the heart rate exceeds 110 beats per minute, the RPP therapy is not delivered at all, etc.

[0249] FIG. 30A shows one embodiment of a method 3000 for controlling blood pressure that may be implemented using the system 2900 of FIG. 29. As shown, method 3000 includes the main steps of providing a hypertension therapy, providing an isolated systolic hypertension therapy, and repeating the therapy as needed to achieve a treatment goal. Specifically, as represented by the solid rectangle, method 3000 may start in step 3002 by delivering a first stimulation pattern that decreases both systolic and diastolic blood pressure, for example, to treat hypertension. The method then may continue in step 3008 by delivering a second stimulation pattern that decreases systolic blood pressure while controlling diastolic blood pressure (e.g., leaving it mostly or entirely unaffected or increasing it) to reduce the difference between systolic and diastolic blood pressure, for example, to treat isolated systolic hypertension. Next, in step 3014, method 3000 may repeat steps 3002 and 3008 as needed to achieve hypertension treatment and ISH treatment. The appropriateness of either hypertension treatment or ISH treatment can be obtained by comparing the patient's systolic and diastolic blood pressure data when the treatment is applied and when it is not applied. For example, a blood pressure measurement can be taken before starting the therapy and its value can be compared with similar measurements taken during the progress of the therapy. Optionally, additional measurements can be taken over time during the therapy to determine appropriateness over time. Also optionally, during the application of the therapy, it can be paused temporarily at different times to enable measuring blood pressure without the application of the therapy and comparing the measured value with the values obtained during the progress of the therapy. Optimally, such blood pressure measurements are repeated several times over different times of the day. When evaluating the appropriateness of the therapy, if a decrease in diastolic blood pressure beyond the desired decrease is observed, a further shortening of the A-A interval should be performed.

[0250] In an embodiment, method 3000 may include optional steps for performing the ISH therapy represented by the dashed rectangle in FIG. 30A. As shown, prior to delivering the second stimulation pattern, method 3000 may, at step 3004, obtain an indication of the intrinsic heart rate and, as described above, set the heart rate to be increased for the ISH therapy to be higher than the intrinsic heart rate. Method 3000 may also, at step 3006, calibrate the first stimulation pattern to the second stimulation pattern, as described above. Although shown after step 3002, steps 3004 and 3006 may be completed at other times, such as before step 3002.

[0251] FIG. 30B shows one embodiment of a method 3020 that includes steps 3004 and 3006 of FIG. 30A for determining an increased heart rate appropriate for controlling diastolic blood pressure while lowering systolic blood pressure with respect to a second stimulation pattern. As shown, the method 3020 may begin at step 3022 by measuring the drops in systolic and diastolic blood pressure that occur when using a hypertension therapy (such as the hypertension therapy applied in step 3002 of FIG. 30A). In other words, step 3022 may determine the diastolic blood pressure drop and / or systolic blood pressure drop resulting from the first stimulation pattern. The method 3020 may then continue at step 3024 by applying different increased heart rates and measuring the increases in systolic and diastolic blood pressure that occur at the different increased heart rates. The increases in systolic and diastolic blood pressure at different heart rates may be determined by actively stimulating the patient at different heart rates and then determining the diastolic blood pressure drop and / or systolic blood pressure drop and the increases in systolic and diastolic blood pressure at the different heart rates. The method 3020 may then continue at step 3026 by determining an appropriate heart rate to achieve a desired pulse pressure in view of the previous measurement data. Further, at step 3028, the method 3020 may continue by applying an ISH therapy using the determined heart rate. In other words, step 3028 may transmit a second stimulation pattern (step 3008 of FIG. 30A) using the determined increased heart rate to control the diastolic blood pressure as desired. Thus, in achieving this control, the second pattern may combine a stimulation pattern that drops blood pressure and a stimulation that increases heart rate.The control provided by this combination of a stimulus pattern that lowers blood pressure and a stimulus that increases heart rate may include: (1) lowering systolic blood pressure while having little or no effect on diastolic blood pressure; (2) lowering systolic blood pressure while increasing diastolic blood pressure; (3) lowering systolic blood pressure while controlling diastolic blood pressure so that it is between a lower allowable value and an upper allowable value; (4) controlling 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 percentage; and / or (5) lowering systolic blood pressure while maintaining diastolic blood pressure above a specified minimum value.

[0252] Referring again to FIG. 30A, the embodiment may include control provisions during the delivery of the second stimulus pattern. In particular, as shown, method 3000 may include, at step 3010, monitoring the heart for state limits as described above and also, as described above, stopping the second stimulus pattern if a limit is reached.

[0253] An example of Method 3000 will be described below. A patient with a measured blood pressure of 145 / 75 mmHg requires therapy. This blood pressure value indicates ISH. The natural heart rate at rest is measured and is 66 bpm. Hypertension therapy is applied (step 3002 in Figure 30A), and the resulting blood pressure is 135 / 70 mmHg. The diastolic blood pressure value is 5 mmHg lower than the original level. Referring to Figure 28A, Graph B does not show a diastolic blood pressure of 70 mmHg, but at a heart rate of 66 bpm, the peripheral diastolic blood pressure is approximately 82 mmHg, and at a heart rate of approximately 76 bpm, a value 5 mmHg higher (87 mmHg) is brought about, with the heart rate increasing by 10 bpm. Step 3004 in Figure 30A will then consist of calculating a new A-A interval for the therapy that embodies an increase of approximately 10 beats per minute that is expected to return the diastolic blood pressure value to the value before therapy application. A further part of step 3004 will consist of calculating the predicted effect on the systolic blood pressure. Using Graph A in Figure 28A, the peripheral systolic blood pressure value is approximately 137 mmHg at a heart rate of 66 bpm, whereas at 76 bpm it is approximately 139 mmHg, and thus an increase in systolic blood pressure of 2 mmHg is expected. Therefore, the overall predicted effect of this change (a 10 bpm increase) is an increase in blood pressure value from 135 / 70 mmHg to 137 / 75 mmHg, i.e., a decrease of 8 mmHg in only the systolic blood pressure value, i.e., an 8 mmHg decrease in pulse pressure (relative to the original 145 / 75 mmHg value). This modified stimulation pattern should be applied in step 3008 in Figure 30A, and blood pressure measurements should be used to determine the diastolic and systolic blood pressure levels. If the diastolic blood pressure level does not return to the initial value, a further increase in heart rate calculated using the same process as described above is recommended. If the diastolic blood pressure value is too high, a decrease in heart rate considering the effect of a lower heart rate on the diastolic blood pressure in Graph B of Figure 28A is recommended. If the systolic blood pressure value is too high, a moderate decrease in heart rate is recommended to lower the systolic blood pressure value while minimizing the decrease in the diastolic blood pressure value.

[0254] Therefore, in the present embodiment, a first stimulus that decreases both systolic blood pressure and diastolic blood pressure is combined with a second stimulus that increases the heart rate to increase both diastolic blood pressure and systolic blood pressure, resulting in a systolic blood pressure reduced from the original value while returning the diastolic blood pressure to the original value (no increase or decrease).

[0255] Other embodiments of method 3000, as would be understood by one of ordinary skill in the art, can use the relationships described above and in FIG. 28A to provide different effects on systolic and diastolic blood pressure. For example, another embodiment of method 3000 may provide an overall effect of not only preventing a drop in diastolic blood pressure but also lowering systolic blood pressure while raising diastolic blood pressure. In this example, the patient may have an original measured blood pressure of 145 / 75 mmHg. Similar to the previous example, a hypertension therapy may be applied such that the blood pressure becomes 135 / 70 mmHg and the diastolic blood pressure value is 5 mmHg lower than the original level (step 3002 in FIG. 30A). Referring to graph B in FIG. 28A, by increasing the heart rate from the starting heart rate of 66 bpm to approximately 80 bpm by about 14 bpm, the peripheral diastolic blood pressure becomes approximately 90 mmHg, which represents an increase of about 8 mmHg from the peripheral diastolic blood pressure of approximately 82 mmHg at a heart rate of 66 bpm. Next, step 3004 in FIG. 30A may comprise calculating a new A-A interval for a therapy that embodies an increase of about 14 beats per minute that is expected to raise the diastolic blood pressure value by about 8 mmHg from the value before therapy application. A further part of step 3004 is calculating the expected effect on systolic blood pressure. Using graph A in FIG. 28A, at a heart rate of 66 bpm, the peripheral systolic value is approximately 137 mmHg, and at 80 bpm it is approximately 140 mmHg, so for systolic blood pressure, an increase of 3 mmHg is expected. Thus, in this example, the overall effect expected from the change (a 14 bpm increase) is that the blood pressure value rises from 135 / 70 mmHg to 138 / 78 mmHg, which means (compared to the original 145 / 75 mmHg value), a 7 mmHg drop in systolic blood pressure (i.e., a 7 mmHg drop in pulse pressure), and a 3 mmHg increase in diastolic blood pressure. This modified stimulation pattern should be applied in step 3008 in FIG. 30A, and blood pressure measurements should be used to determine the diastolic and systolic blood pressure levels.Therefore, in the present embodiment, a first stimulus that decreases both systolic blood pressure and diastolic blood pressure is combined with a second stimulus that increases the heart rate to increase both diastolic blood pressure and systolic blood pressure, resulting in a diastolic blood pressure increased from the original value and a systolic blood pressure decreased from the original value.

[0256] Figure 31 is a table showing data collected from actual hypertensive patients. As is clear from the baseline data on the left side of the table, the initial systolic BP was approximately 178 mmHg, the diastolic blood pressure was approximately 85 mmHg, and the resulting pulse pressure was 93. A hypertensive therapy using a short atrioventricular (AV) delay value (see, for example, those described later in Section II) was applied to the patient, and the use of a pacemaker induced an increase in the patient's heart rate (60, 70, 80, and 90 beats per minute). The systolic blood pressure decreased by an amount of approximately 10 mmHg for each heart rate. This decrease was considered to have no relation to the heart rate. However, the diastolic blood pressure was apparently increased as the heart rate increased. Thus, it is clear that the application of a similar therapy that results in a decrease in diastolic blood pressure at the initial heart rate can offset, by increasing the patient's heart rate (for example, by applying cardiac pacing), the increase in diastolic blood pressure that offsets the decrease caused by the therapy by an amount that can offset the decrease. Note that the pulse pressure decreases due to both the presence of the therapy and the increase in heart rate.

[0257] Embodiments of the present invention present the following items: Item 1: A system for controlling blood pressure, comprising a stimulation circuit configured to transmit a stimulation pulse to at least one heart chamber of a patient, and at least one controller configured to execute transmission of stimulation pulses of one or more stimulation patterns to the at least one heart chamber, wherein in a first operating mode, a first stimulation pattern of the one or more stimulation patterns reduces both the systolic blood pressure and the diastolic blood pressure of the patient, and in a second operating mode, a second stimulation pattern of the one or more stimulation patterns reduces the systolic blood pressure of the patient while controlling the diastolic blood pressure so as to reduce the difference between the systolic blood pressure and the diastolic blood pressure.

[0258] Item 2: In the system of Item 1, the second stimulation pattern may reduce the systolic blood pressure while having little or no effect on the diastolic blood pressure.

[0259] Item 3: In the system of Item 1, the second stimulation pattern may reduce the systolic blood pressure while limiting the effect on the diastolic blood pressure to a level that does not prevent the achievement of a therapeutically effective reduction in pulse pressure.

[0260] Item 4: In the system of Item 1, the second stimulation pattern may reduce the systolic blood pressure of the patient while increasing the diastolic blood pressure.

[0261] Item 5: In the system according to any one of Items 1 to 4, the at least one controller may be configured to treat the patient's hypertension using the first stimulation pattern or to treat the patient's isolated systolic hypertension using the second stimulation pattern.

[0262] Item 6: In the system of Item 1 or Item 2, the second stimulation pattern may combine a stimulation pattern for reducing blood pressure and a stimulation for increasing heart rate to reduce the systolic blood pressure while having little or no effect on the diastolic blood pressure.

[0263] Item 7: In the system of Item 1 or Item 3, the second stimulation pattern may combine a stimulation pattern that decreases blood pressure and a stimulation that increases heart rate to decrease systolic blood pressure while restricting the effect on diastolic blood pressure to a level that does not prevent the achievement of a therapeutically effective decrease in pulse pressure.

[0264] Item 8: In the system of Item 1 or Item 4, the second stimulation pattern may combine a stimulation pattern that decreases blood pressure and a stimulation that increases heart rate to decrease systolic blood pressure while increasing diastolic blood pressure.

[0265] Item 9: In the system according to any one of Items 1 to 8, the second stimulation pattern may combine a stimulation pattern that decreases blood pressure and a stimulation that increases heart rate to decrease systolic blood pressure while controlling the diastolic blood pressure so that the diastolic blood pressure is between a lower allowable value and an upper allowable value.

[0266] Item 10: In the system according to any one of Items 1 to 9, the second stimulation pattern may combine a stimulation pattern that decreases blood pressure and a stimulation that increases heart rate to control the systolic blood pressure and the 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.

[0267] Item 11: In the system according to any one of Items 1 to 10, the second stimulation pattern may combine a stimulation pattern that decreases blood pressure and a stimulation that increases heart rate to decrease systolic blood pressure while maintaining a diastolic blood pressure above a specified minimum value.

[0268] Item 12: In the system according to any one of Items 1 to 11, at least one controller may be configured to obtain an indicator of the patient's intrinsic heart rate, and the second stimulation pattern may increase the heart rate up to more than the intrinsic heart rate.

[0269] Item 13: In the system of Item 12, at least one controller may be configured to obtain an index of the intrinsic heart rate from at least one of a heart rate sensor, a fixed value based on the average heart rate of the group, a table of average heart rate values representing different groups, or a value based on previous heart rate measurements performed on the patient.

[0270] Item 14: In the system of Item 12 or Item 13, at least one controller may be configured to obtain an index of the intrinsic heart rate before and / or during the transmission of the second stimulation pattern.

[0271] Item 15: In the system according to any one of Items 12 to 14, the system further comprises an activity sensor configured to detect the activity level of the patient, and at least one controller may be configured to obtain an index of the intrinsic heart rate from an estimated value of the intrinsic heart rate based on the activity level signal received from the activity sensor.

[0272] Item 16: In the system according to any one of Items 1 to 11, at least one controller calibrates the first stimulation pattern to the second stimulation pattern by determining the diastolic blood pressure drop and / or systolic blood pressure drop caused by the first stimulation pattern, determines the increase in systolic blood pressure and diastolic blood pressure at different heart rates by actively stimulating the patient at different heart rates, and sets the second stimulation pattern based on the determined diastolic blood pressure drop and / or systolic blood pressure drop and the increase in systolic blood pressure and diastolic blood pressure at different heart rates so as to bring about a desired increase in heart rate.

[0273] Item 17: In the system of Item 16, at least one controller may be configured to determine the desired increase in heart rate by first finding the heart rate at which the increase in diastolic blood pressure above the intrinsic heart rate is equal to the diastolic blood pressure drop induced by the first stimulation pattern and then subtracting the intrinsic heart rate.

[0274] Item 18: In the system of item 16 or item 17, at least one controller subtracts an increase in systolic blood pressure expected due to an increase in heart rate expected from a decrease in systolic blood pressure caused by a first stimulation pattern, determines whether an overall expected effect on systolic blood pressure is sufficient, and if the overall expected effect on systolic blood pressure is not sufficient, selects a lower increase in heart rate for a desired increase in heart rate, so as to determine a desired increase in heart rate by calculating an overall expected effect on systolic blood pressure using the patient's existing systolic blood pressure data.

[0275] Item 19: In the system according to any one of items 1 to 18, the system further includes a tachyarrhythmia sensor configured to monitor the patient's heart for tachyarrhythmia during a second stimulation pattern and transmit a signal to at least one controller if tachyarrhythmia is detected, and at least one controller may be configured to abort the second stimulation pattern after receiving the signal.

[0276] Item 20: In the system according to any one of items 1 to 11, at least one controller receives data related to a heart rate condition for aborting the transmission of the second stimulation pattern during the transmission of the second stimulation pattern, and may be configured to abort the transmission of the second stimulation pattern if the heart rate condition is met.

[0277] Item 21: In the system of item 20, at least one controller may be configured to automatically receive data related to the heart rate condition based on the measured parameter values.

[0278] Item 22: In the system of item 20 or item 21, the data related to the heart rate condition may include a cut-off heart rate determined according to at least one of time, the patient's activity level, or blood pressure.

[0279] Item 23: In the system according to any one of Items 20 to 22, the heart rate condition may include different levels of a second stimulation pattern at different heart rates.

[0280] II. Hypertension Treatment The human heart has two atria and two ventricles. In a normal cardiac cycle, systole begins with atrial contraction, followed by ventricular contraction. The mechanical process of systole is controlled by the conduction of electricity in the heart. During each heartbeat, a wave of depolarization is induced by cells in the sinoatrial node. Depolarization propagates within the atria, to the atrioventricular (AV) node, and then to the ventricles. In a healthy heart, the atrioventricular delay, i.e., the delay time between the start of atrial excitation and the start of ventricular excitation, is typically between 120 milliseconds (ms) and 200 ms. The relative timing of atrial and ventricular contractions depends particularly on the relative timing of excitation of each chamber and on the time required for the chamber to generate mechanical contraction as a result of electrical activation (depending on differences in size, propagation speed, myocyte characteristics, etc.).

[0281] Before contraction, the myocardium relaxes and blood flows freely from the atria to the ventricles through the valves between them. This period can be divided into a rapid filling phase and a slow filling phase. The rapid filling phase begins immediately after ventricular relaxation, when blood from the venous system and atria rapidly fills the ventricles. The rapid filling phase lasts for about 110 ms and is followed by a slow filling phase that continues until the start of atrial contraction. The duration of the slow filling phase depends on the heart rate. Then, when the atria contract, the pressure increases within the atria, causing blood to flow more rapidly into the ventricles. This contribution of atrial contraction to ventricular filling is known as the "atrial kick". The atrial kick typically accounts for about 10% - 30% of ventricular filling.

[0282] Figure 17 shows the changes in ventricular volume, intraventricular pressure, atrial pressure, and cardiac electrical activity during a single cardiac cycle. As used herein, the cardiac cycle is the period between two relaxations of the ventricles, during which the atria contract only once while the ventricles relax twice. Since the duration of the cardiac cycle is inversely proportional to the heart rate, the cardiac cycle duration increases as the heart rate decreases and decreases as the heart rate increases. At a typical human heart rate of 75 beats per minute, one cardiac cycle is about 0.8 seconds long.

[0283] Referring to Figure 17, the cardiac cycle may be said to begin at the start of atrial excitation when the P wave is observed on the ECG. Then, about 50 - 70 ms later, the atria begin to contract for about 70 - 110 ms. As the atria contract, the pressure inside the atria rises and reaches a maximum value. Thereafter, the atria begin to relax and the pressure decreases. The maximum value is represented by point 1701 in Figure 17. On the other hand, the electrical stimulus propagates to the ventricles, and ventricular excitation begins with an AV delay of about 120 - 200 ms (the AV delay can be about 250 ms or more in some unhealthy individuals). This ventricular excitation appears as the QRS complex on the ECG. As the ventricles contract, the pressure inside the ventricles rises, closing the valves (AV valves) between each atrium and the corresponding ventricle passively, thereby stopping the blood flow from the atria into the ventricles and preventing backflow.

[0284] During the next period of ventricular contraction, that is, during the isovolumetric contraction period, which lasts about 50 ms and is also known as the isovolumetric phase, as shown in Figure 17 by the intraventricular pressure line and the ventricular volume line within vertical lines 1703 and 1704 that demarcate the isovolumetric phase, all the ventricular valves are closed and the volume remains significantly unchanged while the pressure inside the ventricles rises rapidly.

[0285] When the intraventricular pressure further rises, at the time indicated by line 1704 in Figure 17, the valve between the ventricle and the artery opens, and blood is ejected from the ventricle and leaves the heart. This ventricular contraction phase is divided into a rapid ejection phase and a slow ejection phase. The rapid ejection phase lasts about 90 - 110 ms, during which about 2 / 3 of the stroke volume is ejected. The rapid ejection phase is represented in Figure 17 as the period between line 1704 and line 1705.

[0286] During the isovolumic phase and at the beginning of the rapid ejection phase, ventricular contraction typically causes a passive increase in atrial pressure. This increase in atrial pressure is thought to be due to the mechanical effect of ventricular contraction on the associated atrium. For example, this increase in atrial pressure may be due to the fact that the atrium is closely related to the much larger ventricle. When the large ventricular muscle contracts, it affects the connected atrium. The increase in atrial pressure may also be due to the valve bulging backward into the atrium, but this bulging of the valve may be due to the increase in internal pressure in the ventricle. The passive filling of the atrium continues throughout the cardiac cycle (including between point 1701 and point 1702) because there is no valve between the atrium and the vasculature. This continuous passive filling in conjunction with the increase in internal pressure due to the mechanical effect of ventricular contraction may contribute to the increase in atrial pressure.

[0287] Therefore, as represented by point 1702 in Figure 17, the passive atrial pressure increase reaches a peak at some point between the latter half of the isovolumic phase (i.e., about 25 - 35 ms after the start of the isovolumic phase) and the start of the rapid ejection phase (e.g., within the first about 10 ms of the rapid ejection phase). As shown by the high atrial pressure at point 1702 compared to the low atrial pressure at point 1701 in Figure 17, the passive atrial pressure rise may be higher than the maximum atrial pressure due to atrial contraction.

[0288] After the rapid ejection phase, a slow ejection phase follows, which lasts about 130 - 140 ms. Then, all valves close again, and the ventricle relaxes in an isovolumic relaxation state for about 60 - 80 ms, during which the internal pressure of the ventricle decreases. At this time, the valve between the ventricle and the atrium opens again to allow blood to flow freely into the ventricle, and then a new cardiac cycle may begin.

[0289] 〈1. Control of Intracardiac Pressure and Atrial Dilatation〉 In the present disclosure, cardiac stimulation can be used to increase intracardiac pressure and dilatation, thereby reducing blood pressure (BP). By cardiac stimulation, the intracardiac pressure generated by atrial contraction of the atrium overlaps with the passive increase in intracardiac pressure of the atrium in terms of time, so that the intracardiac pressure of the atrium generated by the stimulation is a combination of the intracardiac pressure generated by atrial contraction and the passive increase in pressure, and the heart can be stimulated so that it is higher than the intracardiac pressure of the atrium without stimulation, thereby achieving an increase in intracardiac pressure.

[0290] In an embodiment, the maximum intracardiac pressure may be reached by causing maximum atrial contraction during the period when the maximum passive increase in intracardiac pressure overlaps. For example, cardiac stimulation can be used to reach the maximum intracardiac pressure generated by atrial contraction between about 25 to 35 ms after the start of the isovolumic period and about 10 ms after the end of the isovolumic period. The increase in intracardiac pressure (due to the intracardiac pressure generated by atrial contraction overlapping with the passive increase in intracardiac pressure) increases atrial dilatation, and it is known that this affects blood pressure through the hormonal pathway and / or the neuronal pathway. For example, an increase in atrial dilatation may cause the secretion of atrial natriuretic hormone or atrial natriuretic peptide, thereby reducing blood pressure.

[0291] In an embodiment, cardiac stimulation may be applied long - term or temporarily to increase the atrial pressure and atrial dilation and to cause the secretion of atrial natriuretic hormone or atrial natriuretic peptide. Long - term application of cardiac stimulation is not necessary, and a temporary stimulation may be sufficient to increase the atrial pressure and atrial dilation, cause hormone secretion, and lower blood pressure. The change in atrial dilation may be transient as observed in a pressure plot, and a transient dilation may be more effective than a long - term dilation in causing the release of atrial natriuretic hormone or atrial natriuretic peptide and lowering blood pressure. Beneficially, in an embodiment, a temporary increase in atrial pressure may not result in a long - term increase in atrial pressure.

[0292] In some embodiments, if the maximum atrial pressure generated by atrial contraction completely or at least partially coincides with the maximum passive increase in atrial pressure, the maximum atrial pressure generated by atrial contraction is considered to occur during a period that overlaps with the maximum passive increase in atrial pressure. For example, if the maximum atrial contraction is predicted to occur within about 20 ms before or after the predicted maximum passive increase in atrial pressure, the maximum atrial pressure generated by atrial contraction is considered to occur during a period that overlaps with the maximum passive increase in atrial pressure.

[0293] In some embodiments, the maximum atrial pressure means the highest part of the systolic or passive pressure increase and has a pressure value that is at least about 25% higher than the remaining atrial pressure values. Optionally, if only one peak or two peaks are observed in the pressure from atrial contraction and passive pressure increase, the maximum atrial pressure generated by atrial contraction is considered to occur during a period that overlaps with the maximum passive increase in atrial pressure, and the maximum atrial pressure generated by atrial contraction and the maximum passive increase in atrial pressure are separated by no more than about 30 ms. Optionally, the temporal overlap is mathematically detectable by analyzing the measured values and / or visually, for example, by plotting the atrial pressure over a period or the change in atrial pressure over a period.

[0294] BP or a change in BP may be measured as systolic BP (SysBP), diastolic BP, mean arterial BP, BP of one or more chambers, and / or any other relevant BP parameter. In some embodiments, an electrical stimulation device, such as a pacemaker or other type of device having a pulse generator, may be used to stimulate the patient's heart to lower blood pressure. Electrodes electrically connected to the electrical stimulation device by a wired or wireless connection may be disposed adjacent to a heart chamber. The electrical stimulation device may be operative to transmit a pulse to the heart chamber via the electrodes.

[0295] In some embodiments, stimulating the heart such that the atrium reaches an increased (preferably, maximum) atrial pressure that results from atrial contraction during a period that overlaps (preferably, the maximum) passive pressure increase of the atrial pressure may, as a result, lower blood pressure. For the sake of brevity, in the following description, such stimulation is referred to as "AC (Atrial Contraction) stimulation". AC stimulation may include transmitting at least one stimulation pulse to at least one chamber of the heart such that the atrium reaches a maximum atrial pressure that results from atrial contraction during a period from the latter half of the isovolumetric period to the first approximately 10 ms of the rapid ejection period. Such a stimulation pulse is referred to herein as an "AC stimulation pulse" or an "AC pulse".

[0296] When used in the present invention, a "stimulating pulse" may include a sequence of one or more excitatory electrical pulses (or stimulating pulses) transmitted to one or more chambers of the heart within the time frame of a single cardiac cycle (where a single cardiac cycle is defined as the period between two relaxations of the ventricles, during which atrial contraction occurs only once while the ventricles relax twice). Optionally, such excitatory electrical pulses (or stimulating pulses) are further referred to as pacing pulses. For example, in some embodiments, the stimulating pulse may include one or more electrical pulses transmitted to one or more locations of the ventricles and / or one or more electrical pulses transmitted to one or more locations of the atria. Thus, in some embodiments, the stimulating pulse may include a first electrical pulse transmitted to the atria and a second electrical pulse transmitted to the corresponding ventricles. In some embodiments, the stimulating pulse may include a first electrical pulse transmitted to the atria, a second electrical pulse transmitted to the corresponding ventricles, and a third electrical pulse transmitted to the atria after the refractory period associated with the first pulse has ended. In some embodiments, the stimulating pulse may include a single pulse transmitted to multiple locations of one or more chambers of the heart.

[0297] In some embodiments, the AC pulse may be transmitted at a timing such that the atrial intracardiac pressure generated by the stimulation is higher than the atrial intracardiac pressure without stimulation by a combination of the atrial intracardiac pressure generated by atrial contraction and the passive pressure increase, with respect to the cardiac cycle, overlapping in time with the passive pressure increase of the atria. Preferably, the AC pulse may be transmitted at a time overlapping with the maximum passive pressure increase of the atria to reach the maximum atrial intracardiac pressure generated by atrial contraction. Optionally, the timing of transmission of this AC pulse is set according to one or more detected events, for example, events related to the cardiac cycle.

[0298] For example, atrial and / or ventricular excitation may be detected, and an AC pulse may be transmitted to the atrium and / or ventricle accordingly. For example, the pacing pulse may be transmitted to the atrium at a timing predicted to be within about -20 to 30 ms from ventricular detection or pacing and within at least about 20 milliseconds from the end of the atrial refractory period. Optionally, the heart rate and ventricular excitation or contraction may be detected, the timing of the next ventricular contraction or excitation may be estimated, and the AC pulse may be transmitted such that the atrial pressure generated by atrial contraction in a subsequent beat overlaps in time with the passive increase in atrial pressure. Optionally, the AC pulse may be transmitted such that atrial contraction in a subsequent beat reaches the maximum atrial pressure generated by atrial contraction at the time when it overlaps in time with the maximum passive increase in atrial pressure of the atrium. For example, the AC pulse may include a stimulus transmitted to the atrium about 30 to 0 ms before the predicted ventricular excitation or about 50 to 120 ms before the predicted start of ventricular contraction.

[0299] In some embodiments, the stimulation pulse may include a first atrial excitation that is detected or paced, an electrical pulse transmitted to the corresponding ventricle, and another electrical pulse transmitted to the atrium after the atrium has ended its refractory period associated with the first excitation. For example, the period from the transmission of the first atrial excitation (e.g., the transmission of the first excitatory pulse to the atrium) to the transmission of another excitatory pulse to the atrium may be about 150 to 250 ms.

[0300] In some embodiments, the AC pulse includes a first electrical pulse transmitted to the atrium and a second electrical pulse transmitted to the corresponding ventricle. The relative timing of the first electrical pulse and the second electrical pulse is controlled to contract the atrium at a point in time within the period from the second half of the isovolumetric period to the beginning of the rapid ejection period of the heart during that beat. Since the time from the transmission of the excitatory pulse to the start of contraction is longer for the ventricle than for the atrium, the delay in the transmission of the first pulse and the second pulse may have a negative value such as about -20 to 0 ms.

[0301] This exact timing may vary depending on the different patients and different conditions (e.g., different arrangements of one or more electrodes in the chamber). Thus, in some embodiments, the AC pulse settings may be adjusted, for example, at the time of device implantation and / or periodically, such as during a regular check or during use (e.g., based on feedback from one or more relevant sensors).

[0302] For example, different settings of AC pulses may be delivered to the patient and the intracardiac pressure may be sensed until the desired intracardiac pressure resulting from atrial contraction that coincides in time with the passive increase in atrial pressure is detected. In some embodiments, the desired intracardiac pressure may be any intracardiac pressure that is higher than the intracardiac pressure that the atrium would reach without stimulation. Optionally, the desired intracardiac pressure may be selected as the highest intracardiac pressure (or one of the highest intracardiac pressures) among a plurality of intracardiac pressures generated by a plurality of AC pulses having different settings. For example, the AC pulses may vary by 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 for use for a period of time for a given patient may be selected.

[0303] For example, different settings of AC pulses may be delivered to the patient and the intracardiac pressure may be sensed until a desired degree of overlap is observed between the maximum value of the highest intracardiac pressure resulting from atrial contraction and the maximum value of the passive increase in atrial pressure. For example, the AC pulses may vary by 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 for use for a period of time for a given patient may be selected.

[0304] Optionally, the AC pulses may be delivered as part of a pacing pattern where the settings of the various pulses within the pattern differ, and one or more patterns may be selected for repeated use based on pulse selection configured to reduce or prevent atrial stimulation and one or more parameters related to the aforementioned overlap of internal pressures.

[0305] 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 output, the time interval between electrical pulses contained in a single stimulation pulse (e.g., AV delay or the delay between two atrial pulses), the delivery cycle relative to the natural rhythm of the heart, the length of the stimulation pulse or a portion thereof, and the delivery site between two or more chambers and / or within a single chamber. The AC stimulation settings, i.e., the “AC settings,” may include the settings of one or more AC pulses.

[0306] In some embodiments, sensing may include sensing one or more of the electrical activities of one or more chambers of the heart, e.g., atrial excitation and / or ventricular excitation. In some embodiments, sensing includes detecting cardiac activity using the sounds of the cardiac cycle. For example, the closure of the AV valve results in the first heart sound. This closure further means the start of the isovolumic phase. Optionally, based on the timing of the closure of the AV valve and the heartbeat, the pulse settings may be selected for subsequent AC pulses. For example, the stimulation pulse may be delivered to the atrium approximately 80 to 10 milliseconds before the next predicted closure of the AV valve.

[0307] Optionally, the refractory period of a heart chamber (e.g., an atrium) may be inferred as is known in the art. The AC pulse may include transmitting a stimulation pulse that induces atrial contraction to the atrium. For example, the stimulation pulse may be timed for transmission after the end of the refractory period, or if transmitted during the associated refractory period, the stimulation pulse may have electrical properties such that it induces contraction despite relatively fast timing.

[0308] In some embodiments, heartbeats are detected as is known in the art, e.g., based on electrical activity, sound, pressure, and / or any other means.

[0309] In some embodiments, one or more AC pulses may be provided as part of a sequence of pulses or as a pacing pattern that includes multiple beats. The pacing pattern may include multiple pacing pulses with different settings. Optionally, the pulses may all be AC pulses, or some may have different pulse settings than others. Optionally, only a portion of the pulses of a given pattern may be configured to produce an increased or peak atrial intracardiac pressure caused by atrial contraction during the period from the latter half of the isovolumic phase to the beginning of the rapid ejection phase.

[0310] It should further be noted that one or more pulse settings (e.g., the timing between detected and / or transmitted events) may be optimized and / or adjusted to accommodate the differences in a particular patient and / or the patient's cardiac function.

[0311] For example, a patient's heart rate may vary for many reasons including activity and time. A change in heart rate may result in a change in the relative timing of cardiac events. Accordingly, one or more of the following parameters may be detected or used to optimize and / or adjust the pulse settings.

[0312] For example, using the aortic pressure and / or sound associated with the opening of one or both heart valves, the timing of the start and / or end of the isovolumic period and / or the start of the rapid ejection period can be accurately targeted. Such timing may be compared to the time at which a pulse is delivered and / or a cardiac event is detected so that the timing of the desired contraction is achieved more accurately and / or more repetitively.

[0313] In another example, the timing from the transmission or detection of an excitatory stimulus (to the atrium and / or ventricle) to the time at which a peak pressure (due to contraction or passive pressure rise) is detected in the atrium may be measured.

[0314] Another option may be to adjust the AC pulse settings according to one or more of the heart rate, patient activity, posture, and / or respiratory rate.

[0315] In fact, the above combinations may be used for adjustment and / or optimization. For example, one or more of the timing between atrial excitation and the maximum atrial pressure generated by atrial contraction, ventricular excitation, maximum atrial passive pressure, and the timing of the isovolumic and / or rapid ejection periods may be measured. Optionally, the atrial pressure generated by the delivery of the stimulation pulse may be measured, and the adjustment may include selecting a stimulation setting according to the measured generated pressure. These measurements may further be related to the patient's heart rate under various conditions. Specific measurements of the patient may be used to adjust or optimize the pulse settings.

[0316] The optimizations and / or adjustments as described above may be implemented, for example, in some cases as a closed loop in which the sensor is associated with an implantable stimulation device. Alternatively, the optimizations and / or adjustments may be implemented as an open loop. The optimizations and / or adjustments may be an ongoing process (especially, for example, if the sensor is implanted according to the heart rate), and / or may be implemented during implantation when the patient has the device, sometimes, and / or when needed. Finally, the optimizations and / or adjustments may be automated and / or may involve a physician.

[0317] Embodiments may implement different pacing techniques to achieve AC stimulation and a desired overlap between the atrial pressure generated by atrial contraction and the passive increase in atrial pressure. In some embodiments, the AC stimulation may include pacing the atrium at an atrial rate that is substantially equal to the intrinsic ventricular rate or pacing the atrium at an atrial rate that is higher than the intrinsic ventricular rate. Additionally, different pacing techniques may be implemented to achieve a desired AC stimulation where the atrium contracts once or the atrium contracts twice.

[0318] For one atrial contraction, the pacing technique to achieve the desired AC stimulation may include, for example, the following.

[0319] a. Atrial sensing (optionally including anticipating atrial activation) and ventricular pacing, b. Ventricular sensing and atrial pacing, which may require pacing the atrium before the time of the anticipated ventricular sensing, or c. Atrial pacing and ventricular pacing.

[0320] For two atrial contractions, the pacing technique to achieve the desired AC stimulation may include, for example, the following.

[0321] a. Detect atrial activation first, detect the ventricles, and pace the atria in the same cardiac cycle to cause a second contraction. b. Detect the atria, pace the ventricles, and pace the atria in the same cardiac cycle to cause a second contraction. c. Pace the atria, detect the ventricles, and pace the atria again, or d. Pace the atria, pace the ventricles, and pace the atria again.

[0322] Other pacing techniques may be utilized to achieve the desired AC stimulation and the overlap between the atrial pressure generated by atrial contraction and the passive increase in atrial pressure. Thus, despite the specific merits associated with the pacing techniques described herein, this embodiment should be considered broadly applicable to any pacing technique that provides the desired AC stimulation and overlap.

[0323] Figures 18-19 are graphs showing two different stimulation patterns transmitted to the heart of a healthy anesthetized dog, showing the electrocardiogram (ECG), right ventricular pressure (RV pressure), right atrial pressure (RA pressure), aortic pressure (Ao pressure), and left ventricular pressure (LV pressure) traced over a period of time. According to one embodiment, Figure 18 shows the change from sinus rhythm stimulation to atrial and ventricular pacing with a 2 ms AV delay, which pacing results in an overlap between the pressure due to atrial contraction and the atrial pressure due to passive pressure increase. In this embodiment, pacing with a 2 ms AV delay caused a time overlap between the maximum pressure due to atrial contraction and the maximum atrial pressure due to passive pressure increase, and a measurable increase in atrial pressure, thus also causing atrial dilation. For comparison purposes, Figure 19 shows a 40 ms AV delay, which had a small degree of overlap and did not result in a significant increase in atrial pressure. Optionally, a greater degree of overlap may be defined as a function of the proximity of the maximum atrial pressures, i.e., the closer the maxima are to each other, the greater the degree of overlap, until finally the maxima completely overlap and a single maximum pressure is observed. Optionally, the degree of overlap is a function of the detected maximum atrial pressure, with a higher maximum pressure value being characterized by a greater degree of overlap.

[0324] In the experiments related to Figures 18-19, a pacemaker configured with an algorithm enabling pacing at a specific AV delay was attached to the heart of a healthy dog. The pacemaker was connected to the heart via two pacing electrodes, one in the right atrial appendage and the other in the right ventricular apex. Four solid-state pressure sensors were inserted into the right atrium, right ventricle, left ventricle, and aorta. Additionally, a unipolar-derived ECG was also connected to the animal. The sensors were connected to an amplifier and a data acquisition system (DAQ system), and the signals were sampled at a rate of 1 kHz, providing the graphs shown in Figures 18-19. As shown, the graphs include plots of ECG, RV pressure, RA pressure, Ao pressure, and LV pressure from bottom to top.

[0325] In each experiment, for several beats, the heart was contracted using natural sinus rhythm, and then both the atrium and ventricle were paced using a specified AV delay.

[0326] Referring to each of FIGS. 18-19, during the period of sinus rhythm 1802, two separate increases in atrial pressure are seen. The first increase in atrial pressure 1804 occurs following atrial electrical activity (P wave 1806) and corresponds to atrial contraction. The second increase in atrial pressure 1808 occurs during ventricular isovolumic contraction (characterized by a rapid increase in ventricular pressure) and persists for a short initial period of the rapid ejection phase (starting when aortic pressure begins to rise). The second increase in atrial pressure 1808 is caused by the effect of ventricular contraction on atrial pressure. As shown in the RA pressure plots of FIGS. 18-19, the maximum atrial pressure reached during isovolumic contraction is slightly higher than the maximum atrial pressure reached during atrial contraction.

[0327] As described above, one embodiment includes preparing to maximize atrial pressure and thus maximize atrial dilation. More specifically, the stimulus is delivered to the atrium at a timing such that, for the cardiac cycle, it reaches the atrium at a point that overlaps with the maximum passive increase in atrial pressure and causes the atrium to reach the maximum atrial pressure produced by atrial contraction. FIG. 18 shows one example of the timing at which the atrium and ventricle are paced with a 2 ms AV delay, as represented by the ventricular pace 1812 following the atrial pace 1810 by 2 ms. FIG. 18 shows three examples of this pacing.

[0328] Referring to the plotted portions of the right atrial pressure (RA pressure) in FIG. 18, in these three examples of pacing, significant increases in atrial pressure can be seen at points 1814, 1816, and 1818. These significant increases in internal pressure are caused by simultaneous or nearly simultaneous increases in atrial pressure due to atrial contraction and ventricular contraction. That is, when comparing the sinus rhythm portion 1802 of the right atrial pressure plot with the AV delay pacing portion 1803 of the right atrial pressure plot, the first increase 1804 and the second increase 1808 in atrial pressure in the sinus rhythm portion 1802 are essentially superimposed on the AV delay pacing portion 1803 such that the combination of the atrial pressure increase 1804 and the atrial pressure increase 1808 results in higher atrial pressure increases 1814, 1816, and 1818.

[0329] Optionally, the AC pulse may have a setting that includes a predetermined AV delay between the sensed or paced atrial excitation and the paced or sensed ventricular excitation. The AV delay may be selected such that the atrial pressure generated by atrial contraction and the passive atrial pressure increase essentially overlap as described above, and such that the atrial pressure, which is a combination of the atrial pressure generated by atrial contraction and the passive pressure increase, is higher than the atrial pressure of the atrium in the absence of stimulation (or with a different stimulation). The AV delay may be selected such that the maximum atrial pressure and the maximum passive atrial pressure increase generated by atrial contraction essentially overlap as described above. This setting may vary by patient and may even vary over time for a given patient. Nevertheless, in most cases, an AV delay of about 30 ms to about 0 ms is expected to be effective. For some patients (such as in the example shown by the heart of a healthy dog as shown in FIG. 18), the AV delay between atrial excitation and ventricular excitation may be about 30 ms to about 0 ms, or about 20 ms to about 0 ms.

[0330] When detecting cardiac events using sensing and an AV delay is set for them, the following may optionally be taken into account, namely, first, it should be noted that there is a delay between the actual excitation and its detection when electrical excitation is sensed. This may be due to the location of the sensing electrodes and the limitations of the sensing system. Thus, for example, the period from the sensed atrial excitation to the delivery of the pacing pulse to the ventricle will be shorter than the desired AV delay. When sensing is based on mechanical events (such as contractions or valve closures), the time between the actual excitation and the occurrence of the mechanical event also needs to be taken into account. Some examples of the relative timing between the sensed event and the delivery of the pacing pulse are disclosed herein. Additionally, as described in detail in this application, the settings may be adjusted to match the patient's specific timing at the time of implantation and / or periodically.

[0331] In contrast to the surprising beneficial results achieved by pacing using an AV delay that causes atrial contraction of the atrium to coincide in time with the passive increase in atrial pressure, such that the combination of the atrial pressure generated by atrial contraction and the passive increase in pressure results in an atrial pressure higher than that of the atrium in the absence of stimulation (as in the example of FIG. 18), FIG. 19 shows a short AV delay compared to a normal AV delay (e.g., 140 ms in a dog heart), but does not result in a significant increase in atrial pressure. As shown in FIG. 19, during the AV delay pacing portion 1803, the heart was paced with an AV delay of 40 ms, as represented by the ventricle pace 1912 following 40 ms after the atrial pace 1910 after the sinus rhythm portion 1802.

[0332] FIG. 19 shows two examples of this pacing. Referring to the trace portion of the atrial pressure (RA pressure) after a short time following pacing, despite an AV delay of 40 ms, which is shorter than the normal 140 ms AV delay, the 40 ms AV delay did not result in a significant increase in atrial pressure in response to the atrial pressure increases 1804 and 1808 in the sinus rhythm portion 1802. Instead, as shown in FIG. 19, the 40 ms AV delay resulted in two separate atrial pressure increases 1904 and 1908, which were approximately equal to the previous atrial pressure increases 1804 and 1808.

[0333] Thus, by comparing FIGS. 18 and 19, it is shown that a significantly increased atrial pressure occurs when atrial contraction and the latter half of ventricular isovolumetric contraction or the beginning of the rapid ejection phase occur simultaneously or almost simultaneously, as in FIG. 18. This significant increase in atrial pressure may result in the release of desired stress-related hormones to lower blood pressure. Thus, embodiments pace the atrium and ventricle with an AV delay of about 2 ms.

[0334] Figures 20A to 20C show some theoretical examples for combining the atrial pressure due to atrial contraction and the passive pressure increase in the atrium. In these examples, as detailed below, different degrees of overlap are shown, and the pressures due to atrial contraction and passive pressure increase are summed. First, for example, as shown during the sinus rhythm 1802 period in FIGS. 18 and 19, the atrial pressure was traced during a natural cardiac cycle. From this trace, the atrial pressures due to atrial contraction 1804 and passive pressure increase 1804 were extracted. In FIG. 20A, assuming a 60 ms delay from the start of atrial contraction to the start of passive pressure increase, two pressure curves (corresponding to 1802 and 1804 in FIG. 18) were summed. As can be seen, atrial contraction continued for about 60 ms and the maximum pressure reached approximately 1.5 mmHg, while the passive pressure increase continued for about 50 ms and reached a maximum pressure slightly higher than 2 mmHg. Since atrial contraction continued for about 60 ms (which is approximately the same as the assumed delay), the two pressure increases are observed as separate parts in this trace, having two different peaks, and the observed maximum pressure is the maximum pressure of the passive pressure increase 1804.

[0335] FIG. 20B shows in more detail the theoretical combination of the atrial pressure due to atrial contraction and the passive pressure increase in the atrium. In this trace, the start of the passive pressure increase 1804 (dashed line) is assumed to occur 30 ms after the start of atrial contraction 1802 (dotted line), as shown. Summing the two traces, the sum is traced as the pressure trace 204 (solid line). As seen in this example, due to some overlap, the combined line 204 had a maximum pressure slightly higher than the maximum pressure observed in the non - overlapping passive pressure increase 1804 (dashed line), but two peaks were still seen, each corresponding to the respective combined traces 1802 and 1804.

[0336] The timing such that the maximum atrial pressure due to atrial contraction occurs simultaneously with the maximum passive pressure rise so that the maximum of the atrial pressure occurs as a single event may result in the highest achievable atrial pressure, but embodiments may result in a significant and beneficial increase in the atrial pressure during a period after this single event. In other words, to obtain an atrial pressure higher than the atrial pressure of the atrium without stimulation by stimulating the heart with a combination of the atrial pressure generated by atrial contraction and the passive pressure rise, it is only necessary that the combination (e.g., sum) of the atrial pressure generated by atrial contraction and the passive pressure rise becomes higher than the maximum internal pressure of the atrium that occurs without stimulation depending on the timing of the stimulation. When the maximum atrial pressure due to atrial contraction occurs simultaneously with the maximum passive pressure rise of the atrium, the combination (e.g., sum) of these internal pressures is likely to be higher than the individual internal pressures. However, providing a composite atrial pressure higher than both of the individual internal pressures is not limited to a single event that produces simultaneous maximum values, but also holds for a certain range of periods where the internal pressures overlap each other, as described in more detail below.

[0337] In FIG. 20C, the internal pressure due to atrial contraction and the passive pressure rise are combined with various theoretical degrees of overlap between them, thus illustrating that how to control the relative timing of atrial contraction and ventricular contraction may affect the composite atrial pressure. In this example, similar to FIG. 20B, a time delay from the start of atrial contraction to the start of the passive pressure rise is assumed, and thus, at each time point, the atrial pressure due to atrial contraction is summed with the passive pressure rise at the same time point, thus providing a composite internal pressure. The composite (e.g., summed) internal pressures of various examples are traced in FIG. 20C.

[0338] The trace 201 in FIG. 20C is the same as the trace shown in FIG. 20A, and there is a delay of 60 ms from the start of the internal pressure due to atrial contraction to the passive internal pressure increase. On the other hand, in trace 207, the atrial internal pressure and the passive internal pressure increase due to atrial contraction are combined so that their peaks approach and overlap (the delay between the starts of the two changes in internal pressure may not exactly coincide due to different durations, and the delay is 0 ms), that is, it is assumed that both the atrial internal pressure and the passive internal pressure increase due to atrial contraction start almost simultaneously. As can be seen, in this case, trace 207 shows the sum of the internal pressures reaching a single peak of about 3.5 mmHg. Similarly, at a delay of 10 ms (trace 206), a single peak with a peak value slightly lower than that of trace 207 and slightly delayed from trace 207 was observed. As the time delay is increased, in trace 205 (20 ms delay), the traces begin to separate but still result in a single peak value (between 2.5 mmHg and 3 mmHg). Trace 204 (a 30 ms delay identical to the trace shown in FIG. 20B) clearly shows two peaks but still overlaps sufficiently, and the sum of the atrial internal pressures is slightly higher than the peak of trace 201. Finally, even with a smaller degree of overlap, in traces 203 (40 ms delay) and 202 (50 ms delay), the internal pressure due to atrial contraction and the passive internal pressure increase overlap somewhat, while in each trace, the two peaks are more than 30 ms apart, and the maximum internal pressure is almost the same as that of trace 201 where no overlap is shown at all.

[0339] In some embodiments, blood pressure may be lowered by using a stimulation pattern to intermittently apply exclusively a stimulation pattern that includes or consists of one or more AC pulses. For example, by applying intermittent AC pulses, natural pulsation may occur between pulses configured such that the atrial pressure due to the AC pulse and / or atrial contraction does not overlap (or their respective peaks do not overlap) with the atrial pressure due to passive pressure rise, thereby providing an atrial pressure that is higher than the atrial pressure of the atrium without stimulation by the combination of the atrial pressure generated by atrial contraction and the passive pressure rise. Optionally, the time during which the AC pulse is applied may be selected according to the time constant of the secretion and / or absorption of natriuretic peptide such that sufficient stimulation is transmitted to provide the desired effect essentially without overstimulating. This may have the advantage of reducing the power used by an implantable device and / or reducing the degree of operation of the heart.

[0340] An exemplary method 230 for controlling atrial pressure is schematically illustrated in FIG. 23. Method 230 may be performed by an implantable device as described herein. Thus, the device may be configured to perform any or all steps of method 230. Similarly, method 230 may include any steps configured to be performed by the device. For example, method 230 may include any of the functions discussed below with respect to device 50 of FIG. 14.

[0341] In some embodiments, method 230 may include detecting a cardiac event, as shown in step 231. This event(s) may include electrical and / or mechanical events and may be detected as is known in the art and as described in further detail herein. For example, the detected event may include detecting the excitation of the atria and / or ventricles and / or the mechanical activity of the heart, such as the timing of the opening and / or closing steps of one or more heart valves. The detected event may include inferring the relative timing between cardiac events. In some embodiments, step 231 may include triggering one or more cardiac events, such as atrial excitation or ventricular excitation. Optionally, step 231 may include detecting or setting a native heart rate. For example, step 231 may include defining the start of the isovolumic phase by detecting the closure of the AV valve and / or defining the point in time when the rapid ejection phase begins by detecting the opening of the aortic valve. Step 231 may further include determining the time difference between the detection of ventricular activation or ventricular stimulation and the closure of the AV valve that defines the start of the isovolumic phase.

[0342] Method 230 may include step 232 where a pulse setting is selected. Selecting may include or may have included setting the time interval between atrial excitation and ventricular excitation. Selecting may include choosing the ratio of atrial excitation to ventricular excitation for a given stimulus pulse. Selecting may include a power setting based on the timing of the detected or inferred excitatory pulse transmission in the relative refractory period of the target chamber.

[0343] Method 230 may include step 233 of delivering at least one stimulation pulse using a pulse setting that may optionally be set in step 232, where the pulse setting may be selected based on the timing of the event detected in step 231. In some embodiments, the excitatory current may be applied to both ventricles, either simultaneously or in sequence. In some embodiments where both ventricles are paced in sequence, the time interval from the onset of excitation of at least one atrium (e.g., the right atrium) to the onset of excitation of the corresponding ventricle (e.g., the right ventricle) being paced may be measured. In some embodiments where the time interval is set to be zero or negative, step 233 may be performed before or simultaneously with step 231. In some embodiments, the time interval may be measured in milliseconds.

[0344] The pulse settings selected in step 232 may be selected based on feedback. In such a case, method 230 may include sensing the intracardiac pressure as shown in step 234. For example, the feedback information may be obtained during and / or periodically, e.g., during implantation and / or during a periodic examination, by using an implantable sensor for feedback and adjustment of the pulse settings. Method 230 may include step 235 of estimating the time overlap between the intracardiac pressure caused by atrial contraction (preferably, the maximum intracardiac pressure) and the passive intracardiac pressure rise of the atrium (preferably, the maximum passive pressure rise). For example, the estimating in step 235 may include detecting the number and duration of the peaks of the intracardiac pressure and / or the time distance between the peaks, and / or detecting the number of the peaks and valleys of the intracardiac pressure, and estimating the duration of the contraction or the change in the intracardiac pressure based on the time between the peaks and valleys, and / or detecting the maximum value of the intracardiac pressure compared to the intracardiac pressure of the same heart without stimulation. This comparison may be performed using a stored value corresponding to the intracardiac pressure measured before the start of treatment, and / or may include a step of sensing the intracardiac pressure of at least one beat without transmitting a stimulation pulse according to method 230.

[0345] Method 230 may include step 236 of adjusting the pulse settings selected in step 232 based on the detected overlap estimated in step 235. For example, step 236 may include adjusting the time interval to provide the greatest degree of overlap observed among a plurality of settings. Optionally, the greater degree of overlap may be defined as a function of the proximity of the maximum intracardiac pressures, i.e., the closer the peaks are to each other, the greater the degree of overlap, until finally the peaks completely overlap and a single maximum intracardiac pressure is observed. Optionally, the degree of overlap is a function of the detected maximum intracardiac pressure, and the higher the intracardiac pressure, the greater the degree of overlap is characterized.

[0346] As indicated by the arrow from step 236 to step 231 in FIG. 23, step 231, step 232, step 233, step 234, and / or step 235 may be repeated after step 236 is executed. In some embodiments, the time pulse setting may first be set to a first value in step 231, and based on the feedback detection executed between step 234 and step 235, the pulse setting may be adjusted during step 236 until the degree of overlap is within a given range (or exceeds a given value or is less than a given value) (for example, reducing or increasing the time interval).

[0347] The steps of method 230 may be executed in any order. For example, the steps may be executed in the order indicated by the arrows shown in FIG. 23. In another embodiment, step 232 may be executed before step 231.

[0348] The timing of atrial contraction, atrial excitation, ventricular contraction, closure and / or opening of the AV valve, and / or the flow or lack of blood from one or more atria to the corresponding ventricles, and / or blood pressure may be detected by any method known in the art and may be used as feedback control. In some embodiments, the onset of excitation may be used as a trigger for the transmission of excitatory stimuli to one or more heart chambers (for example, one or two ventricles, or the atria and ventricles). The detected information may be used additionally or alternatively in adjusting the timing intervals of the device.

[0349] In an embodiment, a method for adjusting the pulse settings of a system for controlling blood pressure may be provided. The method may include receiving intracardiac pressure data related to the atrium of the patient's heart during at least one cardiac cycle. The intracardiac pressure data may result from the system transmitting a stimulation pulse having a first pulse setting to the heart. The method may further include analyzing the intracardiac pressure data and providing a second pulse setting different from the first pulse setting adjusted according to this analysis. Analyzing may include analyzing the intracardiac pressure data to estimate the temporal overlap between the intracardiac pressure caused by atrial contraction and the passive intracardiac pressure increase of the atrium. Analyzing may further include plotting the intracardiac pressure data and / or mathematically analyzing the intracardiac pressure data.

[0350] One embodiment may provide a system for lowering blood pressure. The system may comprise components such as those shown in FIG. 14. The system may comprise means for providing information about the intracardiac pressure variations in the atrium during at least one cardiac cycle of the heart, means for generating a stimulation pulse, and means for applying the stimulation pulse to at least one cardiac chamber. The means for generating the stimulation pulse may be configured to generate the stimulation pulse so as to control the timing of atrial contraction relative to the timing of ventricular contraction during a single cardiac cycle according to the information about the intracardiac pressure variations in the atrium. In one aspect of the implementation, the means for providing information may first detect information (e.g., intracardiac pressure and the time during which the intracardiac pressure changes), and the means for generating the stimulation pulse may then determine the timing of the stimulation based on this information.

[0351] Information about the intracardiac pressure fluctuations in the atrium may include information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction. The information may include information about the relative timing between the maximum intracardiac pressure caused by atrial contraction and the maximum passive atrial pressure rise. The information may include information related to the occurrence and / or timing of one or more cardiac events as described herein, including, for example, one or more of atrial contraction, ventricular contraction, opening of the atrioventricular valve, closing of the atrioventricular valve, atrial electrical activity, ventricular electrical activity, blood flow, atrial refractory period, and heart rate.

[0352] The means for generating the stimulation pulses may be configured to generate at least one atrial stimulation pulse that causes atrial contraction and / or at least one ventricular stimulation pulse that causes ventricular contraction for at least one cardiac cycle. The means for generating the stimulation pulses may be configured to generate at least one atrial stimulation pulse based on information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction in a relationship that synchronizes with the occurrence of atrial contraction and / or the occurrence of ventricular contraction, and / or to generate at least one ventricular stimulation pulse based on information about the occurrence of ventricular contraction and / or information about the occurrence of atrial contraction in a relationship that synchronizes with the occurrence of ventricular contraction and / or the occurrence of atrial contraction. The information about the occurrence of atrial contraction may include information about the occurrence of the P wave pattern in the natural stimulation pattern of the cardiac cycle. The information about the occurrence of ventricular contraction may include information about the occurrence of the QRS complex in the natural stimulation pattern of the cardiac cycle.

[0353] The timing of atrial contraction relative to ventricular contraction may correspond to an AV delay within the range of about 30 ms to about 0 ms. The means for generating a stimulation pulse provides an excitatory stimulus to the atrium within the range of about 30 ms to about 0 ms before ventricular excitation occurs, provides an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms after atrial excitation occurs, and / or provides an excitatory stimulus to the atrium and then provides an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms after that, and may be configured to generate a stimulation pulse.

[0354] Other embodiments may provide another system for lowering blood pressure. The system may comprise components such as those shown in FIG. 14. In these other embodiments, the system for lowering blood pressure may comprise means for providing information about the timing of one or more cardiac activity events, means for generating a stimulation pulse, and means for applying the stimulation pulse to at least one cardiac chamber. The information about the timing of one or more cardiac activity events may include at least one of the occurrence of atrial contraction of the atrium, the occurrence of ventricular contraction of the ventricle, the opening of the atrioventricular valve, the closing of the atrioventricular valve, the electrical activity of the atrium, the electrical activity of the ventricle, blood flow, the atrial intracardiac pressure of the atrium, the change in the atrial intracardiac pressure of the atrium, the refractory period of the atrium, and the heart rate. The means for generating a stimulation pulse may be configured to generate a stimulation pulse so as to set the timing of atrial contraction relative to ventricular contraction based on the information.

[0355] The timing of atrial contraction relative to ventricular contraction may correspond to an AV delay within the range of about 30 ms to about 0 ms. The means for generating a stimulation pulse provides an excitatory stimulus to the atrium within the range of about 30 ms to about 0 ms before ventricular excitation occurs, provides an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms after atrial excitation occurs, and / or provides an excitatory stimulus to the atrium and then provides an excitatory stimulus to the ventricle within the range of about 30 ms to about 0 ms after that, and may be configured to generate a stimulation pulse.

[0356] Information about the timing of one or more cardiac activity events may include information about the timing between two or more cardiac activity events within a single cardiac cycle.

[0357] The means for generating stimulation pulses may be configured to generate at least one atrial stimulation pulse that causes atrial contraction and / or at least one ventricular stimulation pulse that causes ventricular contraction for at least one cardiac cycle. The means for generating stimulation pulses may be configured to generate at least one atrial stimulation pulse based on information about the occurrence of atrial contraction and / or information about the occurrence of ventricular contraction in a relationship that synchronizes with the occurrence of atrial contraction and / or the occurrence of ventricular contraction, and / or to generate at least one ventricular stimulation pulse based on information about the occurrence of ventricular contraction and / or information about the occurrence of atrial contraction in a relationship that synchronizes with the occurrence of ventricular contraction and / or the occurrence of atrial contraction. The information about the occurrence of atrial contraction may include information about the occurrence of the P-wave pattern in the natural stimulation pattern of the cardiac cycle. The information about the occurrence of ventricular contraction may include information about the occurrence of the QRS complex in the natural stimulation pattern of the cardiac cycle.

[0358] 〈2. Control of atrial stimulation〉 In some embodiments, by stimulating the heart such that the contribution of atrial contraction (atrial stimulation) to ventricular filling is reduced or even prevented, cardiac filling at the end of diastole is reduced, and as a result, blood pressure decreases. For the sake of simplicity, in the following description, such stimulation is referred to as "BPR (Blood Pressure Reducing) stimulation". BPR stimulation may include delivering at least one stimulation pulse to at least one chamber of the heart such that atrial stimulation is reduced or even prevented. Such a pulse is referred to herein as a "BPR stimulation pulse" or a "BPR pulse". As described above, a "stimulation pulse" may include a sequence of one or more electrical pulses transmitted to one or more chambers of the heart within a single beat or the time frame of the cardiac cycle. For example, in some embodiments, the stimulation pulse may include one or more electrical pulses transmitted to one or more locations of the ventricle and / or one or more electrical pulses transmitted to one or more locations of the atrium. Thus, in some embodiments, the stimulation pulse may include a first electrical pulse transmitted to the atrium and a second electrical pulse transmitted to the corresponding ventricle. In some embodiments, the stimulation pulse may include a single pulse transmitted to multiple locations of one or more chambers of the heart.

[0359] A "stimulation setting" means one or more parameters of one or more stimulation pulses transmitted in a single cardiac cycle. For example, these parameters may include power, the time interval between electrical pulses included in a single stimulation pulse (e.g., AV delay), the period of transmission relative to the natural rhythm of the heart, the length of the stimulation pulse or a portion thereof, and / or one or more of the locations of transmission between two or more chambers and / or within a single chamber. A BPR stimulation setting, i.e., a "BPR setting", may include the setting of one or more BPR pulses.

[0360] The stimulation pattern may include a series of pulses having the same stimulation settings, or the stimulation pattern may include a plurality of pulses each having a different stimulation setting. For example, the stimulation pattern may have one or more pulses having a first setting and one or more pulses having a second setting different from the first setting. When the stimulation pattern has a certain setting, this is understood to mean that the stimulation pattern may include at least one stimulation pulse having this setting. In some embodiments, it is also understood that the stimulation pattern may include one or more cardiac cycles in which no stimulation pulse is delivered, in which case the pulse can be considered to be delivered with zero power. The stimulation pattern may include a sequence of pulses including a plurality of identical pulses or pulses including two or more different settings. Two stimulation sequences in one pattern may differ in the order of the pulses provided within one setting. Two or more stimulation sequences may preferably also differ in their length (in the 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 not having a BPR setting.

[0361] Examples of stimulation settings configured to reduce or prevent atrial kick in at least one ventricle may include the stimulation settings disclosed herein configured to cause a reduction in the patient's ventricular filling volume from the pre-treatment ventricular filling volume. This may be caused by allowing at least some atrial contraction to occur against a closed AV valve. Some of such examples may include the following.

[0362] a. Transmitting one or more stimulation pulses to the patient's ventricle 0 to 50 ms before the onset of excitation in the patient's atrium. Preferably, this delay is set based on the setting of atrial excitation. Preferably, this includes transmitting one or more stimulation pulses to the atrium 0 to 50 ms after the transmission of the stimulation pulse to the ventricle. Preferably, this is performed at a number slightly higher than the patient's natural heart rate.

[0363] b. Transmitting one or more stimulation pulses to the patient's ventricle 0 to 70 ms after the onset of excitation in the patient's atrium. Preferably, this delay is set based on the detection of atrial excitation. Preferably, this includes transmitting one or more stimulation pulses to the atrium 0 to 70 ms before the transmission of the stimulation pulse to the ventricle. Preferably, this is performed at a number slightly higher than the patient's natural heart rate.

[0364] Some embodiments may provide a system for reducing blood pressure configured to transmit stimuli at a number higher than the natural heart rate based on the detected natural heart rate or natural excitation. For example, the system may be configured to detect natural excitation during the transmission of the stimulation pulse, and if natural activity is detected, the system may be configured to inhibit the transmission of the stimulation pulse to the chamber. If the amount of detected activation exceeds a threshold within a given time frame, the natural heart rate may be considered higher than the number of transmitted stimulation pulses, and in that case, the number of transmissions may be increased to accommodate, for example, the patient's increased heart rate. On the other hand, if the amount of detected activation is lower than a threshold (which may be zero) within a given time frame, the natural pulsation may be considered lower than the number of transmitted stimulation pulses, and in that case, the number of transmissions may be reduced to avoid, for example, excessive excitation of the patient's heart.

[0365] To achieve this effect, according to one embodiment, a system for reducing blood pressure may include a sensor for detecting the excitation rate of at least one of the atria and ventricles of a patient's heart, a stimulation circuit configured to transmit stimulation pulses to the atria and ventricles, and a processor circuit coupled to the stimulation circuit. Preferably, the sensor for detecting the excitation rate of at least one of the atria and ventricles may include electrodes for detecting atrial excitation. The processor circuit may be configured to detect the patient's heart rate based on the detection and operate in an operating mode in which stimulation pulses are supplied to at least one of the atria and ventricles respectively. The stimulation pulses may be transmitted at a rate higher than the detected excitation rate and may be configured to stimulate the ventricles during a time between about 50 ms before and about 70 ms after the stimulation of the atria.

[0366] Reducing the atrial kick may have an immediate effect on blood pressure, but the hormone mediated mechanism may take a longer period. Some devices may be configured to have both immediate and hormone mediated effects, but preferably, some of the BPR settings and / or stimulation patterns may be configured to reduce or prevent the atrial kick without a significant increase in atrial dilation. For example, when the AV valve closes at or after the time of peak pressure of atrial contraction, atrial dilation does not increase due to premature closure of the valve.

[0367] Thus, in some embodiments, the device may be configured to produce a relative timing of atrial and ventricular excitations comparable to an AV delay of at least 40 ms in length or at least 50 ms in length. Atrial stretch may be measured, calculated, and / or estimated in a manner known in the art. In some embodiments, atrial stretch determination may include measuring atrial pressure. In some embodiments, atrial stretch determination may include measuring or estimating an atrial dimension (e.g., diameter, size, or circumference).

[0368] In some embodiments, the atrial kick may be reduced because the BPR stimulation setting may be set such that atrial contraction during the cardiac cycle is incomplete when the AV valve is open. In some embodiments, atrial contraction may occur fully or partially against a closed AV valve. In some embodiments, atrial contraction may be effectively prevented or reduced in pressure and / or force.

[0369] In some embodiments, only one or more ventricles may be stimulated, and the stimulation pulses may be time - adjusted to have an abnormal AV delay (e.g., 50 ms before to 120 ms after atrial excitation). In some embodiments, the BPR stimulation setting may include delivery of at least one electrical pulse or stimulation to one or more atria. In some embodiments, this at least one atrial stimulation may cause atrial contraction. In some embodiments, the at least one atrial stimulation may interfere with atrial contraction. In some embodiments, at least one atrial pulse may cause atrial spasm or other types of inefficient atrial contraction.

[0370] The reduction in blood pressure from BPR stimulation may be observed substantially immediately upon application of the stimulation signal (e.g., within 1 or 3 seconds or within 1, 3, or 5 beats), and may reach a minimum blood pressure value within less than 5 beats from the start of the stimulation.

[0371] By controlling the setting of the BPR stimulation, the degree to which the BP is reduced may be controlled. In some cases, this degree is patient-specific and / or related to the exact position of one or more stimulation and / or sensing electrodes within or on the heart.

[0372] By controlling the setting of the BPR stimulation, the degree to which the BP decreases may be controlled. This degree is sometimes patient-specific and / or related to the exact placement of one or more stimulation electrodes and / or sensing electrodes within or on the heart. Since the degree to which the BP changes can be, for example, a function of the AV delay, this functional relationship may be used to select the AV delay that provides the desired change in BP, or vice versa. An example of this functional relationship is shown in FIG. 24, which will be described in more detail later.

[0373] 〈3. Adaptation〉 a. The inventors of the present application have found that during the period when the stimulation is maintained, the blood pressure may exhibit an adaptation pattern in which the blood pressure increases after a certain period of time (some of which often occur within a short period of time of less than 5 minutes, or even less than 1 minute), and (in some cases, at least due to the baroreflex) reaches near the blood pressure value before the stimulation, or even higher. The adaptation may be at least partly due to changes in the characteristics of the cardiovascular system, such as an increase in total peripheral resistance. The inventors of the present application have further found that the end of the stimulation results in the blood pressure quickly returning to the value before the stimulation, or even to a higher value, and thereafter the heart responds to the blood pressure reduction stimulation signal to a similar extent as the heart that has not been stimulated so much. In addition, it has been found that different stimulation patterns with multiple BPR stimulation settings lead to different blood pressure adaptation patterns.

[0374] b. The stimulation pattern may comprise, for example, at least one first stimulation setting and a second stimulation setting different from the first stimulation setting, and the first stimulation setting and the second stimulation setting are configured to reduce or prevent an atrial kick and / or to control either or both of the atrial pressure and atrial dilation. The stimulation pattern may even comprise more than two different stimulation settings. In some embodiments, the second setting has an AV delay longer (e.g., from about 80 ms to about 160 ms) than the first setting. In some embodiments, the second setting may not be configured to reduce the atrial kick and / or to control either or both of the atrial pressure and atrial dilation.

[0375] In FIG. 1, the systolic blood pressure of a hypertensive patient receiving a stimulation signal is plotted against time. The crosses along the plotted line indicate the peak systolic blood pressure for each heartbeat. For approximately the first two minutes plotted, no stimulation signal was transmitted. As can be seen, the patient's initial blood pressure averaged over 150 mmHg. The amplitude of the blood pressure (about ±10 mmHg) is due to the respiratory cycle, as is known in the art.

[0376] Then, a first stimulation pattern was applied during time interval a-a', a second stimulation pattern was applied during time interval b-b', and a third stimulation pattern was applied during time interval c-c'. The heart was not stimulated during the middle of the stimulation pattern and after the third stimulation pattern.

[0377] Here, attention is drawn to FIG. 2, which shows an enlarged portion of the portion of FIG. 1 indicated by the dashed rectangle A. During the time indicated by the dashed rectangle in FIG. 2 corresponding to the time interval a-a' in FIG. 1, a stimulus began and was transmitted to the patient's right atrium and right ventricle, as a result of which the atrium received a BPR stimulation signal (pulse) 2 ms before the ventricle. The stimulus ended at the time indicated by a' in FIGS. 1 and 2. During the time interval a-a', the patient's systolic blood pressure first decreased to a minimum value of less than 110 mmHg and then gradually increased to an intermediate value between the initial blood pressure and the realized minimum value. At point a', the stimulus stopped and an immediate overshoot of the blood pressure to a value exceeding 170 mmHg was observed. Within about a dozen beats, the blood pressure returned to its initial range.

[0378] The changes in blood pressure shown in FIGS. 1 and 2 indicate, at least in part, the cardiovascular system's response to changes in blood pressure, known as the baroreflex. The baroreflex acts to restore blood pressure to its pre-stimulus level by changing cardiovascular characteristics (such as peripheral resistance and / or myocardial contractility). It may be assumed that the reduction in blood pressure resulting from the reduction in ventricular filling induced a baroreflex response directed towards restoring the pre-stimulus blood pressure. The effect of the baroreflex on the cardiovascular system is evident, for example, at point a' in FIG. 2. At this point, the stimulus that affected ventricular filling receded and the blood pressure immediately exceeded the pre-stimulus blood pressure. This may be regarded as indicating a change in the baroreflex for the cardiovascular system (e.g., an increase in peripheral resistance and an increase in contractility). At point a' where the stimulus stopped and the blood pressure peaked, in this case, the baroreflex responded to the increase in blood pressure by changing one or more characteristics of the cardiovascular system again in order to lower the blood pressure back to the level before the change. As can be clearly understood, the baroreflex feedback response to increases and decreases in blood pressure is asymmetric in that the response to an increase in blood pressure is much faster than the response to a decrease in blood pressure. In some embodiments, this asymmetry of the baroreflex may be utilized, for example, by controlling the stimulation pattern accordingly, as detailed herein, to reduce or even prevent the adaptation of the blood pressure reduction due to reduced filling.

[0379] Figure 3A shows an enlarged view of the curve in FIG. 1 between time points a and a'. In FIG. 3A, an exponential function was fitted to the plotted curve showing the adaptation response. The function describes the relationship between time and SysBP and has the following equation.

[0380] P = Pi + DP(1 - e^(-t / k)) In the equation, P (in mmHg) represents systolic blood pressure, Pi (mmHg) is the first mean reduced blood pressure at the start of the BPR stimulus, DP (mmHg) is a constant representing the amount of pressure increase after the initial drop to the new steady-state level, k (seconds) is the response time constant, e is the mathematical constant that is the base of the natural logarithm, and t (seconds) is time.

[0381] In FIG. 3A, the matching function was as follows.

[0382] P = 115 + 23(1 - e^(-t / 15.5)) In the equation, it was found that Pi was 115 mmHg. DP was 23 mmHg. K was 15.5 seconds.

[0383] Figure 3B shows an enlarged view of the portion of FIG. 1 indicated by the dashed rectangle A'. In FIG. 3B, an exponential function was fitted to the plotted curve showing the adaptation response to the end of the BPR stimulus. As can be seen, this response in the reduction of blood pressure was faster than the response to the BPR stimulus.

[0384] In FIG. 3B, the matching function was as follows.

[0385] P = 190 - 35(1 - e^(-t / 4.946)) In the equation, it was found that Pi was 190 mmHg. DP was -35 mmHg. K was 4.946 seconds.

[0386] As described above, the baroreflex response to a decrease in blood pressure is much slower than the baroreflex response to an increase in blood pressure. This is shown as the ratio of the above-described time constant k (from about 15 seconds to about 5 seconds) to a much faster response to an increase in blood pressure. This asymmetry in the speed of the baroreflex response may provide a means of designing a stimulus pattern that produces a reduction in average blood pressure and a reduction or even prevention of adaptation. For example, in a preferred embodiment, the weighted response may alternate between two stimulus settings in a manner that is advantageous for the cardiovascular changes caused by an increase in blood pressure. In this embodiment, a first setting designed to reduce ventricular filling and thereby reduce blood pressure and a second setting designed to have normal ventricular filling or at least a higher ventricular filling than that of the first setting may be used to stimulate the heart with a stimulus pattern having two stimulus settings. This stimulus pattern may include a pulse having a first setting (BPR) that is delivered for a period shorter than the time constant of the baroreflex response to a decrease in blood pressure. In such a case, adaptation may begin to become apparent and the blood pressure may increase from the reduced level, but may not reach the pre-stimulus level.

[0387] The stimulus pattern may also include a pulse having a second setting (e.g., a natural AV delay) that is delivered for a period longer than the time constant of the baroreflex response to an increase in blood pressure. In this case, the baroreflex-induced reduction in blood pressure may be fully utilized and the blood pressure may even return to its level prior to the stimulus pattern switching to this second setting. The weighted baroreflex response in such a pattern may reduce or prevent adaptation, but the average blood pressure may be lower than the pre-stimulus level. The relationship between the time constant and the period assigned to the delivery of pulses having different settings may determine the level of the baroreflex response that is effective throughout the entire stimulus pattern. For a given stimulus setting, if the delivery period is selected to be shorter than the time constant of the response, the baroreflex may not be able to change the cardiovascular system back to the pre-stimulus level, and if the selected period is greater than the time constant, the baroreflex effect may be more pronounced.

[0388] As can be seen from FIG. 1, the second stimulation pattern was transmitted at the interval between point b and point b'. FIG. 4 shows an enlarged version of this part of FIG. 1 (indicated by the dashed rectangle B in FIG. 1). In the second stimulation pattern, a sequence of 12 BPR pulses was transmitted to both the atrium and the corresponding ventricle with a 2 ms AV delay, and then three beats followed in which only atrial stimulation was artificially transmitted and ventricular stimulation was not transmitted. During these last three beats, ventricular excitation occurred through the natural conductance of the AV node resulting in an AV delay of ~180 ms. This second stimulation pattern was repeated while the previously given time interval persisted. In FIG. 4, it was found that the exponential function fitting the curve is as follows.

[0389] P = 112 + 30(1 - e-t / 25.5) As can be seen, both Pi and DP were comparable to the corresponding values of the first stimulation pattern (a-a' in FIG. 3A). However, the k of the second pattern was nearly twice the time constant of the first stimulation pattern. At this time interval, adaptation occurred at a slower rate than in FIG. 3A, but when the pattern switched between stimulation pulses, the blood pressure increased more rapidly than in FIG. 3A. This result demonstrates that the use of stimulation patterns with alternating stimulation settings reduces adaptation.

[0390] The third stimulation pattern was similarly transmitted between point c and point c' as seen in FIG. 1. FIG. 5A shows an enlarged view of the part of FIG. 1 indicated by the dashed rectangle C including the curved portion between point c and point c'. In the third stimulation pattern, a sequence of 12 BPR pulses was transmitted with a 2 ms AV delay, followed by three BPR pulses each having a 120 ms AV delay. This was repeated while the previously given time interval persisted.

[0391] The curved portion of FIG. 5A, shown by the dashed rectangle, is plotted in FIG. 5B. In FIG. 5B, an exponential function was fitted to the plotted curve showing the adaptive response to the delivery of a stimulus pattern of 12 BPR pulses delivered with a 2 ms AV delay, followed by 3 BPR pulses each having a 120 ms AV delay.

[0392] In FIG. 5B, the exponential function was as follows.

[0393] P = 109.7 + 22.3(1 - e-t / 45.4) Wherein, it was found that Pi was 109.7 mmHg. DP was 22.3 mmHg. K was 45.4 seconds. As can be seen, the initial reduction in blood pressure was comparable to that shown in FIG. 3A (Pi = 115 or 109.5), but the adaptation time constant (k) was higher (45.4 seconds vs. 15.5 seconds). This means that a lower blood pressure was maintained for a period approximately three times longer than in FIG. 3A.

[0394] Now, turn to FIG. 6. In FIG. 6, the heart of a hypertensive patient was stimulated with a stimulus pattern having a sequence of 12 BPR pulses delivered with a 2 ms AV delay, followed by 3 BPR pulses each having an 80 ms AV delay.

[0395] As can be seen, in this case, the adaptation rate was very low and hardly detectable within the allotted time interval. The exponential formula could not be fitted, suggesting that the adaptation was extremely slow or non-existent.

[0396] In FIG. 7, a hypertensive patient's heart was stimulated with a stimulation pattern having a sequence of 12 BPR pulses transmitted with a 2 ms AV delay, followed by three BPR pulses each having a 40 ms AV delay. The stimulation started at point t1 and ended at point t2. There was no measured adaptive response, and the applicable curve was actually a straight line, having a fixed mean reduced blood pressure of about 112 mmHg, which was about 31 mmHg lower than the blood pressure immediately before and after the time interval t1 - t2.

[0397] As is apparent from the different stimulation patterns described above, a stimulation pattern comprising at least one BPR stimulation can be set to at least approximate one or more goals. For example, in some embodiments, the stimulation pattern may be set to cause an initial reduction (systolic and / or diastolic) in blood pressure that will exceed a predetermined threshold or will be within a predetermined range. In more detailed embodiments, the blood pressure may be reduced by at least a given percentage or by at least a given measure (e.g., even 10 or 20 mmHg or 30 mmHg), or the blood pressure may be reduced to be within a given range (e.g., 90 - 130 mmHg SysBP) or below a given target (e.g., SysBP below 130 mmHg). In some embodiments, the goal may include maintaining the reduced blood pressure within a reduced average range for an extended period. For example, a given blood pressure may be reduced to a given average blood pressure over a period or a number of beats.

[0398] In another embodiment, the goal may include bringing a given percentage of the heartbeat into a reduced range / threshold state. In some embodiments, the goal may include reducing blood pressure while also reducing the level of the sharp increase during the stimulation pulse. For example, the stimulation pattern may be used to lower the blood pressure to a constant blood pressure during a predetermined time interval. In some embodiments, the stimulation pattern may be used to lower the blood pressure without significantly affecting the cardiac output. For example, by applying intermittent BPR pulses, pulses with a higher (or even sufficient) atrial kick may occur during the BPR pulses. Pulses with a higher (or even sufficient) atrial kick can prevent the BPR pulses from significantly reducing the cardiac output.

[0399] In another embodiment, by reducing the adaptation associated with reducing the total peripheral resistance along with the reduction of blood pressure (afterload), it is possible to dynamically affect the cardiac output by affecting the flow through the vascular system. In yet another embodiment, by pacing at a higher rate than the patient's natural rhythm, it is possible to avoid the negative impact on the cardiac output that may be associated with a lower stroke volume.

[0400] When setting the stimulation pattern to approach one or more targets, providing different values of blood pressure reduction may include adjusting the stimulation parameters that affect the AV delay. For example, stimulation parameters that provide a shorter AV delay can reduce the blood pressure to a greater extent than stimulation parameters that provide a longer AV delay. In an embodiment, a stimulation setting that reduces atrial stimulation may provide an AV delay that varies from about 5 ms to about 30 ms (e.g., between day and night, or between intense activity and light activity), and the shorter the AV delay, the greater the reduction in blood pressure.

[0401] Providing different levels of blood pressure reduction may involve varying stimulation parameters other than the short AV delay period. For example, in some embodiments, the ratio of the short AV delay to the longer AV delay may be adjusted. As another example, in other embodiments where pulses with a short AV delay are delivered while comparing to a heart rate with a longer AV delay, the heart rate may be adjusted.

[0402] In some embodiments, a time constant of the 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 the amount of pacing time or number set as a specific percentage of the calculated time constant. For example, in FIGS. 3A and 3B, k was measured to be about 15 seconds for the rate of increase in blood pressure during delivery of the BPR pulse and about 4.9 seconds for the rate of adaptation to the end of delivery of the BPR pulse. In some embodiments, it may be desirable to prevent the blood pressure from increasing beyond a given value, in which case the duration of delivery of the BPR pulse may be selected to be significantly less than k (e.g., 30% - 60% of k). In this embodiment, the interval may be selected to be less than 15 seconds. Such an interval may include about 6 - 10 seconds or 8 - 14 beats corresponding to a heart rate of about 80 beats per minute.

[0403] Preferably, it is desirable to utilize the adaptive response to the recoil of the BPR pulse. In such a case, a larger portion of k may be applied. For example, based on FIG. 3B, a period of 3 - 5 beats may be selected (wherein k is about 4.9 seconds). In this way, for example, based on FIGS. 3A and 3B, the inventors applied the stimulation pattern of FIG. 4.

[0404] The stimulation pattern may be set, for example, to be the best of a plurality of stimulation patterns (i.e., the one closest to the set target parameters), and / or may be selected as the first tested stimulation pattern that matches the set target.

[0405] <4. Embodiment Based on Slow Baroreflex Response> In experiments using dogs, the inventors have found that when treatment is terminated after a treatment period, it can take a relatively long time for blood pressure to return to its pre-treatment value. This slow baroreflex response can be utilized. In particular, in an embodiment, long-term treatment (e.g., normal pacing or no pacing at all) can be interrupted, thereby enabling savings in the battery power of the stimulation device and a longer service life.

[0406] As an example of the slow baroreflex response, refer to FIG. 27. This figure is a graph showing the effect of the blood pressure lowering treatment of the dogs disclosed in this specification, and plots the change over time (days) of the systolic blood pressure (mmHg). As shown in the graph, the blood pressure value before treatment is indicated by a baseline ("BL") marked with diamond data points, the value during the treatment period is indicated by a treatment line marked with square data points, and the value after treatment is indicated by a device off ("Dev Off") line marked with triangular data points. In this experiment, an implantable sensor that transmits systolic blood pressure to the receiver was used to continuously measure systolic blood pressure over 24 hours. Each data point on the graph represents the average value of the measured values over 24 hours.

[0407] The dog subject showed a blood pressure of approximately 210 mmHg as indicated by the baseline in FIG. 27. Immediately upon applying the blood pressure lowering treatment disclosed throughout this disclosure, the dog's blood pressure decreased to approximately 170 mmHg as shown by the treatment line in FIG. 27. During the treatment period, the dog's blood pressure fluctuated between approximately 150 mmHg and approximately 175 mmHg (i.e., approximately 35 - 60 mmHg lower than the pre-treatment value). This treatment was applied for 30 days.

[0408] When the treatment was stopped (pacing was no longer applied to the dog's heart), the dog's blood pressure increased slightly to about 180 mmHg as shown by the device offline in FIG. 27. This value was significantly about 30 mmHg lower than the blood pressure before treatment. The dog's blood pressure remained near that blood pressure for about 20 days and then began to gradually increase and return to nearly the pre-treatment value.

[0409] Considering the mechanism of the slow baroreflex response, such as the response illustrated in FIG. 27, an embodiment may provide a method for treating hypertension that includes alternating between a first stimulation pattern (i.e., the treatment stimulation pattern) configured to lower blood pressure and a second stimulation pattern (i.e., the "rest" stimulation pattern) configured such that the degree of blood pressure decrease is smaller, and these two patterns are each applied over a period of several days, several weeks, or more. In an embodiment, the two patterns may each be applied for at least one week and may provide treatment over a weekly time scale. The rest stimulation pattern may or may not involve stimulation.

[0410] In an embodiment, the periods of the first stimulation and the second stimulation pattern may be the same or different.

[0411] For example, the period of the rest stimulation pattern may be shorter than the period of the treatment stimulation pattern, for example, 25% - 90% of it, or in some cases 50% - 80%. In one implementation aspect, the period of the rest stimulation pattern may be about 2 / 3 of the period of the treatment stimulation pattern.

[0412] The period of the rest stimulation pattern may depend on or be proportional to the degree of blood pressure decrease by the treatment stimulation pattern. For example, if the treatment stimulation pattern is configured to lower blood pressure by at least 50 mmHg, the rest stimulation pattern may last longer than when the treatment stimulation pattern is configured to lower blood pressure by only 30 mmHg.

[0413] Optionally, the duration of the rest stimulation period may be 2 weeks to 1 month (e.g., 14 to 31 days) or less, regardless of the duration of the therapeutic stimulation pattern.

[0414] Each stimulation pattern may include a plurality of stimulation patterns, and at least some of the plurality of stimulation patterns may include one or more atrial stimulation reduction pulse settings according to, for example, one or more of the patterns described in the present disclosure. For example, during the therapeutic stimulation pattern period, the treatment may include variations as needed (e.g., alternating between daytime and nighttime settings).

[0415] In an embodiment, the rest stimulation pattern may be selected from (1) no application of pacing, (2) pacing without atrial stimulation reduction, and (3) pacing with a smaller reduction in overall and / or average atrial stimulation than the therapeutic stimulation pattern. Optionally, the rest stimulation pattern may include a switch from one rest stimulation pattern to another. The rest stimulation pattern may not necessarily completely stop the blood pressure reduction. For example, it may include the application of atrial stimulation reduction pulses at a very low frequency (e.g., 10 pulses or less in a 20-minute period), or alternating between one degree of blood pressure reduction and another different degree of blood pressure reduction.

[0416] In other embodiments, three or more stimulation patterns may be used in one or more of the therapeutic stimulation period and the rest period. For example, a first stimulation pattern providing a 2 ms AV delay may be applied in the first week, followed by no pacing for one week, then a stimulation pattern providing an AV delay of about 0 to 20 ms for one month (alternating the stimulation patterns), and then a stimulation pattern providing an AV delay of about 140 ms for 3 weeks or 6 weeks, provided that a stimulation period with an AV delay of about 30 ms is provided once a day during those 3 weeks or 6 weeks.

[0417] Such a stimulation approach may minimize the duration and degree of electrical stimulation applied to the heart while maintaining the desired long-term blood pressure level. <5. Method for Setting and / or Selecting Stimulation Patterns> A method 600 for setting and / or selecting stimulation patterns is schematically shown in FIG. 8. The method 600 may be performed during the embedding of a device for performing BPR and / or AC stimulation, and / or periodically for adjusting device operation parameters, and / or continuously during operation. The method 600 may be performed by a system 700 described below. Accordingly, the system 700 may be configured to perform the steps of the method 600. Similarly, the method 600 may include steps configured to be performed by the system 700. For example, the method 600 may include the functions described below for the system 700. In addition, the method 600 may be performed by a device 50 described with reference to FIG. 14 below. The method 600 may include steps configured to be performed by the device 50.

[0418] Throughout the present disclosure, the terms "first," "second," and "third" do not always mean to imply an order of events. In some cases, these terms are used to distinguish individual events from each other without referring to an order.

[0419] In some embodiments, step 601 may include setting a target blood pressure value. This target may be an absolute blood pressure value (e.g., a target blood pressure range, a target threshold for a rapid increase value, and / or the number or portion of rapid increases within a given time frame), a relative value (e.g., compared to the patient's pre-treatment blood pressure or as a comparison between multiple tested stimulation patterns), or both. The target blood pressure value may be a blood pressure value (e.g., measured in mmHg) and / or a value associated with an equation calculated to conform to blood pressure measurements of the stimulation pattern. This target blood pressure value may be set before, during, and / or after other method steps and may be corrected, for example, if not reached by a tested stimulation pattern.

[0420] Step 602 may include delivery of one or more stimulation patterns, including a first stimulation pattern, to one or more chambers of a patient's heart. The first stimulation pattern may be a generic stimulation pattern or may already be selected to be patient specific (e.g., when an implantable device is implanted). The first stimulation pattern may include at least one stimulation pattern configured to reduce or prevent an atrial kick in at least one ventricle and / or control either or both of atrial pressure and atrial dilation during a first time interval.

[0421] Step 603 may include detecting one or more parameters before, during, and / or after the transmission of each of the one or more stimulation patterns (step 602). The detected parameters may include detecting the intracardiac pressure to evaluate the overlap between the maximum value of the intracardiac pressure due to atrial contraction and the maximum value of the intracardiac pressure due to ventricular contraction. The detected parameters may include detecting the intracardiac pressure as a result of the transmission of each of the one or more stimulation patterns (step 602), evaluating the intracardiac pressure obtained by the stimulation, and optionally comparing this intracardiac pressure with one or more of the intracardiac pressures obtained by different stimulations or without stimulation. Optionally, the parameters may include blood pressure values or parameters related to blood pressure (such as changes in blood pressure). In some embodiments, the detected parameters may include information related to the timing and / or degree of closure and / or opening of the AV valve. In some embodiments, the detected parameters may include information related to the timing and / or flow rate of blood flow between the atria and ventricles of the heart. In some embodiments, the detected parameters may include detecting the intracardiac pressure of a heart chamber (such as the atria and / or ventricles). In some embodiments, detecting the state or position of the patient's AV valve (i.e., open or closed) may include detecting heart sounds, for example, using an acoustic sensor. In some embodiments, detecting the state of the patient's AV valve may include Doppler detection and / or imaging of the movement of the heart. In some embodiments, the state of the patient's AV valve may be detected by a blood flow sensor.

[0422] In some embodiments, detection of blood flow may be performed by one or more implanted sensors within one or more heart chambers. For example, one or more pressure sensors may be disposed in the right ventricle. In some embodiments, multiple pressure sensors may be disposed in multiple chambers. Preferably, measurements from multiple sensors may be combined. Preferably, pressure changes, trends in pressure changes, and / or pressure change patterns may be used to provide information related to blood flow. In some embodiments, comparison of relative changes between two or more sensors within different chambers may be used.

[0423] When a stimulation pattern is transmitted to the heart (step 602), one or more parameters may be measured at least once, or multiple times, or even continuously during transmission of the stimulation pattern. Each stimulation pattern may be transmitted more than once.

[0424] Step 604 may include analyzing the detected parameters. In some embodiments, analysis may be performed (604) when at least one stimulation pattern is transmitted and the corresponding parameters are detected. In embodiments where multiple parameters are detected, step 604 may include comparing the detected parameter values to a target, comparing the detected parameters between two or more stimulation patterns, comparing calculated values (such as k constants) associated with two or more stimulation patterns, and comparing additional detected parameters between two or more stimulation patterns. In some embodiments, this last function may be performed to determine and select which stimulation pattern produces a higher ejection rate, stroke volume, cardiac output, and / or lower battery usage.

[0425] Step 605 may include setting a pacing (stimulation) pattern. When more than one parameter is detected, the stimulation pattern used in step 605 may be selected based on multiple parameters, multiple target values, and / or multiple target ranges.

[0426] In some embodiments, the steps shown in FIG. 8 may be performed in the order indicated by the arrows in FIG. 8. In another embodiment, the steps may be performed in a different order. For example, step 602 may be performed before setting the target blood pressure value according to step 601. In some embodiments, the stimulation pattern may be set to be performed ambiguously. In some embodiments, the stimulation pattern may be set to be performed for a predetermined period. For example, in some embodiments, the stimulation pattern set during step 605 may be performed for a predetermined period, and then steps 602, 603, and 604 may be repeated to determine how another stimulation pattern affects the patient's blood pressure. Then, based on the analysis performed in step 604, step 605 may also be repeated.

[0427] In some embodiments, method 600 may include the step of adjusting the first stimulation pattern and thus forming the first stimulation pattern into a second stimulation pattern. In some embodiments, step 605 of setting the stimulation pattern may include adjusting the stimulation pattern. For example, step 605 may include adjusting the parameters of the first stimulation setting (e.g., the time interval from step 602). In another embodiment, step 605 may include adjusting the parameters of the first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation. In some embodiments, step 605 may include adjusting the first stimulation setting to be a second stimulation setting configured to cause a reduction in blood pressure by at least a predetermined amount. In some embodiments, this predetermined amount may include, for example, from about 8 mmHg to about 30 mmHg. In some embodiments, this predetermined amount may be about 4% of the patient's blood pressure before treatment. For example, this predetermined amount may be from about 4% to about 30% of the patient's blood pressure before treatment.

[0428] In some embodiments, step 605 may include adjusting the stimulation pattern to be a stimulation pattern configured to cause an immediate reduction in blood pressure by at least a predetermined amount. For example, in some embodiments, step 605 may include adjusting the stimulation pattern to be a stimulation pattern configured to cause a reduction in blood pressure by at least a predetermined amount within about 3 seconds from the application of current to the heart. In some embodiments, step 605 may include adjusting the stimulation pattern to be a stimulation pattern configured to cause a reduction in blood pressure by at least a predetermined amount within at least 5 beats of the applied current. In some embodiments, the reduction in blood pressure resulting from the stimulation pattern set during step 605 may occur within 1 to 3 seconds of the application of current to the heart, or within 1, 3, or 5 beats of the application of current to the heart.

[0429] 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 the minimum blood pressure value within less than 5 beats from the start of the stimulation. For example, step 605 may include adjusting the first stimulation pattern to be 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 during a predetermined time interval. For example, the predetermined time interval may include at least 1 minute or at least 5 minutes.

[0430] In some embodiments, the second stimulation pattern may be configured to maintain blood pressure such that it does not exceed a predetermined average value by more than a predetermined degree for a predetermined interval. For example, this predetermined degree may be a difference of about 20 mmHg or less. In some embodiments, this predetermined degree may be a difference of about 1 mmHg to about 8 mmHg. In some embodiments, the patient's blood pressure may exceed the predetermined average value for some beats, but the patient's average blood pressure may not exceed the predetermined average value.

[0431] In some embodiments, the second stimulation pattern may include a second stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation. The second stimulation setting may be based on at least one blood pressure variation parameter calculated from input data detected during application of the first stimulation pattern.

[0432] In some embodiments, the second stimulation pattern may be configured to reduce or limit the magnitude of a rapid increase in blood pressure between stimulation patterns. In some embodiments, the rapid increase in blood pressure between stimulation pulses may be reduced to a percentage of a basal blood pressure value. For example, the second stimulation pattern may be configured to prevent the blood pressure from increasing by more than about 80% between pulses. That is, the second stimulation pattern may be configured to prevent the blood pressure from rapidly increasing by more than about 80% between pulses. In some embodiments, the second stimulation pattern may be configured to prevent an increase in blood pressure of more than about 40% between pulses. In some embodiments, the second stimulation pattern may be configured to prevent a rapid increase in blood pressure of more than about 10 mmHg to about 30 mmHg between pulses. For example, in some embodiments, the second stimulation pattern may be configured to prevent a rapid increase in blood pressure of more than about 20 mmHg between pulses.

[0433] In some embodiments, the second stimulation pattern may comprise a plurality of stimulation pulses. At least one stimulation pulse of the plurality of stimulation pulses may have a first stimulation setting configured to reduce an atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation. At least one stimulation pulse of the plurality of stimulation pulses may have a second stimulation setting configured to reduce a baroreflex response to the reduction of the atrial kick or the control of the atrial dilation such that an increase in the blood pressure value occurring between the stimulation pulses is limited to a predetermined value. In some embodiments, the second stimulation pattern may be configured to increase the blood pressure and cause a baroreflex response between about one beat and five beats. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting and a plurality of stimulation pulses having a second stimulation setting. In some embodiments, the second stimulation setting may be present between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting and a plurality of stimulation pulses having a second stimulation setting. In such embodiments, the second stimulation setting may be present between about 1% and about 40% of the plurality of stimulation pulses of the stimulation pattern.

[0434] In some embodiments, the stimulation pattern may include a ratio of stimulation pulses having a first stimulation setting to stimulation pulses having a second stimulation setting, based on a ratio of time constants of responses to increases and decreases in blood pressure. For example, the ratio of stimulation pulses having a first stimulation setting to stimulation pulses having a second stimulation setting may be based on a ratio of time constants of changes in blood pressure resulting from each of the first and second settings. In some embodiments, the first stimulation setting may include a first AV delay, the second stimulation setting may include a second AV delay, and the first AV delay may be shorter than the second AV delay. In some embodiments, the second stimulation pattern may include a plurality of stimulation pulses having a first stimulation setting and one or more stimulation pulses having a second stimulation setting. In some embodiments, the second stimulation pattern may include a ratio of stimulation pulses having a first setting of about 8 to about 13 to about 2 to about 5 stimulation pulses having a second setting. In some embodiments, the second stimulation pattern may include at least one stimulation pulse having a stimulation setting configured to cause a hormonal response from the patient's body. In some embodiments, the first stimulation pattern may include at least one stimulation pulse having a stimulation setting configured not to cause a hormonal response from the patient's body. In some embodiments, the second stimulation pattern may be applied prior to the first stimulation pattern in a given sequence of stimulation patterns.

[0435] In some embodiments, method 600 may include alternating between two or more stimulation patterns. For example, method 600 may include alternating between 2 and 10 stimulation patterns.

[0436] In some embodiments, the blood pressure sensor and the controller may be configured to operate at least partially as a closed loop.

[0437] In some embodiments, method 600 may include a controller configured to apply a plurality of stimulation patterns and, during the stimulation, receive corresponding input data related to the patient's blood pressure for each of the stimulation patterns. The plurality of stimulation patterns may include at least two stimulation patterns each comprising at least one stimulation pulse having a stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation. The at least two stimulation patterns may differ from each other by at least the number or length of time during which at least one stimulation pulse is continuously supplied. The at least two stimulation patterns may differ from each other by at least the number or length of time during which a predetermined AV delay occurs continuously. In some embodiments, the stimulation setting may be the same for each of the at least two stimulation patterns. In some embodiments, the stimulation setting may include the same AV delay for each of the at least two stimulation patterns. In some embodiments, the at least two stimulation patterns may differ from each other by one or more stimulation settings included within each of the at least two stimulation patterns.

[0438] In some embodiments, method 600 may include a controller configured to calculate at least one blood pressure variation parameter related to the input data for each of the plurality of stimulation patterns. Method 600 may include a controller configured to adjust the stimulation pattern according to the blood pressure variation parameter. In some embodiments, method 600 may include a controller configured to adjust the stimulation pattern to be a stimulation pattern having the best blood pressure variation parameter. For example, the best blood pressure variation parameter may include a blood pressure variation parameter indicating the lowest degree of baroreflex. The best blood pressure variation parameter may include a blood pressure variation parameter indicating a baroreflex within a predetermined range.

[0439] In some embodiments, the second stimulation pattern may include at least one stimulation pulse having a stimulation setting configured to elicit a hormonal response from the patient's body, although in some embodiments, the first stimulation pattern may include at least one stimulation pulse having a stimulation setting configured not to elicit a hormonal response from the patient's body.

[0440] In some embodiments, the plurality of stimulation patterns may include a first stimulation pattern and a second stimulation pattern applied after the first stimulation pattern. The second stimulation pattern may have at least one stimulation setting set based on an algorithm that uses a blood pressure fluctuation parameter related to the input data of the first stimulation setting.

[0441] 〈6. System for Reducing Blood Pressure〉 FIG. 9 schematically shows a system 700 for reducing blood pressure according to some embodiments. The system 700 may be a single device or, preferably, may include a plurality of devices associated by wired or wireless communication. The device may have a plurality of components disposed within the housing and / or electrically and / or wired-connected to the housing. As shown in FIG. 9, the heart 701 is connected to the system 700 by one or more stimulation electrodes 702. The stimulation electrodes may be configured to stimulate at least one chamber of the patient's heart with stimulation pulses.

[0442] In some embodiments, each of the plurality of electrodes 702 may be disposed in a different chamber of the heart. For example, one electrode may be disposed in the atrium and another electrode may be disposed in the ventricle. In some embodiments, the plurality of electrodes 702 may be disposed in a single chamber. For example, two electrodes may be disposed in the atrium and / or two electrodes may be disposed in the ventricle. In some embodiments, one electrode may be disposed in the first chamber and a plurality of electrodes may be disposed in the second chamber.

[0443] In this embodiment, the electrode 702 may include a common cardiac pacemaker lead, such as a Medtronic Capsure® pacing lead. These leads are used to connect the heart 701 to the system 700. The pacing lead may be composed of an industry standard IS-1 B1 connector (reference standard ISO 5148-3:2013) at one end, an electrode at the other end, and an insulated conductor system therebetween. In some embodiments, the IS-1 B1 connector is constructed using stainless steel for the two electrode contacts and silicon as the insulating material. Some embodiments may use polyurethane as the insulating material.

[0444] Stimulation of one or more cardiac chambers may be achieved by placing a voltage between the two electrodes of the atrial or ventricular cardiac pacing lead described above. The stimulation circuit uses a network of transistors (e.g., MOSFETs) to vary a capacitor to a specific programmable voltage, such as 2.0 V, and then controls the connection to the electrodes for a programmable time period of a fixed duration, such as 0.5 ms. The same network may also manage the discharge of any residual charge that may have accumulated on the electrodes after the stimulation is complete. The same network may control the type of stimulation applied, such as bipolar (between two electrodes) or unipolar (between one electrode and the stimulation device housing).

[0445] 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 each heart chamber and / or to deliver stimulation to each heart chamber. For example, one electrode is implanted in the right ventricle, additional electrodes are placed in the left ventricle through the coronary sinus, and pacing electrodes can be introduced into both ventricles while the system 700 includes means for generating bi-ventricular stimulation of both ventricles to reduce the dyssynchrony caused by ventricular stimulation.

[0446] System 700 includes a controller 703. System 700 may be an electrical stimulation device including a power source 704 (e.g., a battery known in the field of electrical stimulation devices). The controller 703 and / or the electrodes 702 may draw power from the power source 704.

[0447] Preferably, the electrical stimulation device of system 700 may be composed of a sealed housing and a header. The housing may be formed of titanium or other biocompatible materials and may include the power source 704, electronics, and a telemetry coil or communication module 707 for communication with an external device. The power source 704 may be an implantable obliquely sealed primary battery. The battery chemistry may be lithium-iodine. In other embodiments, larger or smaller batteries may be used. In other embodiments, a rechargeable battery such as a Li-ion rechargeable battery may be used. The electronics in some embodiments may be composed of standard off-the-shelf electronics (e.g., transistors and diodes) and / or custom electronics (e.g., ASICs).

[0448] To detect the onset of atrial and / or ventricular excitation, one or more sensing electrodes may be implanted at or near the target location within 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 passed through a bandpass filter with a programmable cut-off frequency to remove unwanted noise and may comply with the international standard for cardiac pacemakers (reference EN45502-2-1:2003). An electrical circuit may be used to amplify the electrical signals generated by the propagating activation of the cardiac chamber and to determine the onset of activation when the electrical signal meets a specific criterion such as crossing a predetermined threshold. The signal may be amplified, for example, by a programmable gain and then passed to a comparator for threshold detection at a programmable detection threshold in steps of 0.2 mV (atrium) and 0.4 mV (ventricle). These means for detecting excitation may introduce a delay between the actual onset of activation in the chamber and its detection. This is because the sensing electrodes may be remote from the origin of the excitation and the time taken for the signal to meet the detection criteria may be non-negligible, being in the range of 5 to 50 ms or more. In such cases, the timing of the onset of excitation may be estimated based on the timing of the detected excitation and the delivery of the stimulation pulses may be calculated to compensate for this delay.

[0449] Preferably, the controller 703 is coupled to an accelerometer to measure the patient's activity level. This patient activity level may be used to adjust the pacing rate and / or BPR setting and / or stimulation pattern based on the patient's needs. The activity level may also be used to control the effect of a desired level on blood pressure. For example, reducing blood pressure at a high activity level may allow for better performance when an increase in blood pressure is required. Preferably, blood pressure may naturally decrease when the patient is not active (e.g., when sleeping), in which case the pacing may be adjusted to avoid reducing blood pressure below a desired threshold. The activity level may also be used to adjust the settings based on baroreflex to allow for better response if necessary. The sensor may be, for example, a piezoelectric sensor. In other embodiments, a MEMS-based accelerometer sensor may be used. In other embodiments, preferably in combination with an accelerometer, a fine ventilation sensor may be used.

[0450] The controller 703 may be configured to transmit an electric current to the heart 701 via one or more electrodes 702. The controller 703 may be configured to execute a stimulation pattern of stimulation pulses according to any embodiment of the present disclosure. In some embodiments, the stimulation pulses may be transmitted to at least the ventricles of the heart. In some embodiments, the stimulation pattern may include a first stimulation setting and a second stimulation setting different from the first stimulation setting, and the first stimulation setting and the second stimulation setting are configured to reduce or prevent atrial stimulation and / or control the atrial internal pressure and / or dilation of the atrium. In some embodiments, the first stimulation setting has an AV delay different from that of the second stimulation setting. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured such that the atrial internal pressure caused by atrial contraction of the atrium overlaps in time with the passive increase in atrial internal pressure, whereby the combination of the atrial internal pressure caused by atrial contraction and the passive increase in internal pressure provides an atrial internal pressure of the atrium that is higher than the atrial internal pressure of the atrium without stimulation. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured such that the maximum atrial dilation is approximately equal to or lower than the maximum atrial dilation of the same heart when not receiving stimulation. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured such that the contractile force of the atrium is maximized when the AV valve is open. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured to change the mechanism of at least one atrial contraction such that the mechanism of at least one atrial contraction is different from the mechanism of the preceding natural atrial contraction. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured to reduce the force of at least one atrial contraction. In some embodiments, the first stimulation setting and / or the second stimulation setting are configured to prevent at least one atrial contraction.

[0451] In some embodiments, the controller 703 may be configured to transmit various different AV delays. The controller 703 may be configured to detect when atrial contraction or excitation occurs (as described herein) and then transmit ventricular stimulation at regular intervals, thereafter, or prior to a future expected atrial excitation or contraction. This interval may be programmable. The controller 703 may also be configured to stimulate the atrium and then transmit ventricular stimulation at a fixed interval, which may also be programmable, thereafter. The programmable interval may be changed, for example, between 2 ms and 70 ms to accommodate a desired therapeutic effect or even to provide a negative AV delay of up to -50 ms.

[0452] In some embodiments, the controller 703 may be configured to repeat a stimulation pattern a plurality of times. For example, the controller 703 may repeat the stimulation pattern twice. In another embodiment, the controller 703 may be configured to repeat the stimulation pattern at least twice during a one-hour period. The stimulation pattern repeated by the controller 703 may include any kind of stimulation pattern. For example, the stimulation pattern may include a stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of atrial pressure and atrial dilation. In another embodiment, the stimulation pattern may include two different stimulation settings, each configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of atrial pressure and atrial dilation. These two stimulation settings may differ by one or more parameters, for example, by an AV delay.

[0453] In some embodiments, the controller 703 may be configured to apply one or more consecutive stimulation patterns during a predetermined time interval. For example, in some embodiments, the time interval may be 10 minutes or more. In another embodiment, the time interval may be 30 minutes or more, 1 hour or more, or 24 hours or more. In some embodiments, the time interval may be monthly, such as from 1 month to 1 year. In some embodiments, the time interval may be 1 year or more.

[0454] In some embodiments, one or more consecutive stimulation patterns may include a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or control either or both of the atrial pressure and atrial dilation during a portion of the time interval. For example, one or more consecutive stimulation patterns may include a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or control either or both of the atrial pressure and atrial dilation during from about 50% to about 100% of the time interval. In another embodiment, one or more consecutive stimulation patterns may include a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or control either or both of the atrial pressure and atrial dilation during from about 50% to about 85% of the time interval. In some embodiments, one or more consecutive stimulation patterns may include a second stimulation setting having an AV delay longer than the first stimulation setting during at least one beat of the time interval.

[0455] In another embodiment, one or more consecutive 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 an atrial kick in at least one ventricle and / or to control either or both of the atrial pressure and atrial dilation. In some embodiments, the second stimulation setting and / or the third stimulation setting may each be configured not to reduce or prevent an atrial kick in at least one ventricle and / or not to control either or both of the atrial pressure and atrial dilation. In some embodiments, the second stimulation setting and / or the third stimulation setting may include from about 0% to about 50% of the time interval. In some embodiments, the second stimulation setting and / or the third stimulation setting may include from about 0% to about 30% of the time interval. In some embodiments, the second stimulation setting and / or the third stimulation setting may include from about 0% to about 20% of the time interval. In some embodiments, the second stimulation setting and / or the third stimulation setting may include from about 5% to about 20% of the time interval.

[0456] Blood pressure is known to vary in a 24-hour cycle, and in some cases, abnormally high blood pressure is present only during a portion of the 24 hours (e.g., at night or during the day or a portion thereof), or is predominant for most of the 24 hours. In addition, blood pressure is known to vary according to physical activity, and a person during activity has a higher blood pressure than at rest. Thus, in some cases, it may be desirable to control the delivery of therapy as needed, for example, by changing the therapy parameters to lower blood pressure or even by not providing cardiac stimulation at all. In other words, the cardiac stimulation may be varied, the stimulation parameters adjusted, or simply turned on / off at different times of the day and / or when the patient is active or at rest. Optionally, such delivery of stimulation may be controlled according to time or adjusted to match the patient's 24-hour cycle BP rhythm.

[0457] Example 1 FIG. 21 shows the systolic BP of an untreated patient monitored for 24 hours. The time average is represented. As shown, the patient's BP was abnormally high during the day (approximately from 10 am to 6 pm). In such a type of case, it may be preferable to deliver pulses configured to reduce atrial stimulation and / or to set the device to provide AC stimulation only during the time period(s) when the BP is expected to be abnormally high (i.e., when needed or when need is anticipated).

[0458] Example 2 Another embodiment is shown in FIG. 22. Here, the patient's untreated blood pressure (represented by the line with the "x" data points in FIG. 22) was found to be abnormally high at night (from 2:00 PM to 7:00 AM). The increase in BP during the day is within the normal range and may be due to increased patient activity. Optionally, this patient may be assumed to need treatment only at night, and the device may be set to deliver stimulation accordingly. Optionally, this patient may be assumed to not need treatment during the day, and the device may be set such that even if an increase in blood pressure is measured during the day, such an increase should not trigger the delivery of treatment to lower the blood pressure. Optionally, the device may be set to not measure the blood pressure during the day.

[0459] In the embodiment shown in FIG. 22, the patient was then treated with a blood pressure reducing pulse having a setting of pacing both the atrium and ventricle with an AV delay of 15 ms for 10 beats, and then pacing the atrium and ventricle with an AV delay of 40 ms for 3 beats. Delivery of the treatment was started at 3:00 PM every day and continued for 13 hours. The resulting BP was plotted (represented by the line with the round data points in FIG. 22), and as can be seen, the BP was essentially within the normal range throughout the day and showed much smaller variations than before treatment (under treatment, the BP varied by only about 30 mmHg or less, while the untreated BP range varied by more than 40 mmHg).

[0460] In some embodiments, the patient-specific (in the absence of stimulation) blood pressure profile is first determined, and based on that specific profile, the stimulation parameters that cause the desired blood pressure reduction are then determined. FIG. 22 shows an example of such an approach. In some embodiments, the blood pressure is measured continuously or intermittently during operation of the device, and based on that, the stimulation parameters that cause the desired blood pressure reduction are then determined.

[0461] As discussed with respect to the exemplary approaches of Example 1 and Example 2 of FIGS. 21 and 22, rather than alternating between a cardiac stimulation period and a period without cardiac stimulation, in other approaches, the stimulation parameters may be adjusted to result in different values of blood pressure reduction in each of two or more periods of a time interval. These periods may be for several minutes or hours over a 24-hour time interval. The different values of blood pressure reduction in each period may be based on needs such as, for example, blood pressure detection feedback, time, patient activity, or a particular patient-specific blood pressure pattern. The stimulation parameters for each period may be selected to achieve different degrees of blood pressure reduction based on the needs during that particular period.

[0462] For example, a first stimulation setting may achieve a higher degree of blood pressure reduction during the day, followed by a second stimulation setting at night that can achieve a lower degree of blood pressure reduction than the first stimulation setting, and further reduce the blood pressure from the blood pressure level when no stimulation is applied. As another example, a first stimulation setting may achieve a higher degree of blood pressure reduction during low patient activity, followed by a second stimulation setting during high patient activity that can achieve a lower degree of blood pressure reduction than the first stimulation setting, and further reduce the blood pressure from the blood pressure level when no stimulation is applied.

[0463] When performing different stimulation settings alternately, in an embodiment, the degree of blood pressure change may be gradually adjusted by a temporary incremental adjustment or a continuous adjustment to a parameter that affects the degree of blood pressure change. For example, when the first stimulation setting uses an AV delay of 30 ms and the second stimulation setting uses an AV delay of 60 ms, when switching from the first stimulation setting to the second stimulation setting, the AV delay may be gradually adjusted in 5 ms increments (e.g., up to 35 ms, then up to 40 ms, etc.) from the first stimulation setting of 30 ms AV delay to the second stimulation setting of 60 ms AV delay. A similar incremental adjustment may be used for the switch back from the second stimulation setting to the first stimulation setting. In other embodiments, this adjustment may be continuous in that the rate of change of a parameter (e.g., AV delay) that affects blood pressure when switching from the first stimulation setting to the second stimulation setting is constant.

[0464] As described above, providing different values of blood pressure reduction may include adjusting a stimulation parameter that affects the AV delay, and this adjustment may be used to switch the stimulation setting. For example, a stimulation parameter that provides a shorter AV delay may reduce blood pressure to a greater extent than a stimulation parameter that provides a longer AV delay. In an embodiment, a stimulation setting that reduces atrial stimulation may provide an AV delay that varies from about 5 ms to about 30 ms (e.g., between day and night, or between intense activity and light activity), and the shorter the AV delay, the greater the reduction in blood pressure.

[0465] FIG. 24 is a graph showing an embodiment of the relationship between the AV delay (100 ms or less in this example) of a specific patient and the reduction in systolic blood pressure. As shown, a stimulation parameter that achieves an AV delay that produces a desired reduction in systolic blood pressure may be selected. Thus, based on the relationship between the AV delay and the blood pressure reduction, the blood pressure reduction therapy may be adjusted to achieve a desired blood pressure reduction based on the patient's needs during a specific period of a certain time interval (e.g., a period of several minutes or several hours over a one-day time interval), as shown in the following two examples.

[0466] Example 3 Figure 25 is a graph of systolic blood pressure over 24 hours for a particular outpatient. As shown, the patient in Figure 25 has very high blood pressure at the beginning of the day (about 140 - 160 mmHg from approximately 6 am to approximately 2 pm), very low blood pressure in the second half of the night (less than 100 mmHg between approximately midnight and approximately 2 am), and intermediate blood pressure values in between (about 120 - 140 mmHg from approximately 3 pm to approximately 11 pm).

[0467] For the type of patient in Figure 25, it may be useful to apply therapies using different sets of stimulation parameters throughout the day. For example, in one implementation aspect, a first set of stimulation parameters that significantly reduces blood pressure may be applied from approximately 6 am to approximately 2 pm (with a relatively very short AV delay), a second set of stimulation parameters that still slightly reduces blood pressure may be applied from approximately 2 pm to approximately midnight, and a third set of stimulation parameters that provides a longer AV delay (e.g., no stimulation or stimulation that provides a normal AV delay) may be applied from approximately midnight to approximately 6 am. Thus, the different stimulation parameters reduce or prevent atrial stimulation, lower blood pressure, and provide a more normalized and controlled blood pressure for the patient overall, according to the needs of the patient during different periods within this time interval.

[0468] Example 4 Figure 26 is a graph of systolic blood pressure over 24 hours for another particular outpatient, different from the patient in Figure 25. The patient in Figure 26 shows high blood pressure at night (over 140 mmHg from approximately midnight to approximately 7 am) and unstable blood pressure during the day.

[0469] The patient type of FIG. 26 may enjoy the benefits of a different set of stimulation parameters than the patient type of FIG. 25. For example, at night, a long AV delay may be applied. Subsequently, the AV delay may be increased periodically and reach normal values from approximately 9:00 a.m. to approximately 2:00 p.m. (when the blood pressure is within a nearly normal range of 120 mmHg or less). Thereafter, from approximately 9:00 p.m. to approximately midnight, a further increase (or set of increases) in the AV delay may apply a longer AV delay (the same as or slightly shorter than that applied at night).

[0470] All of the stimulation patterns of the above embodiments may include a feedback loop and / or may be pre-programmed based on the known 24-hour blood pressure variations of the patient.

[0471] In some embodiments, the controller 703 may be configured to apply one or more continuous stimulation patterns including a sequence of 10 to 60 stimulation pulses having a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of atrial pressure and atrial dilation. In some embodiments, the controller 703 may be configured to apply one or more continuous stimulation patterns including a sequence of 1 to 10 beats embedded within the 10 to 60 stimulation pulses, and the sequence of 1 to 10 beats may have an AV delay longer than the first stimulation setting. For example, the 10 to 60 stimulation pulses may include 5 stimulation pulses having the first stimulation setting, followed by 1 beat having an AV delay longer than the first stimulation setting, followed by 50 stimulation pulses having the first stimulation setting. The sequence of 1 to 10 beats may include at least one stimulation pulse having a first stimulation setting configured to reduce or prevent an atrial kick in at least one ventricle and / or to control either or both of atrial pressure and atrial dilation. The sequence of 1 to 10 beats may include a natural AV delay. The sequence of 1 to 10 beats may occur without stimulation.

[0472] System 700 may further include one or more sensors 705. In some embodiments, such sensors 705 may include one or more sensing electrodes for detecting the electrical activity of the heart. In some embodiments, the one or more sensing electrodes may include one or more stimulating electrodes 702. In some embodiments, sensors 705 may include one or more sensors (implanted or external). In some embodiments, the one or more sensors 705 may include one or more pressure sensors implanted in the heart (e.g., in the atria and / or ventricles). In some embodiments, sensors 705 may include one or more blood flow sensors (implanted or external). For example, the one or more sensors 705 may include ultrasonic detection of blood flow through the AV valve. In some embodiments, sensors 705 may include one or more sensors configured to monitor the timing of closure of the AV valve. One or more of these sensors may be configured to operate as a closed loop with the controller.

[0473] Information from sensors 705 may be supplied to controller 703 by some form of communication including wired and / or wireless communication. Preferably, system 700 may include one or more communication modules 707 for receiving and / or transmitting information between system components and / or to devices external to the system. In some embodiments, controller 703 may be configured to receive input data related to the patient's blood pressure. For example, input data related to the patient's blood pressure may include data indicating BP measured at one or more time points or variations in BP (e.g., a function representing the degree of change and / or the ratio of change or change in blood pressure over time), and / or statistical data related to BP or variations in BP, maximum and / or minimum BP values.

[0474] Preferably, system 700 may include one or more user interfaces 708 for providing information and / or enabling input of information. Providing information may include, for example, displaying operational information related to the system and / or displaying data recorded and / or received by the system during operation. This may include detected parameters and / or the relationship between the detected parameters and operational information (such as stimulation pattern settings and / or relative timing between a given pace and the detected information).

[0475] Preferably, user interface 708 may include a commercially available laptop computer (such as a Windows®-based computer) that executes a software application. The software application may function to generate instructions that are transmitted to an interface connected to a handheld wand that includes a telemetry circuit for communication with an implantable stimulation device. The instructions sent to the wand may be used to set stimulation parameters and / or to retrieve diagnostic messages of the device, device data, heart data, and real-time heart sensing. The interface may also enable connection of a 3-lead ECG, and this data is displayed on the laptop computer screen by the software application. In other embodiments, a 3-lead ECG electronic circuit may not be included, or a 12-lead ECG electronic circuit may be included. In other embodiments, the functionality of the wand, interface, and laptop computer may be incorporated into dedicated hardware components that perform all three functions. In other embodiments, printing capabilities may also be added to user interface 708.

[0476] In some embodiments, interface 708 may be configured to allow a user (e.g., a physician) to supply a set of control instructions to the system (e.g., target values and / or ranges, and / or other limitations or instructions). Preferably, ...

Claims

1. It is a system for controlling blood pressure. A stimulator circuit configured to deliver a stimulatory pulse to at least one cardiac chamber of the patient's heart, The system comprises at least one controller configured to deliver stimulation pulses of one or more stimulation patterns to the at least one cardiac chamber, In the first operating mode, the first stimulation pattern of the one or more stimulation patterns lowers both the patient's systolic and diastolic blood pressure. A system in which, in a second operating mode, the second stimulation pattern of one or more stimulation patterns lowers 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 pattern lowers the systolic blood pressure with little or no effect on the diastolic blood pressure.

3. The system according to claim 1, wherein the second stimulation pattern lowers the systolic blood pressure while limiting its effect on diastolic blood pressure to a level that does not hinder the achievement of therapeutically effective pulse pressure reduction.

4. The system according to claim 1, wherein the second stimulation pattern increases diastolic blood pressure while decreasing systolic blood pressure.

5. The system according to claim 1, wherein the at least one controller is configured to treat a patient's hypertension using the first stimulation pattern and / or treat a patient's isolated systolic hypertension using the second stimulation pattern.

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

7. The system according to claim 1 or 3, wherein the second stimulation pattern combines a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower the systolic blood pressure while limiting the effect on diastolic blood pressure to a level that does not hinder the achievement of therapeutically effective pulse pressure reduction.

8. The system according to claim 1 or 4, wherein the second stimulation pattern combines a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to raise diastolic blood pressure while lowering systolic blood pressure.

9. The system according to claim 1, wherein the second stimulation pattern combines a stimulation pattern that lowers blood pressure and a stimulation that increases heart rate to lower the systolic blood pressure while controlling the diastolic blood pressure so that the diastolic blood pressure is between a lower limit tolerance and an upper limit tolerance.

10. The system according to claim 1, wherein the second stimulation pattern combines a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to control the systolic and diastolic blood pressure so that the resulting pulse pressure is between a lower limit tolerance and an upper limit tolerance, or is lower than the initial pulse pressure by a predetermined amount and / or a predetermined percentage.

11. The system according to claim 1, wherein the second stimulation pattern combines a stimulation pattern that lowers blood pressure with a stimulation that increases heart rate to lower the systolic blood pressure while maintaining a diastolic blood pressure above a specified minimum.

12. The system according to claim 1, wherein the at least one controller is configured to obtain an index of the patient's unique heart rate, and the second stimulation pattern increases the heart rate to a level greater than the unique heart rate.

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

14. The system according to claim 12 or 13, wherein the at least one controller is configured to obtain the intrinsic index of the heart rate before and / or during the transmission of the second stimulation pattern.

15. The system according to claim 12 or 13, further comprising an activity sensor configured to detect a patient's activity level, wherein at least one controller is configured to obtain the index of the intrinsic heart rate from an estimate of the intrinsic heart rate based on the activity level signal received from the activity sensor.

16. The aforementioned at least one controller is The first stimulation pattern is calibrated to the second stimulation pattern by determining the diastolic and / or systolic blood pressure reduction resulting from the first stimulation pattern. By actively stimulating the patient at different heart rates, the increases in systolic and diastolic blood pressure at those different heart rates are determined. The system according to any one of claims 1 to 5 and 9 to 11, wherein the second stimulation pattern is configured to produce a desired increase in heart rate based on the determined diastolic and / or systolic blood pressure decrease and the increase in systolic and diastolic blood pressure at the different heart rates.

17. The system according to 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 the increase in diastolic blood pressure above the intrinsic heart rate is equal to the decrease in diastolic blood pressure induced by the first stimulation pattern, and then subtracting the intrinsic heart rate.

18. The aforementioned at least one controller is Subtracting the expected increase in systolic blood pressure due to the expected increase in heart rate from the decrease in systolic blood pressure caused by the first stimulation pattern, To determine whether the expected overall effect on the systolic blood pressure is sufficient, If the expected overall effect on the systolic blood pressure is insufficient, a lower heart rate increase may be selected for the desired heart rate increase. The system according to claim 16, configured to determine the desired increase in heart rate by using the patient's existing systolic blood pressure data to calculate the expected overall effect on systolic blood pressure.

19. The system further includes a tachyarrhythmia sensor configured to monitor the patient's heart for tachyarrhythmias during the second stimulation pattern and to transmit a signal to at least one controller if a tachyarrhythmia is detected, The at least one controller is configured to discontinue the second stimulation pattern after receiving the signal. The system according to claim 1.

20. The system according to claim 1, wherein the at least one controller is configured to receive data relating to a heart rate condition that should discontinue the transmission of the second stimulation pattern during the transmission of the second stimulation pattern, and to discontinue the transmission of the second stimulation pattern when the heart rate condition is met.

21. The system according to claim 20, wherein the at least one controller is configured to automatically receive the data relating to the heart rate condition based on the measured parameter values.

22. The system according to claim 20 or 21, wherein the data relating to the heart rate conditions includes a cutoff heart rate determined according to at least one of time, patient activity level, or blood pressure.

23. The system according to claim 20 or 21, 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 using an implantable myocardial stimulator associated with the patient's heart, To transmit a first stimulation pattern to at least one cardiac chamber of the patient's heart that lowers both the patient's systolic and diastolic blood pressure, To reduce the difference between the systolic and diastolic blood pressure, a second stimulation pattern is transmitted to at least one cardiac chamber of the patient's heart, which controls the patient's diastolic blood pressure while lowering the patient's systolic blood pressure. Methods that include...

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