Treatment of cardiac decompensation, pulmonary congestion and dyspnea

Abstract

To provide a novel method and device that may be used for treatment of cardiac decompensation, amelioration of dyspnea and prevention and treatment of deterioration to pulmonary congestion and pulmonary edema.SOLUTION: A method for treatment of cardiac problems includes performing modulation of a cardiac rhythm of a patient by increasing a number of heart beats of the patient during a time interval with high pleural pressure relative to the number during low (negative) pleural pressure, where an amplitude of the modulation of the cardiac rhythm between these segments is determined by severity of a respiratory effort and lung congestion of the patient.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to novel methods and devices for the treatment of heart failure and pulmonary congestion, and the prevention of atrial fibrillation, including, but not limited to, the treatment of cardiac decompensation, the amelioration of dyspnea, and the prevention of worsening pulmonary congestion and pulmonary edema. The present invention is applicable to patients with acute or chronic heart failure of any etiology. [Background technology]

[0002] Heart failure (HF) is a major pandemic associated with reduced quality of life and high morbidity and mortality. There are various treatments for HF, including various drugs, cardiac resynchronization therapy (CRT, cardiac resynchronization therapy) by pacing the heart at various sites, cardiac contraction modulation, neurohumoral stimulation, mechanical assist devices, attempts to utilize stem cell therapy for myocardial regeneration, and the use of various materials for tissue rejuvenation. Despite significant advances in all proposed technologies and treatments, mortality and morbidity remain high and quality of life is very low. Furthermore, with the aging population, the prevalence of HF is expected to increase in the near future.

[0003] A major problem with all known solutions for treating heart failure is their very limited effectiveness. Current solutions may improve the rate of heart failure progression, but have only had limited success in altering the course of the disease. Thousands of assist devices are implanted each year in patients with end-stage heart failure. While this technology significantly extends survival, these patients represent only a small fraction of the population suffering from severe heart failure—only a few thousand of the more than 1.5 million patients with stage III-IV heart failure in the United States alone. Furthermore, assist device technology is associated with a high incidence of complications, including gastrointestinal bleeding, stroke, and right heart failure. Additionally, it is a very expensive technology.

[0004] Cardiac resynchronization therapy (CRT) is another advanced technique, but it is effective in only a small percentage of patients with severe systolic heart failure (those with an ejection fraction less than 35% and a significantly prolonged QRS). Interestingly, more than half of patients with heart failure suffer from diastolic heart failure, a problem with left ventricular filling. The underlying mechanisms of this type of heart failure are not well understood, and there are no effective treatments for this type of heart failure. Diastolic heart failure (or heart failure with preserved ejection fraction) in this group is steadily increasing with the aging population. Therefore, there is a significant unmet need to develop new techniques for the treatment of heart failure.

[0005] Three major paradigms have been proposed to explain the development of heart failure: (1) cardiorenal and volume overload, (2) coupling of cardiac circulation and cardiac function with peripheral impedance, and (3) activation of the neurohumoral and sympathetic nervous systems. Currently available drug therapies and various technologies relate to these three paradigms. Summary of the Invention

[0006] The present invention provides novel methods and devices for the treatment of heart failure and pulmonary congestion and the prevention of atrial fibrillation, and may be used, without limitation, to treat cardiac decompensation, improve dyspnea, and prevent worsening pulmonary congestion and pulmonary edema.

[0007] The present invention may be used to treat worsening heart failure, referred to as the "vicious cardiopulmonary cycle." The most significant symptom of severe heart failure and the leading cause of hospital readmission is severe dyspnea. The inventors of the present invention have discovered that not only are respiratory effort and the associated sensation of dyspnea characteristic of cardiac decompensation, but that respiratory effort plays a vital role in the "vicious cardiopulmonary cycle," leading to progressive deterioration.

[0008] This new therapy represents a breakthrough in the management of heart failure for the following key reasons: 1. Based on a novel paradigm for understanding the worsening of heart failure. 2. It interferes with the normal physiological control of cardiac pacing. 3. It is independent of the various etiologies of heart failure and can treat all of them. 4. Assess the severity of cardiac decompensation and provide immediate treatment proportionate to the severity of decompensation. 5. Detect deterioration early and provide treatment before patients become symptomatic - providing personalized medicine through early detection and prevention.

[0009] Advantages of the present invention include, but are not limited to: 1. It applies to the huge market of heart failure and can be used for all patients with stage 3 and 4 heart failure. 2. Applies to all forms of heart failure, regardless of etiology, whether it is heart failure with reduced or preserved ejection fraction. 3. Immediately treat any detected episodes of respiratory distress or increased intrapulmonary blood pressure (hemodynamic congestion). 4. The slow progression of the disease can be detected and treated before patients become symptomatic, thus providing prevention and reducing hospitalization rates. 5. Represents a novel autonomic control (diagnosis and therapy) of the human autonomic cardiac system. Close monitoring of hemodynamic congestion changes and the effectiveness of treatment allows for close continuous monitoring of heart failure patients. 6. Easy to implement. It is based on the integration of pacing technology with respiratory effort detection and novel algorithms. 7. It requires less power because it uses the power of the "respiratory pump" and cardiac contractions to push blood out of the lungs, reducing hemodynamic congestion. 8. Low expected adverse effects. Adverse effects are related to the presence of pacing electrodes in the heart and rate control, both of which have well-known low rates of adverse effects. Rate control is not expected to have adverse effects because patients with atrial fibrillation who have their rate controlled have the same prognosis as patients who have their rhythm tightly controlled.

[0010] According to non-limiting embodiments of the present invention, there is provided a method for treating a cardiac problem, the method comprising modulating a patient's cardiac rhythm by increasing the heart rate during time segments with high intrathoracic pressure relative to the heart rate during other time segments with relatively low intrathoracic pressure, the amplitude of the modulation being determined by the patient's respiratory effort and the severity of pulmonary congestion, the high intrathoracic pressure being closer to zero than the relatively low intrathoracic pressure.

[0011] The method may further use modulation of cardiac pacing to remove fluid from the patient's lungs and reduce pressure within the patient's pulmonary blood vessels, thereby reducing the effort of breathing and the sensation of dyspnea.

[0012] The method may further use adjustments in cardiac pacing to reduce resistance to blood flow within the patient's pulmonary circulation, reducing respiratory effort and thereby reducing the workload of both the right and left ventricles.

[0013] The cardiac pacing regulation further includes sensors in the patient's pleural cavity or / and intrathoracic vessels and / or cardiac chambers or / and chest and upper abdominal surface that record and measure respiratory waves, with respiratory effort being defined as the peak-to-peak amplitude of the respiratory waves.

[0014] Regulation of cardiac pacing further involves the use of a long-term central control system with a memory and communication unit that records past history of heart rate, respiratory dynamics, and hemodynamic indices.

[0015] Regulation of cardiac pacing further involves the use of a long-term central control system with a central processing unit that analyzes changes in hemodynamic congestion or pressure, respiratory effort, and / or heart rate.

[0016] Regulation of cardiac pacing further involves the use of a long-term central control system that sets threshold levels for dividing the respiratory cycle into intervals of relatively high and relatively low intrathoracic pressure.

[0017] Modulation of cardiac pacing further includes inhibiting normal sinus node pacing.

[0018] Modulation of cardiac pacing further includes intentionally increasing heart rate during time intervals with high intrathoracic pressure, inhibiting sinus node pacing during time intervals of relatively low pressure by the patient's autonomic nervous system in response to a transient increase in cardiac output during time intervals of high intrathoracic pressure.

[0019] The cardiac pacing adjustment further includes an algorithm for adaptive control of adjustment within the long-term control system using feedback from a sensor assessing respiratory effort level to control the cardiac pacing adjustment, the control of adjustment including determining the number of pacing beats per minute (NpM) to be added during time intervals of high intrathoracic pressure, the depth of adjustment (NpM) increasing with the severity of the monitored respiratory effort.

[0020] The method further includes using a long-term central control system to determine the respiratory rate (RR) interval of the induced pacing based on a past history of electrocardiogram (ECG) recordings.

[0021] The method further includes using a real-time control unit that accepts thresholds for respiratory wave segmentation, the required number of additional pacing (NpM), and the RR interval of induced pacing, identifies in real time the start of each interval of high intrathoracic pressure, and calculates pacing time based on the most recent heart rate, the number of most recently delivered pacing, and the identification of the required NpM.

[0022] The method further includes using a real-time control unit and an output power unit to perform real-time supplemental pacing.

[0023] Regulation of cardiac pacing may be performed by pacing electrodes positioned in at least one of the heart chambers. [Brief explanation of the drawings]

[0024] The present invention will be more fully understood and appreciated from the following detailed description taken in conjunction with the drawings in which:

[0025] [Figure 1] Figure 1 is a simplified diagram of a novel embodiment of the cardiopulmonary reverse circulation therapy (CPRS) of the present invention, which is called "cardiopulmonary reverse circulation" because it breaks the "vicious cardiopulmonary cycle" and reverses the various interactions that contribute to progressive deterioration. [Figure 2] Figure 2 is a simplified diagram of "respiratory sinus arrhythmia," which is the normal physiological increase in heart rate during inspiration and decrease in heart rate during expiration (indicated by the arrows). The cardiopulmonary reverse circulation therapy of the present invention counteracts this normal physiology, increasing heart rate only at the end of expiration and the beginning of inspiration, when intrathoracic pressure is near zero. [Figure 3] Figure 3 is a simplified diagram illustrating the effects of physiological respiratory sinus arrhythmia on pulmonary congestion. During normal breathing, there is a progressive increase in heart rate and pulmonary inflow during inspiration that is offset by an increase in outflow during expiration. In contrast, the proposed cardiopulmonary countercirculation therapy causes a net decrease in hemodynamics and pulmonary congestion by increasing the absolute number of cardiac contractions during time intervals with near-zero intrathoracic pressure over time intervals with deep negative intrathoracic pressure. [Figure 4]Figure 4 shows an example of proposed synchronization of cardiac pacing to changes in intrathoracic pressure and respiratory wave swings, based on data from a patient with heart failure. The top bar shows imposed pacing (red bar) relative to the natural regular sinus pacing (blue bar) on the recorded ECG. The bottom trace shows the measured change in intrathoracic pressure. Note that the patient is suffering from severe dyspnea with a respiratory effort (peak-to-peak amplitude) of 15 mmHg, approximately five times the normal respiratory effort. The novel algorithm sets a threshold (-5 mmHg in this example) and divides the respiratory cycle into two time intervals: (1) a time interval of deep negative intrathoracic pressure (red) at the end of inspiration and early expiration, and (2) a time interval where intrathoracic pressure is near zero (green). The system adds excitation when intrathoracic pressure approaches zero (green), providing cardiopulmonary countercirculation and reducing hemodynamic and pulmonary congestion. [Figure 5]Figure 5 shows a schematic diagram of the adaptive control of excitation composed of two subsystems. One system analyzes long time intervals and the changes in the patient's condition and the severity of dyspnea and heart failure (long-term analysis). The second system functions in real time, detects a window suitable for excitation in real time, and introduces appropriate pacing (real-time control). The inputs to the two subsystems are the measured pressures (Pra, Rv) by various pressure transducers among the ECG, direct measurements of intrathoracic pressure (Ppl if directly measured), or other possible measurements described in this embodiment. The long-term analysis subsystem measures the average heart rate (HR) and the associated normal average RR interval (tRRorg), respiratory rate (BR), and average respiratory effort. Based on these measurements and the recorded patient's medical history, this system determines the following three parameters that determine the performance of the real-time control subsystem. (1) The RR interval of pacing excitation (tRRnew, tRRnew < tRRorg), that is, the time interval between the last normal heartbeat and the paced beat. (2) A threshold level (Pth) that divides the respiratory cycle into time intervals of deep negative pressure where additional pacing should be avoided and time intervals of intrathoracic pressure close to zero where pacing is permitted. (3) The number of additional pacings (NpM) that need to be introduced per minute. The latter determines the depth of regulation. When the patient breathes normally and the respiratory effort is normal (about 3 mmHg), pacing is not performed (NpM = 0). As the respiratory effort increases, it is necessary to increase NpM to provide cardiopulmonary counterpulsation therapy.

Mode for Carrying Out the Invention

[0026] The present invention provides a novel cardiopulmonary counterpulsation therapy for treating what is referred to herein as "cardiopulmonary vicious cycle". There is no prior art related to the important role of respiratory effort in the onset of cardiac decompensation.

[0027] The objectives of the novel "cardiopulmonary reverse circulation" (CPRC) are to: 1. break all cardiopulmonary vicious feedback loops that lead to cardiac decompensation; 2. prevent hemodynamic and pulmonary congestion by utilizing large changes in intrathoracic pressure (respiratory pump / machine action) to pull blood and fluid from the lungs back into the peripheral circulation; 3. reduce transmural pressure across the pulmonary capillaries and left atrium, thereby improving pulmonary compliance; 4. ameliorate dyspnea problems; and 5. reduce the workload of both the right and left ventricles. The "cardiopulmonary vicious cycle" leads to a progressive increase in pulmonary capillary pressure and pulmonary congestion, increasing the workload of both ventricles. The device provides cardiopulmonary reverse circulation by reversing these effects, which are precursors to the vicious cycle.

[0028] This device utilizes the work generated by the respiratory system (the "respiratory pump") and cardiac contractions to remove fluid from the lungs, reduce pressure in the pulmonary vasculature, and reduce resistance to blood flow in the pulmonary circulation. These effects relieve hemodynamic and pulmonary congestion. The pressure in the pulmonary circulation (hemodynamic congestion) and the volume of blood and fluid in the lungs (pulmonary congestion) are primarily determined by the inflow of blood into the lungs through the right ventricle and the outflow of blood from the lungs through the left ventricle back to the peripheral circulation. However, these inflows and outflows through the right and left ventricles are regulated by intrathoracic pressure. When deep negative intrathoracic pressure is present, inflow into the lungs is greater than outflow from the lungs. When positive intrathoracic pressure is near zero, the opposite occurs. Thus, inflow and outflow are regulated by the respiratory pump. This device utilizes the pressure generated by the respiratory pump to move blood out of the lungs and reduce pressure in the pulmonary circulation. This is done by pacing the heart and increasing the heart rate when intrathoracic pressure is near zero compared to the rate during deep negative intrathoracic pressure.

[0029] The expected pacing rate is very low, approximately one pace per 100 normal heartbeats. The average cardiac output in an adult is approximately 70 ml. Assume that each pace at an appropriate time interval (when intrathoracic pressure is near zero) moves only 0.2 ml of blood (0.3% of stroke volume) from the lungs, i.e., right and left ventricular stroke volumes of 69.9 ml and 70.1 ml, respectively. Therefore, to move a relatively large volume of 200 ml of blood from the lungs, an additional 1,000 cardiac beats are required over an appropriate time frame. However, we average approximately 20,000 breaths and 100,000 heart rates per day. Therefore, only moderate pacing of once every 20 respiratory cycles or 100 heartbeats is necessary. Furthermore, it is well established that cardiac decompensation in patients with chronic heart failure develops and progresses slowly over 2–3 weeks. Therefore, retrograde circulation can be prolonged for several days.

[0030] It is important to note that in contrast to other patents (%) that aim to modify heart rate depending on breathing rate or phase, the device has only a small effect on heart rate (less than 1%).

[0031] It is important to note that the device does not directly alter respiratory rate, as suggested in various other patents (U.S. Patent Nos. 8,509,902, 8,483,833, and 9,149,642), but rather utilizes a respiratory pump to expel blood from the lungs. Furthermore, in contrast to these patents, which propose pacing the heart only when the patient is asleep, this device operates around the clock and also aims to reduce respiratory effort during physical activity.

[0032] Furthermore, in contrast to other patents, pacing is adjusted based on intrathoracic pressure levels rather than simply segmenting the respiratory cycle into inspiratory and expiratory phases, as shown in Figure 4. Inspiration is defined as the time interval from inhalation when intrathoracic pressure drops from near-zero to the lowest negative intrathoracic pressure. Therefore, pacing during the inspiratory phase, as suggested in other patents (U.S. Patent Nos. 8,509,902 and 8,483,833), does not provide the expected cardiopulmonary countercirculation. Similarly, pacing during the expiratory phase is ineffective because intrathoracic pressure is very low at the beginning of the expiratory phase. The appropriate pacing window crosses the inspiratory and expiratory phases, beginning before the end of exhalation and ending after the onset of inspiration. This division of the respiratory cycle is unique to this embodiment compared to all other proposed cardiac pacing techniques (U.S. Patent Nos. 8,509,902 and 8,483,833).

[0033] Surprisingly, the present invention achieves this by using a counterintuitive cardiac pacing mode that is opposite to the physiological autonomic regulation of cardiac pacing by respiration, referred to as "respiratory sinus arrhythmia." In physiological respiratory sinus arrhythmia, the heart rate increases during inspiration, but as the intrathoracic pressure decreases to the deepest negative pressure, as shown in Figures 2 and 4, the CPRC implements the opposite mode of pacing, increasing the heart rate as the intrathoracic pressure approaches zero. Furthermore, the amplitude of cardiac pacing regulation is determined by respiratory effort and the severity of pulmonary congestion.

[0034] The new CPRC includes the following elements: A. A means for inhibiting normal sinus node pacing to reduce the normal pacing rate when intrathoracic pressure is below a threshold, which includes at least one of the following: a. The convenient use of drugs that reduce heart rate, such as beta-blockers or specific suppressors (which inhibit specific currents) of sinus node rhythm, such as ivabradine (101 in Figure 1). b. Any invasive or minimally invasive method for suppressing sinus node activity (102 in Figure 1). c. Selectively add cardiac pacing only during periods when intrathoracic pressure exceeds a threshold and approaches zero. As noted above, this mode itself induces cardiopulmonary reversal. Furthermore, the addition of cardiac pacing, improvement of dyspnea symptoms, and reduction of thermal load downregulate the sympathetic nervous system of the autonomic nervous system, reducing the normal sinus node rate. B. A sensor that can monitor breathing, detect inspiration and expiration phases, and quantify changes in intrathoracic pressure. a. Pressure sensor inserted into the thoracic cavity (201 in Figure 1). b. Sensors in either the intrathoracic arterial or venous vessels (202 in Figure 1), because intravascular pressure is regulated by changes in intrathoracic pressure. The heart and great vessels are located in the mediastinum and are surrounded by intrathoracic pressure. The intrapulmonary vessels are connected to the great vessels in the mediastinum. Therefore, breathing changes intrathoracic pressure, which affects the function and pressure of the right and left ventricles and also regulates pressure throughout the pulmonary circulation. c. Any sensors capable of monitoring chest wall movement and detecting respiratory phases (203 in Figure 1), including any belts (piezo, impedance, inductance, optical) used to monitor respiration (204 in Figure 1). d. Sensors within the heart (e.g., right atrium or / and left atrium) (205 in Figure 1), since pressure within the cardiac chambers, particularly the right and left atria, is regulated by changes in intrathoracic pressure. e. Impedance techniques between intrathoracic or extrathoracic electrodes or main units used to quantify changes in impedance during the respiratory phase (206 in Figure 1). f. Analysis of respiratory-induced changes in the electrocardiogram (ECG), such as monitoring chest impedance via ECG electrodes and monitoring cardiac axis changes during the respiratory cycle. g. Sensors that quantify changes in airflow, such as thermistors, microphones, vibration accelerometers, and stethoscopes. C. Sensors to Quantify the Severity of Respiratory Effort. All of the above sensors (201 through 206, sections a through g above) can be used to quantify the severity of respiratory effort and dyspnea. The intrapleural sensors can measure the peak-to-peak amplitude of intrathoracic pressure changes and can distinguish between the severity of inspiratory and expiratory effort. Similarly, all of the intravascular pressure sensors within the thorax can quantify the amplitude of intravascular pressure modulation due to respiratory effort. D. A sensor that quantifies cardiac function and severity of heart failure, including: a. Pressure in the left atrium (301 in Figure 1) b. Pulmonary artery pressure (302 in Figure 1) c. Pressure in the right ventricle (303 in Figure 1) that provides the pulmonary artery pressure and right ventricular end-diastolic pressure during the ejection phase. d. Pressure in the right atrium to assess the severity of right heart failure (304 in Figure 1). e. Pressure in the left atrium using a transseptal catheter or sensor located in the left atrium. e. Assessment of changes in cardiac output. The catheter in the right ventricle (305 in Figure 1) is an impedance catheter that measures right ventricular volume and stroke volume. This catheter can also be used to assess cardiac output using a thermodilution approach. f. Assessment of pulmonary congestion, for example, by impedance techniques. Impedance can be measured between any intrathoracic or extrathoracic electrode and the central unit (306 in FIG. 1), or between any other set of intrathoracic electrodes. E. The new CPRC pacing is adjusted depending on the severity of the respiratory effort. If the patient feels well (low respiratory effort of approximately 3 mmHg), there is no need to force CPRC. When a more serious deterioration of hemodynamic congestion is detected, there is an urgent need to reverse the effects of the cardiopulmonary vicious cycle, so the device strengthens the pacing rate and increases the heart rate during time intervals above the threshold (intrathoracic pressure close to zero) and below the threshold (deep negative pleural pressure). The severity of the respiratory effort can be assessed by all of the sensors mentioned above (201-206). F. Pacing electrodes in the right or left atrium and / or ventricle. Left atrial or left ventricular pacing is rarely indicated. a. Pacing of the right atrium (401 in FIG. 1) is the simplest mode. CPRC pacing is induced before normal atrial flutter (tRRew < tRRorg) and resets the sinoatrial node. Atrial pacing is a preferred mode for pacing the heart when there is no atrial arrhythmia such as atrial fibrillation or conduction abnormalities, as it maintains normal ventricular activity with narrow QRS complexes. b. Pacing of the right ventricle (402 in FIG. 1). When there is atrial fibrillation, direct pacing of the right ventricle is necessary. When there is an atrioventricular block, the device can sense the right atrium, adjust the pacing of the right ventricle, and set an appropriate AV delay. c. This system can also resynchronize left ventricular function using electrodes on the left side (left ventricle), similar to normal cardiac resynchronization therapy (CRT). d. If the patient has an implanted cardioversion device (ICD), the device can be integrated with the ICD and use the electricity of the ICD to adjust the pacing of the heart, or additional electrodes can be used in the heart cavity. G. Implantable main control unit (500 in FIG. 1) for controlling the system. The implanted unit acquires data, executes new algorithms, provides new CPRC pacing, records the patient's condition, and communicates with an external device. This unit can be implanted under the pectoral muscle as a normal pacemaker. As shown in FIG. 5, the implantable unit includes two subsystems. The long-term control system provides communication with the external device, records and stores data on the patient's electrical and various hemodynamic indicators, determines the severity of dyspnea, and sets parameters necessary for the operation of the actual control subsystem. The actual control subsystem identifies an appropriate pacing window based on the respiratory wave and identifies the pacing at the appropriate time following the latest heart based on the designed RR interval. It is important to note that the pacing is synchronized with the respiratory wave, which is very irregular, with the respiratory rate, amplitude, and shape changing instantaneously, so the pacing time cannot be predicted in advance like most cardiac pacemakers. H. Extracorporeal Unit (600 in Figure 1). The extracorporeal unit communicates with the implanted main unit and, if necessary, with the Web. The extracorporeal unit allows for setting various parameters of the implanted device and checks the proper functioning of various sensors and thresholds of various pacing electrodes. It can record past history for analysis of various cardiac and respiratory events. The system provides an easy-to-use interface for medical staff and allows remote monitoring by medical staff and field specialists.

[0035] Placing the heart within the thoracic cage has two physiological advantages. The thoracic cage protects the heart and major blood vessels from external influences, and the "respiratory pump" increases cardiac output by increasing venous return. Normal physiological control of heart rate aims to increase cardiac output during exercise and is efficient in healthy subjects. The increased work of breathing by the "respiratory pump" (the diaphragm and all respiratory and accessory muscles) reduces intrathoracic pressure during inspiration and promotes venous return to the right atrium. Left ventricular cardiac output is equal to and limited by venous return at steady state. Under normal physiological conditions, increased venous return and subsequent right atrial distension promote the pacing rate of the sinus node. Heart rate increases, especially during inspiration, because venous return increases during inspiration. This phenomenon is called "respiratory sinus arrhythmia" and is illustrated in Figure 2. The increase in cardiac output during exercise is due to increased venous return to the heart and an increase in heart rate.

[0036] However, apart from this positive effect of the "respiratory pump" on cardiac output under normal physiological conditions, increased respiratory effort has profound adverse effects on the pulmonary circulation and cardiac workload. Increased respiratory effort increases (1) intrapulmonary capillary pressure (PCWP), (2) pulmonary vascular resistance (PVR), pulmonary artery pressure (PAP), and right ventricular afterload, (3) pulmonary congestion due to blood shift to the lungs, (4) left ventricular afterload, and (5) metabolic demand due to increased respiratory muscle work. All these mechanisms are explained in more detail in the accompanying supplement. These five adverse effects of increased respiratory effort lead to accelerated decompensation in the presence of cardiac or pulmonary disease.

[0037] It is important to note that intrathoracic (pleural) pressure has a significant effect on pulmonary hemodynamics and pulmonary congestion. Negative intrathoracic pressure increases the blood pool in the lungs, increasing pulmonary bed pressure. This is because: 1. It reduces the transvascular diameter of the post-capillary pulmonary tree, increasing resistance to inflow into the left atrium and decreasing outflow from the lungs. 2. Increases pulmonary vascular resistance throughout the pulmonary system, elevating pulmonary capillary and pulmonary arterial pressures (compared to the instantaneous ambient intrathoracic pressure). 3. Increases right atrial preload and venous return to the right ventricle, increasing right ventricular output. 4. Increases left ventricular afterload and decreases left ventricular stroke volume. Thus, inflow through the right ventricle increases and outflow through the left ventricle decreases during inspiration. These effects are accentuated with increasing respiratory effort. This is because.

[0038] All of these effects are reversed when intrathoracic pressure is near or just above zero. At this stage, the following occurs: 1. Increased transvascular pressure in the post-capillary pulmonary tree, accompanied by a decrease in resistance to flow from the lungs to the left atrium, increasing left atrial preload. 2. Dilation of pulmonary blood vessels under high pressure, resulting in a decrease in overall transpulmonary resistance. 3. Decreased preload and venous return to the right atrium and decreased inflow of blood to the lungs through the right ventricle. 4. A decrease in left ventricular afterload increases the left ventricular stroke volume. Therefore, negative intrathoracic pressure increases the movement of blood from the periphery through the right ventricle to the lungs. In contrast, near-zero intrathoracic pressure is associated with an increase in the diameter of the pulmonary vasculature (reducing resistance to flow through the pulmonary system) and the movement of blood from the lungs through the left ventricle.

[0039] At steady state, the cardiac stroke volume averages approximately 70 ml, with approximately 70 ml of blood entering the lungs through the right ventricle and an equal volume of 70 ml being expelled through the left ventricle, as shown in Figure 4. However, as intrathoracic pressure decreases, the inflow into the right ventricle increases, from 70 to 70.5 ml in the example shown in Figure 3. Simultaneously, the outflow from the lungs through the left ventricle decreases from 70.0 ml to 69.5 ml. As intrathoracic pressure approaches zero, the image inverts, as shown in Figure 4, and the blood volume in the lungs reaches a steady state. Figure 3 also illustrates the physiological "respiratory sinus arrhythmia," in which the heart rate increases during inspiration. The main strategy behind this innovation is to utilize the "respiratory pump" (part of the work of inspiration and expiration) and cardiac contraction to pump blood out of the lungs and relieve hemodynamic congestion. This is done by adjusting the heart's pacing in response to changes in intrathoracic pressure, but counterintuitively, it works against normal physiology, increasing the heart rate during end-expiration and early inspiration. During end-expiration and early inspiration, when intrathoracic pressure is negative and the "respiratory pump" increases right ventricular preload and left ventricular afterload, the new device slows the pacing rate, reducing net inflow to the lungs. During late expiration and early inspiration, when the "respiratory pump" decreases right ventricular preload and increases left ventricular preload, the device increases the pacing rate to expedite blood removal from the lungs.

[0040] In the example shown in Figure 3, the average heart rate is 72 bpm under normal conditions with respiratory sinus arrhythmia and cardiopulmonary reversal circulation therapy (CPRC). However, the device imposes a higher pacing rate during the late expiration and early inspiration phases, in contrast to conventional pacing. As a result, there are only two beats during the two seconds of inspiration, but four beats during the three seconds of expiration. If pulmonary inflow increases by 0.5 ml (+0.7% of stroke volume) and outflow through the left ventricle decreases by 0.5 ml (-0.7%), then for every heartbeat during the negative intrathoracic pressure interval, each beat during this interval increases pulmonary blood volume by 1 ml. Overall, if the heart rate decreases to two beats during the negative pressure interval, blood movement during this time interval decreases to only 2 ml (instead of 3). During intervals with high intrathoracic pressure, the image is inverted, as shown in Figure 3. With each heartbeat, there is a 0.5 ml decrease in inflow to the lungs (-0.7% of stroke volume) and a 0.5 ml increase in outflow through the left ventricle (+0.7%). CPRC increases the heart rate to four beats (instead of three) during intervals of high intrathoracic pressure, increasing the movement of blood from the lungs to 4 ml (instead of 3 ml). Thus, CPRC generates a net movement of 2 ml from the lungs during one respiratory cycle (within 5 seconds). While the effect within one respiratory cycle is small, it is cumulative; as shown in Figure 3, a respiratory rate of 12 bpm results in a net outflow of 24 ml from the lungs within 1 minute and 120 ml in just 10 minutes. It is important to note that under normal conditions, there is only approximately 500 ml of blood in the lungs, and the cumulative effect within 10 ml is very large (theoretically, it could reduce pulmonary blood volume by 24%). The effect of CPRC diminishes over time as the pulmonary blood pool may decrease. However, pulmonary congestion, increased respiratory effort, and deeper modulation of CPRC (larger heart rate difference between inspiration and expiration) enhance the effect of CPRC in a coordinated mode, which cooperatively helps to relieve hemodynamics and pulmonary congestion.

[0041] Additionally, please note the following: (1) One simple implementation of the proposed "cardiopulmonary reverse circulation therapy" would include the following: A. Quantification of the severity of respiratory effort, a proxy for respiratory distress, by measuring the amplitude of respiratory waves in the thoracic cage. B. Setting of an appropriate threshold by the long-term central control subsystem and segmentation of the respiratory cycle into time segments below the threshold (deep negative phase) and above the threshold (intrathoracic pressure close to zero). C. Place one pacing electrode in the right atrium (if the patient does not have either atrial arrhythmia or atrioventricular block). D. Increased pacing rate when intrathoracic pressure is near zero (end-expiration and early-inspiration, as shown in Figure 4) without the need for artificial suppression of the normal sinus node. Pacing is controlled by a real-time central control subsystem. E. Provides adaptive control of pacing rate. Pacing is adjusted according to the severity of respiratory effort. The long-term central subsystem decides to provide this adaptive control of pacing based on acquired sensing. A single cable can contain the required sensing (A) and pacing (C). (2) Recent studies have shown that pulmonary congestion occurs over a long period of time in patients with heart failure. Pulmonary capillary wedge pressure and pulmonary artery pressure increase slowly and gradually over a period of 2–3 weeks before more aggressive treatment or hospitalization becomes necessary. Therefore, the proposed method induces a slight movement of fluid from the lungs to the periphery, but does so slowly and sustainably over a long time interval, thereby preventing the gradual progression of pulmonary congestion. (3) Both an increase in the amplitude of respiratory effort and an extension of the inspiratory phase from 20-25% of the respiratory cycle to 50% of the cycle promote pulmonary congestion. The former increases blood movement to the lungs with each heartbeat, while the latter increases the heart rate during each inspiratory phase. Hemodynamic and pulmonary congestion increase respiratory effort. The proposed "cardiopulmonary reverse circulation therapy" is expected to break the "cardiopulmonary vicious cycle" and reduce hemodynamic congestion, associated respiratory effort, and inspiratory time. Therefore, cardiopulmonary reverse circulation therapy can be adjusted according to respiratory effort. (4) The device has a significant effect on pulmonary congestion but a minor effect on cardiac output. Because the effect on heart rate is small, the effect on cardiac output is minor. Despite this negligible effect on cardiac output, there is a large cumulative effect on the pulmonary blood pool and a large shift of blood from the lungs back to the periphery. (5) A further advantage of the present invention is its protective effect against atrial fibrillation in patients with heart failure. Hemodynamic and pulmonary congestion are associated with significant respiratory effort. Respiratory effort and the resulting significant decrease in intrathoracic pressure (above -20 mmHg, as observed in patients with heart failure) significantly increases transmural atrial pressure, leading to atrial dilation. This mechanism promotes a decrease in atrial function, leading to atrial dilation and the onset of atrial fibrillation. Therefore, preventing hemodynamic congestion and reducing transmural atrial pressure can prevent the onset of atrial fibrillation.

[0042] Applications of the present invention include, but are not limited to, the treatment of patients with heart failure, including all types of heart failure. The purpose of the present invention is to reduce the likelihood of progressive hemodynamic or pulmonary congestion. The present invention can provide an accurate diagnosis of the severity of decompensation based on the assessment of the severity of respiratory effort and hemodynamic congestion. Furthermore, it provides immediate, proportionate, and appropriate treatment to prevent further deterioration and restore normal conditions. Dyspnea is the most important symptom of heart failure, and this technology directly targets this symptom.

[0043] It is important to note that: (1) Although there is no effective treatment for heart failure that preserves ejection fraction, this technique can alleviate symptoms in these patients. (2) The present invention provides instant diagnosis and real-time treatment, which is not available in the prior art. (3) Unlike diuretic therapy, which can cause excessive dehydration with a concomitant decrease in cardiac output, the present invention has only a small effect on cardiac output and can even increase it. Unlike typical prior art diuretic therapy, which does not control the balance between the peripheral and pulmonary blood pools, the present invention can provide this important control over the movement of blood between the peripheral and pulmonary blood pools.

Claims

1. A system for controlling cardiac pacing, comprising: The system is configured to increase a pacing rate during pacing windows corresponding to elevated intrathoracic pressure.

2. In the system described in claim 1, at least one sensor; and circuitry for determining the time period based on a signal from the at least one sensor.

3. In the system described in claim 2, The system, wherein the at least one sensor comprises at least one of a pressure sensor, an impedance sensor, and an ECG sensor.

4. The system described in claim 3, characterized in that it includes a subsystem that determines the pacing time frame based on respiration.

5. In the system described in claim 4, configured to generate a pacing signal for a cardiac pacing rate; (a) determining a time window corresponding to elevated intrathoracic pressure; (b) responsive to the determination of the time periods, increasing a rate of generation of pacing signals during the time periods for a plurality of time periods.

6. The system of claim 5, wherein the rate increase is an amount suitable for reversing a vicious cardiopulmonary cycle when applied to an adult with heart failure.

7. A system as described in claim 5 or 6, characterized in that the rate increase, when applied to an adult with heart failure, is an amount suitable for at least one of treating heart failure, relieving dyspnea, and preventing progression to pulmonary congestion and pulmonary edema.

8. A system as described in any one of claims 5 to 7, characterized in that the time period of high intrathoracic pressure includes both inhalation and exhalation portions.

9. A system as described in any one of claims 5 to 8, characterized in that the system is configured to determine the time window using pressure detection.

10. A system as claimed in any one of claims 5 to 8, characterized in that the system is configured to determine the time window using ECG detection.

11. A system as described in any one of claims 5 to 10, characterized in that the time period of high intrathoracic pressure includes a time when the intrathoracic pressure is close to zero.

12. A system described in any one of claims 5 to 11, characterized in that the system divides the respiratory cycle based on a threshold value to obtain the time frame.

13. A system as described in any one of claims 5 to 12, characterized in that the increase in the rate is performed according to the severity of the respiratory effort and / or the severity of pulmonary congestion.

14. A system as described in any one of claims 5 to 13, characterized in that the increase in the rate is performed in response to detection of symptoms of cardiac dysfunction before they appear.

15. A system as described in any one of claims 5 to 14, characterized in that the pacing signal is not generated when respiratory effort is normal.

16. A system as described in any one of claims 5 to 15, characterized in that it comprises an extracorporeal unit for recording respiratory history and setting parameters of the implanted unit for pacing.

17. A system as described in any one of claims 5 to 16, characterized in that it is configured to generate a signal suitable for inhibiting sinus node pacing during periods of low intrathoracic pressure.

18. A system as described in any one of claims 5 to 17, characterized in that increasing the rate includes determining the number of beats to add in the time frame.

19. A system described in any one of claims 5 to 18, characterized in that the increase in rate is an amount appropriate for transferring body fluid per day from the pulmonary circulation to the systemic circulation when applied to an adult with heart failure.

20. A system as described in any one of claims 5 to 19, characterized in that when applied to an adult with heart failure, the increase in rate is such that the amount of fluid in the additional pulses caused by the increased rate is suitable for transferring fluid from the pulmonary circulation to the systemic circulation.

21. A method of operating a pacing system that generates a pacing signal, comprising: (a) determining a time frame; (b) increasing the rate of generation of pacing signals during a plurality of time periods in response to the determination of the time periods.

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