Patent Application
20080114408
This invention pertains to apparatus and methods for the treatment of heart disease and to devices providing electrostimulation to the heart such as cardiac pacemakers.
Heart failure (HF) is a debilitating disease that refers to a clinical syndrome in which an abnormality of cardiac function causes a below normal cardiac output that can fall below a level adequate to meet the metabolic demand of peripheral tissues. Heart failure can be due to a variety of etiologies with ischemic heart disease being the most common. Inadequate pumping of blood into the arterial system by the heart is sometimes referred to as “forward failure,” with “backward failure” referring to the resulting elevated pressures in the lungs and systemic veins which lead to congestion. Backward failure is the natural consequence of forward failure as blood in the pulmonary and venous systems fails to be pumped out. Forward failure can be caused by impaired contractility of the ventricles due, for example, to coronary artery disease, or by an increased afterload (i.e., the forces resisting ejection of blood) due to, for example, systemic hypertension or valvular dysfunction. One physiological compensatory mechanism that acts to increase cardiac output is due to backward failure which increases the diastolic filling pressure of the ventricles and thereby increases the preload (i.e., the degree to which the ventricles are stretched by the volume of blood in the ventricles at the end of diastole). An increase in preload causes an increase in stroke volume during systole, a phenomena known as the Frank-Starling principle. Thus, heart failure can be at least partially compensated by this mechanism but at the expense of possible pulmonary and/or systemic congestion.
When the ventricles are stretched due to the increased preload over a period of time, the ventricles become dilated. The enlargement of the ventricular volume causes increased ventricular wall stress at a given systolic pressure. Along with the increased pressure-volume work done by the ventricle, this acts as a stimulus for hypertrophy of the ventricular myocardium which leads to alterations in cellular structure, a process referred to as ventricular remodeling. Ventricular remodeling leads to further dysfunction by decreasing the compliance of the ventricles (thereby increasing diastolic filling pressure to result in even more congestion) and causing eventual wall thinning that causes further deterioration in cardiac function. It has been shown that the extent of ventricular remodeling is positively correlated with increased mortality in HF patients.
A myocardial infarction (MI) is the irreversible damage done to a segment of heart muscle by ischemia, where the myocardium is deprived of adequate oxygen and metabolite removal due to an interruption in blood supply. It is usually due to a sudden thrombotic occlusion of a coronary artery, commonly called a heart attack. If the coronary artery becomes completely occluded and there is poor collateral blood flow to the affected area, a transmural or full-wall thickness infarct can result in which much of the contractile function of the area is lost. Over a period of one to two months, the necrotic tissue heals, leaving a scar. The most extreme example of this is a ventricular aneurysm, where all of the muscle fibers in the area are destroyed and replaced by fibrous scar tissue. Even if the ventricular dysfunction as a result of the infarct is not immediately life-threatening, a common sequela of a transmural myocardial infarction, or any major MI, especially in the left ventricle, is heart failure brought about by ventricular remodeling in response to the hemodynamic effects of the infarct that causes changes in the shape and size of the ventricle. The remodeling is initiated in response to a redistribution of cardiac stress and strain caused by the impairment of contractile function in the infarcted area as well as in nearby and/or interspersed viable myocardial tissue with lessened contractility due to the infarct. Following an MI, the infarcted area includes tissue undergoing ischemic necrosis and is surrounded by normal myocardium. Until scar tissue forms and even after it forms, the area around the infarcted area is particularly vulnerable to the distending forces within the ventricle and undergoes expansion over a period of hours to days. Over the next few days and months after scar tissue has formed, global remodeling and chamber enlargement occur due to complex alterations in the architecture of the ventricle involving both infarcted and non-infarcted areas. It has been found that the extent of left ventricular remodeling in the late period after an infarction, as represented by measurements of end-systolic and end-diastolic left ventricular volumes, is an even more powerful predictor of subsequent mortality than the extent of coronary artery disease.
Remodeling is thought to be the result of a complex interplay of hemodynamic, neural, and hormonal factors that occur primarily in response to myocardial wall stress. As noted above, one physiological compensatory mechanism that acts to increase cardiac output is increased diastolic filling pressure of the ventricles as an increased volume of blood is left in the lungs and venous system, thus increasing preload. The ventricular dilation resulting from the increased preload causes increased ventricular wall stress at a given systolic pressure in accordance with Laplace's law. Along with the increased pressure-volume work done by the ventricle, this acts as a stimulus for compensatory hypertrophy of the ventricular myocardium. Hypertrophy can increase systolic pressures but, if the hypertrophy is not sufficient to meet the increased wall stress, further and progressive dilation results. This non-compensatory dilation causes wall thinning and further impairment in left ventricular function. It also has been shown that the sustained stresses causing hypertrophy may induce apoptosis (i.e., programmed cell death) of cardiac muscle cells. Thus, although ventricular dilation and hypertrophy may at first be compensatory and increase cardiac output, the process ultimately results in further deterioration and dysfunction.
It has long been known that the heart muscle responds favorably to exercise so as to result in greater pumping efficacy. Studies have shown that HF and post-MI patients can improve their cardiac function and prognosis with regular periods of exercise. Many HF and post-MI patients, however, are either debilitated and cannot exercise or do not tolerate exercise well enough to exercise effectively.
Clinical studies have shown that HF and post-MI patients who follow a regular (e.g. 20 min/day, 3 times a week) exercise regimen have symptomatic improvement compared to those who are sedentary. However, not all HF and post-MI patients can exercise due to their cardiac disease or other debilitating conditions. This disclosure describes methods and devices that use short durations of pacing therapy designed to mimic exercise in order to provide protection from heart failure development and/or attenuation/reversal of cardiac disease progression.
When cardiac output is insufficient to meet the increased metabolic demand, the body responds to the situation with increased activity of the sympathetic nervous system that, among other things, increases heart rate, myocardial contractility, and blood volume. Although acutely beneficial, the long-term effects of increased sympathetic activity are deleterious and lead to ventricular remodeling such as described above. A characteristic feature of chronic cardiac disease is an abnormal autonomic tone with an attenuated level of parasympathetic activity relative to sympathetic activity. When the heart is stressed on a periodic short-term basis, however, such as occurs with regular exercise, the effect is beneficial on both myocardial function and autonomic tone, leading to an increased level of parasympathetic activity. In order to mimic the effects of exercise, pacing therapy can be delivered on a short-term basis in a manner that stresses the heart similar to exercise. Such pacing therapy is referred to herein as simulated exercise pacing. Simulated exercise pacing may generally involve pacing the heart in a manner that temporarily compromises cardiac output by producing relatively inefficient ventricular contractions and/or some degree of atrio-ventricular dyssynchrony.
As described below, a device for delivering such simulated exercise pacing may be a device with the capability of also delivering bradycardia pacing, CRT, cardioversion/defibrillation shocks, and/or neural stimulation (e.g., vagal nerve stimulation). The device may be programmed to deliver simulated exercise pacing for a prescribed amount of time per day (e.g. 30 min). The time when therapy delivery is started may be random (once per day at a random time), at a specific time each day, or triggered by a specific event (e.g. when the patient falls asleep, the patient wakes up, or the patient's exertion level falls below a certain threshold).
The sensing circuitry 20 receives atrial and/or ventricular electrogram signals from sensing electrodes and includes sensing amplifiers, analog-to-digital converters for digitizing sensing signal inputs from the sensing amplifiers, and registers that can be written to for adjusting the gain and threshold values of the sensing amplifiers. The sensing circuitry of the pacemaker detects a chamber sense, either an atrial sense or ventricular sense, when an electrogram signal (i.e., a voltage sensed by an electrode representing cardiac electrical activity) generated by a particular channel exceeds a specified detection threshold. Pacing algorithms used in particular pacing modes employ such senses to trigger or inhibit pacing, and the intrinsic atrial and/or ventricular rates can be detected by measuring the time intervals between atrial and ventricular senses, respectively.
The pulse generation circuitry 30 delivers pacing pulses to pacing electrodes disposed in the heart and includes capacitive discharge or current source pulse generators, registers for controlling the pulse generators, and registers for adjusting pacing parameters such as pulse energy (e.g., pulse amplitude and width). The device allows adjustment of the pacing pulse energy in order to ensure capture of myocardial tissue (i.e., initiating of a propagating action potential) by a pacing pulse. The pulse generation circuitry may also include a shocking pulse generator for delivering a defibrillation/cardioversion shock via a shock electrode upon detection of a tachyarrhythmia.
A telemetry transceiver 80 is interfaced to the controller which enables the controller to communicate with an external device such as an external programmer and/or a remote monitoring unit. An external programmer is a computerized device with an associated display and input means that can interrogate the pacemaker and receive stored data as well as directly adjust the operating parameters of the pacemaker. The external device may also be a remote monitoring unit that may be interfaced to a patient management network enabling the implantable device to transmit data and alarm messages to clinical personnel over the network as well as be programmed remotely. The network connection between the external device and the patient management network may be implemented by, for example, an internet connection, over a phone line, or via a cellular wireless link. A magnetically or tactilely actuated switch 24 is also shown as interfaced to the controller in this embodiment to allow the patient to signal certain conditions or events to the implantable device. The controller may be programmed to use actuation of the switch 24 to initiate and/or cease exercise simulation pacing.
A pacing channel is made up of a pulse generator connected to an electrode, while a sensing channel is made up of a sense amplifier connected to an electrode. Shown in the figure are electrodes 401 through 40N where N is some integer. The electrodes may be on the same or different leads and are electrically connected to a MOS switch matrix 70. The switch matrix 70 is controlled by the controller and is used to switch selected electrodes to the input of a sense amplifier or to the output of a pulse generator in order to configure a sensing or pacing channel, respectively. The device may be equipped with any number of pulse generators, amplifiers, and electrodes that may be combined arbitrarily to form sensing or pacing channels. The device is therefore capable of delivering single-site or multiple site ventricular pacing for purposes of exercise simulation as well as conventional pacing. One or more pacing channels may also be configured, by appropriate lead placement and pulse energy/frequency settings, for delivering electrical stimulation to stimulate sympathetic and/or parasympathetic nerves. For example, a lead with a stimulation electrode may be placed in proximity to the vagus nerve in order to stimulate that nerve and increase parasympathetic activity. The switch matrix 70 also allows selected ones of the available implanted electrodes to be incorporated into sensing and/or pacing channels in either unipolar or bipolar configurations. A bipolar sensing or pacing configuration refers to the sensing of a potential or output of a pacing pulse between two closely spaced electrodes, where the two electrodes are usually on the same lead (e.g., a ring and tip electrode of a bipolar lead or two selected electrodes of a multi-polar lead). A unipolar sensing or pacing configuration is where the potential sensed or the pacing pulse output by an electrode is referenced to the conductive device housing or another distant electrode.
The controller is capable of operating the device in a number of programmed pacing modes which define how pulses are output in response to sensed events and expiration of time intervals. Most pacemakers for treating bradycardia are programmed to operate synchronously in a so-called demand mode where sensed cardiac events occurring within a defined interval either trigger or inhibit a pacing pulse. Inhibited demand pacing modes utilize escape intervals to control pacing in accordance with sensed intrinsic activity such that a pacing pulse is delivered to a heart chamber during a cardiac cycle only after expiration of a defined escape interval during which no intrinsic beat by the chamber is detected. Escape intervals for ventricular pacing can be restarted by ventricular or atrial events, the latter allowing the pacing to track intrinsic atrial beats and/or follow atrial paces. An exertion level sensor (such as the accelerometer 26 or the minute ventilation sensor 25 shown in
The pacing device just described may be configured to deliver pacing therapy in a number of pacing modes with different configurations of pacing channels and different pacing parameter settings. For example, the device may be programmed to deliver single-site ventricular pacing, biventricular pacing, or multi-site ventricular pacing. Such pacing may be delivered using atrial tracking modes (e.g., DDD or VDD) and AV sequential modes (e.g., DVI, DDI) where a ventricular pace(s) is delivered upon expiration of an AV delay interval following an atrial sense or pace if no ventricular sense occurs before expiration. Pacing can also be delivered in non-atrial tracking modes such as VVI where a pace is delivered upon expiration of a ventricular escape interval started by a ventricular sense or pace if no ventricular sense occurs before expiration. These pacing modes are examples of bradycardia pacing modes because they were originally developed to treat bradycardia by enforcing some minimum heart rate. Pacing delivered in conjunction with such bradycardia pacing modes, however, can also be used to treat conditions other than bradycardia. It has been shown that some heart failure patients suffer from intraventricular and/or interventricular conduction defects (e.g., bundle branch blocks) such that their cardiac outputs can be increased by improving the synchronization of ventricular contractions with electrical stimulation. In order to treat these problems, implantable cardiac devices have been developed that provide appropriately timed electrical stimulation to one or more heart chambers in an attempt to improve the coordination of atrial and/or ventricular contractions, termed cardiac resynchronization therapy (CRT). Ventricular resynchronization is useful in treating heart failure because, although not directly inotropic, resynchronization can result in a more coordinated contraction of the ventricles with improved pumping efficiency and increased cardiac output. Currently, a most common form of CRT applies stimulation pulses to both ventricles, either simultaneously or separated by a specified biventricular offset interval, and after a specified atrio-ventricular delay interval with respect to the detection of an intrinsic atrial contraction or delivery of an atrial pace.
As discussed above, myocardial infarction and/or heart failure can cause deleterious ventricular remodeling. It has been shown that remodeling and/or patient quality of life can be improved in MI/HF patients with a regimen of regular exercise (e.g., 30 minutes a day for 3 times a week). Thus, short intervals of stress to the body provide a chronic benefit (i.e., a training effect). A similar benefit may be elicited by applying short intervals of stress isolated to the ventricles with intermittent pacing therapy designed to compromise cardiac output, referred to herein as simulated exercise pacing. Simulated exercise pacing may include any or all of the following: 1) pacing a ventricle in an atrial tracking or AV sequential pacing mode using a shortened AV delay that causes diminished left ventricular filling during diastole, 2) pacing a ventricle in a VVI mode to limit the atrial contraction contribution to left ventricular filling during diastole, 3) pacing one or both ventricles at a site or sites that produce an asynchronous and inefficient ventricular contraction, 4) biventricular pacing with an interventricular pacing delay designed to produce inefficient cardiac contractions, and 5) rapid pacing (atrial or ventricular) using any pacing mode at a rate that prevents adequate ventricular filling. In response to such simulated exercise pacing, the body compensates for the reduced cardiac output by increasing heart rate, increasing myocardial contractility, and/or increasing blood volume. Stressing the heart continuously in this manner would be detrimental, but delivering additional stress intermittently provides a training effect and is beneficial to the heart. Simulated exercise pacing may be applied, for example, for a few minutes each day or delivered intermittently on some other basis. Following these short periods of stress, the parasympathetic system may be activated, thereby providing therapeutic benefit. Similar to the benefits that transient exercise provides the entire body, intermittent stress localized to the ventricles brought about by simulated exercise pacing allows the heart to become stronger and more resistant to future stressful situations.
Stressing the heart by delivering simulated exercise pacing as described above may or may not cause a drop in cardiac output, depending upon how an individual patient responds. Some patients, for example, may be capable of responding to the stress of simulated exercise pacing in a manner that prevents a significant decrease in cardiac output. In other patients, after an MI or during heart failure, the compromised ventricles may be less then capable of maintaining normal cardiac output. A feedback mechanism may be implemented that analyze cardiac performance indicators and modulates delivery of the therapy accordingly. For example, a cardiac output sensor may be incorporated into the device that measures ventricular volumes using an impedance technique. Simulated exercise pacing may then be delivered or not delivered in accordance with whether the cardiac output is found to be above or below a specified threshold value, where the specified threshold may be made to be dependent upon a measured exertion level. As described below, simulated exercise pacing may also be initiated and/or ceased depending upon the detection of certain conditions related to the patient's physiological status. Simulated exercise pacing therapy may also be combined with other device therapies such as bradycardia, tachycardia, cardiac resynchronization, or post-MI pacing.
As described above, pacing can be delivered to the heart in a way that mimics the beneficial effects of exercise. Chronic simulated exercise pacing, however, would overstress the heart in HF or post-MI patients and could be hazardous. Accordingly, simulated exercise pacing should be delivered on an intermittent basis. A device such as shown in
In order to provide intermittent simulated exercise pacing, the device switches from its normal operating mode to the simulated exercise mode based upon lapsed time intervals and/or in response to detection of one or more particular triggering conditions or events. In another embodiment, the device may switch to the simulated exercise mode upon receiving a command to do so for some specified period of time, where such a command may be received from an external programmer, or received via a patient management network. A defined schedule may specify switching to the simulated exercise mode at periodic intervals (e.g., for five minutes each day) or at a random time during each day or other specified time period. Such a defined schedule could also specify a time for switching to the simulated exercise mode when a patient is expected to be awake or when a patient is expected to be sleeping. A defined schedule may also prescribe an amount of time over a specified time period for which the device is to operate in the simulated exercise mode. For example, the defined schedule may prescribe that simulated exercise pacing be delivered for one hour each day. The controller may then be programmed to opportunistically switch to the simulated exercise mode when one or more specified triggering conditions are met in order to meet the prescriptions of the defined schedule. Examples of possible triggering conditions are a measured exertion level being within a specified entry range, a measured heart rate being within a specified entry range, and actuation of a magnetically or tactilely actuated switch incorporated into the device by the patient that initiates simulated exercise pacing. In such embodiments, the simulated exercise pacing delivered in response to the triggering events may then be limited in amount or duration over some specified period of time. For example, the device could be programmed to deliver no more than 30 minutes of simulated exercise pacing per day in response to such triggering events.
In order to reliably provide the desired hemodynamic effects when switched to the simulated exercise mode, the device can be programmed use escape intervals designed for that purpose during the simulated exercise mode. For example, the simulated exercise pacing may be delivered to the ventricles in an atrial triggered synchronous mode (e.g., DDD or VDD) with predefined atrio-ventricular (AV) and ventricular-ventricular (VV) escape intervals or in a non-atrial triggered ventricular pacing mode (e.g., VVI) with a pre-defined ventricular escape interval where the length of the escape intervals may be set to values which result in a diminished end-diastolic ventricular filling volume. It may be desirable, however, to incorporate additional steps into the algorithm before switching. For example, the escape intervals for the simulated exercise mode may be dynamically determined before the mode switch in order to ensure the desired hemodynamic effect. In an embodiment where the simulated exercise mode is a non-atrial triggered pacing mode, the device may measure the patient's intrinsic heart rate before the mode switch and then set the ventricular escape interval so that the pacing rate for the simulated exercise pacing mode is higher than the intrinsic rate. If the patient is receiving rate-adaptive ventricular pacing therapy in the normal operating mode, the ventricular escape interval for the simulated exercise pacing mode may be similarly modulated by an exertion level measurement. In an embodiment where the simulated exercise pacing is delivered in an atrial triggered pacing mode, the device may measure the patient's intrinsic AV interval before the mode switch (e.g., as an average over a number of cycles preceding the mode switch) so that the AV escape interval for delivering ventricular pacing can be set to a value that results in some degree of atrio-ventricular dyssynchrony.
As discussed above, it may be desirable for the device to switch to the simulated exercise mode according to a defined schedule only if one or more specified entry conditions are satisfied. Whether or not entry conditions are employed, it may also be desirable for the device to exit the simulated exercise mode if one or more specified exit conditions occur. Finally, a defined schedule for switching to the simulated exercise mode may employ one or more specified triggering conditions that when satisfied cause the mode switch. Discussed below are examples of conditions that can be detected by appropriately configured implantable device and used as entry, exit, and/or triggering conditions.
One example of a triggering and/or entry condition is if the measured exertion level is within a specified range, where the exertion level may be measured, for example, as minute ventilation with a minute ventilation sensor, as an activity level with an accelerometer, or some combination of such measurements. Another example of a triggering and/or entry condition is if the patient's heart rate is within a specified range, where the heart rate is measured via a cardiac sensing channel. With some patients, it may be desirable for the simulated exercise mode to take place when the patient is not active as reflected by a measured exertion level and/or heart rate below a specified value. With other patients, on the other hand, it may be desirable to switch to the simulated exercise mode only when the patient is deemed to be active, as determined by an exertion level and/or heart rate above a specified value. A measured exertion level and/or heart rate either above or below a specified value may also be used as a triggering event to initiate the simulated exercise mode for some specified period of time. A measured exertion level or heart rate may also be used as an exit condition such that the device is programmed to revert from the simulated exercise mode back to the normal operating mode if the measured exertion level and/or heart rate falls outside of a specified permissible range.
It may also be desirable to inhibit a switch to the simulated exercise mode and/or revert to the normal operating mode if the patient is presently experiencing some degree of cardiac ischemia and/or a cardiac arrhythmia is detected. The device may be configured to detect cardiac ischemia from a morphology analysis of an electrogram collected during an intrinsic or a paced beat, the latter sometimes referred to as an evoked response. The electrogram for detection of ischemia is recorded from a sensing channel that senses the depolarization and repolarization of the myocardium during a cardiac cycle. The sensing channel used for this purpose may be a sensing channel used for detecting cardiac arrhythmias and/or intrinsic beats or may be a dedicated channel. In order to detect an ischemic change, the electrogram can be compared with a reference electrogram to see if a current of injury is present. The comparison may involve, for example, cross-correlating the recorded and reference electrograms or comparing ST segment amplitudes, slopes, or integrations with reference values. If a change in a recorded electrogram indicative of ischemia is detected and/or a cardiac arrhythmia is detected, the controller may be programmed to inhibit switching to simulated exercise mode and/or programmed to revert back to the normal operating mode. Detection of cardiac ischemia or cardiac arrhythmias may also be logged as clinically significant events in the pacemaker's memory, where the event log and/or the recorded electrogram exhibiting the ischemia or arrhythmia may then be later downloaded to a clinician for analysis via an external programmer and/or a patient management network. Information derived from other analyses or other sensing modalities may also be used to more specifically detect cardiac ischemia. For example, dyspnea or other abnormal breathing patterns may be detected using a minute ventilation sensor by programming the controller to compare the transthoracic impedance signal from the sensor with a template representing the abnormal pattern.
In many instances, simulated exercise pacing as described above may be only needed for some temporary period of time. For example, some post-MI and HF patients may over time recover sufficiently so that they can exercise normally and do not need simulated exercise. For these patients, a conventionally implanted pacing device such as illustrated in
A particularly suitable embodiment of a pacing device for delivering simulated exercise therapy on temporary basis is one that is incorporated entirely into a lead. That is, rather than having the pacing circuitry illustrated in
Integrating a pacing device into a lead requires that the components of the pacing device be small and able to be packaged into a relatively thin lead. In some embodiments, depending on the type of batteries used, the requirement that the batteries be small may limit the amount of energy that can be stored in them. In these embodiments, the pacing device will only function for some limited period of time and may be appropriately used only for temporary applications. As has been noted, one important temporary application of pacing therapy may be to deliver simulated exercise pacing. In other embodiments, the batteries are rechargeable, allowing the device to be used for permanent pacing. Recharging techniques such as acoustic and/or inductive coupling can be utilized. In still other embodiments, highly efficient batteries may be used to extend the time for which the integrated lead/pacing device may function so that other applications of pacing therapy with the device are appropriate. In any event, an integrated lead/pacing device as described below may be used not only for simulated exercise pacing but also for other applications such as conventional bradycardia pacing, cardiac resynchronization pacing, stress reducing post-MI pacing, or monitoring-only applications.
Although the invention has been described in conjunction with the foregoing specific embodiments, many alternatives, variations, and modifications will be apparent to those of ordinary skill in the art. Other such alternatives, variations, and modifications are intended to fall within the scope of the following appended claims.
