Patent Application
20060004413
The invention generally relates to a methods and systems for the prediction of cardiac arrhythmias of the type that can result in sudden cardiac death.
Sudden cardiac death (SCD) is a major public health problem that accounts for more than half of all cardiovascular deaths. SCD takes the lives of approximately 450,000 people in the United States each year, more than lung cancer, breast cancer, stroke, and AIDS combined. Most cases of SCD are due to ventricular arrhythmias and there is often an element of underlying ischemic heart disease. Ventricular tachycardia (VT) and ventricular fibrillation (VF) are different types of ventricular arrhythmias. VT is an abnormally fast ventricular heart rhythm which is, by itself, typically not fatal. VF is a chaotic ventricular heart rhythm which produces little or no net blood flow from the heart, such that there is little or not net blood flow to the brain and other organs. VF, if not terminated, results in death. Patient groups most at risk of ventricular arrhythmias leading to SCD include those with an acute or chronic myocardial infarction. Accordingly, deaths from SCDs may be lowered by preventing the specific heart rhythm disturbances (ventricular arrhythmias) associated with it.
Different treatment options exist for SCD. The most common treatment includes implantable cardiac defibrillators (ICD) and drug therapy. ICDs have been available in the United States since the mid-1980s and have a well-documented success rate in decreasing the rate of death of patients at high risk for SCD. A major trial conducted by the U.S. National Institutes of Health (the Anti-arrhythmics Versus Implantable Defibrillator or AVID trial) compared therapy with the best available anti-arrhythmic drugs with ICD therapy for patients with spontaneous ventricular tachycardia or ventricular fibrillation. The overall death rate in the ICD patient group was found to be 39% lower than the death rate of patients treated with anti-arrhythmic drugs after only 18 months mean follow-up.
An ICD has two basic components: the ICD generator and the lead system for pacing and shock delivery to which it is connected. An ICD generator contains sensing circuits, memory storage, capacitors, voltage enhancers, a telemetry module, and a control microprocessor. Advances in miniaturization and complexity in all of these components have permitted a tremendous reduction in size of the generator itself despite increased functionality, such as added programming options, anti-tachycardia pacing, single- and dual-chamber rate-responsive pacing for bradycardia, biphasic defibrillation waveforms, enhanced arrhythmia detection features, and innovations in lead systems.
Current ICD technology, however, provides for the detection and recognition of an arrhythmia based on the sensed heart rate once it has already started. This leaves very little time to protect the individual from death resulting from SCD. Although there have been several attempts at developing new technology for predicting the onset of a cardiac arrhythmia, many of these methods and systems appear to rely primarily on events occurring within the heart, such as sensed heart rate and electrocardiography (ECG). For example, U.S. Pat. No. 6,308,094 discloses a method and device for predicting cardiac arrhythmias by gathering and processing electrocardiographic data, such as intervals between heart beats (RR-series) or other heart signals, to predict the occurrence of a cardiac arrhythmia. U.S. Pat. No. 6,516,219 discloses a method and apparatus for forecasting arrhythmia based on real-time intact intracardiac electrograms.
Methods and systems are provided for determining an increased likelihood of the occurrence of a cardiac arrhythmia in a patient. The methods and systems disclosed herein generally comprise monitoring the sympathetic neural discharges of a patient from the left stellate ganglion, the thoracic ganglia, and/or any other sympathetic nerve identified as having an influence over the heart rate of a patient. Other sympathetic nerves suitable for use in connection with the prediction of cardiac arrhythmias may be determined by analyzing simultaneous recordings of the neural discharges and the heart rate, as disclosed in the examples contained herein.
In one embodiment, the sympathetic neural discharges may be monitored by a sensor or electrode that is implanted in the left stellate ganglion of the patient. The electrode may directly sense electrical activity of the left stellate ganglion and transmit this data to a processor. The processor may then analyze the data acquired from the electrode and, upon the determination that the sympathetic neural discharges have increased beyond a defined value, produce an output signal indicating the likely onset of an arrhythmia.
In another embodiment, an increase in the sympathetic neural discharge in the patient may be determined by comparing the parameters for the sensed and normal sympathetic neural discharges in the patient. In yet another embodiment, an increase in the sympathetic neural discharge may be determined by detecting increases in the amplitude and frequency of the sensed sympathetic neural discharge beyond defined values, such as the sensed electrical activity of the left stellate ganglion and/or the thoracic ganglia.
The defined value represents a value above or beyond which is indicative of an impending arrhythmic condition of the heart and may be determined with reference to the normal baseline sympathetic neural discharge. For example, a two-fold or greater increase in the amplitude of the sensed sympathetic neural discharge from the normal baseline amplitude of sympathetic neural discharge may be used as a suitable defined value. A second defined value reflecting the frequency of the sympathetic neural discharge above or beyond which is indicative of an impeding arrhythmic condition of the heart may similarly be provided. The defined values may be a preset or user-defined programmable value.
An output signal may be generated in response to a determined increase in the sympathetic neural discharge. In one embodiment, the output signal may be an audible sound, a radio-transmitted signal, or any other type of signal that would alert the patient or physician to the possibility of an impending arrhythmia. In another embodiment, the output signal may be an analog or digital command signal directing the delivery of anti-arrhythmic therapy.
Anti-arrhythmic therapy suitable for use in connection with the methods and systems are known in the art and may include any one or a combination of the following: delivering one or more pharmacological agents; stimulating myocardial hyperinnervation in the sinus node and right ventricle of the heart of the patient; and applying cardiac pacing, cardioversion or defibrillation shocks, to name a few.
Pharmacologic agents which may be used in connection with the delivery of anti-arrhythmic therapy include those which are known to exert anti-arrhythmic effect, such as sodium channel blockers, β-blockers, potassium channel blockers, such as amiodarone and solatol, and calcium channel blockers, such as verapamil and diltiazem. Other suitable pharmacologic agents include anti-convulsant agents, including but not limited to phenyloin, carbamazepine, valproate, and phenobarbitone, to name a few.
The methods and systems described herein may be incorporated into any number of implantable medical devices including, but not limited to, implantable cardiac rhythm management systems such as pacemakers, cardioverters, defibrillators, and the like. The present methods and systems may also be incorporated in external unimplanted devices of the same sort, as well as in external monitors, programmers and recorders.
The above and other objects, features and advantages will become apparent to those skilled in the art from the following description of the preferred embodiments.
Methods and systems are disclosed for determining an increased likelihood of the occurrence of a cardiac arrhythmia in a patient. The methods and systems disclosed herein comprise monitoring the sympathetic neural discharges of a patient; determining an increase in the sympathetic neural discharges in the patient beyond defined values; and producing an output signal upon a determined increase in the sympathetic neural discharges in the patient. In one embodiment, the output signal may be an audible sound, a radio-transmitted signal, or any other type of signal that would alert the patient or physician to the possibility of an impending arrhythmia. In another embodiment, the output signal may be a command signal directing the delivery of anti-arrhythmic therapy.
The sympathetic neural discharges of a patient may be monitored by a sensor or electrode that is implanted in the left stellate ganglion, the thoracic ganglia, and/or any other sympathetic nerve for which the rate of neural discharge influences the heart rate in a patient. The sensor or electrode may directly sense electrical activity of the left stellate ganglion, the thoracic ganglia or other suitable sympathetic nerve of the patient and transmit this data to a processor for immediate processing or to a memory for storage.
In a preferred embodiment, sympathetic nerve recordings obtained from the left stellate ganglion, the thoracic ganglia, or both. Increased neural discharges from the left stellate ganglion has been observed to precede the onset of cardiac arrhythmias. Consistent with this observation, partial or complete ablation of the left stellate ganglion, together with the thoracic ganglia T2 to T4, was demonstrated to be effective in reducing the incidence of SCD in patients after a first myocardial infarction. Schwartz P J, et al. Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome. Circulation. 2004; 109:1926-1833. These findings suggest that the left stellate ganglion and the thoracic ganglia are important for ventricular arrhythmogenesis and SCD among high risk patients.
Indeed, it has previously been found that simulation of the left stellate ganglion has been found to result in a significant increase in incidence of ventricular arrhythmias and SCD in canine subjects. A method for inducing ventricular arrhythmias in an animal model is disclosed in U.S. Pat. No. 6,351,668, which is incorporated herein in its entirety. Such an animal model is useful in collecting data pertinent to predictors of heart arrhythmias and for testing techniques intended to predict the onset of heart arrhythmias, the disclosures for which are provided in U.S. Pat. Nos. 6,353,757 and 6,398,800, which are incorporated herein in their entirety.
Previous studies have demonstrated heterogeneous sympathetic hyperinnervation in the left ventricle in canine models for sudden cardiac death. Cao J-M, Chen L S, KenKnight B H et al. Nerve sprouting and sudden cardiac death. Circ. Res. 2000; 86:816-21. In contrast, stimulation of the right stellate ganglion has been shown to be anti-arrhythmic. The electrical heterogeneity does not have significant clinical consequences in normal hearts. However, when the ion channels in the heart are altered by either genetic mutations or electrical remodeling after a myocardial infarction and atrioventricular block, this heterogeneity may be amplified and cause arrhythmia.
Accordingly, different sympathetic nerves may exert very different effects on the heart rate. For example, increased neural discharges from the left stellate ganglion exert an anti-arrhythmic effect, whereas increased neural discharges from the right stellate ganglion is believed to be anti-arrhythmic.
In one embodiment, the sensor or electrode may be a nanoelectrode array. As shown in
Data acquired from the sensor or electrode may be filtered to produce optimal signal-to-noise ratio. The amplitude of a signal from a sympathetic nerve is typically −35 to +35 μV and the electrode noise is on average 10 μV for an ideal electrode resistance between 100 kΩ and 10 MΩ at 37° C. for a bandwidth of 1 kHz. Much of the noise during in vivo recording results from the interfacial effects between the neuron, epineurium, electrolyte and the electrode, which is dominated by the charge transfer resistance and the coupling resistance. Cross-talk from parasitic capacitances may also result in the generation of unwanted signals when using conventional electrodes to record sympathetic neural discharges.
Wide band pass filter (1 to 3000 Hz) allows recording of sympathetic neural discharges but also allows for a significant amount of noise generated by cardiac and respiratory related movement artifacts. A greater high pass filter setting (30 to 100 Hz) removes some of the noise and achieves a more stable baseline of the recorded sympathetic neural discharge signals.
The data acquired from the sensor or nanoelectrode may be continuously monitored to detect increases in the sympathetic neural discharges. In one embodiment, an increase in the sympathetic neural discharges in the patient may be determined by detecting an increase in the amplitude and frequency of the sensed sympathetic neural discharges beyond defined values. In another embodiment, an increase in the sympathetic neural discharges in the patient may be determined by comparing the parameters for the sensed sympathetic neural discharges in the patient with the parameters defined for normal sympathetic neural discharges.
The defined value represents a value above and beyond which is indicative of an impending arrhythmic condition of the heart and may be determined with reference to the normal baseline sympathetic neural discharge. For example, a two-fold or greater increase in the amplitude of the sensed sympathetic neural discharge from the normal baseline amplitude of sympathetic neural discharge may be used as a suitable defined value. A second defined value with respect to the frequency of the sympathetic neural discharge may be similarly provided. The defined values may be a preset or user-defined programmable value.
Once an increase in the sympathetic neural discharges has been determined, an output signal may be generated. In one embodiment, the output signal may be an audible sound, a radio-transmitted signal, or any other type of signal that would alert the patient or physician to the possibility of an impending arrhythmia. Upon the generation of the output signal, the patient or physician may then take precautionary or therapeutic measures to avoid or reduce the likelihood of an impending cardiac arrhythmia.
In another embodiment, the output signal may be a command signal directing the delivery of anti-arrhythmic therapy. Anti-arrhythmic therapy suitable for use in connection with the methods and systems are known in the art and may include any one or a combination of the following: delivering one or more pharmacological agents; stimulating myocardial hyperinnervation in the sinus node and right ventricle of the heart of the patient; and cardiac pacing, cardioversion, or defibrillation shocks. A suitable drug delivery system for an implantable cardiac device is disclosed in U.S. Pat. No. 6,361,522, which is incorporated herein in its entirety.
Anti-arrhythmic pharmacologic agents may include those which are known to exert an anti-arrhythmic effect, such as sodium channel blockers, β-blockers, potassium channel blockers, such as amiodarone and solatol, and calcium channel blockers, such as verapamil and diltiazem.
Other suitable anti-arrhythmic pharmacologic agents include anti-convulsant agents, such as phenyloin, carbamazepine, valproate, and phenobarbitone. The left stellate ganglion is capable of high frequency neuronal discharges and these discharges directly increase heart rate. Anti-convulsants work by selectively suppressing high frequency neuronal discharges in the central and peripheral nervous system. Anti-convulsants are also known to suppress cardiac sympathetic nerve discharges. Because of the importance of the autonomic nervous system in arrhythmogenesis, drugs that prevent the release of adrenergic neurotransmitters may thereby decrease the sympathetic outflow are useful for controlling cardiac arrhythmia.
It has been shown, for example, that phenyloin can also be used to suppress cardiac arrhythmia induced by digitalis toxicity. The action of phenyloin is related to use- and frequency-dependent selective suppression of high-frequency neuronal activity. The molecular mechanism for this is a voltage-dependent blockade of membrane sodium channels responsible for the action potential. Through this action, phenyloin obstructs the positive feedback that underlies the development of maximal seizure activity.
Anti-convulsants may block the sympathetic nerve discharges through two actions. One is frequency-dependent block of sodium currents and the second is a block of calcium currents. A combined channel blockade may account for the effects of anticonvulsant drugs. In addition to epilepsy, anti-convulsants, such as phenyloin and carbamazepine, are also useful in treating neuropathic pain, which is characterized by abnormal spontaneous and increased evoked activity from damaged areas of the peripheral nervous system.
Anti-arrhythmic therapy may also be administered by stimulating myocardial hyperinnervation in the sinus node and right ventricle of the heart of the patient by applying electrical stimulation to the right stellate ganglion of the patient or by applying Nerve Growth Factor or other neurotropic substances to the right stellate ganglion, as disclosed in U.S. Pat. No. 6,487,450, which is incorporated herein in its entirety.
The methods disclosed herein may be carried out by a programmable implantable or external device, including, but not limited to, implantable cardiac rhythm management systems such as pacemakers, cardioverters, ICDs, and the like. In one embodiment, the system may comprise a microprocessor, memory, bidirectional data bus, a sympathetic nerve activity (SNA) sensing unit, an output unit and a telemetry interface.
The microprocessor may communicate with the memory through the data bus and execute the program stored in the memory. The microprocessor may include a comparator, such as a summing amplifier, operation amplifier, or other methods of comparing the levels of analog voltage signals. Furthermore, if the sensors or the electrodes produce digital values reflecting the sympathetic neural discharges, then numerous methods known to one of skill in the art may be utilized to digitally compare the respective sympathetic neural discharges.
The memory may comprise any suitable combination of read-only memory (ROM) containing the device operating software, random access memory (RAM) for data storage, and on-board or off-board cache memory associated with the microprocessor. The data bus permits communication between the microprocessor, memory, SNA sensing unit, output unit and the telemetry interface. The telemetry interface may be used for downloading stored data to an external programmer and for receiving telemetry from the programmer to modify programmable parameters and/or change the device operating software.
The SNA sensing unit may comprise one or more electrodes or sensors coupled to sympathetic nerves of the patient, such as the left stellate ganglion, and interface circuits that receive and process the sensed signals from the electrodes. Accordingly, the SNA sensing unit may receive electrical signals from the sympathetic nerves of the patient, filter those signals, and convert them into digital data or otherwise make the data available to the microprocessor.
Accordingly, in one embodiment, the microprocessor may instruct the SNA sensing unit to collect data from the sympathetic nerve, which is then transmitted over bus to the microprocessor for immediate processing or to the memory for storage and subsequent processing as appropriate. The microprocessor may then execute the programming resident in memory to identify increases in the sympathetic neural discharges of the patient and command the output unit to produce an output signal in response thereto.
The methods and systems illustrated with reference to the drawings and described herein are merely illustrative of the principles of the invention which may be implemented in alternative embodiments to achieve other ends than those specifically described herein. Accordingly, the following examples are set forth for the purpose of illustration only and are not construed as limitations on the method disclosed herein.
A standard wire electrode and a nanoelectrode array was implanted on the renal sympathetic nerve of a New Zealand white rabbit. Simultaneous recordings of the ECG and renal sympathetic neural discharges were obtained. The renal sympathetic neural discharges was recorded with both a standard wire electrode and a nanoelectrode array and amplifier. The signals were digitized with a band pass filter of 30 to 500 Hz and a digitization rate of 1 K/sec.
The relationship between the sympathetic neural discharges of the left stellate ganglion and the heart rate was investigated in a normal canine subject. A normal canine subject was anesthetized with isoflurane and the chest was opened at the third intercostal space. The left stellate ganglion was identified and a nanoelectrode was implanted under the fibrous capsule. The fibrous capsule was then closed with a 4-0 silk suture and additional sutures were placed on the wire to secure the nanoelectrodes. The nanoelectrodes were then connected to a DSI transmitter (DSI TL 10M3-D70-EEE, Data Sciences, International) with a band pass filter of 0.05 to 100 Hz and a digitization rate of 1 K/sec. An additional bipolar pair of the DSI transmitter was used for ECG recordings between the right and left chest. All recordings shared a common ground.
The cross-correlation between the sympathetic neural discharges and the heart rate over an hour is depicted in
Anti-convulsant drugs may exert an anti-arrhythmic effect by suppressing the high frequency sympathetic nerve discharges from the left stellate ganglion. Phenyloin (Dilantin®) is one of the most commonly used anti-convulsants and has been shown to suppress the sympathetic neural discharges in ambulatory dogs within the therapeutic range of 10-20 mg/L.
After confirming the successful recording of sympathetic neural discharges from the canine subject, 400 mg (approximately 18 mg/kg) of phenyloin was administered intravenously to the canine subject.
The serum concentration of the canine subject two hours after the initial injection was 12.9 mg/L, which was within the therapeutic range of 10-20 mg/L. The results showed that sympathetic neural discharges appeared to decrease significantly 3-12 hours after the initial injection. There was an increase in the sympathetic neural discharges observed roughly 20 hours after the initial injection, which may represent a rebound sympathetic neural discharges hyper-activation.
An oral dose of phenyloin was also administered to the canine subject (800 mg single dose, or roughly 30 mg/kg) after serum levels from the initial injection of phenyloin dropped to zero. The serum level 2 hours after the oral dose was 2.2 mg/L, which is sub-therapeutic. At this dose, there were little changes in the sympathetic neural discharges. These data show that a therapeutic dose of phenyloin can suppress sympathetic neural discharges from the left stellate ganglion and that a sub-therapeutic dose has little effect. The data also suggest that a dose-response relationship may be present.
This invention was made in part with government support under Grant R01 HL66389, awarded by the National Institutes of Health. The government has certain rights to this invention.
