Patent Publication Number: US-2010114231-A1

Title: Methods and systems to monitor ischemia

Description:
FIELD OF THE INVENTION 
     Embodiments of the present invention pertain generally to implantable and external medical devices and more particularly pertain to methods and systems that monitor ischemia. 
     BACKGROUND OF THE INVENTION 
     An implantable medical device is implanted in a patient to monitor, among other things, electrical activity of a heart and to deliver appropriate electrical and/or drug therapy, as required. Implantable medical devices (“IMDs”) include, for example, pacemakers, cardioverters, defibrillators, implantable cardioverter defibrillators (“ICD”), and the like. The electrical therapy produced by an IMD may include, for example, pacing pulses, cardioverting pulses, and/or defibrillator pulses to reverse arrhythmias (e.g., tachycardias and bradycardias) or to stimulate the contraction of cardiac tissue (e.g., cardiac pacing) to return the heart to its normal sinus rhythm. 
     Cardiac ischemia is a condition whereby the heart tissue does not receive adequate amounts of oxygen and usually is caused by a blockage of an artery leading to the heart tissue. Ischemia arises during angina, coronary angioplasty, and any other condition that compromises blood flow to a region of tissue. When blockage of an artery is sufficiently severe, the cardiac ischemia becomes an acute myocardial infarction (“AMI”), which also is referred to as a myocardial infarction (“MI”) or a heart attack. 
     Many patients at risk of cardiac ischemia have pacemakers, ICDs or other medical devices implanted therein. Electrocardiograms (“ECG”) are useful for diagnosing ischemia and locating damaged areas within the heart. ECGs are composed of various waves and segments that represent the heart depolarizing and repolarizing. The ST segment in an ECG represents the portion of the cardiac signal between ventricular depolarization and ventricular repolarization. While P-waves, R-waves, and T-waves in the ECG may generally be considered features of a surface ECG, for convenience and generality, herein the terms R-wave, T-wave, and P-wave are also used to refer to the corresponding internal cardiac signal, such as an intra-cardiac electrogram (“IEGM”) signal. Techniques have been developed for detecting cardiac ischemia using implanted medical devices by identifying variations in the ST segment from the baseline cardiac signal that occur during cardiac ischemia. Deviation of the ST segment from a baseline is a result of injury to cardiac muscle, variations in the synchronization of ventricular muscle depolarization, drug or electrolyte influences, or the like. Some conventional techniques monitor the initiation of ischemia by determining a change in the ST segment. But not all ischemic events progress to the state of an AMI. One difference between ischemia and AMI is that ischemia generally is reversible without producing permanent cardiac tissue damage. Therefore, ischemia may occur but may not present itself as an AMI. 
     Conventional ischemia detection techniques have been proposed to detect and monitor ischemia. Conventional ischemia detection techniques primarily rely on identifying variations in the ST segment from the baseline cardiac signal that occur during cardiac ischemia. Yet, the ST segment is influenced by a large number of factors unrelated to ischemia. By way of example only, the ST segment may be influenced by the presence of drugs; electrolyte abnormalities; neurogenic factors such as a previous stroke, hemorrhage, tumor, and the like; and metabolic factors such as hypoglycemia and hyperventilation. Thus, relying solely on identifying variations in the ST segment to diagnose ischemia can be an unreliable manner of monitoring ischemia. An improved method and system are needed to detect and monitor ischemia. 
     BRIEF SUMMARY OF THE INVENTION 
     In one embodiment, an implantable medical device is provided that includes leads, a segment monitoring module, an impedance detection module and an ischemia module. The leads include electrodes that are configured to be positioned within a heart and that are capable of sensing cardiac signals having a segment of interest. The segment monitoring module determines segment variations of the segment of interest in the cardiac signals. The impedance detection module measures impedance vectors between predetermined combinations of the electrodes. The ischemia detection module monitors ischemia based on changes in the segment variations of the segment of interest and based on changes in the impedance vectors. 
     In another embodiment, a method is provided for monitoring ischemia that includes providing leads having electrodes configured to be positioned within a heart and sensing, with the electrodes, cardiac signals having a segment of interest. Additionally, the method also includes determining segment variations of the segment of interest in the cardiac signals and measuring impedance vectors between predetermined combinations of the electrodes. The method includes monitoring ischemia based on changes in the segment variations of the segment of interest and based on changes in the impedance vectors. 
     In another embodiment, a computer readable storage medium for use in a medical device includes a memory and a programmable controller. The computer readable storage medium includes instructions to direct the memory to store cardiac signals sensed by electrodes positioned within a heart. The cardiac signals have a segment of interest. The instructions also direct the memory to store impedance vectors that are measured between predetermined combinations of the electrodes. The instructions direct the controller to determine segment variations of the segment of interest in the cardiac signals and to monitor ischemia based on changes in the segment variations of the segment of interest and based on changes in the impedance vectors. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       In the drawings, which are not necessarily drawn to scale, like numerals describe substantially similar components throughout the several views. Like numerals having different letter suffixes represent different instances of substantially similar components. The drawings illustrate generally, by way of example, but not by way of limitation, various embodiments discussed in the present document. 
         FIG. 1  illustrates an IMD that is coupled to a heart according to one embodiment. 
         FIG. 2  illustrates a single cardiac cycle that includes a P-wave, a Q-wave, an R-wave, an S-wave, and a T-wave. 
         FIG. 3  illustrates a block diagram of exemplary internal components of the IMD shown in  FIG. 1 . 
         FIG. 4  illustrates a process for monitoring ischemia in accordance with one embodiment. 
         FIG. 5  illustrates the ischemia-related parameters obtained at and ischemia indicators calculated at according to one embodiment. 
         FIG. 6  illustrates an alternative manner of measuring the third impedance vector Z 3 . 
         FIG. 7  illustrates the third impedance vector Z 3  over a range of frequencies of the current I 3 . 
         FIG. 8  illustrates a functional block diagram of an external device that is operated to interface with the IMD shown in  FIG. 1  according to one embodiment. 
         FIG. 9  illustrates a distributed processing system in accordance with one embodiment. 
         FIG. 10  illustrates a block diagram of exemplary manners in which embodiments of the present invention may be stored, distributed and installed on a computer-readable medium. 
     
    
    
     DETAILED DESCRIPTION 
     In the following detailed description, reference is made to the accompanying drawings which form a part hereof, and in which are shown by way of illustration specific embodiments in which the present invention may be practiced. These embodiments, which are also referred to herein as “examples,” are described in sufficient detail to enable those skilled in the art to practice the invention. It is to be understood that the embodiments may be combined or that other embodiments may be utilized, and that structural, logical, and electrical variations may be made without departing from the scope of the present invention. For example, embodiments may be used with a pacemaker, a cardioverter, a defibrillator, and the like. The following detailed description is, therefore, not to be taken in a limiting sense, and the scope of the present invention is defined by the appended claims and their equivalents. In this document, the terms “a” or “an” are used, as is common in patent documents, to include one or more than one. In this document, the term “or” is used to refer to a nonexclusive or, unless otherwise indicated. 
       FIG. 1  illustrates an IMD  100  that is coupled to a heart  102 . The IMD  100  may be a cardiac pacemaker, an ICD, a defibrillator, an ICD coupled with a pacemaker, and the like, implemented in accordance with one embodiment of the present invention. The IMD  100  may be a dual-chamber stimulation device capable of treating both fast and slow arrhythmias with stimulation therapy, including cardioversion, defibrillation, and pacing stimulation, as well as capable of detecting heart failure, evaluating its severity, tracking the progression thereof, and controlling the delivery of therapy and warnings in response thereto. As explained below in more detail, the IMD  100  may be controlled to monitor cardiac signals and based thereof, to identify potentially abnormal physiology (e.g. ischemia). 
     The IMD  100  includes a housing  104  that is joined to a header assembly  106  (e.g., an IS-4 connector assembly) that holds receptacle connectors  108 ,  110 ,  112  that are connected to a right ventricular lead  114 , a right atrial lead  116 , and a coronary sinus lead  118 , respectively. The leads  114 ,  116 , and  118  may be located at various locations, such as an atrium, a ventricle, or both to measure the physiological condition of the heart  102 . One or more of the leads  114 ,  116 , and  118  detect IEGM signals that form an electrical activity indicator of myocardial function over multiple cardiac cycles. To sense atrial cardiac signals and to provide right atrial chamber stimulation therapy, the right atrial lead  116  has at least an atrial tip electrode  120 , which typically is implanted in the right atrial appendage, and an atrial ring electrode  122 . The IEGM signals represent analog signals that are subsequently digitized and analyzed to identify waveforms or segments of interest. Examples of waveforms or segments of interest identified from the IEGM signals include the P-wave, T-wave, the R-wave, the QRS complex, the ST segment, and the like. The waveforms of interest may be collected over a period of time. 
     The coronary sinus lead  118  receives atrial and ventricular cardiac signals and delivers left ventricular pacing therapy using at least a left ventricular (“LV”) tip electrode  124 , delivers left atrial (“LA”) pacing therapy using at least a left atrial ring electrode  126 , and delivers shocking therapy using at least an LA coil electrode  128 . The coronary sinus lead  118  also is connected with a LV ring electrode  130  disposed between the LV tip electrode  124  and the left atrial ring electrode  126 . The LV ring electrode  130  may be used as a defibrillation electrode. The right ventricular (“RV”) lead  114  has an RV tip electrode  136 , an RV ring electrode  132 , an RV coil electrode  134 , and an SVC coil electrode  138 . The RV lead  114  is capable of receiving cardiac signals, and delivering stimulation in the form of pacing and shock therapy to the right ventricle. The RV coil electrode  134  may be used as a defibrillation electrode. For purposes of measuring impedance vectors (as described below), the housing  104  may be referred to as an electrode. 
     The electrodes  124 - 138  may have intrinsic impedances that vary among the electrodes  124 - 138 . For example, the impedance of each electrode  124 - 138  may vary based on the type of electrode  124 - 138 . The impedance of an electrode is related to the size of the electrode. Typically, the larger the size of the electrode, the lower the impedance of the electrode. Pacing electrodes such as the RV and LV tip electrodes  136 ,  124  tend to be smaller than defibrillating electrodes such as the RV coil electrode  134  and the LV ring electrode  130 . As a result, the RV coil electrode  134  and the LV ring electrode  130  may have a lower impedance than the RV and/or LV tip electrodes  136 ,  124 . For example, the LV and RV electrode tips  124  and  136  may have intrinsic impedances of at least 500 ohms while the RV coil electrode  134  and/or LV ring electrode  130  may have intrinsic impedances of approximately 100 ohms or less. 
     The IMD  100  monitors ischemia in the heart  102  by determining variations in impedance vectors and cardiac signals of the heart  102  between different sets of cardiac cycles. The IMD  100  measures and/or calculates several ischemia-related parameters to monitor and determine variations in the impedance measurements and cardiac signals. As described in more detail below, the IMD  100  may determine that the heart  102  is ischemic based on the number of differences and/or the extent of the differences among the cardiac signals and/or impedance vectors measured in different sets of cardiac cycles. 
     In the myocardium, healthy points or regions exhibit an impedance characteristic that is representative of the impedance of the tissue and the impedance of the blood at the point or in the regions. When the myocardium develops ischemia, regions of the myocardium that are ischemic exhibit a different impedance characteristic as compared to the same regions before becoming ischemic. Also, ischemic regions exhibit a different impedance characteristic as compared to surrounding healthy regions of the myocardium. The impedance characteristics of different regions can be measured to obtain impedance parameters. 
     The IMD  100  is configured to measure and compare impedance parameters for different sets of cardiac cycles to determine if the heart  102  is ischemic. An impedance parameter includes an impedance vector that represents the impedance measured along a path (generally a linear path) between at least two points. One or more impedance vectors measured by the IMD  100  may extend through the heart  102 . The impedance vectors that extend through the heart  102  represent the impedance of the myocardium and the blood in the heart  102  along the paths of the impedance vectors. Impedance vectors along different paths that pass through the heart  102  may provide an indication of whether certain regions or points in the heart  102  are ischemic. For example, the IMD  100  may measure impedance vectors that traverse the heart  102  for multiple sets of cardiac cycles. The IMD  100  compares the averages of the impedance vectors for each cardiac cycle and compares the average impedance vectors. In a healthy, non-ischemic heart  102 , the average impedance vectors over time may remain approximately the same over multiple sets of cardiac cycles. 
     For example, the myocardium of the non-ischemic heart  102  may have an intrinsic impedance of 50 ohms. In an ischemic heart  102 , the impedance of the myocardium in the heart  102  may increase as the impedance vectors are measured by the IMD  100 . For example, the intrinsic impedance of the myocardium of the heart  102  may increase by approximately 5 ohms or more. As a result, the average impedance vectors of a previous set of cardiac cycles may be less than the average impedance vectors of more recent set of cardiac cycles. If the difference between the average impedance vectors between the sets of cardiac cycles is larger than a predetermined threshold, the IMD  100  may determine that the heart  102  is ischemic. 
     By way of example only, the impedance vectors measured by the IMD  100  may include first, second and third impedance vectors Z 1 , Z 2  and Z 3  ( FIG. 1 ) that are measured using predetermined combinations of the housing  104  and the electrodes  124 - 138 . The housing  104  may be referred to herein as an electrode and as one of the electrodes used to measure one or more of the impedance vectors Z 1 , Z 2  and Z 3 . As shown in  FIG. 1 , the first impedance vector Z 1  extends along a path between the RV coil electrode  134  and the housing  104  that primarily traverses the heart  102 . The second impedance vector Z 2  extends along a path that primarily traverses a non-myocardial path between the SVC coil electrode  138  and the housing  104 . For example, the second impedance vector Z 2  extends along a path that primarily traverses outside of the heart  102 . 
     The IMD  100  may calculate the third impedance vector Z 3  using a four terminal measurement technique in one embodiment. The four terminal measurement technique may reduce the impact that the intrinsic impedance of the electrodes has on the third impedance vector Z 3 . As described above, the intrinsic impedances of the electrodes  124 - 138  may be large when compared to the change in the impedance of the heart  102  caused by ischemia. For example, the LV and RV electrode tips  124 ,  136  may have intrinsic impedances of 500 ohms or more while the change in impedance of the myocardium in the heart  102  caused by ischemia may be approximately 5 ohms or less. The four terminal measurement technique can eliminate the intrinsic impedances of the LV and RV electrode tips  124 ,  136  from the measured third impedance vector Z 3 . 
     The four terminal measurement technique involves applying a current I 3  across a predetermined combination of the electrodes  124 - 136  while measuring a voltage V 3  between a different combination of the electrodes  124 - 136 . As shown in  FIG. 1 , the current I 3  may be supplied between the RV coil electrode  134  and the LV ring electrode  130 . The current I 3  can be supplied by electrically connecting the RV coil electrode  134  and the LV ring electrode  130  to a source of electric current, such as a battery  256  (shown in  FIG. 3 ). The amount of current I 3  may controlled by an impedance detection module  272  (shown in  FIG. 3 ). The voltage V 3  is measured between the LV tip electrode  124  and the RV tip electrode  136 . The voltage V 3  represents the voltage difference measured between the LV tip electrode  124  and the RV tip electrode  136  when the current I 3  is supplied between the LV ring electrode  130  and the RV coil electrode  134 . Using the voltage V 3  and the current I 3 , the third impedance vector Z 3  may be calculated using the relationship: 
     
       
         
           
             
               
                 
                   
                     Z 
                     3 
                   
                   = 
                   
                     
                       V 
                       3 
                     
                     
                       I 
                       3 
                     
                   
                 
               
               
                 
                   ( 
                   
                     Eqn 
                     . 
                     
                         
                     
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                     1 
                   
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     In one example, the IMD  100  measures one or more of the three impedance vectors Z 1 , Z 2  and Z 3  for each cardiac cycle in a first set of cardiac cycles. By way of example only, the set may include 10 cardiac cycles. The IMD  100  calculates an average value of one or more of the impedance vectors Z 1 , Z 2  and Z 3  for the first set of cardiac cycles. The IMD  100  then measures one or more of the three impedance vectors Z 1 , Z 2  and Z 3  for each cardiac cycle in a second set of cardiac cycles. The IMD  100  calculates an average value of one or more of the impedance vectors Z 1 , Z 2  and Z 3  for the second set of cardiac cycles. The average values of one or more of the impedance vectors Z 1 , Z 2  and Z 3  between the sets of cardiac cycles are then compared. If the difference between the averages of the impedance vectors Z 1 , Z 2  and Z 3  is great enough, the IMD  100  may determine that the heart  102  is ischemic. 
     One or more of the impedance vectors Z 1 , Z 2  and Z 3  may be impacted by physiological conditions unrelated to ischemia. For example, the measured value of one or more of the impedance vectors Z 1 , Z 2  and Z 3  may be different from the actual value of the impedance vectors Z 1 , Z 2  and Z 3  if the patient being monitored breathes or has fluid in his/her lungs. The patient&#39;s breathing or fluid in the lungs can cause one or more of the impedance vectors Z 1 , Z 2  and Z 3  to be measured as a different value than would otherwise be measured if the patient were holding his/her breath or did not have fluid in his/her lungs. 
     With respect to the variations in the cardiac signals, the IMD  100  can measure and identify ischemia-related parameters from cardiac signals of the heart  102 . The ischemia-related parameters can include one or more segments of interest and/or variations in the segments of interest. For example, the IMD  100  can measure the R-wave in a QRS complex, the ST segment that follows the QRS complex, and variations in the R-wave and/or ST segment in multiple sets of cardiac cycles. 
       FIG. 2  illustrates a single cardiac cycle  700  that includes a P-wave  702 , a Q-wave  704 , an R-wave  706 , an S-wave  708 , and a T-wave  710 . The cardiac cycle  700  may represent cardiac signals, such as IEGM signals, ECG signals, and the like. The horizontal axis  712  represents time, while the vertical axis  714  is defined in units of voltage. A QRS complex  716  is composed of the Q-wave  704 , the R-wave  706 , and the S-wave  708 . The QRS complex  716  is used to locate the R-wave  706  to determine a baseline  718 . The portion of the signal between the S-wave  708  and T-wave  710  constitutes an ST segment  720 . 
     In a non-ischemic heart  102 , the R-wave  706  and the ST segment  720  remain approximately the same for a plurality of cardiac cycles and/or a plurality of sets of cardiac cycles. For example, an amplitude  730  of the R-wave  706  may be approximately the same for each R-wave  706  in a plurality of cardiac cycles in a set, and approximately the same for the cardiac cycles in a plurality of sets of cardiac cycles. In another example, the ST segment  720  may be located at approximately the same location with respect to a baseline  718  for each cardiac cycle in a set of cardiac cycles, and approximately the same for the cardiac cycles in a plurality of sets of cardiac cycles. 
     In an ischemic heart  102 , however, the R-wave  706  and/or the ST segment  720  may differ between cardiac cycles or between sets of cardiac cycles. For example, the amplitude  730  of the R-wave  706  may increase or decrease between cardiac cycles or sets of cardiac cycles. In another example, the ST segment  720  may shift above  722 ,  724  or below  726  the baseline  718 . The ST segment variations  722 - 726  may occur above or below the baseline  718  for an ischemic heart  102 . For example, the ST segment variations  722 - 726  may arise because of differences in the electrical potential between cells that have become ischemic and those that are still receiving normal blood flow. Thus, the ST segment variations  722 - 726  may be some indicators of the possibility of ischemia. In one example, the IMD  100  may determine that the heart  102  is not ischemic if the R-wave  706  and/or ST  720  segment do not significantly change between multiple sets of cardiac cycles. Conversely, the IMD  100  may determine that the heart  102  is ischemic if the R-wave  706  and/or ST  720  segment do significantly change between the sets of cardiac cycles. 
       FIG. 3  illustrates a block diagram of exemplary internal components of the IMD  100 . The IMD  100  is for illustration purposes only, and it is understood that the circuitry could be duplicated, eliminated or disabled in any desired combination to provide a device capable of treating the appropriate chamber(s) of the heart with cardioversion, defibrillation and/or pacing stimulation. The housing  104  for IMD  100  (shown schematically in  FIG. 2 ), is often referred to as the “can”, “case” or “case electrode” and may be programmably selected to act as the return electrode for all “unipolar” modes. The housing  104  further includes a connector (not shown) having a plurality of terminals, namely a right atrial tip terminal (A R  TIP)  202 , a left ventricular tip terminal (V L  TIP)  204 , a left atrial ring terminal (A L  RING)  206 , a left atrial shocking terminal (A L  COIL)  208 , a right ventricular tip terminal (V R  TIP)  210 , a right ventricular ring terminal (V R  RING)  212 , a right ventricular shocking terminal (RV COIL)  214 , an SVC shocking terminal (SVC COIL)  216 , a right ventricular coil terminal (V R  COIL)  218  and a left ventricular ring terminal (V L  RING)  220 . 
     The IMD  100  includes a programmable microcontroller  222 , which controls the operation of the IMD  100  based on acquired cardiac signals and impedance vectors. The microcontroller  222  (also referred to herein as a processor module or unit) typically includes a microprocessor, or equivalent control circuitry, is designed specifically for controlling the delivery of stimulation therapy and may further include RAM or ROM memory, logic and timing circuitry, state machine circuitry, and I/O circuitry. Typically, the microcontroller  222  includes the ability to process or monitor input signals (e.g., data) as controlled by a program code stored in a memory. Among other things, the microcontroller  222  receives, processes, and manages storage of digitized data from the various electrodes  104 ,  124 - 138  (shown in  FIG. 1 ). The microcontroller  222  may also analyze the data, for example, in connection with collecting, over a period of time, variations in a segment of interest and impedance vectors. For example, the microcontroller  222  monitors variations in one or more of segments of interest such as the ST segment  720  (shown in  FIG. 2 ) and the R-wave  706  (shown in  FIG. 2 ) and variations in impedance vectors between predetermined electrodes  104  and  124  through  138  to monitor and determine a potential ischemic condition. 
     The modules in the microcontroller  222  that monitor ischemia include a segment monitoring module  270 , the impedance detection module  272  and an ischemia detection module  274 . The segment monitoring module  270  determines segment variations such as ST segment variations  722 - 726  (shown in  FIG. 2 ) and changes in the amplitude  730  (shown in  FIG. 2 ) of the R-wave  706  (shown in  FIG. 2 ). The impedance detection module  272  measures and/or calculates one or more of the first, second and third impedance vectors Z 1 , Z 2  and Z 3  (shown in  FIG. 1 ). The ischemia detection module  274  monitors a potential ischemic condition based on changes in the segment variations monitored by the segment monitoring module  270  and based on changes in the impedance vectors monitored by the impedance detection module  272 . 
     The IMD  100  includes an atrial pulse generator  224  and a ventricular/impedance pulse generator  226  to generate pacing stimulation pulses. In order to provide stimulation therapy in each of the four chambers of the heart  102  (shown in  FIG. 1 ), the atrial and ventricular pulse generators  224  and  226 , may include dedicated, independent pulse generators, multiplexed pulse generators, or shared pulse generators. The pulse generators,  224  and  226 , are controlled by the microcontroller  222  via appropriate control signals,  228  and  230 , respectively, to trigger or inhibit the stimulation pulses. 
     Switch  232  includes a plurality of switches for connecting the desired electrodes, including the electrodes  104  and  124  through  138  (shown in  FIG. 1 ), to the appropriate I/O circuits, thereby providing complete electrode programmability. The switch  232 , in response to a control signal  268  from the microcontroller  222 , determines the polarity of stimulation pulses (e.g., unipolar, bipolar, etc.) by selectively closing the appropriate combination of switches (not shown) as is known in the art. Atrial sensing circuits  234  and ventricular sensing circuits  236  may also be selectively coupled to the leads  114 ,  116  and  118  (shown in  FIG. 1 ) through the switch  232  for detecting the presence of cardiac activity in each of the four chambers of the heart  102  (shown in  FIG. 1 ). Control signals  238  and  240  from microcontroller  222  direct output of the atrial and ventricular sensing circuits  234  and  236  that are connected to the microcontroller  222 . In this manner, the atrial and ventricular sensing circuits  234  and  236  are able to trigger or inhibit the atrial and ventricular pulse generators  224  and  226 . 
     The cardiac signals are applied to the inputs of an analog-to-digital (A/D) data acquisition system  242 . The data acquisition system  242  is configured to acquire IEGM signals, convert the raw analog data into a digital IEGM signals, and store the digital IEGM signals in a memory  244  for later processing and/or telemetric transmission to an external device  246 . 
     A control signal  245  from the microcontroller  222  determines when the A/D  242  acquires signals, stores them in memory  244 , or transmits data to the external device  246 . The A/D  242  is coupled to the right atrial lead  116  (shown in  FIG. 1 ), the coronary sinus lead  118  (shown in  FIG. 1 ), and the right ventricular lead  114  through the switch  232  to sample cardiac signals across any combination of desired electrodes  124 - 138  (shown in  FIG. 1 ). The microcontroller  222  is coupled to the memory  244  by a suitable data/address bus  248 , wherein the programmable operating parameters used by the microcontroller  222  are stored and modified, as required, in order to customize the operation of IMD  100  to suit the needs of a particular patient. The memory  244  may also store data indicative of myocardial function, such as the IEGM data, ST segment shifts, reference ST segment shifts, ST segment shift thresholds, R wave amplitudes, R wave amplitude changes, impedance vectors, trend information associated with ischemic episodes, and the like for a desired period of time (e.g., 6 hours, 12 hours, 18 hours or 24 hours, and the like). 
     The operating parameters of the IMD  100  may be non-invasively programmed into the memory  244  through a telemetry circuit  250  in communication with the external device  246 , such as an external device  400  (shown in  FIG. 6 ), a trans-telephonic transceiver or a diagnostic system analyzer. The telemetry circuit  250  is activated by the microcontroller  222  by a control signal  252 . The telemetry circuit  250  allows intra-cardiac electrograms and status information relating to the operation of IMD  100  (as contained in the microcontroller  222  or memory  244 ), to be sent to the external device  246  through an established communication link  254 . The IMD  100  additionally includes the battery  256 , which provides operating power to all of the circuits shown within the housing  104 , including the microcontroller  222 . The IMD  100  also includes a physiologic sensor  266  that may be used to adjust pacing stimulation rate according to the exercise state of the patient. 
     In the case where IMD  100  is intended to operate as an ICD device, the IMD  100  detects the occurrence of an ST segment shift  722 - 726  (shown in  FIG. 2 ) that indicates an arrhythmia, and automatically applies an appropriate electrical shock therapy to the heart aimed at terminating the detected arrhythmia. To this end, the microcontroller  222  further controls a shocking circuit  262  by way of a control signal  264 . The shocking circuit  262  generates shocking pulses of low (up to 0.5 joules), moderate (0.5-10 joules) or high energy (11 to 40 joules). Such shocking pulses are applied to the heart  102  (shown in  FIG. 1 ) of the patient through at least two shocking electrodes, and as shown in this embodiment, selected from the left atrial coil electrode  128  (shown in  FIG. 1 ), the RV coil electrode  134  (shown in  FIG. 1 ), and/or the SVC coil electrode  138  (shown in  FIG. 1 ). 
     The IMD  100  includes an impedance measuring circuit  258  which is enabled by the microcontroller  222  via a control signal  260 . Alternatively, the impedance measuring circuit  258  is included in the impedance detection module  272 . The impedance measuring circuit  258  is advantageously coupled to the switch  232  so that impedance at any desired electrode may be obtained. For example, the impedance measuring circuit  258  may measure impedance vectors between predetermined combinations of the electrodes  104  and  124  through  138  (shown in  FIG. 1 ) to monitor and determine a potential ischemic condition. 
       FIG. 4  illustrates a process  1000  for monitoring ischemia in accordance with one embodiment. At  1002 , a plurality of leads  114 ,  116 , and  118  (shown in  FIG. 1 ) with electrodes  104  and  120 - 138  (shown in  FIG. 1 ) is provided. The electrodes  120 - 138  are positioned within a heart  102  (shown in  FIG. 1 ). As described above, the electrodes  104  and  120 - 138  can include pacing electrodes and defibrillation electrodes. 
     The IMD  100  determines several ischemia-related parameters at  1004 - 1009  for cardiac cycles in a set of cardiac cycles. For example, the segment monitoring module  270  may sense cardiac signals of the heart  102  at least some of the electrodes  104  and  120 - 138  at  1004 . The cardiac signals are used to identify segments of interest, including one or more of the ST segment  720  (shown in  FIG. 2 ) and the R-wave  706  (shown in  FIG. 2 ), as described above. The IMD  100  (shown in  FIG. 1 ) determines variations in one or more of the segments of interest at  1006 . For example, the segment monitoring module  270  (shown in  FIG. 3 ) may determine one or more variations  722 - 726  in the ST segment  720 . In one example, the segment monitoring module  270  may determine the amplitude  730  of the R-wave  706  at  1006 . The IMD  100  also measures and calculates the impedance vectors Z 1 , Z 2  and Z 3  at  1008 . For example, the impedance detection module  274  (shown in  FIG. 3 ) and/or the impedance measuring circuit  258  (shown in  FIG. 3 ) measure the first and second impedance vectors Z 1  and Z 2  and calculate the third impedance vector Z 3 , as described above. 
     The IMD  100  calculates additional impedance parameters at  1009 . For example, the impedance detection module  272  may calculate one or more additional impedance parameters. The additional impedance parameters  1009  may be calculated for each cardiac cycle in a set of cardiac cycles. The additional impedance parameters  1009  include an impedance normalization parameter Z N . The normalized impedance parameter Z N  can be used to at least partially correct for variations in or more of the impedance vectors Z 1 , Z 2  and Z 3  that are due to physiologic characteristics unrelated to ischemia. As described above, the measured value of one or more of the impedance vectors Z 1 , Z 2  and Z 3  may be different from the actual value of the impedance vectors Z 1 , Z 2  and Z 3  if the patient being monitored breathes during measurement of the vectors or has fluid in his/her lungs. The normalized impedance parameter Z N  may be defined by the following relationship: 
     
       
         
           
             
               
                 
                   
                     Z 
                     N 
                   
                   = 
                   
                     
                       Z 
                       1 
                     
                     
                       Z 
                       2 
                     
                   
                 
               
               
                 
                   ( 
                   
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                   ) 
                 
               
             
           
         
       
     
     where Z 1  is the first impedance vector and Z 2  is the second impedance vector. 
     The impedance detection module  272  may calculate a contractility parameter C 3  and a normalized contractility parameter C N  at  1009 . The contractility parameters C 3 , C N  represent quantifiable parameters of the ability of the heart  102  to contract. Significant changes in one or more of the contractility parameters C 3 , C N  between sets of cardiac cycles may indicate that the heart  102  is ischemic. The contractility parameter C 3  represents the rate of change in the third impedance vector Z 3  with respect to time. The contractility parameter C 3  may be represented by the following relationship: 
     
       
         
           
             
               
                 
                   
                     C 
                     3 
                   
                   = 
                   
                     max 
                      
                     
                        
                       
                         
                            
                           
                             Z 
                             3 
                           
                         
                         
                            
                           t 
                         
                       
                        
                     
                   
                 
               
               
                 
                   ( 
                   
                     Eqn 
                     . 
                     
                         
                     
                      
                     3 
                   
                   ) 
                 
               
             
           
         
       
     
     For example, the contractility parameter C 3  may be the maximum value of the absolute value of the rate of change in the third impedance vector Z 3  with respect to time during a single cardiac cycle. 
     The normalized contractility parameter C N  represents the rate of change in the normalized impedance parameter Z N  with respect to time. The normalized contractility parameter C N  may be represented by the following relationship: 
     
       
         
           
             
               
                 
                   
                     C 
                     N 
                   
                   = 
                   
                     max 
                      
                     
                        
                       
                         
                            
                           
                             Z 
                             N 
                           
                         
                         
                            
                           t 
                         
                       
                        
                     
                   
                 
               
               
                 
                   ( 
                   
                     Eqn 
                     . 
                     
                         
                     
                      
                     4 
                   
                   ) 
                 
               
             
           
         
       
     
     For example, the normalized contractility parameter C N  may be the maximum value of the absolute value of the change in the normalized impedance parameter Z N  with respect to time during a single cardiac cycle. 
     The segment monitoring module  270  may calculate a segment of interest (“SOI”) parameter at  1009 . The SOI parameter represents a factor indicative of segment variations  722 - 726  (shown in  FIG. 2 ) in the ST segment  720  (shown in  FIG. 2 ) compared to the amplitude  730  (shown in  FIG. 2 ) of the R-wave  706  (shown in  FIG. 2 ). For example, if the segment variation  722 - 726  is small when compared to the amplitude  730 , then the SOI parameter may have a small numerical value. Conversely, if the segment variation  722 - 726  approaches or exceeds the amplitude  730 , then the SOI parameter may have a numerical value that approaches or exceeds 1. In one embodiment, the SOI parameter is the absolute value of the ratio of the ST segment parameter ST to the R-wave parameter R W . For example, the SOI parameter may be defined by the following relationship: 
     
       
         
           
             
               
                 
                   
                     S 
                      
                     
                         
                     
                      
                     O 
                      
                     
                         
                     
                      
                     I 
                   
                   = 
                   
                      
                     
                       ST 
                       
                         R 
                         w 
                       
                     
                      
                   
                 
               
               
                 
                   ( 
                   
                     Eqn 
                     . 
                     
                         
                     
                      
                     5 
                   
                   ) 
                 
               
             
           
         
       
     
     where the ST segment parameter ST constitutes the segment variation  722 - 726  and the R-wave parameter R W  constitutes the amplitude  730  for a cardiac cycle. 
     In one embodiment, the IMD  100  determines the parameters at  1004 - 1009  for each cardiac cycle in a set of cardiac cycles. The IMD  100  performs the actions described at  1004 - 1009  for each cardiac cycle in the set until the cardiac signals, segment variations and impedance vectors have been determined for all of the cardiac cycles in the set. As shown in  FIG. 4 , the IMD  100  repeats the actions at  1004 - 1009  in a loop-wise manner until the parameters Z 1 , Z 2 , Z 3 , Z N , ST, R W , C 3 , C N  and SOI have been determined for all of the cardiac cycles in the set. The IMD  100  repeats the actions at  1004 - 1009  in a loop-wise manner for each cardiac cycle in another set of cardiac cycles. 
     With continued reference to  FIG. 4 ,  FIG. 5  is a schematic illustration of the ischemia-related parameters obtained at  1004 - 1009  and ischemia indicators calculated at  1010  according to one embodiment. As shown in  FIG. 5 , the IMD  100  obtains several ischemia-related parameters for each cardiac cycle  1200 - 1206  in a first set  1208  of cardiac cycles and for each cardiac cycle  1210 - 1216  in a second set  1218  of cardiac cycles. For example, the IMD  100  may determine each of the impedance parameters Z 1 , Z 2 , Z 3 , and Z N , the cardiac signal parameters ST and R W , the contractility parameters C 3  and C N  and the segment of interest parameter SOI for each of the cardiac cycles  1210 - 1216  in the first set  1208  and for each cardiac cycle  1210 - 1216  in the second set  1210 . 
     The IMD  100  calculates ischemia indicators at  1010 . The ischemia indicators may be calculated by the ischemia detection module  274 . The ischemia indicators are representations of the degree or amount of change in the ischemia-related parameters between different sets of cardiac cycles. For example, the ischemia indicators represent how much the various ischemia-related parameters change between sets of cardiac cycles. A large change in the ischemia indicators between sets of cardiac cycles may indicate an ischemic or a potentially ischemic condition. For example, if a minimum number of the ischemia indicators exceed a minimum threshold, then the ischemia detection module  274  determines that the heart  102  is ischemic or potentially ischemic. By way of non-limiting example only, the ischemic detection module  274  determines how many of the ischemic indicators are at least 3%, or 0.03. Other thresholds such as 1%, 5%, 8%, 10%, and the like, may be used in place of the 3% individual threshold. The individual threshold may be stored in the memory  244  (shown in  FIG. 3 ). 
     In one embodiment, the ischemia detection module  274  calculates the ischemia indicators by calculating a group  1220 ,  1222  of statistical parameters for each set  1208 ,  1218  of cardiac cycles. For example, the ischemia detection module  274  may calculate several statistical parameters for a first group  1220  and for a second group  1222 . The statistical parameters are functions of one or more of the ischemia-related parameters for each set  1208 ,  1218  of cardiac cycles. For example, the ischemia detection module  274  may calculate a statistical impedance parameter ζ 3  for each set  1208 ,  1218  of cardiac cycles. The statistical impedance parameter ζ 3  may be defined by the following relationship: 
       ζ 3   =f ( Z   3 )  (Eqn. 6) 
     where ζ 3  is the statistical impedance parameter for one set  1208 ,  1218  of cardiac cycles and ƒ(Z 3 ) is a function of the third impedance vector Z 3 . The function ƒ(Z 3 ) may be a statistical function of the third impedance vector Z 3 . For example, the function ƒ(Z 3 ) may be an average, mean, deviation, standard deviation, maximum, minimum, and the like, of the third impedance vector Z 3 . In one specific example, the statistical impedance parameter ζ 3  is the average of the third impedance vector Z 3  in the first set  1208 . The statistical impedance parameter ζ 3  is calculated for the first and second groups  1208  and  1218 . 
     The ischemia detection module  274  may calculate a statistical impedance normalization parameter ζ N  for each set  1208 ,  1218  of cardiac cycles. The statistical impedance normalization parameter ζ N  may be defined by the following relationship: 
       ζ N   =f ( Z   N )  (Eqn. 7) 
     where ζ N  is the statistical impedance normalization parameter for one set  1208 ,  1218  of cardiac cycles and ƒ(Z N ) is a function of the impedance normalization parameter Z N . The function ƒ(Z N ) may be a statistical function of the impedance normalization parameter Z N . For example, the function ƒ(Z N ) may be an average, mean, deviation, standard deviation, maximum, minimum, and the like, of the impedance normalization parameter Z N . In one specific example, the statistical impedance normalization parameter ζ N  is the average of the impedance normalization parameter Z N  measured for each of the cardiac cycles  1200 - 1206  in the first set  1208 . The statistical impedance parameter ζ N  is calculated for the first and second sets  1208  and  1218 . 
     The ischemia detection module  274  may calculate a statistical contractility parameter χ 3  for each set  1208 ,  1218  of cardiac cycles. The statistical contractility parameter χ 3  may be defined by the following relationship: 
       χ 3 =ƒ( C   3 )  (Eqn. 8) 
     where χ 3  is the statistical contractility parameter for one set  1208 ,  1218  of cardiac cycles and ƒ(C 3 ) is a function of the contractility parameter C 3 . The function ƒ(C 3 ) may be a statistical function of the contractility parameter C 3 . For example, the function ƒ(C 3 ) may be an average, mean, deviation, standard deviation, maximum, minimum, and the like, of the contractility parameter C 3 . In one specific example, the statistical contractility parameter C 3  is the average of the contractility parameter C 3  measured for each of the cardiac cycles  1200 - 1206  in the first set  1208 . The statistical contractility parameter C 3  is calculated for the first and second sets  1208  and  1218 . 
     The ischemia detection module  274  may calculate a statistical contractility normalization parameter χ N  for each set of cardiac cycles. The statistical contractility normalization parameter χ N  may be defined by the following relationship: 
       χ N =ƒ( C   N )  (Eqn. 9) 
     where χ N  is the statistical contractility normalization parameter for one set  1208 ,  1218  of cardiac cycles and ƒ(C N ) is a function of the contractility normalization parameter C N . The function ƒ(C N ) may be a statistical function of the contractility normalization parameter C N . For example, the function ƒ(C N ) may be an average, mean, deviation, standard deviation, maximum, minimum, and the like, of the contractility normalization parameter C N . In one specific example, the statistical contractility normalization parameter χ N  is the average of the contractility normalization parameter C N  measured for each of the cardiac cycles  1200 - 1206  in the first set  1208 . The statistical contractility parameter χ N  is calculated for the first and second sets  1208  and  1218 . 
     The ischemia detection module  274  may calculate a statistical ST segment of interest parameter σ for each set  1208 ,  1218  of cardiac cycles. The statistical ST segment of interest parameter σ may be defined by the following relationship: 
       σ=ƒ( SOI )  (Eqn. 10) 
     where σ is the statistical ST segment of interest parameter for one set  1208 ,  1218  of cardiac cycles and ƒ(SOI) is a function of the segment of interest parameter SOI. The function ƒ(SOI) may be a statistical function of the segment of interest parameter SOI. For example, the function ƒ(SOI) may be an average, mean, deviation, standard deviation, maximum, minimum, and the like, of the segment of interest parameter SOI. In one specific example, the statistical ST segment of interest parameter σ is the average of the segment of interest parameter SOI measured for each of the cardiac cycles  1200 - 1206  in the first set  1208 . The statistical ST segment of interest parameter σ is calculated for the first and second sets  1208  and  1218 . 
     As described above, the ischemia detection module  274  calculates ischemia indicators at  1010  to monitor ischemia in the heart  102  (shown in  FIG. 1 ). The ischemia detection module  274  calculates a group of ischemia indicators for a plurality of sets of cardiac cycles. For example, the ischemia detection module  274  may calculate a group  1224  of ischemia indicators for the first and second sets  1208  and  1218 . The group  1224  of ischemia indicators is used to compare the degree of amount of change in the statistical parameters between the first and second statistical parameter groups  1220  and  1222 . 
     The ischemia detection module  274  calculates ischemia indicators from the statistical impedance parameter ζ 3 , the statistical impedance normalization parameter ζ N , the statistical contractility parameter ζ 3 , the statistical contractility normalization parameter χ N , and the statistical ST segment of interest parameter σ for the first and second sets  1208 ,  1218  of cardiac cycles. For example, the ischemia detection module  274  calculates the amount of change for one or more of the statistical impedance parameter ζ 3 , the statistical impedance normalization parameter ζ N , the statistical contractility parameter χ 3 , the statistical contractility normalization parameter χ N , and the statistical ST segment of interest parameter σ between the first and second sets  1208  and  1218 . In one embodiment, the ischemia detection module  274  calculates an impedance ischemia indicator ΔZ 3  for each of a plurality of sets  1208 ,  1218  of cardiac cycles. For example, the ischemia detection module  274  may calculate the impedance ischemia indicator ΔZ 3  that is the absolute value of the difference between the statistical impedance parameters ζ 3  calculated for the first and second sets  1208  and  1210 . The impedance ischemia indicator ΔZ 3  may be represented by the following equation: 
     
       
         
           
             
               
                 
                   
                     Δ 
                      
                     
                         
                     
                      
                     
                       Z 
                       3 
                     
                   
                   = 
                   
                      
                     
                       
                         
                           ζ 
                           
                             3 
                              
                             
                               ( 
                               i 
                               ) 
                             
                           
                         
                         - 
                         
                           ζ 
                           
                             3 
                              
                             
                               ( 
                               
                                 i 
                                 + 
                                 1 
                               
                               ) 
                             
                           
                         
                       
                       
                         ζ 
                         
                           3 
                            
                           
                             ( 
                             
                               i 
                               + 
                               1 
                             
                             ) 
                           
                         
                       
                     
                      
                   
                 
               
               
                 
                   ( 
                   
                     Eqn 
                     . 
                     
                         
                     
                      
                     11 
                   
                   ) 
                 
               
             
           
         
       
     
     where ζ 3(i)  is the statistical impedance parameter ζ 3  for the first set  1208 , ζ 3(i+1)  is the statistical impedance parameter ζ 3  for the second set  1210 , and the impedance ischemia indicator ΔZ 3  is the absolute value of the ratio of the difference between the statistical impedance parameters ζ 3(i)  and ζ 3(i+1)  to the statistical impedance parameter ζ 3(i+1) . 
     The ischemia indicators may include an impedance normalization ischemia indicator ΔZ N . The ischemia detection module  274  may calculate the impedance normalization ischemia indicator ΔZ N  for each of a plurality of sets of cardiac cycles. For example, the ischemia detection module  274  may calculate the impedance normalization ischemia indicator ΔZ N  that is the absolute value of the difference between the statistical impedance normalization parameters ζ N  calculated for the first and second sets  1208  and  1210 . The impedance normalization ischemia indicator ΔZ N  may be represented by the following equation: 
     
       
         
           
             
               
                 
                   
                     Δ 
                      
                     
                         
                     
                      
                     
                       Z 
                       N 
                     
                   
                   = 
                   
                      
                     
                       
                         
                           ζ 
                           
                             N 
                              
                             
                               ( 
                               i 
                               ) 
                             
                           
                         
                         - 
                         
                           ζ 
                           
                             N 
                              
                             
                               ( 
                               
                                 i 
                                 + 
                                 1 
                               
                               ) 
                             
                           
                         
                       
                       
                         ζ 
                         
                           N 
                            
                           
                             ( 
                             
                               i 
                               + 
                               1 
                             
                             ) 
                           
                         
                       
                     
                      
                   
                 
               
               
                 
                   ( 
                   
                     Eqn 
                     . 
                     
                         
                     
                      
                     12 
                   
                   ) 
                 
               
             
           
         
       
     
     where ζ N(i)  is the statistical impedance normalization parameter ζ N  for the first set  1208 , ζ N(i+1)  is the statistical impedance normalization parameter ζ N  for the second set  1210 , and the impedance normalization ischemia indicator ΔZ N  is the absolute value of the ratio of the difference between the statistical impedance normalization parameters ζ N(i)  and ζ N(i+1)  to the statistical impedance parameter ζ N(i+1) . 
     The ischemia indicators may include a contractility ischemia indicator ΔC 3 . The ischemia detection module  274  may calculate the contractility ischemia indicator ΔC 3  for each of a plurality of sets of cardiac cycles. For example, the ischemia detection module  274  may calculate the contractility ischemia indicator ΔC 3  that is the absolute value of the difference between the statistical contractility parameters χ 3  calculated for the first and second sets  1208  and  1210 . The contractility ischemia indicator ΔC 3  may be represented by the following equation: 
     
       
         
           
             
               
                 
                   
                     Δ 
                      
                     
                         
                     
                      
                     
                       C 
                       3 
                     
                   
                   = 
                   
                      
                     
                       
                         
                           χ 
                           
                             3 
                              
                             
                               ( 
                               i 
                               ) 
                             
                           
                         
                         - 
                         
                           χ 
                           
                             3 
                              
                             
                               ( 
                               
                                 i 
                                 + 
                                 1 
                               
                               ) 
                             
                           
                         
                       
                       
                         χ 
                         
                           3 
                            
                           
                             ( 
                             
                               i 
                               + 
                               1 
                             
                             ) 
                           
                         
                       
                     
                      
                   
                 
               
               
                 
                   ( 
                   
                     Eqn 
                     . 
                     
                         
                     
                      
                     13 
                   
                   ) 
                 
               
             
           
         
       
     
     where χ 3(i)  is the statistical contractility parameter χ 3  for the first set  1208 , χ 3(i+1)  is the statistical contractility parameter χ 3  for the second set  1210 , and the contractility ischemia indicator ΔC 3  is the absolute value of the ratio of the difference between the statistical contractility parameters χ 3(i)  and χ 3(i+1)  to the statistical contractility parameter χ 3(i+1) . 
     The ischemia indicators may include a contractility normalization ischemia indicator ΔC N . The ischemia detection module  274  may calculate the contractility normalization ischemia indicator ΔC N  for each of a plurality of sets of cardiac cycles. For example, the ischemia detection module  274  may calculate the contractility normalization ischemia indicator ΔC N  that is the absolute value of the difference between the statistical contractility normalization parameters χ N  calculated for the first and second sets  1208  and  1210 . The contractility normalization ischemia indicator ΔC N  may be represented by the following equation: 
     
       
         
           
             
               
                 
                   
                     Δ 
                      
                     
                         
                     
                      
                     
                       C 
                       N 
                     
                   
                   = 
                   
                      
                     
                       
                         
                           χ 
                           
                             N 
                              
                             
                               ( 
                               i 
                               ) 
                             
                           
                         
                         - 
                         
                           χ 
                           
                             N 
                              
                             
                               ( 
                               
                                 i 
                                 + 
                                 1 
                               
                               ) 
                             
                           
                         
                       
                       
                         χ 
                         
                           N 
                            
                           
                             ( 
                             
                               i 
                               + 
                               1 
                             
                             ) 
                           
                         
                       
                     
                      
                   
                 
               
               
                 
                   ( 
                   
                     Eqn 
                     . 
                     
                         
                     
                      
                     14 
                   
                   ) 
                 
               
             
           
         
       
     
     where χ N(i)  is the statistical contractility normalization parameter χ N  for the first set  1208 , χ N(i+1)  is the statistical contractility normalization parameter χ N  for the second set  1210 , and the contractility normalization ischemia indicator ΔC N  is the absolute value of the ratio of the difference between the statistical contractility normalization parameters χ N(i)  and χ N(i+1)  and the statistical contractility normalization parameter χ N(i+1) . 
     The ischemia indicators may include a segment of interest ischemia indicator ΔSOI. The ischemia detection module  274  may calculate the segment of interest ischemia indicator ΔSOI for each of a plurality of sets of cardiac cycles. For example, the ischemia detection module  274  may calculate the segment of interest ischemia indicator ΔSOI that is the absolute value of the difference between the statistical ST segment of interest parameters σ calculated for the first and second sets  1208  and  1210 . The segment of interest ischemia indicator ΔSOI may be represented by the following equation: 
     
       
         
           
             
               
                 
                   
                     Δ 
                      
                     
                         
                     
                      
                     S 
                      
                     
                         
                     
                      
                     O 
                      
                     
                         
                     
                      
                     I 
                   
                   = 
                   
                      
                     
                       
                         
                           σ 
                           
                             ( 
                             i 
                             ) 
                           
                         
                         - 
                         
                           σ 
                           
                             ( 
                             
                               i 
                               + 
                               1 
                             
                             ) 
                           
                         
                       
                       
                         σ 
                         
                           ( 
                           
                             i 
                             + 
                             1 
                           
                           ) 
                         
                       
                     
                      
                   
                 
               
               
                 
                   ( 
                   
                     Eqn 
                     . 
                     
                         
                     
                      
                     15 
                   
                   ) 
                 
               
             
           
         
       
     
     where σ (i)  is the statistical ST segment of interest parameter σ for the first set  1208 , σ (i+1)  is the statistical ST segment of interest parameter σ for the second set  1210 , and the segment of interest ischemia indicator ΔSOI is the absolute value of the ratio of the difference between the statistical ST segment of interest parameters σ (i)  and σ (i+1)  to the statistical ST segment of interest parameter σ (i+1) . 
     The ischemia detection module  274  determines how many of the ischemia indicators ΔZ 3 , ΔZ N , ΔC 3 , ΔC N , and ΔSOI exceed a predetermined minimum threshold at  1012 . If a relatively small number of the ischemia indicators do not exceed the threshold, then the ischemia detection module  274  classifies the second cardiac cycle  1218  as non-ischemic. For example, if only one or none of the ischemia indicators exceeds the threshold, then the ischemia detection module  274  classifies the second cardiac cycle  1218  as non-ischemic at  1014 . If a relatively large number of the ischemia indicators exceed the threshold, then the ischemia detection module  274  classifies the second cardiac cycle  1218  as ischemic. For example, if four or more of the ischemia indicators exceed the threshold, then the ischemia detection module  274  classifies the second cardiac cycle  1218  as ischemic at  1016 . If an intermediate number of the ischemia indicators exceed the threshold, then the ischemia detection module  274  classifies the second cardiac cycle  1218  as potentially ischemic. For example, if two or three of the ischemia indicators exceed the threshold, then the ischemia detection module  274  classifies the second cardiac cycle  1218  as potentially ischemic at  1018 . While the above examples compare the ischemia indicators to a single threshold, multiple thresholds may be used in another embodiment. Moreover, the number of ischemia indicators that must exceed the threshold before classifying the second set  1218  as ischemic, potentially ischemic or non-ischemic may differ from those described above. 
     If the ischemia detection module  274  classifies the second set  1218  of cardiac cycles  1210 - 1216  as potentially ischemic at  1018 , then the ischemia detection module  274  may perform a secondary check on whether the heart  102  (shown in  FIG. 1 ) is ischemic. For example, the ischemia detection module  274  may calculate a sum Σ of two or more of the ischemia indicators at  1020  and compare this sum Σ is a predetermined minimum sum, or threshold, at  1022 . The sum Σ may be represented as follows: 
       Σ=Δ Z   3   +ΔZ   N   +ΔC   3   +ΔC   N   +ΔSOI   (Eqn. 16) 
     If the sum Σ exceeds the predetermined minimum sum, then the ischemia detection module  274  classifies the second set  1218  of cardiac cycle  1210 - 1216  as ischemic at  1016 . If the sum Σ does not exceed the minimum sum, then the ischemia detection module  274  classifies the second set  1218  of cardiac cycles  1210 - 1216  as  1014 . By way of nonlimiting example only, the predetermined minimum sum is 10%. Other minimum sums may be used, such as 8%, 6%, 12%, 14%, and the like. The predetermined minimum sum may be stored at the memory  244  (shown in  FIG. 3 ). 
     Alternatively, the ischemia detection module  274  compares the sum Σ to a plurality of predetermined minimum sums. The ischemia detection module  274  may compare the sum Σ to a lower predetermined minimum sum and an upper predetermined minimum sum. By way of non-limiting example only, the ischemia detection module  274  may compare the sum Σ to a lower minimum sum of 5% and to an upper minimum sum of 10%. If the sum Σ does not exceed the lower minimum sum, the ischemia detection module  274  classifies the current cardiac cycles as non-ischemic. If the sum Σ exceeds the lower minimum sum but does not exceed the upper minimum sum, the ischemia detection module  274  classifies the second set  1218  of cardiac cycles  1210 - 1216  as potentially ischemic. If the sum Σ exceeds the upper minimum sum, the ischemia detection module  274  classifies the second set  1218  of cardiac cycles  1210 - 1216  as ischemic. 
     In another embodiment, the ischemia detection module  274  detects ischemia in the heart  102  (shown in  FIG. 1 ) when the ischemia detection module  274  classifies a plurality of sets  1208 ,  1218  of cardiac cycles as ischemic. The ischemia detection module  274  may notify an operator of the IMD  100  that ischemia is detected when a predetermined minimum number of sets  1208 ,  1218  of cardiac cycles are classified as ischemic according to one or more of the embodiments described above. For example, the ischemia detection module  274  may determine that ischemia is detected when at least a minimum number of consecutive sets  1208 ,  1218  of cardiac cycles are classified as being ischemic, as described above. Alternatively, the ischemia detection module  274  may notify an operator of the IMD  100  that ischemia is detected when consecutive sets  1208 ,  1218  of cardiac cycles are classified as ischemic for a minimum amount of time according to one or more of the embodiments described above. The predetermined minimum time may be stored in the memory  244  (as shown in  FIG. 3 ). For example, the ischemia detection module  274  may determine that ischemia is detected when the cardiac cycles over a previous time period are classified as ischemic according to one or more embodiments described above. 
     The ischemia detection module  274  may communicate the classification of the second set  1218  of cardiac cycles  1210 - 1216  as ischemic, potentially ischemic or non-ischemic to an operator of the IMD  100 . For example, the classification of the second set  1218  of cardiac cycles  1210 - 1216  may be visually communicated on a display  424  (shown in  FIG. 8 ). The process  1000  may continue to monitor the heart  102  for ischemia after the second set  1218  of cardiac cycles  1210 - 1216  is classified by the ischemia detection module  274  as ischemic, non-ischemic or potentially ischemic. For example, the process  1000  may continue in a loop-wise manner as shown in  FIG. 4 . 
       FIG. 6  illustrates an alternative manner of measuring the third impedance vector Z 3  according to one embodiment. The positions of first, second and third impedance vectors Z 1 , Z 2  and Z 3  shown in  FIG. 6  are approximate and are provided as illustrations. The actual positions of the first, second and third impedance vectors Z 1 , Z 2  and Z 3  may slightly differ from the positions shown in  FIG. 6 . Similar to the embodiment shown in  FIG. 1 , the first impedance vector Z 1  extends between the housing  104  and the RV coil electrode  134  and the second impedance vector Z 2  extends between the housing  104  and the SVC coil electrode  138 . The current I 3  is supplied between the SVC coil electrode  138  and the LV ring electrode  130 . The current I 3  is supplied by electrically connecting the SVC coil electrode  138  and the LV ring electrode  130  to a source of electric current, such as the battery  256  (shown in  FIG. 3 ). Similar to the embodiment shown in  FIG. 1 , the voltage V 3  is measured between the LV electrode tip  124  and the RV electrode tip  136  in one embodiment. The voltage V 3  includes the voltage difference between the LV and RV electrode tips  124  and  136  measured from the current I 3 . The third impedance vector Z 3  can be calculated as described above. The SVC coil electrode  138  may have a lower intrinsic impedance than other electrodes in the IMD  100 . For example, the SVC coil electrode  138  may have an intrinsic impedance of approximately 100 ohms or less. Using electrodes with lower intrinsic impedances to supply the current I 3 , measure the voltage V 3 , the first impedance vector Z 1  and/or the second impedance vector Z 2  can increase the sensitivity of the IMD  100  to smaller changes in the impedance of the myocardium of the heart  102 . 
     The current I 3  may be applied at one or more of a variety of frequencies in one or more of the embodiments described herein. One or more frequencies at which the current I 3  is applied may cause the IMD  100  to be more sensitive to smaller changes in one or more of the impedance vectors Z 1 , Z 2  and Z 3 . For example, the IMD  100  may measure a relatively small change in the third impedance vector Z 3  when the current I 3  is applied at a first frequency but not measure the same change in the third impedance vector Z 3  when the current I 3  is applied at a second, different frequency. 
       FIG. 8  illustrates a functional block diagram of the external device  400 , such as a programmer, that is operated by a physician, a health care worker, or a patient to interface with IMD  100  (shown in  FIG. 1 ). The external device  400  may be utilized in a hospital setting, a physician&#39;s office, or even the patient&#39;s home to communicate with the IMD  100  to change a variety of operational parameters regarding the therapy provided by the IMD  100  as well as to select among physiological parameters to be monitored and recorded by the IMD  100 . For example, the external device  400  may be used to program coronary episode related parameters, such as ischemia-related and AMI-related ST segment shift thresholds, duration thresholds, and the like. Further, the external device  400  may be utilized to interrogate the IMD  100  to determine the condition of a patient, to adjust the physiological parameters monitored or to adapt the therapy to a more efficacious one in a non-invasive manner. 
     External device  400  includes an internal bus  402  that connects/interfaces with a Central Processing Unit (CPU)  404 , ROM  406 , RAM  408 , a hard drive  410 , a speaker  412 , a printer  414 , a CD-ROM drive  416 , a floppy drive  418 , a parallel I/O circuit  420 , a serial I/O circuit  422 , the display  424 , a touch screen  426 , a standard keyboard connection  428 , custom keys  430 , and a telemetry subsystem  432 . The internal bus  402  is an address/data bus that transfers information (e.g., either memory data or a memory address from which data will be either stored or retrieved) between the various components described. The hard drive  410  may store operational programs as well as data, such as reference ST segments, ST thresholds, impedance thresholds, other thresholds, timing information and the like. 
     The CPU  404  typically includes a microprocessor, a micro-controller, or equivalent control circuitry, designed specifically to control interfacing with the external device  400  and with the IMD  100  (shown in  FIG. 1 ). The CPU  404  may further include RAM or ROM memory, logic and timing circuitry, state machine circuitry, and I/O circuitry to interface with the IMD  100 . Typically, the microcontroller  222  (shown in  FIG. 2 ) includes the ability to process or monitor input signals (e.g., data) as controlled by program code stored in memory (e.g., ROM  406 ). 
     The display  424  (e.g., may be connected to a video display  434 ) and the touch screen  426  display text, alphanumeric information, data and graphic information via a series of menu choices to be selected by the user relating to the IMD  100 , such as for example, status information, operating parameters, therapy parameters, patient status, access settings, software programming version, ST segment thresholds, impedance thresholds, other thresholds, and the like. The touch screen  426  accepts a user&#39;s touch input  436  when selections are made. The keyboard  428  (e.g., a typewriter keyboard  438 ) allows the user to enter data to the displayed fields, operational parameters, therapy parameters, as well as interface with the telemetry subsystem  432 . Furthermore, custom keys  430  turn on/off  440  (e.g., EVVI) the external device  400 . The printer  414  prints hard-copies of reports  442  for a physician/healthcare worker to review or to be placed in a patient file, and speaker  412  provides an audible warning (e.g., sounds and tones  444 ) to the user in the event a patient has any abnormal physiological condition occur while the external device  400  is being used. The parallel I/O circuit  420  interfaces with a parallel port  446 . The serial I/O circuit  422  interfaces with a serial port  448 . The floppy drive  418  accepts diskettes  450 . The CD-ROM drive  416  accepts CD ROMs  452 . 
     The telemetry subsystem  432  includes a central processing unit (CPU)  454  in electrical communication with a telemetry circuit  456 , which communicates with both an ECG circuit  458  and an analog out circuit  460 . The ECG circuit  458  is connected to ECG leads  462 . The telemetry circuit  456  is connected to a telemetry wand  464 . The analog out circuit  432  includes communication circuits, such as a transmitting antenna, modulation and demodulation stages (not shown), as well as transmitting and receiving stages (not shown) to communicate with analog outputs  466 . The external device  400  may wirelessly communicate with the IMD  100  and utilize protocols, such as Bluetooth, GSM, infrared wireless LANs, HIPERLAN, 3G, satellite, as well as circuit and packet data protocols, and the like. A wireless RF link utilizes a carrier signal that is selected to be safe for physiologic transmission through a human being and is below the frequencies associated with wireless radio frequency transmission. Alternatively, a hard-wired connection may be used to connect the external device  400  to IMD  100  (e.g., an electrical cable having a USB connection). 
       FIG. 9  illustrates a distributed processing system  500  in accordance with one embodiment. The distributed processing system  500  includes a server  502  that is connected to a database  504 , a programmer  506  (e.g., similar to external device  400  described above and shown in  FIG. 8 ), a local RF transceiver  508  and a user workstation  510  electrically connected to a communication system  512 . The communication system  512  may be the internet, a voice over IP (VoIP) gateway, a local plain old telephone service (POTS) such as a public switched telephone network (PSTN), and the like. Alternatively, the communication system  512  may be a local area network (LAN), a campus area network (CAN), a metropolitan area network (MAN), or a wide area network (WAM). The communication system  512  serves to provide a network that facilitates the transfer/receipt of cardiac signals, processed cardiac signals, histograms, trend analysis and patient status, and the like. 
     The server  502  is a computer system that provides services to other computing systems (e.g., clients) over a computer network. The server  502  acts to control the transmission and reception of information (e.g., cardiac signals, processed cardiac signals, ST segments, R-waves, thresholds, impedances, histograms, statistical analysis, trend lines, and the like). The server  502  interfaces with the communication system  512 , such as the internet or a local POTS based telephone system, to transfer information between the programmer  506 , the local RF transceiver  508 , the user workstation  510  as well as a cell phone  516 , and a personal data assistant (PDA)  518  to the database  504  for storage/retrieval of records of information. For instance, the server  502  may download, via a wireless connection  526 , to the cell phone  516  or the PDA  518  the results of processed cardiac signals, ST segment trends, impedance vectors, or a patient&#39;s physiological state (e.g., is the patient having or has had an ischemia) based on previously recorded cardiac information. On the other hand, the server  502  may upload raw cardiac signals (e.g., unprocessed cardiac data) from a surface ECG unit  520  or an IMD  522  via the local RF transceiver  508  or the programmer  506 . 
     Database  504  is any commercially available database that stores information in a record format in electronic memory. The database  504  stores information such as raw cardiac data, processed cardiac signals, statistical calculations (e.g., averages, modes, standard deviations), histograms, cardiac trends (e.g., STS trends), and the like. The information is downloaded into the database  504  via the server  502  or, alternatively, the information is uploaded to the server from the database  504 . 
     The programmer  506  is similar to the external device  400  shown in  FIG. 6  and described above, and may reside in a patient&#39;s home, a hospital, or a physician&#39;s office. Programmer  506  interfaces with the surface ECG unit  520  and the IMD  522  (e.g., similar to the IMD  100  described above and shown in  FIG. 1 ). The programmer  506  may wirelessly communicate with the IMD  522  and utilize protocols, such as Bluetooth, GSM, infrared wireless LANs, HIPERLAN, 3G, satellite, as well as circuit and packet data protocols, and the like. Alternatively, a hard-wired connection may be used to connect the programmer  506  to IMD  100  (e.g., an electrical cable having a USB connection). The programmer  506  is able to acquire cardiac signals from the surface of a person (e.g., ECGs), or the programmer is able to acquire intra-cardiac electrogram (e.g., IEGM) signals from the IMD  522 . The programmer  506  interfaces with the communication system  512 , either via the internet or via POTS, to upload the cardiac data acquired from the surface ECG unit  520  or the IMD  522  to the server  502 . The programmer  506  may upload more than just raw cardiac data. For instance, the programmer  506  may upload status information, operating parameters, therapy parameters, patient status, access settings, software programming version, ST segment thresholds, calculated or measured impedance vectors, and the like. 
     The local RF transceiver  508  interfaces with the communication system  512 , either via the internet or via POTS, to upload cardiac data acquired from the surface ECG unit  520  or the IMD  522  to the server  502 . In one embodiment, the surface ECG unit  520  and the IMD  522  have a bi-directional connection with the local RF transceiver via a wireless connection. The local RF transceiver  508  is able to acquire cardiac signals from the surface of a person (e.g., ECGs), or acquire intra-cardiac electrogram (e.g., IEGM) signals from the IMD  522 . On the other hand, the local RF transceiver  508  may download stored cardiac data from the database  504  or the analysis of cardiac signals from the database  504  (e.g., ST segment statistical analysis, ST segment trends, impedance vectors, and the like) information to the surface ECG unit  520  or the IMD  522 . 
     The user workstation  510  may interface with the communication system  512  via the internet or POTS to download information via the server  502  from the database  504 . Alternatively, the user workstation  510  may download raw data from the surface ECG unit  520  or IMD  522  via either the programmer  506  or the local RF transceiver  508 . Once the user workstation  510  has downloaded the cardiac information (e.g., raw cardiac signals, ST segments, impedance vectors, and the like), the user workstation  510  may process the cardiac signals, create histograms, calculate statistical parameters, or determine cardiac trends and determine if the patient is suffering from ischemia or another physiological condition. Once the user workstation  510  has finished performing its calculations, the user workstation  510  may either download the results to the cell phone  516 , the PDA  518 , the local RF transceiver  508 , the programmer  506 , or to the server  502  to be stored on the database  504 . 
       FIG. 7  is an illustration of the third impedance vector Z 3  over a range of frequencies of the current I 3  according to one embodiment. The horizontal axis  900  represents the frequency of the current I 3  supplied to the electrodes according to one or more of the embodiments described herein. The vertical axis  902  represents the third impedance vector Z 3  determined according to one or more of the embodiments described herein. As described above, an operator may sweep the frequency of the current I 3  from a lower frequency  904  to a higher frequency  906 . At frequencies near the lower frequency  904 , the third impedance vector Z 3  remains approximately constant at an upper impedance  908 . For example, at frequencies proximate to 500 Hz, the third impedance vector Z 3  may be approximately 100 ohms. As the frequency of the current I 3  is increased to the higher frequency  906 , the third impedance vector Z 3  may gradually decrease as shown by the curve  910 . At frequencies that approach the higher frequency  906 , the third impedance vector Z 3  becomes approximately constant to a lower impedance  912 . For example, at frequencies proximate to 10 kHz, the third impedance vector Z 3  may reduce to approximately 50 ohms. 
     An operator can determine a frequency of the current I 3  that is more sensitive to changes in the third impedance vector Z 3  brought on by ischemia by examining the sensitivity or degree of change in the third impedance vector Z 3  over a range of frequencies before and after ischemia is induced in the patient. For example, the operator can sweep the frequencies at which the current I 3  is applied between a lower frequency  904  of 100 Hz and a higher frequency  906  of 50 kHz. The frequency may be swept through this frequency range once or repeated times over a 10 to 30 second time interval. The curve  908  defining the third impedance vector Z 3  over the frequency range may be displayed to the operator and/or stored in the memory  244  (shown in  FIG. 3 ). Ventricular fibrillation may then be induced in the patient by, for example, inflating an angioplasty balloon in the patient. As ventricular fibrillation is induced, the heart  102  can become more ischemic. The frequency of the current I 3  is then swept between the lower and higher frequencies  904  and  906 , and another curve  908  that defines the third impedance vector Z 3  over this frequency range is obtained. These two curves  908  may be compared to determine the frequency or frequencies at which the current I 3  is applied that are more sensitive to changes in the third impedance vector Z 3  brought about by ischemia. For example, the previous curve  908  that is obtained prior to inducing ischemia may be used as a baseline to compare the later obtained curve  908 . Variations between the previous and later obtained curves  908  at one or more frequencies can reveal the frequencies at which the IMD  100  is more sensitive to changes in the impedance of the heart  102  brought about by ischemia. 
       FIG. 10  illustrates a block diagram of exemplary manners in which embodiments of the present invention may be stored, distributed and installed on a computer-readable medium. In  FIG. 10 , the “application” represents one or more of the methods and process operations discussed above. For example, the application may represent the process carried out in connection with  FIGS. 1 through 9  as discussed above. 
     As shown in  FIG. 10 , the application is initially generated and stored as source code  1100  on a source computer-readable medium  1102 . The source code  1100  is then conveyed over path  1104  and processed by a compiler  1106  to produce object code  1108 . The object code  1108  is conveyed over path  1110  and saved as one or more application masters on a master computer-readable medium  1112 . The object code  1108  is then copied numerous times, as denoted by path  1114 , to produce production application copies  1116  that are saved on separate production computer-readable medium  1118 . The production computer-readable medium  1118  is then conveyed, as denoted by path  1120 , to various systems, devices, terminals and the like. In the example of  FIG. 10 , a user terminal  1122 , a device  1124  and a system  1126  are shown as examples of hardware components, on which the production computer-readable medium  1118  are installed as applications (as denoted by  1128  through  1132 ). For example, the production computer-readable medium  1118  may be installed on the IMD  100  (shown in  FIG. 1 ) and/or the controller  400  (shown in  FIG. 8 ). 
     The source code may be written as scripts, or in any high-level or low-level language. Examples of the source, master, and production computer-readable medium  1102 ,  1112  and  1118  include, but are not limited to, CDROM, RAM, ROM, Flash memory, RAID drives, memory on a computer system and the like. Examples of the paths  1104 ,  1110 ,  1114 , and  1120  include, but are not limited to, network paths, the internet, Bluetooth, GSM, infrared wireless LANs, HIPERLAN, 3G, satellite, and the like. The paths  1104 ,  1110 ,  1114 , and  1120  may also represent public or private carrier services that transport one or more physical copies of the source, master, or production computer-readable medium  1102 ,  1112  or  1118  between two geographic locations. The paths  1104 ,  1110 ,  1114  and  1120  may represent threads carried out by one or more processors in parallel. For example, one computer may hold the source code  1100 , compiler  1106  and object code  1108 . Multiple computers may operate in parallel to produce the production application copies  1116 . The paths  1104 ,  1110 ,  1114 , and  1120  may be intra-state, inter-state, intra-country, inter-country, intra-continental, inter-continental and the like. 
     The operations noted in  FIG. 10  may be performed in a widely distributed manner world-wide with only a portion thereof being performed in the United States. For example, the application source code  1100  may be written in the United States and saved on a source computer-readable medium  1102  in the United States, but transported to another country (corresponding to path  1104 ) before compiling, copying and installation. Alternatively, the application source code  1100  may be written in or outside of the United States, compiled at a compiler  1106  located in the United States and saved on a master computer-readable medium  1112  in the United States, but the object code  1108  transported to another country (corresponding to path  1114 ) before copying and installation. Alternatively, the application source code  1100  and object code  1108  may be produced in or outside of the United States, but production application copies  1116  produced in or conveyed to the United States (for example, as part of a staging operation) before the production application copies  1116  are installed on user terminals  1122 , devices  1124 , and/or systems  1126  located in or outside the United States as applications  1128  through  1132 . 
     As used throughout the specification and claims, the phrases “computer-readable medium” and “instructions configured to” shall refer to any one or all of (i) the source computer-readable medium  1102  and source code  1100 , (ii) the master computer-readable medium and object code  1108 , (iii) the production computer-readable medium  1118  and production application copies  1116  and/or (iv) the applications  1128  through  1132  saved in memory in the terminal  1122 , device  1124  and system  1126 . 
     In accordance with certain embodiments, methods and systems are provided that are able to monitor ischemia using variations in one or more segment of interest and variations in one or more impedance vectors. The use of both segment and impedance variations can improve the accuracy of detecting ischemia in a patient. 
     It is to be understood that the above description is intended to be illustrative, and not restrictive. For example, the above-described embodiments (and/or aspects thereof) may be used in combination with each other. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from its scope. While the dimensions and types of materials described herein are intended to define the parameters of the invention, they are by no means limiting and are exemplary embodiments. Many other embodiments will be apparent to those of skill in the art upon reviewing the above description. The scope of the invention should, therefore, be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled. In the appended claims, the terms “including” and “in which” are used as the plain-English equivalents of the respective terms “comprising” and “wherein.” Moreover, in the following claims, the terms “first,” “second,” and “third,” etc. are used merely as labels, and are not intended to impose numerical requirements on their objects. Further, the limitations of the following claims are not written in means-plus-function format and are not intended to be interpreted based on 35 U.S.C. § 112, sixth paragraph, unless and until such claim limitations expressly use the phrase “means for” followed by a statement of function void of further structure. 
     This written description uses examples to disclose the invention, including the best mode, and also to enable any person skilled in the art to practice the invention, including making and using any devices or systems and performing any incorporated methods. The patentable scope of the invention is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.