Patent Publication Number: US-2009234414-A1

Title: Apparatus and methods of optimizing atrioventricular pacing delay intervals

Description:
FIELD 
     This invention relates to cardiac pacing systems, and more particularly to apparatus and methods for improving cardiac function by optimizing atrioventricular (AV) timing intervals for a cardiac pacing system, such as a dual-chamber or a triple-chamber cardiac resynchronization therapy (CRT) delivery system. 
     BACKGROUND 
     Cardiac resynchronization therapy (CRT) is a promising and accepted device therapy for patients with systolic heart failure classified in New York Heart Association (NYHA) class III and IV. Indications include patients who, despite optimal medication, are symptomatic, and who demonstrate LV asynchrony. The latter occurs in patients with left bundle branch block (LBBB) and typically presents with a QRS width (measured on an ECG machine) of greater than about 130-150 ms. Herein, “asynchrony” is characterized by a delay in systolic contraction between the intraventricular septum and the left ventricular (LV) free wall. 
     Currently available CRT bi-ventricular pacing generally employs one lead positioned in operative communication with the right ventricle (RV) and one lead in operative communication with a portion of one of the tributaries of the coronary venous system. The myocardial venous system provides a pathway for deployment of LV stimulation of the lead (and associated electrodes) to operatively communicate with the LV. In most patients, an additional lead is deployed to the right atrium (RA) for atrioventricular (AV) synchronization during pacing. Exceptions for placement of the atrial lead include patients suffering from chronic atrial fibrillation (AF) or having a relatively high AF “burden.” According to such CRT delivery, electrical stimulation of both the RV and LV operates to assist ventricular asynchrony and increase contractility (as measured by ventricular pressure development (dP/dt). 
     CRT has been established as an effective treatment for heart failure patients (NYHA III, IV) with long QRS duration (QRSd&gt;120 ms) and low ejection fraction (EF&lt;35%). A number of acute studies demonstrated a significant dependence of various indices of cardiac function on the programmed values of the atrio-ventricular (AV) and inter-ventricular (VV) delays. The most commonly used methods of AV and VV delay interval optimization are based on echocardiographic evaluation of filling characteristics, cardiac output (CO), and ventricular dyssynchrony for different interval settings. A few chronic studies demonstrated limited evidence of long-term benefit of echo-guided interval optimization. However, considering supposedly incremental benefit of interval optimization such methods seem to be too time and resource-consuming. For certain patients, further optimization of the AV interval can be performed on the guidance of echocardiographic or hemodynamic parameters as is known in the art. However, such methods of optimization of the programmed AV delays in triple chamber (e.g., CRT delivery) implantable medical devices (IMDs) involve complexities. With supposedly incremental benefit of optimization, echocardiographic evaluation simply takes too much time and effort for clinicians (and clinics) and requires coordination between implanting physicians and imaging personnel and equipment. Besides the time, effort and coordination required, the patient is typically lying down and essentially stationary during the procedure. Accordingly, the patient&#39;s hemodynamic state during optimization simply does not correlate to the state during activities of daily living (ADL); this is, when the patient is ambulatory. 
     Thus, there is a need in the art for an improved, easily optimized pacing therapy delivery system that does not need take the above-noted factors into consideration while preserving the benefits of the pacing system described above. Specifically, there is a need for apparatus and methods to easily and efficiently optimize AV intervals to beneficially support and appropriately control pacing therapy and CRT delivery. 
     SUMMARY 
     Embodiments of the invention provide relatively simple apparatus and methods of AV timing optimization based on intracardiac electrograms, subcutaneous, or surface ECG. Such apparatus and methods are highly desirable as a simple and effective means of assuring optimized CRT delivery. Certain embodiments provide complex echocardiographic interval optimization by being based on surface, subcutaneous (so-called leadless arrays providing electrode vectors) ECG and/or intracardiac EGM signals and can be performed acutely and chronically. 
     Of course, the algorithm is not the exclusive manner of determining PWend and PWd, however, as other methods could be utilized such as by determining changes to the slope of the P-wave signal, threshold crossings, changing polarity of the signal, and the like. 
     In on form, apparatus, methods, and computer readable media are used to implement dynamic adjusting of an operating atrio-ventricular (AV) interval in a cardiac resynchronization therapy (CRT) delivery device. Wherein an operating AV interval that produces a predetermined fixed period of time between an end of a P-wave (PWend) and the beginning of one of: a corresponding paced QRS complex (QRSbeg) and delivery of a ventricular pacing stimulus (Vp). This is accomplished by monitoring cardiac activity and detecting an atrial depolarization. The associated P-wave is located and the end of a PWend associated with the atrial depolarization also determined, thus the P-wave duration (PWd) can be determined by measuring an elapsed amount of time from the PWend to the one of the QRSbeg and the Vp. Then the predetermined fixed period of time and the measured elapsed amount of time are compared to determine if they are within a prescribed tolerance (or window). A nominal tolerance could be on the order of less than about 10 ms to about 20 ms or 30 ms. That is, if the predetermined fixed period of time and the measured elapsed amount of time are within about the prescribed tolerance, the operating AV interval is stored as an optimized AV (AVopt) interval in a memory of the pacing therapy delivery device. And, if the predetermined fixed period of time and the measured elapsed amount of time are not within the prescribed tolerance, the operating AV interval is modified and the foregoing repeated until an AVopt is established. In terms of modifying the operating AV interval, the interval should be increased if the measured (elapsed) amount of time is too short and decreased if the measured amount of time is too long. 
     Cardiac activity may be sensed with a far-field sensing system; such as a shroud or surround-type subcutaneous electrode array (SEA), such as that disclosed and depicted in co-pending application Ser. No. 11/687,465 filed 16 Mar. 2007, the contents of which are incorporated herein by reference. The inventors note that so-called far field electrode vectors, such as via a SEA or a coil-to-can vector, often produce less noise than near field (e.g., tip-to-ring) vectors although a variety of different vectors can be tested and compared for the one that best senses P-waves. Of course, any temporary or chronically implantable medical electrical lead can be used to sense cardiac activity (e.g., intracardiac, transvenous, and/or epicardial electrodes) deployed about the heart and used to define appropriate sensing vectors to capture the signals (esp. P-waves) from the cardiac activity. As noted above, surface electrodes coupled to a display or to an IMD programming device can also be used. Such electrodes can be coupled to a medical device programmer or ECG machine each optionally having hard print capability and/or a display. Currently available programming devices and ECG equipment can be utilized. Although exemplary programmers, among others, include U.S. Pat. No. 7,209,790 entitled Multi-mode Programmer for Medical Device Communication and U.S. Pat. No. 6,931,279 entitled Method and Apparatus for Implementing Task-oriented Induction Capabilities in an Implantable Cardioverter Defibrillator and Programmer, the contents of which are incorporated herein by reference. 
     The foregoing and other aspects and features will be more readily understood from the following detailed description of the embodiments thereof, when considered in conjunction with the drawings, in which like reference numerals indicate similar structures throughout the several views. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a pair of illustrations of a cardiac depolarization and repolarization waveforms with the PQRST complex indicated by a corresponding letter and the P-wave duration (herein PWd), PR interval, QRS duration (QRSd) and QT interval of a normal intrinsic electrical activation sequence. 
         FIG. 2  is a schematic diagram depicting a three channel, atrial and bi-ventricular, pacing system. 
         FIG. 3  is a simplified block diagram of one embodiment of IPG circuitry and associated leads employed in the system of  FIG. 2  for providing three sensing channels and corresponding pacing channels that functions to provide therapy to and/or monitor a subject. 
         FIG. 4  is an elevational side view depicting an exemplary far-field shroud assembly coupled to an IMD, which illustrates electrical conductors disposed in the header, or connector, portion of the IMD that are configured to couple to end portions of medical electrical leads as well as couple to operative circuitry within the IMD housing. 
         FIG. 5  is a perspective view of the IMD depicted in  FIG. 4  further illustrating the shroud assembly and two of the three electrodes. 
         FIG. 6  is a perspective view of an opposing major side  10 ″ of the IMD  10  depicted in  FIGS. 4 and 5  and three self-healing grommets  21  substantially hermetically coupled to openings of a like number of threaded bores. 
         FIGS. 7A-C  are paired depictions of a (too) short AV interval, a recommended AV interval, and a (too) long AV interval wherein the lower is a doppler echocardiographic image of mitral flow resulting from the different AV intervals. 
         FIGS. 8A-C  depict signals from a pair of surface electrodes (lead I and II) wherein a paced-AV (PAV) interval varies from 130 ms (“short AV”), to 170 ms (adjusted AV), to 220 ms (long AV) showing how the relative location of the P-wave and the beginning of the QRS complex changes with differing PAV interval. 
         FIGS. 9A-C  are paired images illustrating an embodiment wherein an optimized AV interval, AVopt, is shortened during increased heart rate excursion and then returned to the AVopt interval following the increased heart rate excursion. 
         FIG. 10A  is a flow chart illustrating an embodiment for measuring the end of a P-wave (PWend) and/or the duration of a P-wave (PWd) and  FIG. 10B  is a depiction of a portion of the process depicted in  FIG. 10A . 
         FIG. 11  is a flow chart illustrating a method of calculating the linear relationship between an optimal atrioventricular interval (AVopt) and PWd, QRS complex duration (QRSd), intrinsic P-R interval (PR), and heart rate (HR) so that chronic, dynamic control of the AVopt interval can be realized via the linear relationship or via a look up table (LUT). 
         FIG. 12  is a flow chart depicting an embodiment wherein a rate adaptive atrio-ventricular (RAAV) interval is dynamically adjusted during an increasing heart rate excursion, subject to a lower limit for a subject receiving cardiac resynchronization therapy. 
         FIG. 13  is a flow chart illustrating a diagnostic and monitoring method for measuring P-wave duration, P-wave end-time, and the duration of the QRS complex (QRSd) to provide notifications, alarm, and/or intervention in the event that one or more of the values acutely or chronically changes from historical values. 
     
    
    
     DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS 
     A Methods and apparatus are provided to optimize timing intervals for and/or monitor a subject receiving cardiac resynchronization therapy (CRT) to improve the hemodynamics of the subject to closely mimic a normal depolarization-repolarization cardiac cycle sequence. 
       FIG. 1  is a pair of illustrations of a cardiac depolarization and repolarization waveforms with the PQRST complex indicated by a corresponding letter and the P-wave duration (herein PWd) indicated at reference numeral  1 , PR interval  2 , QRS duration (QRSd)  3  and QT interval  4  of a normal intrinsic electrical activation sequence. 
       FIG. 2  is a schematic representation of an implanted, triple-chamber cardiac pacemaker comprising a pacemaker IPG  14  and associated leads  16 ,  32  and  52 . The pacemaker IPG  14  is implanted subcutaneously in a patient&#39;s body between the skin and the ribs. The three endocardial leads  16 , 32 , 52  operatively couple the IPG  14  with the RA, the RV and the LV, respectively. Each lead includes at least one electrical conductor and pace/sense electrode, and a remote indifferent can electrode  20  is formed as part of the outer surface of the housing of the IPG  14 . As described further below, the pace/sense electrodes and the remote indifferent can electrode  20  (IND_CAN electrode) can be selectively employed to provide a number of unipolar and bipolar pace/sense electrode combinations for pacing and sensing functions, particularly sensing far field signals (e.g. far field R-waves). The depicted positions in or about the right and left heart chambers are also merely exemplary. Moreover other leads and pace/sense electrodes may be used instead of the depicted leads and pace/sense electrodes that are adapted to be placed at electrode sites on or in or relative to the RA, LA, RV and LV. In addition, mechanical and/or metabolic sensors can be deployed independent of, or in tandem with, one or more of the depicted leads. 
     The depicted bipolar endocardial RA lead  16  is passed through a vein into the RA chamber of the heart  10 , and the distal end of the RA lead  16  is attached to the RA wall by an attachment mechanism  17 . The bipolar endocardial RA lead  16  is formed with an in-line connector  13  fitting into a bipolar bore of IPG connector block  12  that is coupled to a pair of electrically insulated conductors within lead body  15  and connected with distal tip RA pace/sense electrode  19  and proximal ring RA pace/sense electrode  21 . Delivery of atrial pace pulses and sensing of atrial sense events is effected between the distal tip RA pace/sense electrode  19  and proximal ring RA pace/sense electrode  21 , wherein the proximal ring RA pace/sense electrode  21  functions as an indifferent electrode (IND_RA). Alternatively, a unipolar endocardial RA lead could be substituted for the depicted bipolar endocardial RA lead  16  and be employed with the IND_CAN electrode  20 . Or, one of the distal tip RA pace/sense electrode  19  and proximal ring RA pace/sense electrode  21  can be employed with the IND_CAN electrode  20  for unipolar pacing and/or sensing. 
     Bipolar, endocardial RV lead  32  is passed through the vein and the RA chamber of the heart  10  and into the RV where its distal ring and tip RV pace/sense electrodes  38  and  40  are fixed in place in the apex by a conventional distal attachment mechanism  41 . The RV lead  32  is formed with an in-line connector  34  fitting into a bipolar bore of IPG connector block  12  that is coupled to a pair of electrically insulated conductors within lead body  36  and connected with distal tip RV pace/sense electrode  40  and proximal ring RV pace/sense electrode  38 , wherein the proximal ring RV pace/sense electrode  38  functions as an indifferent electrode (IND_RV). Alternatively, a unipolar endocardial RV lead could be substituted for the depicted bipolar endocardial RV lead  32  and be employed with the IND_CAN electrode  20 . Or, one of the distal tip RV pace/sense electrode  40  and proximal ring RV pace/sense electrode  38  can be employed with the IND_CAN electrode  20  for unipolar pacing and/or sensing. 
     In this illustrated embodiment, a bipolar, endocardial coronary sinus (CS) lead  52  is passed through a vein and the RA chamber of the heart  10 , into the coronary sinus and then inferiorly in a branching vessel of the great cardiac vein to extend the proximal and distal LV CS pace/sense electrodes  48  and  50  alongside the LV chamber. The distal end of such a CS lead is advanced through the superior vena cava, the right atrium, the ostium of the coronary sinus, the coronary sinus, and into a coronary vein descending from the coronary sinus, such as the lateral or posteriolateral vein. 
     In a four chamber or channel embodiment, LV CS lead  52  bears proximal LA CS pace/sense electrodes  28  and  30  positioned along the CS lead body to lie in the larger diameter CS adjacent the LA. Typically, LV CS leads and LA CS leads do not employ any fixation mechanism and instead rely on the close confinement within these vessels to maintain the pace/sense electrode or electrodes at a desired site. The LV CS lead  52  is formed with a multiple conductor lead body  56  coupled at the proximal end connector  54  fitting into a bore of IPG connector block  12 . A small diameter lead body  56  is selected in order to lodge the distal LV CS pace/sense electrode  50  deeply in a vein branching inferiorly from the great vein GV. 
     In this embodiment, the CS lead body  56  would encase four electrically insulated lead conductors extending proximally from the more proximal LA CS pace/sense electrode(s) and terminating in a dual bipolar connector  54 . The LV CS lead body would be smaller between the LA CS pace/sense electrodes  28  and  30  and the LV CS pace/sense electrodes  48  and  50 . It will be understood that LV CS lead  52  could bear a single LA CS pace/sense electrode  28  and/or a single LV CS pace/sense electrode  50  that are paired with the IND_CAN electrode  20  or the ring electrodes  21  and  38 , respectively for pacing and sensing in the LA and LV, respectively. 
     Further,  FIG. 3  depicts bipolar RA lead  16 , bipolar RV lead  32 , and bipolar LV CS lead  52  without the LA CS pace/sense electrodes  28  and  30  coupled with an IPG circuit  300  having programmable modes and parameters of a bi-ventricular DDDR type known in the pacing art. In addition, at least one physiologic sensor  41  is depicted operatively coupled to a portion of myocardium and electrically coupled to a sensor signal processing circuit  43 . In turn the sensor signal processing circuit  43  indirectly couples to the timing circuit  330  and via bus  306  to microcomputer circuitry  302 . The IPG circuit  300  is illustrated in a functional block diagram divided generally into a microcomputer circuit  302  and a pacing circuit  320 . The pacing circuit  320  includes the digital controller/timer circuit  330 , the output amplifiers circuit  340 , the sense amplifiers circuit  360 , the RF telemetry transceiver  322 , the activity sensor circuit  322  as well as a number of other circuits and components described below. 
     Crystal oscillator circuit  338  provides the basic timing clock for the pacing circuit  320 , while battery  318  provides power. Power-on-reset circuit  336  responds to initial connection of the circuit to the battery for defining an initial operating condition and similarly, resets the operative state of the device in response to detection of a low battery condition. Reference mode circuit  326  generates stable voltage reference and currents for the analog circuits within the pacing circuit  320 , while analog to digital converter ADC and multiplexer circuit  328  digitizes analog signals and voltage to provide real time telemetry if a cardiac signals from sense amplifiers  360 , for uplink transmission via RF transmitter and receiver circuit  332 . Voltage reference and bias circuit  326 , ADC and multiplexer  328 , power-on-reset circuit  336  and crystal oscillator circuit  338  may correspond to any of those presently used in current marketed implantable cardiac pacemakers. 
     If the IPG is programmed to a rate responsive mode, the signals output by one or more physiologic sensor are employed as a rate control parameter (RCP) to derive a physiologic escape interval. For example, the escape interval is adjusted proportionally the patient&#39;s activity level developed in the patient activity sensor (PAS) circuit  322  in the depicted, exemplary IPG circuit  300 . The patient activity sensor  316  is coupled to the IPG housing and may take the form of a piezoelectric crystal transducer as is well known in the art and its output signal is processed and used as the RCP. Sensor  316  generates electrical signals in response to sensed physical activity that are processed by activity circuit  322  and provided to digital controller/timer circuit  330 . Activity circuit  332  and associated sensor  316  may correspond to the circuitry disclosed in U.S. Pat. Nos. 5,052,388 and 4,428,378. Similarly, embodiments of this invention may be practiced in conjunction with alternate types of sensors such as oxygenation sensors, pressure sensors, pH sensors and respiration sensors, all well known for use in providing rate responsive pacing capabilities. Alternately, QT time may be used as the rate indicating parameter, in which case no extra sensor is required. Similarly, embodiments of the invention may also be practiced in non-rate responsive pacemakers. 
     Data transmission to and from the external programmer is accomplished by means of the telemetry antenna  334  and an associated RF transmitter and receiver  332 , which serves both to demodulate received downlink telemetry and to transmit uplink telemetry. Uplink telemetry capabilities will typically include the ability to transmit stored digital information, e.g. operating modes and parameters, EGM histograms, and other events, as well as real time EGMs of atrial and/or ventricular electrical activity and Marker Channel pulses indicating the occurrence of sensed and paced depolarizations in the atrium and ventricle, as are well known in the pacing art. 
     Microcomputer  302  contains a microprocessor  304  and associated system clock  308  and on-processor RAM and ROM chips  310  and  312 , respectively. In addition, microcomputer circuit  302  includes a separate RAM/ROM chip  314  to provide additional memory capacity. Microprocessor  304  normally operates in a reduced power consumption mode and is interrupt driven. Microprocessor  304  is awakened in response to defined interrupt events, which may include A-TRIG, RV-TRIG, LV-TRIG signals generated by timers in digital timer/controller circuit  330  and A-EVENT, RV-EVENT, and LV-EVENT signals generated by sense amplifiers circuit  360 , among others. The specific values of the intervals and delays timed out by digital controller/timer circuit  330  are controlled by the microcomputer circuit  302  by means of data and control bus  306  from programmed-in parameter values and operating modes. In addition, if programmed to operate as a rate responsive pacemaker, a timed interrupt, e.g., every cycle or every two seconds, may be provided in order to allow the microprocessor to analyze the activity sensor data and update the basic A-A, V-A, or V-V interval, as applicable. In addition, the microprocessor  304  may also serve to define variable AV delays and the uni-ventricular, pre-excitation pacing delay intervals (A-LVp) from the activity sensor data, metabolic sensor(s) and/or mechanical sensor(s). 
     In one embodiment, microprocessor  304  is a custom microprocessor adapted to fetch and execute instructions stored in RAM/ROM unit  314  in a conventional manner. It is contemplated, however, that other implementations may be suitable. For example, an off-the-shelf, commercially available microprocessor or microcontroller, or custom application-specific, hardwired logic, or state-machine type circuit may perform the functions of microprocessor  304 . 
     Digital controller/timer circuit  330  operates under the general control of the microcomputer  302  to control timing and other functions within the pacing circuit  320  and includes a set of timing and associated logic circuits of which certain ones pertinent to this discussion are depicted. The depicted timing circuits include URI/LRI timers  364 , V-V delay timer  366 , intrinsic interval timers  368  for timing elapsed V-EVENT to V-EVENT intervals or V-EVENT to A-EVENT intervals or the V-V conduction interval, escape interval timers  370  for timing A-A, V-A, and/or V-V pacing escape intervals, an AV delay interval timer  372  for timing the A-LVp delay (or A-RVp delay) from a preceding A-EVENT or A-TRIG, a post-ventricular timer  374  for timing post-ventricular time periods, and a date/time clock  376 . 
     The AV delay interval timer  372  is loaded with an operating AV interval for the ventricular chamber to time-out starting from a preceding atrial event whether paced or intrinsic in nature, herein Ap and As, respectively. In one form, the AV interval is set to a nominal value such as 40 milliseconds as measured from the detected end of the P-wave to the beginning of the QRS complex. 
     Another embodiment involves adjustment of the time interval between the end of P-wave (PWend) and the end of paced QRS (QRSend) to a fixed predetermined value (e.g. 150 ms). In the most generic embodiment of ECG-based optimization the optimal AV delay is calculated as a linear function of baseline P-wave duration (PWd), baseline PR (intrinsic) interval, baseline or paced QRS duration (QRSd) and heart rate (HR): 
       AVopt= a *PWd+ b *QRSd+ c *PR+ d *HR+ f;    
     In addition the inventors discovered that the heart rate (HR) has an effect upon value of an optimal AV delay. If Rate-Adaptive AV (RAAV) feature is programmed on, the minimum AV in the RAAV feature should be programmed to AVopt-(PWend-to-QRSbeg/end-ε ms) where ε is a fixed value, such as a nominal 40 ms. RAAV should then be programmed as to decrease the sensed AV (SAV) and paced-AV (PAV) by one ms for every one beat per minute (bpm) increase in the HR. 
     The post-event timers  374  time out the post-ventricular time periods following an RV-EVENT or LV-EVENT or a RV-TRIG or LV-TRIG and post-atrial time periods following an A-EVENT or A-TRIG. The durations of the post-event time periods may also be selected as programmable parameters stored in the microcomputer  302 . The post-ventricular time periods include the PVARP, a post-atrial ventricular blanking period (PAVBP), a ventricular blanking period (VBP), and a ventricular refractory period (VRP). The post-atrial time periods include an atrial refractory period (ARP) during which an A-EVENT is ignored for the purpose of resetting any AV delay, and an atrial blanking period (ABP) during which atrial sensing is disabled. It should be noted that the starting of the post-atrial time periods and the AV delays can be commenced substantially simultaneously with the start or end of each A-EVENT or A-TRIG or, in the latter case, upon the end of the A-PACE that may follow the A-TRIG. Similarly, the starting of the post-ventricular time periods and the V-A escape interval can be commenced substantially simultaneously with the start or end of the V-EVENT or V-TRIG or, in the latter case, upon the end of the V-PACE that may follow the V-TRIG. The microprocessor  304  also optionally calculates AV delays, post-ventricular time periods, and post-atrial time periods that vary with the sensor based escape interval established in response to the RCP(s) and/or with the intrinsic atrial rate. 
     The output amplifiers circuit  340  contains a RA pace pulse generator (and a LA pace pulse generator if LA pacing is provided), a RV pace pulse generator, and a LV pace pulse generator or corresponding to any of those presently employed in commercially marketed cardiac pacemakers providing atrial and ventricular pacing. In order to trigger generation of an RV-PACE or LV-PACE pulse, digital controller/timer circuit  330  generates the RV-TRIG signal at the time-out of the A-RVp delay or the LV-TRIG at the time-out of the A-LVp delay provided by AV delay interval timer  372  (or the V-V delay timer  366 ). Similarly, digital controller/timer circuit  330  generates an RA-TRIG signal that triggers output of an RA-PACE pulse (or an LA-TRIG signal that triggers output of an LA-PACE pulse, if provided) at the end of the V-A escape interval timed by escape interval timers  370 . 
     The output amplifiers circuit  340  includes switching circuits for coupling selected pace electrode pairs from among the lead conductors and the IND_CAN electrode  20  to the RA pace pulse generator (and LA pace pulse generator if provided), RV pace pulse generator and LV pace pulse generator. Pace/sense electrode pair selection and control circuit  350  selects lead conductors and associated pace electrode pairs to be coupled with the atrial and ventricular output amplifiers within output amplifiers circuit  340  for accomplishing RA, LA, RV and LV pacing. 
     The sense amplifiers circuit  360  contains sense amplifiers corresponding to any of those presently employed in contemporary cardiac pacemakers for atrial and ventricular pacing and sensing. As noted in the above-referenced, commonly assigned, &#39;324 patent, a very high impedance P-wave and R-wave sense amplifiers may be used to amplify the voltage difference signal that is generated across the sense electrode pairs by the passage of cardiac depolarization wavefronts. The high impedance sense amplifiers use high gain to amplify the low amplitude signals and rely on pass band filters, time domain filtering and amplitude threshold comparison to discriminate a P-wave or R-wave from background electrical noise. Digital controller/timer circuit  330  controls sensitivity settings of the atrial and ventricular sense amplifiers  360 . 
     The sense amplifiers are uncoupled from the sense electrodes during the blanking periods before, during and after delivery of a pace pulse to any of the pace electrodes of the pacing system to avoid saturation of the sense amplifiers. The sense amplifiers circuit  360  includes blanking circuits for uncoupling the selected pairs of the lead conductors and the IND_CAN electrode  20  from the inputs of the RA sense amplifier (and LA sense amplifier if provided), RV sense amplifier and LV sense amplifier during the ABP, PVABP and VBP. The sense amplifiers circuit  360  also includes switching circuits for coupling selected sense electrode lead conductors and the IND_CAN electrode  20  to the RA sense amplifier (and LA sense amplifier if provided), RV sense amplifier and LV sense amplifier. Again, sense electrode selection and control circuit  350  selects conductors and associated sense electrode pairs to be coupled with the atrial and ventricular sense amplifiers within the output amplifiers circuit  340  and sense amplifiers circuit  360  for accomplishing RA, LA, RV and LV sensing along desired unipolar and bipolar sensing vectors. 
     Right atrial depolarizations or P-waves in the RA-SENSE signal that are sensed by the RA sense amplifier result in a RA-EVENT signal that is communicated to the digital controller/timer circuit  330 . Similarly, left atrial depolarizations or P-waves in the LA-SENSE signal that are sensed by the LA sense amplifier, if provided, result in a LA-EVENT signal that is communicated to the digital controller/timer circuit  330 . Ventricular depolarizations or R-waves in the RV-SENSE signal are sensed by a ventricular sense amplifier result in an RV-EVENT signal that is communicated to the digital controller/timer circuit  330 . Similarly, ventricular depolarizations or R-waves in the LV-SENSE signal are sensed by a ventricular sense amplifier result in an LV-EVENT signal that is communicated to the digital controller/timer circuit  330 . The RV-EVENT, LV-EVENT, and RA-EVENT, LA-SENSE signals may be refractory or non-refractory, and can inadvertently be triggered by electrical noise signals or aberrantly conducted depolarization waves rather than true R-waves or P-waves. 
     Operative circuitry  300  of  FIG. 3  includes RR interval comparator  301 , coupled to RV sensing electrodes coupled to lead  32 , LV pacing electrodes coupled to LV pacing electrodes coupled to lead  52 . In one embodiment, an AV interval adaptation circuit  305  operates to adjust and maintain the AV delay interval at an optimized value. The AV interval adaptation circuit  305  may include circuitry for modifying the optimum AV interval value in the case a rate-adaptive AV feature is programmed “on” such that the interval will decrease approximately one millisecond (ms) for each one bpm a subject&#39;s heart rate increases. In another aspect, the circuit  305  (in conjunction with memory structures) includes tracking capability so that as, for instance, the end of the P-wave (PWend) or the duration of the P-wave (PWd) changes and thus, the AV interval varies, these values can be subsequently reviewed. One of a pair of output signals from the AV interval adaptation circuit  305  operatively connect to atrial sensing and pacing electrodes that are coupled to atrial lead  16 . The other of the pair of output signals from the AV interval adaptation circuit  305  operatively connects to LVp electrodes coupled to pacing electrodes coupled to the lead  52 . 
     As noted hereinabove, a subcutaneous electrode array (SEA) can be used to sense P-waves from a location spaced from the heart. On such SEA that can be coupled to or incorporated into an subcutaneously implanted device is shown in  FIG. 4  which is an elevational side view depicting an exemplary shroud assembly coupled to an IMD which illustrates electrical conductors disposed in the header, or connector, portion of the IMD which is configured to receive a proximal end portion of medical electrical leads (not shown). 
       FIG. 4  depicts an exemplary shroud assembly  141  coupled to an IMD  101  which illustrates electrical conductors  25 , 26 , 28 ′ disposed in the header, or connector, portion  12  of the IMD  10  which are configured to couple to end portions of medical electrical leads as well as couple to operative circuitry within the IMD housing (not shown). The shroud assembly  141  surrounds IMD  101  and mechanically couples to the header portion  12  and includes at least three discrete electrodes  16 , 18 , 201  adapted for sensing far-field, or extra-cardiac electrogram (EC-EGM) signals.  FIG. 4  also depicts an aperture  22  formed within the header  12  which can be used to receive thread used to suture the header  12  (and thus the IMD  101 ) to a fixed surgical location (also known as a pocket) of a patient&#39;s body. 
     As partially depicted in  FIG. 4 , an elongated conductor  18 ′ couples to electrode  18 , elongated conductor  16 ′ couples to electrode  16 , and conductor segment  201 ′ couples to electrode  201 . Furthermore, three of the conductors (denoted collectively with reference numeral  24 ) couple to three cuff-type conductors  25 , 26 , 28 ′ adapted to receive proximal portions of medical electrical leads while another three of the conductors couple to conductive pads  25 ′, 26 ′, 28 ″ which are aligned with, but spaced from the conductors  25 , 26 , 28 ′ along a trio of bores (not shown) formed in header  12 . 
       FIG. 5  is a perspective view of the IMD  101  depicted in  FIG. 4  further illustrating the shroud assembly  141  and two of the three electrodes  18 , 201 . In addition, two of a plurality of adhesive ports  31  and a mechanical joint  132  between the elongated portion of the shroud assembly  141  and the header  12  are also depicted in  FIG. 5 . The ports  31  can be used to evacuate excess medical adhesive disposed between the shroud assembly  14  and the IMD  10  and/or used to inject medical adhesive into one or more of the ports  31  to fill the void(s) therebetween. In one form of the invention, a major lateral portion  12 ′ of header  12  remains open to ambient conditions during assembly of the IMD  101 . Subsequent to making electrical connections between the plurality of conductors of the shroud assembly  141  and the header  12 , the open lateral portion  12 ′ is sealed (e.g., automatically or manually filled with a biocompatible substance such as a substantially clear medical adhesive, such as Tecothane® made by Noveon, Inc. a wholly owned subsidiary of The Lubrizol Corporation). Thus most if not all of the plurality of conductors of the shroud assembly  141  and the IMD  101  are visible and can be manually and/or automatically inspected to ensure long term operability and highest quality of the completed IMD  101 . 
     Referring again to  FIG. 4 , the terminal ends of conductors  24  are depicted to include the optional shaped-end portion which provides a target for reliable automatic and/or manual coupling (e.g., laser welding, soldering, and the like) of the terminal end portions to respective conductive pins of a multi-polar feedthrough assembly (not shown). As is known in the art, such conductive pins hermetically couple to operative circuitry disposed within the IMD  101 . 
       FIG. 6  is a perspective view of an opposing major side  101 ′ of the IMD  101  depicted in  FIGS. 4 and 5  and three self-healing grommets  23  substantially hermetically coupled to openings of a like number of threaded bores (not shown). As is known, the threaded bores are configured to receive a threaded shank and the grommets  23  are fabricated to temporarily admit a mechanical tool (not shown). The tool is used to connect and allow a physician or clinician to manually tighten the conductors  25 , 26 , 28 ′, for example, with compression and/or radially around conductive rings disposed on proximal portions of medical electrical leads (not shown). In addition, two of the plurality of ports  31  are also depicted in  FIG. 6 . 
       FIGS. 7A-C  are paired depictions of a (too) short AV interval, a recommended AV interval, and a (too) long AV interval wherein the lower is a doppler echocardiographic image of mitral flow resulting from the different AV intervals. In  FIG. 7A , the ventricular pacing stimulus Vp impinges up the P-wave (PW) thereby not allowing adequate atrial “kick” nor complete ventricular filling. In  FIG. 7B , a nominal 40 ms time interval is maintained following the end of the P-wave (PWend), which can be located per the algorithm detailed at  FIG. 10  hereinbelow.  FIG. 7C  depicts an AV interval that is too long and wherein the mitral flow is inhibited due to the lack of coordination of atrial and ventricular function. 
       FIGS. 8A-C  depict signals from a pair of surface electrodes (lead I and II) wherein a paced-AV (PAV) interval varies from 130 ms (“short AV”), to 170 ms (adjusted AV), to 220 ms (“long AV”) showing how the relative location of the P-wave (PW) and the beginning of the QRS complex (QRS) changes with differing PAV interval. In  FIG. 8A , it is apparent that when the PAV is set to 130 ms the PW is truncated and as depicted the trace from the lead labeled ECG Lead 1 literally collides with the QRS complex and related fluid and electromechanical activity. Also, in  FIG. 8A  the ECG Lead II did not even pick up the PW from that particular cardiac cycle. In  FIG. 8B , at a PAV of 170 ms the PW ends approximately 20-40 ms before the beginning of the QRS complex and as noted in  FIGS. 7A-C  the concomitant ventricular filling is maximized. In  FIG. 8C  at a PAV of 220 ms, approximately 60 ms elapses after the end of the P-Wave but before the QRS complex commences. 
       FIGS. 9A-C  are paired images illustrating an embodiment wherein an optimized AV interval, AVopt, is shortened during increased heart rate excursion and then returned to the AVopt interval following the increased heart rate excursion. The AVopt interval is shortened to not less than a minimum value defined as AVopt less the interval between the end of the P-wave and either the beginning or end of the QRS complex (and less a nominal additional amount, such as about 40 ms). When the patient&#39;s heart rate stabilizes then the AVopt interval can resume operation (or an adapted value can be utilized according to certain of the embodiments described hereinbelow. 
       FIG. 10A  is a flow chart illustrating an embodiment for measuring the end of a P-wave (PWend) and/or the duration of a P-wave (PWd).  FIG. 10A  can be reviewed along with the simplified illustration of  FIG. 10B , which provides a depiction of a waveform being processed according to method  100 . Now The method  100  begins at  102  with collection of cardiac signals following either a sensed or paced atrial event (As or Ap). The sensed signals are then filtered at  104  and the time derivative (dPW/dt) is taken at  106 . The resulting waveform is of course sinusoidal as the P-wave is a generally smoothly rising and then falling signal. At step  108  the derived sinusoidal P-wave is rectified thus resulting in a dual-humped signal. A peak of this signal is located at step  110  from either peak (P 1  or P 2 ) and a threshold is set based at least in part upon the amplitude of either peak P 1  or P 2  at step  112 . The threshold can be a nominal value but a value of about ten to thirty percent (10%-30%) of the peak amplitude of P 1  or P 2  will suffice. At step  114  a temporal window is scaled from either of the peaks (P 1  or P 2 ) until the values of the signal beneath the window are all sub-threshold ( 116 ). At that point the end of the P-wave (PWend) has been located and the duration of the P-wave (PWd) can be calculated (at  120 ) as the time elapsed from the atrial event (As or Ap) until PWend was located. Then optionally, according to certain embodiments, the value of PWd can be sorted and/or compared to prior PWd values, thereby providing clinical benefit to a subject as an indicator of cardiac status and/or condition. In addition, the duration of the QRS complex (QRSd) can be measured and compared to prior values. Thus, a notification, alert or notation that the subject is either benefiting or declining status can be performed as will be described hereinbelow. 
       FIG. 11  is a flow chart illustrating a method  200  of calculating the linear relationship between an optimal atrioventricular interval (AVopt) and PWd, QRS complex duration (QRSd), intrinsic P-R interval (PR), and heart rate (HR) so that chronic, dynamic control of the AVopt interval can be realized via the linear relationship or via a look up table (LUT). The cardiac cycle of subject is monitored at  202  and the P-wave duration (PWd) is measured and stored at  204  as previously described. The duration of the QRS complex of the subject is measured and stored at step  206 . The intrinsic P-R interval of the subject is measured as the time between an intrinsic atrial event (As) and a resulting intrinsic ventricular event (Vs) and stored at  208 . The heart rate (HR) is then measured as the time between successive QRS complexes (R-R interval) and stored. Then at  212  a confirmed optimized AV interval (AVopt) is obtained, for example using convention echocardiography or other method. Then at  214  the linear relationship is calculated that relates AVopt to PWd, QRSd, PR, and HR (including coefficients). This thus provides a method to dynamically recalculate the AVopt interval based on detected changes to one or more of the four values. That is, the AVopt interval equation can be recalculated or a look up table (LUT) populated with values that correlate the four values. In a related embodiment, the LUT can be simplified somewhat due to the fact that QRSd and PWd change little, if any, over a fairly large ranges of heart rates for most cardiac patients receiving cardiac resynchronization therapy (CRT). So, at step  216 , in the event that one or more of the values change the AVopt can be modified at  220 . In the event that the values have not changed (or have only changed slightly) at step  218  the CRT delivery continues at the prior value of AVopt preferably using the same gradual rate utilized to previously shorten the AV interval (e.g., one ms per one bpm that the heart rate changes). 
       FIG. 12  is a flow chart depicting an embodiment  400  wherein a subject receiving cardiac resynchronization therapy and has a rate adaptive atrio-ventricular (RAAV) interval that is dynamically adjusted during an increasing heart rate excursion, subject to a lower limit for a subject receiving cardiac resynchronization therapy. At step  402  the cardiac cycle is monitored and the heart rate metric is calculated. At  404  whether or not the heart rate is increasing or not is determined. If the heart rate is determined not to be increasing then the CRT delivery continues. If, however, the heart rate is determined to be increasing then at  406  the operating AV (AVopt) interval is decreased at a rate of about one millisecond (ms) for every one beat per minute (bpm) the heart rate increases, subject to a limit defined as the AVopt interval less the interval between the end of the P-wave (PWend) and either the beginning or end of the QRS complex (QRSbeg or QRSend) less a nominal value such as 40 ms. In the event that the heart is trending lower then at  410  the value of the operating AV interval is returned to the prior optimized AV interval value (AVopt). If the heart rate is not lowering, then the cardiac cycle continues to be monitored at  402  and process  400  continues. 
       FIG. 13  is a flow chart illustrating a diagnostic and monitoring method  500  for measuring the parameters P-wave duration (PWd), P-wave end-time (PWend), and the duration of the QRS complex (QRSd) to provide notifications, alarm, and/or intervention in the event that one or more of the values acutely or chronically changes from historical values. According to this embodiment, the parameters PWd, PWend or QRSd are monitored at step  502  and the values are stored at step  504 . The stored values can then be compared at  506  with prior values or evaluated to discern if any trend is occurring in one or more of the parameters. At step  508  any acute changes or trend from prior or historical values is used to trigger a logical flag, provide a notification to a clinic or clinician or the like, store a recent temporal record of recently measured or recorded physiologic events, set a patient alert or the like. 
     Of course, certain of the above-described structures, functions and operations of the pacing systems of the illustrated embodiments are not necessary to practice the present invention and are included in the description simply for completeness of an exemplary embodiment or embodiments. It will also be understood that there may be other structures, functions and operations ancillary to the typical operation of an implantable pulse generator that are not disclosed and are not necessary to the practice of the present invention. 
     In addition, it will be understood that specifically described structures, functions and operations set forth in the above-referenced patents can be practiced in conjunction with the present invention, but they are not essential to its practice. It is therefore to be understood, that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described without actually departing from the spirit and scope of the present invention.