Abstract:
For cardiac rhythm management a combination of cardiac pacing and a noninvasive heart monitoring is proposed for the determination of a set of programmable pacing parameters hemodynamically most beneficial to the patient. The apparatus incorporates a cardiac pacemaker ( 130 ) and a thoracic electrical bioimpedance (TEB) heart monitor ( 120 ). This combination allows the creation of a closed-loop system that conveniently and effectively obtains pacing parameter settings providing hemodynamically optimal pacing therapy to the patient as determined by measuring and recording of stroke volume (SV), cardiac output (GO), and other indices of ventricular performance by the heart monitor during an optimization cycle automatically employing different permutations of values of pacing parameters such as atrioventricular delays, inter-atrial delay, inter-ventricular delay, or heart rate, that are sequentially programmed to the pacemaker. The hemodynamically optimal permutation of pacing parameter values is determined from all recordings and programmed to the pacemaker for permanent or temporary pacing therapy.

Description:
FIELD OF INVENTION  
         [0001]    The invention relates generally to cardiac rhythm management, and more particularly to a combination of cardiac pacing and optimizing pacing parameter values.  
         DISCUSSION OF PRIOR ART  
         [0002]    Dual-Chamber Pacemakers  
           [0003]    Dual-Chamber pacemakers are used increasingly in patients with varying degrees of heart block, symptomatic bradydysrhythmias, and drug-refractory cardiomyopathy. Clinical benefits of the dual-chamber pacemaker include enhancement of forward blood flow, a feature that can alleviate symptoms of congestive heart failure (CHF), and prevention of atrial fibrillation caused by the atria contracting against a closed valve (Gadler F, Linde C, Darpo B. Modification of atrioventricular conduction as adjunct therapy for pacemaker-treated patients with hypertrophic obstructive cardiomyopathy. Eur Heart J 1998; 19:132-138).  
           [0004]    Dual-chamber pacing can improve hemodynamics in some patients with dilated cardiomyopathy, likely by abolishing diastolic mitral regurgitation through the establishment of mechanical atrial and ventricular synchrony (Nishimura R, Hayes D, Holmes D, Tajik A. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: An acute Doppler and catheterization hemodynamic study. J Am Coil Cardiol 1995; 25:281-288). Despite the benefit of optimization of atrioventricular (AV) delay, dual-chamber pacemakers often are left at the default value, which the manufacturer sets to approximately 170 milliseconds (Kindermann M, Frohlig G, Doerr T, Schieffer H. Optimizing the AV delay in DDD pacemakers with high degree AVE block: Mitral valve Doppler versus impedance cardiography. Pacing Clin Electrophysiol 1997; 20: 2453-2462). It is the consensus of independent researchers that optimization of AV interval is not routinely performed. Procedures for pacemaker optimization, specifically obtaining stroke volume measurements at different AV intervals by aortic Doppler echocardiography , traditionally have been observer-dependent, time-consuming, and costly.  
           [0005]    The goal of AV optimization is the synchronization of the completion of end-diastolic filling exactly at the onset of left ventricular contraction. Obviously, to accomplish this objective, precise physiological measurements of the events of the cardiac cycle must be obtained. Because of a wide range of cardiac conditions, status of the ventricles, and cardioactive medications, each and every patient is unique. Leonelli et al. (Leonelli F, Wang K, Youssef M, Brown D. Systolic and diastolic effects of variable atrioventricular delay in patients with pacemakers. Eur Heart J 1995; 15:1431-1440) observed that an optimal setting of the AV delay value improved stroke volume up to 42%.  
           [0006]    Another application of cardiac pacemakers has recently been discovered: Recent reports are suggesting that biventricular pacing may offer some important options in the treatment of patients with congestive heart failure (CHF). A significant percentage of patients with CHF have conduction abnormalities on EGG. These conduction abnormalities result in abnormal activation of ventricular myocardium and asynchronous activation of the atrial and ventricular chambers. Biventricular pacing attempts to activate the right and left ventricles simultaneously, producing what is termed “ventricular resynchronization”.  
           [0007]    Studies have confirmed acute and short-term hemodynamic benefits of biventricular pacing. In addition, studies have documented improvement in the functional status of patients with CHF. Larger, prospective studies investigating the beneficial effects of biventricular pacing and its clinical implications are currently underway.  
           [0008]    In addition to the symptomatic and functional improvements, other important changes have been noted in CHF patients treated with biventricular pacing. Parameters of cardiac function such as left ventricular dimensions and myocardial performance index have improved markedly. Elevated plasma norepinephrine levels, which are associated with increased mortality in CHF, improve in biventricular pacing. Decreased heart rate variability, also associated with increased risk of sudden death in CHF, has been shown to improve. These findings have lead investigators to hypothesize the potential for biventricular pacing to improve survival. This being said, no trial to date has demonstrated a survival benefit to biventricular pacing. Furthermore, no studies are known that investigate the effects, and potential benefits, of biventricular pacing forcing a small delay between right ventricular and left ventricular contraction, or vice versa.  
           [0009]    Optimization Techniques  
           [0010]    When optimizing the AV delay, or any other delay such as a delay between the contraction of right and left ventricles, it must be tailored to the individual patient. For almost two decades, stroke volume measurements by means of thoracic electrical bioimpedance (TEB) have been favorably considered for optimal determination of pacemaker settings. More recently, Hayes et al. (Hayes D, Hayes S, Hyberger L. Atrioventricular interval optimization technique: Impedance measurements vs Echo/Doppler. Presented at the North American Society for Pacing &amp; Electrophysiology&#39;s 19th Annual Scientific Sessions, San Diego, Calif., May 9, 1998) reported that the noninvasive hemodynamic monitoring with TEB permits determination of optimal AV delay within 15 minutes in any clinical settings.  
           [0011]    Despite promising benefits to the patient, the utilization of thoracic electrical bioimpedance (TEB), as with any other aforementioned method, has not been established as a standard optimization procedure for the setting of parameter values of dual-chamber pacemakers. Apparently, the TEB procedure, applied during pacemaker follow-up, is time-consuming and requires active involvement of the physician during the entire optimization period.  
           [0012]    Rate-responsive cardiac pacemakers address the adaptation of the pacing rate according to the physiological demands related to the activity of the pacemaker patient. Sensors determine, for example, posture and movement of the patient, or respiration, characterized by respiration rate and tidal volume, and even stroke volume by measurement of thoracic electrical bioimpedance. The pacemaker adapts the pacing rate depending on the information obtained by the sensors and processed usually by the pacemaker. The pacemaker&#39;s rate adapted to the patient&#39;s activity is not within the scope of the aforementioned optimization techniques, and the invention.  
         SUMMARY OF THE INVENTION  
         [0013]    The new method and apparatus defined in the appended claims incorporate a cardiac pacemaker and thoracic electrical bioimpedance (TEB) measuring approach. With this combination of a diagnostic (TEB) and therapeutic method and apparatus (pacemaker) a closed-loop system is created to obtain, within its confines, an optimal setting of pacing parameter values.  
           [0014]    In a preferred embodiment, a specific optimization cycle, triggered by an operator or upon the expiration of a preset time interval, automatically permutates the values of one or more pacing parameters, such as AV delays, inter-atrial delay, inter-ventricular delay, or heart rate, within operator-defined ranges, and determines at each permutation of parameter values hemodynamic parameters, such as stroke volume (SV), cardiac output (CO), ejection fraction (EF), and other indices of ventricular performance.  
           [0015]    The operator defines one or more pacing parameters, such as atrioventricular delays, inter-atrial delay, inter-ventricular delay, or heart rate, which are subject to variation during an optimization cycle. Furthermore, the operator defines a variation range for values of each pacing parameter and a variation step width for stepping through the variation range during the optimization cycle. The number of pacing parameters subject to variation and the number of applicable variation steps for each parameter determine the number of permutations of pacing parameter values and, thus, the sequence of the optimization cycle. Each permutation of pacing parameter values is applied, for example, for a pre-defined period in the range of 30 to 120 seconds. The pacing parameter value, which results in the maximum value of a hemodynamic parameter, or a combination thereof, is the output of the optimization cycle and adapted by the cardiac pacemaker for further stimulation.  
           [0016]    The hemodynamic measurements are performed utilizing the apparatus and method of Bernstein and Osypka as described in detail in European patent application No. 02007310.2 of the present applicant, Osypka Medical GmbH, Berlin, for APPARATUS AND METHOD FOR DETERMINING AN APPROXIMATE VALUE OF THE STROKE VOLUME AND THE CARDIAC OUTPUT OF THE HEART, filed concurrently herewith (in the following referred to as the Osypka EP application No. 02007310.2), the disclosure of which is incorporated herein by reference.  
           [0017]    The optimization cycle automatically executed for a number of permutations of pacing parameter values to obtain maximal left-ventricular function enhances significantly the time-efficacy of an otherwise cumbersome and time-consuming, but nevertheless beneficial method. This automatic optimization method can be applied during pacing system analysis (PSA) prior to permanent pacemaker implantation, during temporary pacing following cardiothoracic surgery, during follow-up of a patient with an implantable pacemaker, or during the investigation of efficacy of pacing algorithms for patients undergoing treatment for congestive heart failure (CHF).  
           [0018]    Other objects, features and advantages of the invention will become apparent from the following description of a preferred embodiment of the invention. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0019]    [0019]FIG. 1 illustrates a first preferred embodiment where the optimization apparatus and the cardiac pacemaker are integrated into one system.  
         [0020]    [0020]FIG. 2 illustrates a second preferred embodiment where the optimization apparatus and the cardiac pacemaker are separate units.  
         [0021]    [0021]FIG. 3 illustrates a flowchart about the various steps of the automatic optimization process.  
         [0022]    [0022]FIG. 4 illustrates schematically the sensing and pacing sequence of the AVV-Mode.  
         [0023]    [0023]FIG. 5 illustrates the sensing and pacing sequence of the AVAV-Mode. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0024]    [0024]FIG. 1 illustrates a first preferred embodiment which is employed, for example, but not limited to, in a Pacing System Analyzer (PSA) or external cardiac pulse generator (temporary cardiac pacemaker).  
         [0025]    [0025]FIG. 1 shows a patient  10  and his stylized heart containing four chambers: right atrium  12 , right ventricle  14 , left atrium  16  and left ventricle  18 . In the preferred embodiment shown, surface ECG-type electrodes as part of an electrode array are attached to the patient&#39;s right side of neck and the left side of lower thorax. The outer surface electrodes  20 ,  22  are connected to the alternating current (AC) source  122  of the heart monitor  120 , which is part of the optimization apparatus  100 . The inner surface electrodes  24 ,  26  are connected to the voltmeter  124  of the heart monitor  120 . The heart monitor  120  determines from the ratio of the AC applied by  122  and the voltage measured by  124  the thoracic electrical bioimpedance.  
         [0026]    Alternatively, the heart monitor  120  determines from the reciprocal ratio of the AG applied by  122  and the voltage measured by  124  the thoracic electrical bioadmittance. This method is described in the above-mentioned Osypka EP application No. 02007310.2 which is herein incorporated by reference, which describes how the continuous measurement of thoracic electrical bioimpedance is used to determine stroke volume and cardiac output.  
         [0027]    Alternatively, the thoracic electrical bioimpedance (or bioadmittance) can be measured using different electrode configurations, including a second electrode array, and electrodes located on an esophageal catheter/probe, all described in Osypka EP Application No. 02007310.2.  
         [0028]    Furthermore, a cardiac pacemaker  130  integrated into  100  is connected to at least two heart chambers of right atrium (RA)  12 , right ventricle (RV)  14 , left atrium (LA)  16  and left ventricle (LV)  18 . In the event the optimization apparatus  100  is used for pacing system analysis, the connection of the heart chambers and the apparatus is accomplished by permanent pacing leads (indicated by the dashed part of the connection  30  to the right atrium  12 , the dashed part of the connection  32  to the right ventricle  14 , the dashed part of the connection  34  to the left atrium  16 , and the dashed part of the connection  36  to the left ventricle  18 ), all of which are later connected to an implantable pacemaker, and extension cables (indicated by the solid part of the connection  30  to the right atrium  12 , the solid part of the connection  32  to the right ventricle  14 , the solid part of the connection  34  to the left atrium  16 , and the solid part of the connection  36  to the left ventricle  18 ).  
         [0029]    The processing unit  110  of the optimization apparatus  100  processes the permutations of the pacing parameter values, such as heart rate, and atrioventricular (AV), inter-atrial (AA) and inter-ventricular (VV) delays, and records the corresponding measurements of stroke volume, cardiac output, ejection fraction (EF) and other indices of ventricular performance.  
         [0030]    According to the invention, a specific optimization cycle, triggered by an operator or upon the expiration of a preset time interval, automatically varies one or more pacing parameters, such as AV delays, inter-atrial delay, inter-ventricular delay, or heart rate, within operator-defined ranges, and determines at each parameter setting hemodynamic parameters, such as stroke volume (SV), cardiac output (GO), and other indices of ventricular performance. Each application of set pacing parameters is applied, for example, but not limited to, for a period in the range of 30 to 120 seconds. The processing unit records the hemodynamic parameters with each permutation of pacing parameter values, and, upon completion of the optimization cycle, indicates the permutation of pacing parameter values leading to optimal stroke volume, cardiac output and other indices of ventricular performance.  
         [0031]    The results are numerically of graphically shown on a display  140 . In the event the display  140  features a touch screen, patient demographic parameters, such as name, age, and weight, can be entered via the touch screen. Alternatively, the optimization apparatus  100  features an interface  150  to a keyboard or a port allowing communication with peripheral devices.  
         [0032]    Typical applications for the aforementioned preferred embodiment are, but not limited to, Pacing System Analysis (PSA) with permanent pacing leads connected to the apparatus, Temporary Pacing (T.P.) after cardiac surgery using temporary myocardial pacing leads (heart wires), and temporary pacing treatment of congestive heart failure (CHF Pacing).  
         [0033]    [0033]FIG. 2 illustrates a second preferred embodiment which employs, for example, but not limited to, in a combination of a permanent cardiac pacemaker and a corresponding external programmer for permanent pacemakers, with or without an Pacing System Analyzer (PSA) integrated into the programmer. With regards to temporary pacing, this embodiment is employed, for example, but not limited to, in a combination of a temporary cardiac pulse generator (temporary cardiac pacemaker) and a hemodynamic measurement unit interfacing with the pulse generator.  
         [0034]    [0034]FIG. 2 shows the patient  10  after implantation of a permanent cardiac pacemaker  170 . The cardiac pacemaker  170  is connected to at least two heart chambers of right atrium (RA)  12  via a permanent pacing lead  172 , right ventricle (RV)  14  via a permanent pacing lead  174 , left atrium (LA)  16  via a permanent pacing lead  176 , and left ventricle (LV)  18  via a permanent pacing lead  178 . FIG. 2 shows the connections from the permanent cardiac pacemaker to the heart chambers, i.e. the pacing leads, by dashed lines to indicate that these pacemaker leads are implanted into the patient and, thus, not part of the optimization apparatus.  
         [0035]    The optimization apparatus  100  incorporates a heart monitor  120 , a display  140 , an interface  150 , all controlled by a processing unit  110 . The optimization apparatus communicates with the permanent cardiac pacemaker through the interface  150  and an external pacemaker telemetry unit  160 , which, for example, is provided by the manufacturer of the permanent cardiac pacemaker  170 . Alternatively, the telemetry unit  160  is integrated into the optimization apparatus, which is indicated by the dashed lines  162  extending the apparatus  100 .  
         [0036]    The communication between the optimization apparatus  100  and the permanent pacemaker  170  is important to synchronize any new permutation of pacing parameter values with the corresponding hemodynamic parameter measurements performed by the optimization apparatus  100 . If no communication can be established, then, at least, the physician programming the cardiac pacemaker  170  and operating the optimization apparatus  100  must know and record the related set pacing and measured hemodynamic parameters.  
         [0037]    In the preferred embodiment shown, surface ECG-type electrodes as part of an electrode array are attached to the patient&#39;s right side of neck and the left side of lower thorax. The outer surface electrodes  20 ,  22  are connected to the alternating current (AC) source  122  of the heart monitor  120 , which is part of the optimization apparatus  100 . The inner surface electrodes  24 ,  26  are connected to the voltmeter  124  of the heart monitor  120 . The heart monitor  120  determines from the ratio of the AC applied by  122  and the voltage measured by  124  the thoracic electrical bioimpedance.  
         [0038]    Alternatively, the heart monitor  120  determines from the reciprocal ratio of the AC applied by  122  and the voltage measured by  124  the thoracic electrical bioadmittance. The above-mentioned Osypka EP application No. 02007310.2, which is herein incorporated by reference, describes how the continuous measurement of thoracic electrical bioimpedance is used to determine stroke volume and cardiac output.  
         [0039]    Alternatively, the thoracic electrical bioimpedance (or bioadmittance) can be measured using different electrode configurations, including a second electrode array, and electrodes located on an esophageal catheter/probe, all described in the above-mentioned Osypka EP application No. 02007310.2.  
         [0040]    Typical applications for the aforementioned preferred embodiment are, but not limited to, the examination of a pacemaker patient upon a follow-up visit, and hemodynamic optimization during temporary pacing after cardiothoracic surgery.  
         [0041]    [0041]FIG. 3 illustrates a flowchart about the various steps of the optimization process.  
         [0042]    [0042]FIG. 3 illustrates a generalized flowchart about the preparation steps of the optimization cycle, i.e. the process which executes the defined number of permutations of pacing parameter values and leads to a permutation of pacing parameter values providing the patient with maximum stroke volume, cardiac output, and other indices of ventricular performance, or any combination thereof.  
         [0043]    Upon Start  300  of the procedure, the patient is at rest. In order to provide immediate pacing therapy, if required, the pacemaker, which mayor may not be an integral part of the optimization apparatus, is connected to the pacing leads. In the event of pacemaker patient follow-up, the pacing leads are already part of the implanted pacemaker system. The cardiac pacemaker is stimulating on demand, or, asynchronously to the heart rhythm, with a fixed pacing rate  302 . The physician decides whether the heart monitor integrated into the optimization apparatus utilizes the transthoracic electrical bioimpedance approach, where the alternating current is applied, and the resulting voltage measured, through surface electrodes  304 . Alternatively, in patients who are already intubated, the esophageal approach is utilized, where the alternating current is applied, and the resulting voltage measured, through electrodes located on an esophageal catheteprobe  306 .  
         [0044]    The operator defines the pacing parameter, namely the heart rate  310 , defines or determines the variation range for the value of the pacing parameter, and the variation step width for stepping through the variation range of the heart rate  310 . For example, the later optimization cycle for the heart rate shall begin with a heart rate of 70, then increase the heart rate by 5 beats per minute (variation step width=5), until a heart rate of 80 beats per minute. Alternatively, the heart rate can be set to a fixed value, with no range to vary.  
         [0045]    The operator determines the variation range, and the variation step width, for the atrioventricular (AV) delay  312 . In this context, with AV-Delay meant to be the right-sided AV-Delay, the time delay applied between sensing or stimulation in the right atrium and stimulation in the right ventricle. For example, the later optimization cycle of the optimization cycle shall begin with an AV-Delay of 150 ms, then increase the AV-Delay by 50 ms (variation step width =50 ms), until an AV-Delay of 250 ms is reached. Alternatively, the AV-Delay can be set to a fixed value, with no range to vary.  
         [0046]    The operator determines the variation range, and the variation step width, for the inter-atrial (M) delay  314 . In this context, with M-Delay meant to be the time delay applied between sensing or stimulation in the right atrium and stimulation in the left atrium. For example, the later optimization cycle shall begins with an M-Delay of 0 ms, then increase the M-Delay by 5 ms (variation step width =5 ms), until an M-Delay of 10 ms is reached. Alternatively, the M-Delay can be set to a fixed value, for example to 0 ms, with no range to vary .  
         [0047]    The operator determines the variation range, and the variation step width, for the left-sided atrioventricular (LAV) delay  316 . In this context, LAV-Delay is meant to be the left-sided AV-Delay, the time delay applied between sensing or stimulation in the left atrium and stimulation in the left ventricle. For example, the later optimization cycle shall begin with an LAV-Delay of 150 ms, then increase the LAV-Delay by 50 ms (variation step width=50 ms), until an LAV-Delay of 250 ms is reached. Alternatively, the LAV-Delay can be set to a fixed value, with no range to vary.  
         [0048]    The operator determines the variation range, and the variation step width, for the inter-ventricular (VV) delay  314 . In this context, with VV-Delay meant to be the time delay applied between sensing or stimulation in the right ventricle and stimulation in the left ventricle. For example, the later optimization cycle shall begin with an W-Delay of 0 ms, then increase the W-Delay by 5 ms (variation step width=5 ms), until a VV-Delay of 10 ms is reached. Alternatively, the VV-Delay can be set to a fixed value, for example to 0 ms, with no range to vary .  
         [0049]    The operator determines the time interval between a variation of pacing parameter values  320 . Upon a new permutation of pacing parameter values applied for therapy, the patient&#39;s hemodynamic response may take several cardiac cycles to establish. Consequently, the measurement of hemodynamic parameters immediately after the application of a new permutation of pacing parameter values may not reflect the actual hemodynamic changes induced by the changed pacing therapy. For example, within the later optimization cycle, each permutation of pacing parameters shall be held constant for 30 seconds, and measurements of the first cardiac cycles upon each permutation applied may be ignored.  
         [0050]    The order of setting the variation ranges and variation step width for heart rate  310 , M-Delay  314 , AV-Delay  316 , VV-Delay  318  and time interval  320  is arbitrary and can be changed. When setting the variation ranges and variation step widths, as well as the time interval, the physician must take into account that there is a compromise between wide ranges and close step widths of pacing parameters values, and the time the automatic optimization cycle will take, that is, the time the patient can be exposed to the measurements.  
         [0051]    Upon set pacing parameter variation ranges and variation step widths, the optimization apparatus calculates and displays the time required for the automatic optimization cycle or scan  330 . Depending on the calculated time and the time restrictions the patient&#39;s state of heath or situation mandates, the physician is able to readjust the previously set ranges and step widths. In the event the time required for the automatic optimization cycle is acceptable, the physician confirms the start of the automatic optimization cycle through the predefined pacing parameter variation ranges with the predefined variation step widths. The optimization apparatus stores the default set of pacing parameters prior to the start of the automatic optimization cycle, which can be reset upon termination of the automatic optimization cycle.  
         [0052]    Upon termination of the optimization cycle  340 , the hemodynamic parameter values obtained are displayed with the corresponding permutations of pacing parameter values. The results are displayed in form of a table, with the permutation of pacing parameter values leading to maximum stroke volume, cardiac output, ejection fraction and other indices of ventricular performance, marked. Alternatively, two- or three-dimensional graphs are utilized to display a spectrum of pacing parameter value sets and their therapeutical impact on this particular patient.  
         [0053]    The physician then has the choice of applying a preferred permutation of pacing parameter values parameter set, or a modification of it, for therapy, or return to the previously used and stored default set of pacing parameter values  350 .  
         [0054]    During pacing system analysis, any new placement of permanent pacing leads may suggest the execution of a new automatic optimization cycle  360 . The physician has the option to reprogram the previously set pacing parameter value ranges and variation step widths  362 , or initiate a new automatic optimization cycle with the pacing parameter ranges and step widths previously used  364 . Alternatively, the pacemaker optimization is ended  370 .  
         [0055]    [0055]FIG. 4 illustrates schematically the sensing and pacing sequence of the AVV-Mode.  
         [0056]    [0056]FIG. 4 illustrates schematically the four heart chambers, and their respective sensing and pacing channels, right atrium (RA)  200 , right ventricle (RV)  202 , left atrium (LA)  204 , and left ventricle (LV)  206 , and a preferred operating mode (AVV Mode) of the cardiac pacemaker integrated into the optimization apparatus of FIG. 1. The pacemaker provides the functions to measure (sense) in each heart chamber the intrinsic activity, if extant, and to deliver a pacing stimulus.  
         [0057]    In this context, the AV-Delay  210  is the programmed atrioventricular pacing interval, initiated by an atrial stimulus. The M Delay  212  is the programmed inter-atrial pacing interval, initiated by an atrial stimulus. The W-Delay  214  is the programmed inter-ventricular pacing interval, initiated by a ventricular stimulus.  
         [0058]    [0058]FIG. 4 illustrates the most complex sensing and pacing therapy the AVV Mode provides. By disabling the pacing and sensing in specific heart chambers, the function of the complex cardiac is reduced to known and established pacing modes. In the event that no left-atrial sensing and stimulation is required, or applicable, the left-atrial channel is disabled. The three heart chambers remaining, and their respective sensing and pacing channels  216 , right atrium (RA)  200 , right ventricle (RV)  202 , and left ventricle (LV)  206 , are of particular interest in pacing therapy addressing congestive heart failure, known as biventricular, or CHF, pacing. To our knowledge, the application of a VV-Delay, which can assume a positive or negative value, has neither been published nor investigated.  
         [0059]    Upon disabling pacing and sensing in the left ventricle, the two heart chambers remaining, and their respective sensing and pacing channels  218 , right atrium (RA)  200 , and right ventricle (RV)  202 , are of particular interest in classical physiological pacing therapy, known as dual-chamber, or DDD, pacing.  
         [0060]    [0060]FIG. 5 illustrates schematically the sensing and pacing sequence of the AVAV-Mode.  
         [0061]    [0061]FIG. 5 illustrates schematically the 4 heart chambers, and their respective sensing and pacing channels, right atrium (RA)  200 , right ventricle (RV)  202 , left atrium (LA)  204 , and left ventricle (LV)  206 , and another preferred operating mode (AVAV Mode) of the cardiac pacemaker integrated into the optimization apparatus of FIG. 1. The pacemaker provides the functions to measure (sense) in each heart chamber the intrinsic activity, if extant, and to deliver a pacing stimulus.  
         [0062]    In this context, the AV-Delay  210  is the programmed right-sided atrioventricular pacing interval, initiated by an atrial stimulus. The AA Delay  212  is the programmed inter-atrial pacing interval, initiated by an atrial stimulus. The LAV-Delay  220  is the programmed left-sided atrioventricular pacing interval, initiated by a left-atrial stimulus.  
         [0063]    Upon disabling pacing and sensing in the left atrium (LA)  204  and ventricle (L V)  206 , the 2 heart chambers remaining, and their respective sensing and pacing channels  218 , right atrium (RA)  200 , and right ventricle (RV)  202 , are of particular interest in classical physiological pacing therapy, known as dual-chamber, or DDD, pacing.  
         [0064]    As indicated above, it is not only the stroke volume (SV) that can be used in order to optimize the pacing parameters to be programmed onto the pacemaker. In general, most indices of left-ventricular cardiac performance may be suitable measures for optimization. The optimization apparatus measures in any event the heart rate (HR). Therefore, cardiac output (CO), instead of stroke volume SV may be used for the optimization process:  
       CO   =       SV   ·   HR     1000                           
 
         [0065]    where  
         [0066]    SV: Stroke Volume measured in milliliters (mL)  
         [0067]    CO: Cardiac Output measured in liters/minute  
         [0068]    HR: Heart rate measured in beats/minute  
         [0069]    For the calculation of the stroke volume SV, the following equation of the above-mentioned Osypka EP application No. 02007310.2 can be used (but not limited to):  
       SV   =       V   EFF     ·         C   1          (              (            Z        (   t   )              t       )     MIN            Z   0       )       n     ·       (     1     T   RR       )     m     ·     T   LVE                             
 
         [0070]    or, in a special form with n=m=0.5 and C 1 =1:  
       SV   =       V   EFF     ·                (            Z        (   t   )              t       )     MIN            Z   0         ·       FT   C     .                             
 
         [0071]    where V EFF : Volume of electrically participating tissue  
         [0072]    C 1 : Constant  
                (            Z        (   t   )              t       )     MIN          :                         
 
         [0073]    Maximum rate of change of impedance  
         [0074]    Z 0 : Base impedance  
         [0075]    T RR : R-R interval  
         [0076]    T LVE : Left-ventricular ejection time  
         [0077]    FT C : Corrected flow time;  
         FT   C     =       T   LVE         T   RR                               
 
         [0078]    V EFF  is a factor, which is typical for a particular patient, as it is derived, among other factors, from the patient&#39;s weight. V EFF  is considered quasi-constant, because, according to the afore-mentioned Osypka EP application No. 02007310.2, V EFF  depends also on the basic impedance Z 0 . Considering the scope of possible applications, which require only several minutes for the optimization process, Z 0  varies, if at all, only by a small margin, and has practically no measurable influence on the SV or CO measured. If Z 0  and, consequently, V EFF  being constant during the entire application for a particular patient, optimization without compromising accuracy can be achieved without knowledge of the patient&#39;s weight and, thus, VEFF. For example, a “Stroke Index” SI 1  can be determined:  
         SI   1     =         (              (            Z        (   t   )              t       )     MIN            Z   0       )     n     ·       (     1     T   RR       )     m     ·     T   LVE                             
 
         [0079]    with 0.15&lt;n&lt;0.8 and 0≦m≦1.5 according to the aforementioned Osypka EP application.  
         [0080]    A special, dimensionless “Stroke Index” SI 1  is determined with n=m=0.5:  
         SI   1     =                  (            Z        (   t   )              t       )     MIN            Z   0         ·       FT   C     .                             
 
         [0081]    The only shortcoming of such processing is that the user does not obtain (simple) absolute indication of the range in which patient&#39;s stroke volume is determined while the patient is undergoing the various permutations of pacing parameter values. The user, however, obtains relative values of “Stroke Indices” to compare.  
         [0082]    With Z 0  considered constant, Z 0  may be omitted from the equation. The following simplified equation can be used to calculate another form of “Stroke Index” SI 2 :  
         SI   2     =         (              (            Z        (   t   )              t       )     MIN          Ω     )     n     ·       (     1     T   RR       )     m     ·     T   LVE                             
 
         [0083]    A special dimensionless “Stroke Index” SI 2  is determined with n=m=0.5:  
         SI   2     =                  (            Z        (   t   )              t       )     MIN          Ω       ·     FT   C                             
 
         [0084]    A further simplification but compromise in accuracy is to substitute corrected flow time FT C  for left-ventricular ejection time (known also as systolic flow time) T LVE  or even fully omit FT C  or T LVE . Accordingly, a “Stroke Index” Sl 3  is determined:  
         SI   3     =                (            Z        (   t   )              t       )     MIN          Ω                             
 
         [0085]    Alternatively, a “Stroke Index” SI 4  is determined by normalizing  
              (            Z        (   t   )              t       )     MIN                              
 
         [0086]    through division by base impedance Z 0 :  
         Sl   4     =                (            Z        (   t   )              t       )     MIN            Z   0                               
 
         [0087]    Again, omitting corrected flow time FT C  or left-ventricular ejection time (known also as systolic flow time) T LVE  is a simplification that compromises accuracy and may be suitable only within a narrow range of applicable heart rates.  
         [0088]    Stroke volume, cardiac output and the aforementioned “Stroke Indices” are, within their constraints, suitable hemodynamic parameters for determination of the optimal setting of pacing parameters. Alternatively, (left-ventricular) Ejection Fraction (EF) is an at least as suitable hemodynamic index for pacing parameter optimization.