Admittance measurement for tuning bi-ventricular pacemakers

Abstract

An apparatus for treating a heart of a patient includes a first lead and at least a second lead for pacing the heart adapted to be in electrical communication with the heart. The apparatus includes a microcontroller in communication with the first and second leads which triggers the first lead at either different times or the same time from when the microcontroller triggers the second lead. Alternatively, the apparatus includes a microcontroller in communication with the first and second leads that determines heart volume, including stroke volume, end-systolic volume, and calculated values including ejection fraction, from admittance from signals from the first and second leads and uses the admittance as feedback to control heart volume ejected, as measured by stroke volume, calculated values such as ejection fraction, and control end-systolic volume, with respect to the first and second leads. A method for treating the heart of a patient.

Claims

1. An apparatus for treating a heart of a patient comprising: a pacemaker enclosure having: a first existing lead and at least a second existing lead for pacing the heart adapted to be in electrical communication with the heart; a microcontroller in communication with the first and second leads which triggers the first lead as a function of epicardial admittance in real time at either different times or a same time from when the microcontroller triggers the second lead for pacing the heart and takes into account delay between atrial pacing and ventricular pacing, where the admittance is a combination of both muscle and blood conductance and muscle susceptance components, where the blood and muscle components are in series and the admittance has both a real part and an imaginary part; a pacing circuit in communication with the microcontroller which receives a signal from the microcontroller to activate the pacing circuit to control when the first lead and the second lead are activated to pace the heart; and an admittance circuit which measures volume regarding the heart in real time in communication with the microcontroller, the microcontroller controls when the admittance circuit measures volume, the microcontroller determines from the admittance circuit in real time whether stroke volume, ejection fraction and end-systolic volume regarding the heart are increasing or decreasing over time, and changes the pacing circuit's operation in real time from the admittance circuit by cycling through pacing algorithms and changing a pacing algorithm which is used by the microcontroller, the microcontroller to maximize the stroke volume and ejection fraction and to minimize the end-systolic volume.

2. The apparatus of claim 1 including a pacemaker enclosure and wherein the admittance circuit is disposed in the pacemaker enclosure.

3. The apparatus of claim 2 wherein the microcontroller is disposed in the enclosure and including a wireless transmitter disposed in the enclosure which transmits a condition signal indicating whether the heart's condition is getting worse, better, or is without change.

4. The apparatus of claim 3 wherein the pacing circuit paces each ventricle of the heart separately, where each ventricle is paced separately using a variable time delay between a first and a second pace, or takes into account delay between atrial pacing and ventricular pacing, or a combination thereof.

5. The apparatus of claim 4 including at least a third lead for multiple admittance measurements adapted to be in electrical communication with the heart.

6. A method for treating a heart of a patient comprising the steps of: receiving by a pacing circuit in a pacemaker enclosure in communication with a microcontroller in the pacemaker enclosure a signal from the microcontroller to activate the pacing circuit to control when a first existing lead and a second existing lead of the pacemaker enclosure is activated to pace the heart; triggering with the microcontroller the first lead in electrical communication with the heart at various times for pacing the heart as a function of epicardial admittance in real time and takes into account delay between atrial pacing and ventricular pacing, where the admittance is a combination of both muscle and blood conductance and muscle susceptance components, where the blood and muscle components are in series and the admittance has both a real part and an imaginary part; triggering with the microcontroller the second lead in electrical communication with the heart at different times than the various times for pacing the heart so that the microcontroller triggers the first lead at different times from when the microcontroller triggers the second lead; and measuring with an admittance circuit volume regarding the heart in real time in communication with the microcontroller, the microcontroller controlling when the admittance circuit measures volume, the microcontroller determining from the admittance circuit in real time whether stroke volume, ejection fraction and end-systolic volume regarding the heart are increasing or decreasing over time, and changing the pacing circuit's operation in real time from the admittance circuit by cycling through pacing algorithms and changing a pacing algorithm which is used by the microcontroller, the microcontroller to maximize the stroke volume and ejection fraction and to minimize the end-systolic volume.

7. The method of claim 6 including the step of determining stroke volume, and systolic volume, and ejection fraction of the heart using epicardial admittance.

8. The method of claim 7 including the step of pacing the heart by separately pacing each ventricle of the heart using a variable time delay between a first and a second pace, or by taking into account delay between atrial pacing and ventricular pacing, or by a combination thereof.

9. The method of claim 8 including the step of re-measuring stroke volume, and systolic volume, and ejection fraction after changing how the heart is paced.

10. The method of claim 9 including the step of comparing the determining step and the re-measuring step, and repeating them until the stroke volume and ejection fraction are maximal, and end-systolic volume is minimal.

Description

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING

(1) In the accompanying drawings, the preferred embodiment of the invention and preferred methods of practicing the invention are illustrated in which:

(2) FIG. 1a shows a bi-plane left ventriculogram from a patient with CHF and a previously implanted AICD/bi-ventricular pacer demonstrating how the leads span the left ventricle (LV) blood from the RV apical septum to the lateral LV epicardium.

(3) FIG. 1b shows the admittance electric field lines from the RV apical septum to the lateral LV epicardium regarding the apparatus of the present invention.

(4) FIG. 2 shows a typical arrangement of three leads consisting of 2 electrodes each. This allows a normal pacemaker measurement to make 2 (or more) separate measurements of admittance across the heart.

(5) FIG. 3a shows the effect of Neosynephrine on LVEDV in Epicardial Lead Studies. Note that LV G.sub.blood tracks with the standard of LV Crystal Volume.

(6) FIG. 3b shows the same data analyzed without subtracting the muscle component, demonstrating that dynamic removal of the myocardial signal using admittance is critical for detecting increasing LV Volume. The pig number is identified in the legend. There is variation in the absolute volumes in these hearts due to a large variation in porcine size.

(7) FIG. 4 is a flow chart of feedback loop of present invention.

DETAILED DESCRIPTION OF THE INVENTION

(8) Referring now to the drawings wherein like reference numerals refer to similar or identical parts throughout the several views, and more specifically to FIG. 1b thereof, there is shown an apparatus 10 for treating a heart 16 of a patient. The apparatus 10 comprises a first lead 12 and at least a second lead 14 for pacing the heart 16 adapted to be in electrical communication with the heart 16. The apparatus 10 comprises a microcontroller 18 in communication with the first and second leads 12, 14 which triggers the first lead 12 at either different times or the same time from when the microcontroller 18 triggers the second lead 14.

(9) The apparatus 10 may include a pacing circuit 20 in communication with microcontroller 18 which receives a signal from the microcontroller 18 to activate the pacing circuit 20. The apparatus 10 may include an admittance circuit 22 which measures volume regarding the heart 16 in communication with the microcontroller 18. The microcontroller 18 controls when the admittance circuit 22 measures volume. The microcontroller 18 determines from the admittance circuit 22 whether stroke volume, ejection fraction and end-systolic volume regarding the heart 16 are increasing or decreasing over time, and changes the pacing circuit's operation to maximize the stroke volume and ejection fraction and to minimize the end-systolic volume.

(10) The apparatus 10 may include a pacemaker 30 enclosure 24 and wherein the admittance circuit 22 is disposed in the pacemaker 30 enclosure 24. The microcontroller 18 may be disposed in the enclosure 24 and including a wireless transmitter 26 disposed in the enclosure 24 which transmits a condition signal indicating whether the heart's condition is getting worse, better or is without change. The pacing circuit 20 may pace each ventricle of the heart 16 separately, where each ventricle is paced separately using a variable time delay between a first and a second pace, or takes into account delay between atrial pacing and ventricular pacing, or a combination thereof. The apparatus may include at least a third lead 15 for multiple admittance measurements adapted to be in electrical communication with the heart.

(11) The present invention pertains to an apparatus 10 for treating a heart 16 of a patient. The apparatus 10 comprises a first lead 12 and at least a second lead 14 for pacing the heart 16 adapted to be in electrical communication with the heart 16. The apparatus 10 comprises a microcontroller 18 in communication with the first and second leads 12, 14 that determines heart 16 volume, including stroke volume, end-systolic volume, and calculated values including ejection fraction, from admittance from signals from the first and second leads 12, 14 and uses the admittance as feedback to control heart 16 volume ejected, as measured by stroke volume, calculated values such as ejection fraction, and control end-systolic volume, with respect to the first and second leads 12, 14.

(12) The present invention pertains to a method for treating a heart 16 of a patient. The method comprises the steps of triggering with a microcontroller 18 a first lead 12 in electrical communication with the heart 16 at various times for pacing the heart 16. There is the step of triggering with the microcontroller 18 a second lead 14 in electrical communication with the heart 16 at different times than the various times for pacing the heart 16 so that the microcontroller 18 triggers the first lead 12 at different times from when the microcontroller 18 triggers the second lead 14.

(13) There may be the step of determining stroke volume, and systolic volume, and ejection fraction of the heart 16 using epicardial admittance. There may be the step of pacing the heart 16 by separately pacing each ventricle of the heart 16 using a variable time delay between a first and a second pace, or by taking into account delay between atrial pacing and ventricular pacing, or by a combination thereof. There may be the step of re-measuring stroke filing, and systolic volume, and ejection fraction after changing how the heart 16 is paced. There may be the step of comparing the determining step and the re-measuring step, and repeating them until the stroke volume and ejection fraction are maximal, and end-systolic volume is minimal.

(14) The present invention pertains to a method for treating the heart 16 of a patient. The method comprises the steps of determining heart 16 volume, including stroke volume, calculated values such as ejection fraction, and end-systolic volume, from admittance with a microcontroller 18 from signals from a first lead 12 and a second lead 14 in electrical communication with the heart 16. There is the step of using the admittance as feedback to the microcontroller 18 to control heart 16 volume ejected, as measured by stroke volume, calculated values such as ejection fraction, and control end-systolic volume, with respect to the first and second leads 12, 14.

(15) In the operation of the invention, the key elements of this invention include 1) the use of an epicardial admittance measurement to determine improvements in stroke volume and/or end systolic volume, and 2) the ability of this information to determine the best possible pacing algorithm to use based on which algorithm maximizes patient stroke volume, ejection fraction, and minimizes end-systolic volume from the first element.

(16) The invention will determine which pacing algorithm maximizes patient stroke volume, ejection fraction, and minimizing end-systolic volume by cycling through each available timing algorithm (or by changing the timing between stimulation of each site in a multisite pacemaker 30) and measuring the LV volume, and derived stroke volume, end-systolic volume and ejection fraction for each. Maximizing the stroke volume in these situations will directly affect the ejection fraction of the patient, moving the patient into a higher functional NYHA class, and improving quality of life both immediately, and over time.

(17) In regard to FIG. 1b, a pacemaker 30 (pacing) circuit is well known in the field, and little has been done to change its basic design since its invention. However, the method to control when the pacing circuit 20 fires varies with the type of technology. In the present invention, there are two main components: 1) a pacing circuit 20, and 2) a volume measurement (admittance) circuit. A microcontroller 18 will provide the signal to the pacing circuit 20 to control when each individual pacing site is activated. The microcontroller 18 will also control when the admittance circuit 22 measures volume. The microcontroller 18 will be able to determine from the admittance circuit 22 whether the stroke volume, ejection fraction and end-systolic volume are increasing or decreasing over time, and change the pacing algorithm to maximize the stroke volume and ejection fraction, and minimizing the end-systolic volume.

(18) Further, the microcontroller 18 will signal process the results from the admittance circuit 22 within the pacemaker 30 enclosure, and then a signal indicating whether the patient condition is getting worse, better, or staying the same can be sent to the receiver 28 using the wireless transmitter 26. No extra processing will be necessary external to the implanted device, although, if desired, the processing of the data could occur outside of the patient in an alternative embodiment.

(19) For 4 electrodes to measure admittance, only one processing circuit (admittance circuit 22 w/current source) is necessary. An additional embodiment of the current invention is for multiple admittance circuits to measure the volume of the LV from different locations, or for one admittance circuit to measure multiple locations in sequence. This redundancy can be used to increase accuracy in situations where implantation of the leads in their ideal locations is not possible.

(20) Adaptive Pacing Algorithms

(21) The key method for determining if a pacing algorithm is working correctly should be dependent on how effectively the heart 16 is pumping blood. Maximum effectiveness is therefore equivalent to maximum cardiac output.

(22) Algorithm: 1. Determine stroke volume, end systolic volume, and ejection fraction using epicardial admittance. 2. Pace the heart 16 using either: a. A well known pacing method (see pacing algorithm method guide by Bernstein et al.; Journal of Pacing and Clinical Electrophysiology, Volume 25, No. 2, February 2002). b. A bi-ventricular pacing algorithm where each ventricle is paced separately using a variable time delay between the first and the second pace. c. A pacing method that takes into account delay between atrial pacing and ventricular pacing. d. Some combination of the above 3. Measure stroke volume, end systolic volume, and ejection fraction after changing algorithm. 4. Compare step 3 with step 1 and repeat 2-4 until the stroke volume and ejection fraction are maximal, and end-systolic volume is minimal.

(23) Pacing methods (sometimes called algorithms by the medical community): 1. Well-known pacing algorithms such as those described in Bernstein et al. are often chosen for a patient at the time of implantation. However, there is no guarantee that the patient will not benefit from a changing pacing algorithm depending on their activity, long-term health status, or other factors. Switching between these well known pacing algorithms could provide both short-term benefit (such as when exercising), and long-term benefit (such as improved cardiac remodeling). Because the microcontroller 18 is in direct contact with the pacing unit, switching algorithms is a matter of outputting a different pacing pattern to the pacing unit. The specific event that will trigger a switch in pacing is dropping below an adaptive threshold for cardiac output. Over time, if the patient improves, the threshold for aggressive therapy may be changed. This adaptive nature of the threshold for treatment allows the pacer to adapt to changes that occur over a long time span. Cardiac output, stroke volume, ejection fraction and end-systolic volume are measured using the admittance system directly. Therefore, if cardiac output, stroke volume, and ejection fraction start to go down, at some threshold (much like Optivol from Medtronic), the pacing algorithm will be switched to maximize the cardiac output, stroke volume and ejection fraction again. Other currently deployed applications which do not use hemodynamic variables include accelerometers within the pacemaker 30 to determine that increased patient motion is present and hence higher demand is necessary for more rapid pacing. 2. It is possible to pace the heart 16 using leads in both the coronary veins (LV lead) and in the RV apex (RV lead). If the LV lead is paced separately from the RV lead, a nonzero time delay between the LV lead and the RV lead could produce a better cardiac output, stroke volume (SV), and ejection fraction (EF) than has been previously discussed using bi-ventricular pacing (such as Cardiac Resynchronization Therapy devices). Pacing separately is a matter of having multiple pacing circuits controlled by a microcontroller 18. There are already microcontrollers present within most current pacemakers. This measurement can be performed using a microcontroller 18 and multiple pacemakers, or multiple pacing circuits connected one per electrode.

(24) Atrio-ventricular delay is often set at the time of pacemaker 30 implantation to maximize stroke volume and EF, and minimize end-systolic volume (ESV). This type of pacing is currently beneficial to the patient, but it requires a doctor's visit to change the timing delay between atria and ventricle. Real-time feedback from epicardial Admittance can address this problem in real time, like the previous two pacing methods. With the power of the feedback loop and a microcontroller 18 in the pacemaker 30, a doctor's visit will not be necessary. Doctors tune pacemakers using the same process outlined in the algorithm. They measure the volume of the heart 16 (usually using an echo machine), change the pacing algorithm (usually using the help of a clinical engineer), and they re-test the volume of the heart 16 (using another echo). The patient visit, doctor, and engineer are not necessary if the microcontroller 18 implanted within the pacemaker 30 makes these decisions in real time as the patient's heart 16 is changing volume over time. This will save, money, and time for all involved, reducing greatly the amount of time between the patient's onset of disease and treatment.

(25) What will be new and in the enclosure of the pacemaker 30 is:

(26) 1. Microcontroller 18 programming or an equivalent decision making circuit which provides feedback based on whether stroke volume and EF have been maximized, and ESV minimized. A variety of well known control algorithms can be used here, and their application is well known to one skilled in the art. The new feedback loop with the decision making process is shown in FIG. 4.

(27) 2. The admittance circuit 22, is described in U.S. patent application Ser. No. 12/657,832, incorporated by reference herein, but minimized to fit into the size of a pacemaker 30 enclosure. The miniaturization may be achieved by putting the entire admittance circuit 22 onto a chip if desired. See U.S. patent application Ser. No. 12/657,832, incorporated by reference herein. Such circuits can be made small enough without placement on a chip if desired.

(28) 3. An additional pacing circuit 20 is installed in the case where each lead in a bi-ventricular pacemaker 30 will be paced independently. This only mildly increases complexity. Basically, there would be 2 of the flow charts in parallel, delivering pacing pulses at different times. The end result and control algorithm are still the same.

(29) 4. Optionally, any known pacemaker configuration could benefit from this design, with various lead implant locations. However, nothing external to the pacemaker enclosure would need to change.

(30) Calculation Theory and Epicardial Blood Conductance Measurement

(31) Conductance measurements have been available as an invasive tool to detect instantaneous LV volume since 1981..sup.23 Tetrapolar electrodes are usually placed on a catheter located within the LV chamber to determine instantaneous volume by electrical conductance measurement. Conductance systems generate an electric field using a current source, and volume is determined from the instantaneous returning voltage signal. Conductance is the preferred measurement over resistance (or impedance) because it has a direct (not inverse) relationship with volume. Conductance electrodes have not been previously placed on the LV epicardium to interrogate the LV blood volume, as done in the current invention.

(32) The relationship between measured blood conductance and LV blood volume is determined primarily by the shape of the current field in the blood pool and surrounding myocardium. For example, in a uniform electric field approximation the measured time-dependent resistance, R.sub.blood, is proportional to the electrode separation distance, L(t), and inversely proportional to the cross-sectional area of the field, A(t); and the converse for the measured blood conductance, G.sub.blood, where is blood resistivity:

(33) $R_{\mathrm{blood}}=\frac{L\left(t\right)}{A\left(t\right)}$$G_{\mathrm{blood}}=\frac{A\left(t\right)}{L\left(t\right)}$

(34) Some of the measurement electrode positions will produce a blood conductance primarily sensitive to the cross-sectional area change while others are primarily sensitive to the separation distance. As the cross-sectional area of the LV increases, there is a corresponding increase in blood conductance. Thus, for the purposes of the current invention, area-dependent electrode configurations only were focused on.

(35) Dynamic Muscle Conductance Removal

(36) Epicardial admittance is a measurement taken in the complex plane, and has both a magnitude, |Y| (Siemens) and a phase, Y (degrees). The values for admittance are a combination of both the muscle and blood conductance, and the muscle susceptance (C), for both are present in the current field. The process for separating admittance into blood and muscle conductance was outlined previously for the case of a tetrapolar catheter where the blood and muscle are in parallel..sup.17 However, there is no previously proposed model for the separation of blood and muscle components of a cross-chamber epicardial admittance measurement, where the blood and muscle components are in series. This new theory to separate blood and muscle components is presented below.

(37) $R_m=\frac{-\mathrm{Im}\left\{\stackrel{.fwdarw.}{z}\right\}\left(1+{\left(\frac{{}_m}{{}_m}\right)}^2\right)}{\frac{{}_m}{{}_m}}$$R_b=\mathrm{Re}\left\{\stackrel{.fwdarw.}{z}\right\}-\frac{R_m}{1+{\left(\frac{{}_m}{{}_m}\right)}^2}$

(38) Where R.sub.m is the resistance of muscle (), and R.sub.b is the resistance of blood (), .sub.m is the permittivity of muscle (F/m), and .sub.n, is the conductivity of muscle (S/m). The complex impedance {right arrow over (Z)} can be separated into real (Re{{right arrow over (Z)}}) and imaginary parts (Im{{right arrow over (Z)}}). The properties of the myocardium .sub.n, and .sub.m can be calculated using a surface probe measurement..sup.17, 19 In an epicardial measurement the field generated is mostly transverse, while in a surface probe measurement (and in a traditional LV catheter measurement), the field is mostly longitudinal. This difference has been measured by others, and was corrected in the data by multiplying by a factor of 2..sup.24, 25 The penetration depth for the surface probe used to measure the porcine myocardial properties was 3.6 mm, which does not extend into the LV blood volume beneath.

(39) LV Volume Measurement with 2 Dimensional Sonomicrometry

(40) The standard of volume measurement used to validate this invention is two dimensional (2D) sonomicrometry (endocardial) crystals. 2D endocardial crystals is an acceptable alternative to 3D echocardiography in large animal hearts when the two short axes are equal in distance,.sup.26-28 and this distance is maintained during acute LV dilation. Additionally, the porcine myocardium is prone to arrhythmias, and there is significant trauma associated with placing the third crystal plane through the septum. Consequently, 2D endocardial crystals are the practical approach. The two dimensions measured included the anterior-posterior and apex-base planes via pairs of 2 mm piezo-electric ultrasonic transducers positioned on the endocardial surface through a stab wound through the LV myocardium and secured with a purse-string suture. The two crystal pairs were attached to a digital sonomicrometer (Sonometrics Corporation, London, Ontario, Canada) and the digital output was then transformed into volume by fitting the points to a prolate ellipsoid..sup.26, 28

(41) Protocol

(42) This invention was conducted in compliance with the United States Food and Drug Administration (FDA) Good Laboratory Practices Regulations (21 CFR Part 58), following approval of the animal use committee at the University of Texas Health Science Center San Antonio. For n=15 Yorkshire Pigs studied, the body weight ranged from 42 kg to 78 kg (mean=6012.6 kg), 14 were male and 1 was female. Pigs were sedated with Telazol 4 mg/kg IM, intubated and anesthesia was maintained with 1-2% Isoflurane with 100% oxygen. The right neck was dissected to gain access to the jugular vein and carotid artery. A sternotomy was performed and the pericardium was partially opened. Amiodarone 150 mg IV was given over 30 min, and repeated 30 min later. Following loading of Amiodarone, a Lidocaine infusion was initiated at 1 g/min for the remainder of the protocol. Although there was anticipated myocardial depression from this approach, there was greater concern that the porcine model has a low ventricular fibrillation threshold.

(43) Instrumentation

(44) Platinum-Platinum black electrodes were chosen for the experiment because of their low electrode interface impedance (Medtronic, Minneapolis, Minn.). Electrode locations were chosen to simulate the approximate positions of an RV AICD endocardial lead, and the bi-ventricular lead on the lateral LV epicardium. Two sets of 4 electrodes spaced 1 cm apart were sewn onto a felt backing, and each were sewn onto the LV epicardium. The anterior electrodes were sewn parallel to the distal LAD to simulate the RV AICD lead, and the posterior electrodes were sewn parallel to a left marginal vein to simulate the bi-ventricular lead. Electrode pairs were chosen for a cross-ventricular chamber tetrapolar measurement with a current producing and a voltage-sensing electrode on both the anterior and the posterior epicardium.

(45) The pigs were also instrumented with two dimensional endocardial crystals as outlined above, a left carotid pressure sensor (3F, Scisense, London, ON), a 6F sheath in the jugular vein, an RV pressure sensor (inserted directly through the anterior RV wall (1.2 F, Scisense, London, ON), a descending thoracic saline filled balloon occluder (16 or 18 mm diameter, In Vivo Metric, Healdsburg, Calif.) to generate transient occlusion as an alternative method to produce LV dilation, and an aortic flow probe, which was placed in the descending thoracic aorta (Transonic, Ithaca, N.Y.) immediately distal to the balloon occluder to document that occlusion was obtained.

(46) Properties Measurement and Hematocrit

(47) An epicardial probe was applied to the surface of the intact beating open-chest heart. The stimulus current was generated using the instrumentation previously described..sup.29 Real-time |{right arrow over (Y)}| and {right arrow over (Y)} were measured and myocardial permittivity (.sub.m) and conductivity (.sub.m) were calculated as described previously..sup.19 Briefly, the surface probe cell constant, k (m.sup.1), determined in saline of known electrical conductivity, is used to calculate: .sub.m=kG.sub.m and .sub.m=kC.sub.m, where G.sub.m=Re{{right arrow over (Y)}} and C.sub.m=Im{{right arrow over (Y)}}/ and =2f, where k is the cell constant of the probe used (1/m), G.sub.m is the conductance of muscle (S), C.sub.m is the capacitance of the muscle, and f is the frequency of excitation (Hz). Hematocrit was determined both at baseline and at the end of the experiment via capillary tubes and a Clay Adams Readacrit centrifuge (model CT-3400, Becton Dickinson, Sparks, Md.). Whole blood samples were spun for 5 minutes at 8,500 rpm, and the volume of packed red cells was expressed as a percentage of total volume.

(48) Neosynephrine (Phenylephrine) for LV Dilatation

(49) Neosynephrine was chosen to increase afterload and secondarily dilate the LV in a dose-response fashion to simulate LV dilation as would occur in a heart failure patient. Neosynephrine was infused at a constant rate of 75, 150, and 300 g/min in the first n=2 pigs. For the later n=9 pigs, a lower dose of 37.5 g/min was added to this same infusion protocol. Baseline and data from at least 2 doses of Neosynephrine where LV dilation occurred as defined by endocardial crystals, were required for data to be used in analysis. Some doses of Neosynephrine did not result in LV dilation and this varied in every pig. Thus, the doses given in the results section are the baseline, and mean low and high doses of Neosynephrine that achieved LV dilation. Each dose of Neosynephrine was infused for 10 minutes to achieve steady state, and then data were acquired over the subsequent 5 minutes for a total of 15 minutes per dose.

(50) Data acquired included heart rate, carotid pressure (AoP), descending thoracic aortic flow (Ao Flow), short and long axis endocardial crystals, epicardial impedance magnitude (|{right arrow over (Z)}|) and phase angle ({right arrow over (Z)}). Data were acquired while the respirator was suspended at end-expiration for at least 5 cardiac cycles.

(51) Alternative Methods for LV Dilatation

(52) To determine if LV dilation could be detected by epicardial admittance, two additional preparations were examinedacute LAD occlusion and transient aortic occlusion.

(53) LAD Occlusion

(54) A suture was placed under the middle LAD, proximal to the epicardial admittance electrodes, and tied off to produce an acute dilation of the middle and distal anterior myocardium. Data obtained were identical to the Neosynephrine protocol. Due to ventricular fibrillation, complete data were only obtained in n=6 porcine studies.

(55) Transient Aortic Occlusion

(56) Transient aortic occlusion was performed successfully in n=11 pigs. Occlusion was controlled by the introduction of saline into the occluder, and successful occlusion was defined by the reduction of descending thoracic aortic flow to less than 1 L/min. The flow probe was always immediately distal to the balloon occluder.

(57) Pleural Effusion Simulation

(58) Pleural effusions are common in heart failure patients, and are a common source of artifact in the measurement of lung conductance by systems such as Optivol.sup.8, 11, 14 and CorVue, since the electrical fields generated by these devices extend into the lungs. Epicardial admittance generates an electric field, which extends across the LV and thus should not have this source of artifact. To test this hypothesis, the chest cavity was filled with saline during the measurement of LV epicardial admittance (both on the right and left sides of the heart). The pericardium was used as a sling to keep the saline from coming into direct contact with the electrodes, similar to the final implementation of epicardial admittance. Immediately after baseline measurements as outlined above, saline of conductivity close to blood (7941124 S/cm) was introduced into the chest. The introduced volume for n=7 pigs was 42590 mL, and following introduction all measurements were repeated.

(59) Data Analysis

(60) The slope relating blood conductance (mS) and endocardial crystal volume (mL) was determined in 11 animals at up to three doses of Neosynephrine in each of up to 6 vectors, yielding a total of 99 paired measures of blood conductance and crystal volume (FIG. 3). Data were analyzed based on a repeated measures linear model with a compound symmetric autocorrelation matrix and fixed intercepts for each pig and vector. The significance of the relation between blood conductance and crystal volume was assessed using a Wald statistic for testing the null hypothesis that the coefficient of LV blood conductance in the repeated measures linear model is zero. Statistical testing was two-sided with a significance level of 5% using SAS Version 9.2 for Windows (SAS Institute, Cary, N.C.). For LAD occlusion, transient Ao occlusion, and pleural effusion simulation, paired baseline and intervention data were compared using a Student's t test, again with a level of significance of 5%. All results are reported as meanstandard deviation.

(61) Results

(62) Baseline Hemodynamics

(63) The mean systolic aortic pressure was 8013 mmHg, and the heart rate was 8617 bpm. The mean LV end diastolic and end systolic long axis by crystals was 826 and 745 cm, respectively; and the mean LV end diastolic and end systolic short axis by crystals was 474 and 404 cm, respectively. The calculated mean LV EDV was 10031 mL, and the mean LV ESV was 6925 mL measured via endocardial crystals. The mean LVEF was 316%, consistent with a depressed but non-dilated LV preparation from the anesthetics and amiodarone given to minimize ventricular fibrillation. The mean descending thoracic flow was 8.01.8 L/min, and the mean RV systolic pressure was 193 mm Hg.

(64) Hematocrit at the initiation of the protocol was 30.02.3%, and at the end of the protocol 33.04.7%, consistent with hemo-concentration due to minimal fluid administration during the protocol to mitigate changes in blood and myocardial electrical properties as a source of artifact. The mean distance from the LV apex to the most apical epicardial admittance electrode on the anterior surface was 3.00.9 cm, and on the posterior surface was 3.00.5 cm, consistent with the admittance electrodes being parallel to one another on either side of the LV epicardium.

(65) The end diastolic and end systolic epicardial LV admittance magnitudes=1/|{right arrow over (Z)}|) were 15.82.0 and 14.51.9 mS, respectively; and the mean phase angles ({right arrow over (Y)}={right arrow over (Z)}) were 9.23.0 and 7.43.2 degrees, respectively.

(66) Properties Summary

(67) Myocardial properties were determined in each pig for use in the equations to separate the blood and muscle admittance as published previously..sup.19 The myocardial conductivity was .sub.m=0.330.03 S/m, the myocardial permittivity was .sub.m=(197102786)*.sub.0 F/m, and the calculated ratio of a/E for myocardium was 1,923,320179,592 S/F.

(68) Neosynephrine for LV Dilatation

(69) Data from n=11 porcine studies is shown in FIG. 3. The low dose Neo was 9054 g/min, the high dose Neo was 180107 g/min. The blood conductance was computed from the epicardial impedance (|{right arrow over (Z)}|) and phase angle ({right arrow over (Z)}), and plotted against LV volume calculated from endocardial crystals. LV end-diastolic volume (EDV) and complex impedance at end diastole were measured in each pig and the results were converted into the conductance of blood (LV G.sub.blood) using the admittance technique, removing muscle contribution in real time (FIG. 3A). The conductance of blood (G.sub.blood), expressed in milli-Siemens (mS), and LV volume (V), expressed in milliliters (mL), were measured at multiple values of LV volume for between 1 and 6 vectors on each pigs and the within-animal mean slope was computed for FIG. 3A. The slope relating G.sub.blood (mS) and the adjusted volume (mL), 1.160.48 mS/mL, was significantly different from zero (p=0.017). Data were also analyzed using the traditional conductance technique, which does not remove muscle contribution and demonstrates that the ability to detect LV dilation was lost and is dependent upon having access to the imaginary component of the myocardial signal (FIG. 3B).

(70) LAD Occlusion for LV Dilatation

(71) Hemodynamic parameters are shown in Table 1 at baseline and following LAD occlusion. Acute LAD occlusion produced a significant decrease in aortic pressure and flow. The anticipated increase in LV volume was detected by both the standard (endocardial crystals) as well as blood conductance. The large standard deviations in the blood conductance are a result of the wide range of electrode positions, and an offset, which may be caused by variable surface electrode-myocardium contact. On average, an increase of 17% from baseline LV blood conductance corresponded to an LV volume increase of 4%.

(72) Transient Ao Occlusion

(73) Hemodynamic parameters are shown in Table 2 at baseline and peak transient Ao occlusion. AoP and endocardial crystal derived LV volume both increase. Ao flow decreased below 1 L/min since that was the definition for a successful aortic occlusion. The increased afterload increases the LV blood conductance by 7%, and the crystal LV volume by 9%.

(74) Pleural Effusion Simulation

(75) Hemodynamic parameters are shown in Table 3 at baseline and pleural effusion simulation. Neither the LV blood conductance nor the crystal derived LV volume changed with saline placed around the heart 16.

(76) This invention has demonstrated that LV blood conductance can be determined from the epicardial position, despite the current generating and sensing electrodes being in constant motion with the heart 16, and with dynamic removal of the myocardial component of the returning voltage signal. Specifically, it has been demonstrated that (a) a physiologic LV blood conductance signal can be derived, (b) LV dilation in response to dose-response iv Neosynephrine can be detected by blood conductance in a similar fashion to the standard of endocardial crystals when admittance is used, but not when only traditional conductance is used, (c) the physiologic impact of acute LAD occlusion can be detected by blood conductance as LV dilation, and (d) a pleural effusion simulated by placing saline outside the pericardium do not serve as a source of artifact for blood conductance measurements.

(77) Pleural effusions are frequent findings in patients with advanced heart failure. Devices which interrogate the lungs for pulmonary edema use a trans-thoracic resistance measurement from the tip of the RV AICD lead to the case of the battery pack for the pacemaker/defibrillator, and thus provide a wide electric field including the LV, left atrium, thoracic skeletal muscle, ipsilateral lung tissue, intravascular blood volume in the lung, pulmonary interstitial edema and finally pleural effusions to measure a changing fluid index. Having an electrical approach that is focused on the LV myocardium and blood volume would be preferable, but there still exists some electrical field extension into other sources of artifact such as pleural effusions. To determine whether epicardial admittance would artifactually detect pleural effusions, fluid was placed outside the pericardium in the chest cavity to simulate this clinical condition. No alteration in the measurement of LV blood conductance was demonstrated in studies, arguing that epicardial admittance does indeed focus its interrogation on the LV itself.

(78) The admittance technique (FIG. 3A) provides reliable tracking of LV preload similar to endocardial crystals, while traditional conductance does not (FIG. 3B). This increased sensitivity of the admittance technique is due to the use of a phase measurement in the calculation of the admittance, which allows the real-time separation of blood and muscle components. The high resistance of muscle normally swamps a measurement of blood and muscle in series, because the resistivity of muscle is nearly 5 times that of blood. This causes the total measured traditional conductance signal to be low and non-specific (FIG. 3B) when compared to the LV blood conductance determined using admittance (FIG. 3A).

(79) In contradiction, studies by Stahl et al..sup.13, 15 using traditional conductance have shown promise in the detection of LV dilation using existing bi-ventricular leads. Stahl's invention is very different from the current invention for two reasons. The first major difference is that the stimulating electrodes span the LV, while in Stahl's they reside completely within the RV. In Stahl's design, the majority of current will be confined to the RV because the resistivity of muscle is 5 times higher than blood. This limitation is overcome in the current invention by forcing the current across the LV by maintaining the excitation and sink electrodes on opposite sides of the LV. The preferential path for current is therefore the low resistivity blood pool. The second major difference is that the current invention employs complex admittance for determining the relative muscle contribution to the measured signal. As seen in FIG. 3, this separation of blood from muscle provides increased sensitivity to heart failure detection (increasing LV preload). The present invention represents the first evidence that a cross-chamber complex admittance measurement shows improved sensitivity to LV blood pool volume measurement over a traditional conductance (or resistance) measurement.

(80) In summary, a new electrical approach has been developed which can detect LV volume, taking advantage of pre-existing AICD and bi-ventricular pacing lead locations, and maturing the conductance approach to moving source and sensing electrodes while instantaneously removing the myocardial component to generate a final LV blood conductance signal.

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(82) Tables

(83) TABLE-US-00001 TABLE 1 LAD Occlusion. Baseline Occlusion HR (bpm) 88 19 87 20.sup. AoP (mmHg) 88 9 83 11 Crystal Vol (mL) 88 12 91 12 Ao Flow (L/min) 7.0 1.3 6.4 1.3 RVSP (mmHg) 24.5 3.9 23.7 5 G.sub.blood (mS) 73.6 39.8 85.0 51.1 Data from n = 6 pigs with 13 electrode positions are shown. HR is heart rate, Aop is systolic right carotid pressure, Crystal Vol is 2D endocardial crystal LV volume, Ao Flow is descending thoracic aortic flow, RVSP is right ventricular systolic pressure, and G.sub.blood is LV blood conductance derived from epicardial admittance. p < 0.01

(84) TABLE-US-00002 TABLE 2 Transient Aortic Occlusion. Baseline Occlusion HR (bpm) 90 28 97 24.sup. AoP (mmHg) 86 11 124 18 Crystal Vol (mL) 89 21 98 22 Ao Flow (L/min) 6.3 1.2 0.7 0.6 RVSP (mmHg) 22.9 4.4 23.8 4.4 G.sub.blood (mS) 53.5 18.6 57.4 21.6 Data from n = 11 pigs from 27 electrode positions are shown. Occlusion data were defined at the time of peak AoP. HR is heart rate, Aop is systolic right caotid pressure, Crystal Vol is 2D endocardial crystal LV volume, Ao Flow is descending thoraic aortic flow, RVSP is right ventricular systlic pressure, and G.sub.blood is LV blood conductance derived from epicardial admittance. p < 0.01

(85) TABLE-US-00003 TABLE 3 Pleural Effusion Simulation. Baseline Pleural Effusion HR (bpm) 95 19 .sup.96 21 AoP (mmHg) 87 5 86 6 Crystal Vol (mL) 100 29 100 27 G.sub.blood (mS) 53.2 33.5 52.6 27.8 Data from n = 7 pigs from 54 electrode positions are shown. HR is heart rate, Aop is systolic right carotid pressure, Crystal Vol is 2D endocardial crystal LV volume, and G.sub.blood is LV blood conductance derived from epicardial admittance. p < 0.05, p < 0.01

(86) Although the invention has been described in detail in the foregoing embodiments for the purpose of illustration, it is to be understood that such detail is solely for that purpose and that variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention except as it may be described by the following claims.