Abstract:
A method is provided for use with a human subject. The method includes accessing a cardiac site via a vena cava of the subject, and alleviating heart failure of the subject by applying to the cardiac site, during a refractory period of the site, a refractory-period signal that affects the left ventricle of the subject&#39;s heart. Other embodiments are also described.

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS  
       [0001]     The present application is a continuation-in-part of U.S. Ser. No. 10/672,385, filed Sep. 26, 2003, which is:  
         [0002]     a continuation of co-pending, commonly assigned U.S. Ser. No. 09/848,535, filed May 3, 2001, now abandoned, which is based upon commonly assigned U.S. 60/202,382, filed May 4, 2000;  
         [0003]     a continuation-in-part of co-pending, commonly assigned U.S. Ser. No. 10/188,726, filed Jul. 2, 2002, which is a continuation of commonly assigned U.S. Ser. No. 09/254,903, filed Mar. 12, 1999, now U.S. Pat. No. 6,415,178, which is a U.S. National Phase Patent Application of PCT/IL97/00233, filed Jul. 9, 1997, which is based upon U.S. 60/026,392, filed Sep. 16, 1996, and Israeli Patent Application 119,261, filed Sep. 17, 1996; and  
         [0004]     a continuation-in-part of co-pending, commonly assigned U.S. Ser. No. 10/039,845, filed Oct. 23, 2001, which is a continuation of U.S. Ser. No. 09/563,544, filed May 1, 2000, now U.S. Pat. No. 6,363,279, which is a continuation of U.S. Ser. No. 09/101,723, filed Aug. 13, 1998, now U.S. Pat. No. 6,317,631, which is a U.S. National Phase filing of PCT/IL97/00012, filed Jan. 8, 1997, which is based upon U.S. 60/009,769, filed Jan. 11, 1996, U.S. 60/011,117, filed Feb. 5, 1996, U.S. 60/026,392, filed Sep. 16, 1996, U.S. Ser. No. 08/595,365, filed Feb. 1, 1996, now U.S. Pat. No. 5,738,096, and Israeli Patent Application No. 119,261, filed Sep. 17, 1996.  
         [0005]     All of the above references are incorporated herein by reference in their entirety.  
     
    
     FIELD OF THE INVENTION  
       [0006]     The present invention relates generally to invasive devices and methods for treatment of the heart, and specifically to devices and methods for improving cardiac performance.  
       BACKGROUND OF THE INVENTION  
       [0007]     The heart requires precise coordination of its mechanical and electrical behavior to function optimally. The human body normally regulates cardiac output in response to body needs by changing the heart rate, as during physical exercise, and/or by adapting the stroke volume. Under pathological conditions, however, some of the normal regulatory mechanisms may be damaged. For example, heart tissue damaged due to myocardial infarct typically cannot sustain normal pumping function. Alternatively or additionally, normal electrical signals are not generated, or are impaired in their propagation, such that cardiac output and cardiac efficiency (stroke work divided by oxygen consumption) are correspondingly compromised. Standard pacemakers known in the art are able to control the rate of the heart, e.g., to accelerate the heart rate after detecting bradycardia, but are not able to increase contraction strength over the long-term without producing adverse side-effects.  
         [0008]     US Patent Application Publication 2002/0055764 to Malonek et al., which is assigned to the assignee of the present patent application and is incorporated herein by reference, describes a lead for modifying the activity of a tissue, particularly the heart. Electrodes are provided for performing sensing and/or signal delivery functions. A control unit controls the parameters of the electric field provided by signal delivery electrodes to prevent the generation of a propagation action potential in the tissue.  
         [0009]     PCT Patent Publication WO 97/25098, to Ben-Haim et al., entitled “Electrical muscle controller,” and the corresponding U.S. patent application 09/101,723, which are assigned to the assignee of the present patent application and are incorporated herein by reference, describe methods for modifying the force of contraction of at least a portion of a heart chamber by applying a non-excitatory electric signal to the heart at a delay after electrical activation of the portion. The non-excitatory signal is such as does not induce action potentials in cardiac muscle cells, but rather modifies the cells&#39; response to the activation. In the context of the present patent application, the use of such a non-excitatory signal is referred to as Excitable-Tissue Control (ETC). The non-excitatory signal may be applied in combination with a pacemaker or defibrillator, which applies an excitatory signal (i.e., pacing or defibrillation pulses) to the heart muscle.  
         [0010]     PCT Patent Publication WO 98/10832, to Ben-Haim et al., entitled “Cardiac output enhanced pacemaker,” and the corresponding U.S. patent application Ser. No. 09/254,900, which are assigned to the assignee of the present patent application and incorporated herein by reference, describe a pacemaker that gives cardiac output enhancement. This pacemaker applies both excitatory (pacing) and non-excitatory (ETC) electrical stimulation pulses to the heart. By applying non-excitatory pulses of suitable strength, appropriately timed with respect to the heart&#39;s electrical activation, the contraction of selected segments of the heart muscle can be increased or decreased, thus increasing or decreasing the stroke volume of the heart.  
         [0011]     The following patent references are incorporated herein by reference: U.S. Pat. No. 6,714,823, WO 99/55412, U.S. Pat. No. 6,064,906, WO 98/41144, U.S. Pat. No. 5,772,604, WO 97/49143, and U.S. Pat. No. 5,350419.  
       SUMMARY OF THE INVENTION  
       [0012]     It is an object of some aspects of the present invention to provide improved methods and apparatus for stimulating cardiac tissue.  
         [0013]     It is a finer object of some aspects of the present invention to provide improved methods and apparatus for enhancing cardiac performance.  
         [0014]     It is still a further object of some aspects of the present invention to provide improved methods and apparatus for increasing cardiac output.  
         [0015]     In preferred embodiments of the present invention, an electrical cardiac stimulator for improving the performance of the heart of a human subject applies an Excitable-Tissue Control (ETC) signal to the interventricular septum via one or more electrodes passed by catheter into the right ventricle. Preferably, but not necessarily, at least one electrode is screwed or otherwise fixed to the septum, and delivers the ETC signal during a refractory period of excitable tissue of the septum, so as to modify a characteristic of the mechanical behavior thereof.  
         [0016]     An ETC signal is an example of a “refractory-period signal,” which is a signal applied to a cardiac site during the refractory period of the cardiac site.  
         [0017]     It is noted that these embodiments of the present invention simplify the procedure of applying electrical signals to modulate cardiac contraction. It is known in the art to apply pacing signals to the left ventricle by the difficult procedure of passing a catheter through the coronary veins. It is also known in the art to make an incision in a patients chest so as to implant pacing electrodes on the heart. It is further known in the art to pace both ventricles via an electrode placed on the interventricular septum, whereby pacing pulses generated by the electrode cause an activation wave to propagate through the septum, through normal conduction pathways of the heart. These prior art techniques differ from preferred embodiments of the present invention in that the prior art is directed towards stimulating one or both ventricles to contract, while these embodiments of the present invention provide means for modulating the mechanical behavior of the septum itself, substantially without inducing new action potentials.  
         [0018]     Typically, each electrode conveys a particular waveform to the septum, which may differ in certain aspects from the waveforms applied to other electrodes. The particular waveform to be applied to each electrode is preferably determined by a control unit, initially under the control of a physician during a calibration period of the unit. Further preferably, the cardiac stimulator (or elements thereof) is implanted in the patient in a manner similar to that used to implant pacemakers or defibrillators known in the art. After the initial calibration period, the unit is generally able to automatically modify the waveforms as needed to maintain a desired level of performance of the stimulator. In many applications, standard pacing, cardioversion, and/or defibrillation capabilities are additionally incorporated into the stimulator.  
         [0019]     In a preferred embodiment, one or more mechanical sensors, e.g., force transducers, strain gauges, pressure gauges, and/or motion sensors, are positioned in a vicinity of the heart, and are coupled to send mechanical-sensor signals to the control unit indicative of aspects of the heart&#39;s functioning. Alternatively or additionally, one or more physiological sensors, e.g., for measuring mixed venous oxygen saturation (SvO2) or thoracic electrical impedance, send physiological-sensor signals to the control unit. The various sensor signals serve as feedback to enable the control unit to iteratively adjust the ETC signal applied to the septum, so as to cause the sensor signals to converge to desired values. Alternatively or additionally, other sensors, such as sensing electrodes, blood pressure sensors, or flow tranducers, are coupled to the heart or elsewhere on the patient&#39;s body, and send signals to the control unit which are used in determning modifications to parameters of the energy applied to the heart.  
         [0020]     Further alternatively or additionally, the control unit analyzes the sensor signals to detect an onset of arrhythmia, for example, an ectopic heartbeat. In this case, the control unit preferably modifies or terminates application of the ETC signal responsive to the detection.  
         [0021]     There is therefore provided, in accordance with a preferred embodiment of the present invention, a method for applying a signal to a heart of a human subject, including applying an Excitable-Tissue Control (ETC) signal to a site on the right ventricular septum of the heart.  
         [0022]     Typically, applying the ETC signal includes configuring the signal to be capable of modifying contractility of a portion of the heart. For example, configuring the ETC signal may include configuring the signal to be capable of modifying contractility of the left ventricle of the heart, the septum, or the right ventricle of the heart.  
         [0023]     Preferably, configuring the ETC signa includes configuring the signal to be capable of increasing contractility of the portion of the heart. Alternatively, configuring the ETC signal includes configuring the signal to be capable of decreasing contractility of the portion of the heart. In a preferred embodiment, configuring the ETC signal to be capable of decreasing the contractility includes configuring the signal to be capable of decreasing contractility of the septum.  
         [0024]     For some applications, applying the ETC signal includes applying a series of biphasic pulses. Alternatively or additionally, applying the ETC signal includes applying a series of generally square pulses. Further alternatively or additionally, applying the ETC signal includes applying a series of pulses at a rate greater than about 50 Hz. Still further alternatively or additionally, applying the ETC signal includes applyinga series of pulses at a rate less than about 100 Hz.  
         [0025]     Preferably, applying the ETC signal includes applying a series of pulses which are greater than about 8 mA. For some applications, applying the ETC signal includes applying a series of pulses which are greater than about 10 mA.  
         [0026]     In a preferred embodiment of the present invention, applying the ETC signal includes applying the ETC signal to a site at or adjacent to an intersection of the septum and the right venticular free wall.  
         [0027]     There is also provided, in accordance with a-preferred embodiment of the present invention, apparatus for applying a signal to a heart of a human subject, including:  
         [0028]     a set of one or more electrodes, adapted to be coupled to the right ventricular septum of the heart; and  
         [0029]     a control unit, adapted to drive the electrode set to apply an Excitable-Tissue Control (ETC) signal to the septum.  
         [0030]     There is additionally provided, in accordance with an embodiment of the invention, a method for use with a human subject having a heart, including:  
         [0031]     accessing a cardiac site via a vena cava of the subject; and  
         [0032]     alleviating heart failure of the subject by applying to the cardiac site, during a refractory period of the site, a refractory-period signal that affects a left ventricle of the heart.  
         [0033]     In an embodiment, applying the refractory-period signal includes applying an excitatory-tissue control (ETC) signal.  
         [0034]     In an embodiment, applying the refractory-period signal includes configuring the refractory-period signal to increase cardiac output of the heart.  
         [0035]     In an embodiment, accessing the cardiac site includes accessing a plurality of cardiac sites via the vena cava, and applying the signal to the cardiac site includes applying energy to each of the cardiac sites.  
         [0036]     In an embodiment, accessing the cardiac site via the vena cava includes guiding an electrode through a right ventricle of the subject.  
         [0037]     In an embodiment, applying the signal includes applying the signal during a bipolar signal application period.  
         [0038]     In an embodimient, applying the signal includes applying the signal during a monopolar signal application period.  
         [0039]     In an embodiment, applying the refractory-period signal includes applying a series of biphasic pulses.  
         [0040]     In an embodiment, applying the refractory-period signal includes applying a series of generally square pulses.  
         [0041]     In an embodiment, applying the refractory-period signal includes applying a series of pulses at a rate greater than 50 Hz.  
         [0042]     In an embodiment, applying the refractory-period signal includes applying a series of pulses at a rate less than 100 Hz.  
         [0043]     In an embodiment, applying the refractory-period signal includes applying a series of pulses at a rate between 50 Hz and 100 Hz.  
         [0044]     In an embodiment, applying the refractory-period signal includes applying the refractory-period signal to a site at or adjacent to an intersection of an interventricular septum and a right ventricular free wall of the heart.  
         [0045]     In an embodiment, applying the refactory-period signal includes chronically applying the refractory-period signal.  
         [0046]     In an embodiment, chronically applying includes configuring the refractory-period signal to engender long-term alleviation of the heart failure.  
         [0047]     In an embodiment, the method includes applying a pacing signal to the site during an excitatory period of a cardiac cycle, and applying the refractory-period signal includes applying the refractory-period signal during a refractory period of the same cardiac cycle.  
         [0048]     In an embodiment, applying the pacing signal includes applying the pacing signal with no delay following applying the refractory-period signal.  
         [0049]     In an embodiment, applying the pacing signal includes applying the pacing signal following a delay after applying the refractory-period signal.  
         [0050]     In an embodiment, applying the refractory-period signal includes applying a plurality of pulses that are greater than 1 mJ.  
         [0051]     In an embodiment, applying the plurality of pulses includes applying a plurality of pulses that are greater than 5 mJ.  
         [0052]     In an embodiment, the method includes sensing electrical activity of the heart at a sensing site, and applying the refractory-period signal in response to the sensing.  
         [0053]     In an embodiment, the sensing site is different from the cardiac site, and sensing the electrical activity includes sensing at the sensing site that is different from the cardiac site.  
         [0054]     In an embodiment, the sensing site includes the cardiac site, sensing includes sensing using an electrode, and applying the refractory-period signal includes applying the refractory-period signal through the electrode.  
         [0055]     In an embodiment, the method includes detecting arrhythmia of the heart, and applying an anti-arrhythmic signal to the cardiac site in response thereto.  
         [0056]     In an embodiment, detecting the arrhythmia includes detecting fibrillation of the heart, and applying the anti-arrhythmic signal includes applying a defibrillating signal to the cardiac site in response to the detecting of the fibrillation.  
         [0057]     In an embodiment, accessing the cardiac site includes implanting an electrode from a right ventricle of the subject into an interventricular septum of the subject.  
         [0058]     In an embodiment, implanting includes implanting a distal tip of the electrode to a depth of 5-10 mm in the septum.  
         [0059]     In an embodiment, implanting includes implanting a distal tip of the electrode to a depth of 10-20 mm in the septum.  
         [0060]     In an embodiment, implanting includes implanting a distal tip of the electrode to a depth of 20-25 mm in the septum.  
         [0061]     In an embodiment, implanting includes implanting the electrode such that a distal tip of the electrode passes through the septum and protrudes into the left ventricle.  
         [0062]     In an embodiment, the electrode includes a coil electrode, and implanting the electrode includes implanting the coil electrode.  
         [0063]     In an embodiment, implanting the electrode includes screwing the electrode into the septum.  
         [0064]     In an embodiment, the electrode includes a bipolar electrode, and screwing the electrode includes screwing the bipolar electrode into the septum.  
         [0065]     In an embodiment, applying the refractory-period signal includes applying a series of pulses which are greater than 8 mA.  
         [0066]     In an embodiment, applying the refractory-period signal includes applying a series of pulses which are greater than 10 mA.  
         [0067]     In an embodiment, applying the refractory-period signal includes configuring the signal to be capable of modifying contractility of the left ventricle of the heart.  
         [0068]     In an embodiment, configuring the refractory-period signal includes configuring the signal to be capable of modifying contractility of an interventricular septum of the heart.  
         [0069]     In an embodiment, configuring the refractory-period signal includes configuring the signal to be capable of modifying contractility of a right ventricle of the heart.  
         [0070]     In an embodiment, configuring the refractory-period signal includes configuring the signal to be capable of increasing contractility of the left ventricle of the heart.  
         [0071]     In an embodiment, configuring the refractory-period signal includes configuring the signal to be capable of decreasing contractility of a portion of the heart.  
         [0072]     In an embodiment, configuring the refractory-period signal to be capable of decreasing the contractility includes configuring the signal to be capable of decreasing contractility of an interventricular septum of the heart.  
         [0073]     There is yet additionally provided, in accordance with an embodiment of the invention, apparatus for applying a signal to a heart of a human subject, including:  
         [0074]     a set of one or more electrodes, configured to be passed through a vena cava of the subject and coupled to a cardiac site; and  
         [0075]     a control unit, configured to alleviate heart failure of the subject by driving the electrode set to apply to the cardiac site, during a refractory period of the site, a refractory-period signal that affects a left ventricle of the heart.  
         [0076]     In an embodiment, the control unit is configured to configure the refractory-period signal to increase cardiac output of the heart.  
         [0077]     In an embodiment, the control unit is configured to drive the electrode set to apply a series of biphasic pulses.  
         [0078]     In an embodiment, the control unit is configured to drive the electrode set to apply a series of generally square pulses.  
         [0079]     In an enbodiment, the control unit is configured to drive the electrode set to apply a series of pulses at a rate greater than 50 Hz.  
         [0080]     In an embodiment, the control unit is configured to drive the electrode set to apply a series of pulses at a rate less than 100 Hz.  
         [0081]     In an embodiment, the control unit is configured to drive the electrode set to apply a series of pulses at a rate between 50 Hz and 100 Hz.  
         [0082]     In an embodiment, the control unit is configured to drive the electrode set to apply the signal to a site at or adjacent to an intersection of an interventricular septum and a right ventricular free wall.  
         [0083]     In an embodiment, at least one of the electrodes includes a material selected from the group consisting of: titanium coated with iridium oxide, titanium coated with titanium nitride, platinum iridium coated with iridium oxide, platinum iridiun coated with titanium nitride, platinum iridium coated with sintered platinum, titanium, platinum iridium, and pyrolytic carbon.  
         [0084]     In an embodiment, at least one of the electrodes is shaped to define an effective external surface area of between 30 mm2 and 250 mm2.  
         [0085]     In an embodiment, at least one of the electrodes has an impedance that is between 50 ohm and 1000 ohm.  
         [0086]     In an embodiment, at least one of the electrodes has an impedance that is between 200 ohm and 700 ohm.  
         [0087]     In an embodiment, at least one of the electrodes has a capacitance between 300 microfarads.  
         [0088]     In an embodiment, the refractory-period signal includes an excitatory-tissue control (ETC) signal, and the control unit is configured to drive the electrode set to apply signal to the cardiac site.  
         [0089]     In an embodiment, the one or more electrodes include a plurality of electrodes, configured to be implanted at a respective plurality of cardiac sites.  
         [0090]     In an embodiment, the electrode set includes a bipolar electrode.  
         [0091]     In an embodiment, the electrode set includes a monopolar electrode.  
         [0092]     In an embodiment, the control unit configures the refractory-period signal to include a series of biphasic pulses.  
         [0093]     In an embodiment, the control unit is configured to configure the signal to be capable of modifying contractility of a portion of the heart.  
         [0094]     In an embodiment, the control unit is configured to configure the signal to be capable of increasing contractility of the left ventricle of the heart.  
         [0095]     In an embodiment, the control unit is configured to configure the signal to be capable of modifying contractility of an interventricular septum of the heart.  
         [0096]     In an embodiment, the control unit is configured to configure the signal to be capable of modifying contractility of a right ventricle of the heart.  
         [0097]     In an embodiment, the control unit is configured to configure the signal to be capable of increasing contractility of the portion of the heart.  
         [0098]     In an embodiment, the control unit is configured to configure the signal to be capable of decreasing contractility of the portion of the heart.  
         [0099]     In an embodiment, the control unit is configured to configure the signal to be capable of decreasing contractility of an interventricular septum of the heart.  
         [0100]     In an embodiment, the control unit configures the refractory-period signal to include a series of pulses which are greater than 8 mA.  
         [0101]     In an embodiment, the control unit configures the refractory-period signal to include a series of pulses which are greater than 10 mA.  
         [0102]     In an embodiment, the control unit is configured to drive the electrode set to apply the refractory-period signal chronically.  
         [0103]     In an embodiment, the control unit is configured to configure the refractory-period signal to engender long-term alleviation of the heart failure.  
         [0104]     In an embodiment, the control unit is configured to drive the electrode set to apply a pacing signal to the site during an excitatory period of a cardiac cycle, and to apply the refractory-period signal during a refractory period of the same cardiac cycle.  
         [0105]     In an embodiment, the control unit is configured to drive the electrode set to apply the refractory-period signal with no delay following application of the pacing signal.  
         [0106]     In an embodiment, the control unit is configured to drive the electrode set to apply the refractory-period signal following a delay after application of the pacing signal.  
         [0107]     In an embodiment, the control unit configures the refractory-period signal to include a plurality of pulses that are greater than 1 Mj.  
         [0108]     In an embodiment, the control unit configures the refractory-period signal to include a plurality of pulses that are greater than 5 mJ.  
         [0109]     In an embodiment, the control unit is configured to receive a sensed signal indicative of electrical activity of the heart at a sensing site, and to drive the electrode set to apply the refractory-period signal in response to the sensed signal.  
         [0110]     In an embodiment, the apparatus includes a sensing electrode which is not an electrode from the electrode set, and the control unit is configured to receive the sensed signal from the sensing electrode.  
         [0111]     In an embodiment, the control unit is configured to receive the sensed signal from one of the one or more electrodes in the electrode set, and to drive the one of the one or more electrodes to apply the refactory-period signal in response to the sensed signal.  
         [0112]     In an embodiment, the control unit is configured to detect arrhythmia of the heart, and to drive at least one of the electrodes in the electrode set to apply an anti-arrhythmic signal in response thereto.  
         [0113]     In an embodiment, the control unit is configured to detect fibrillation of the heart, and to drive the at least one of the electrodes to apply a defibrillating signal to the cardiac site in response to detecting fibrillation.  
         [0114]     In an embodiment, the electrode set is configured to be implanted from a right ventricle of the subject into an interventricular septum of the subject.  
         [0115]     In an embodiment, at least one of the electrodes is configured to penetrate to a depth of 5-10 mm in the septum.  
         [0116]     In an embodiment, at least one of the electrodes is configured to penetrate to a depth of 10-20 mm in the septum.  
         [0117]     In an embodiment, at least one of the electrodes is configured to penetrate to a depth of 20-25 mm in the septum.  
         [0118]     In an embodiment, at least one of the electrodes is configured to penetrate through the septum and emerge in the left ventricle.  
         [0119]     In an embodiment, at least one of the electrodes includes a coil electrode.  
         [0120]     In an embodiment, at least one of the electrodes includes a screw electrode, configured to be screwed into the septum.  
         [0121]     In an embodiment, the screw electrode includes a bipolar screw electrode.  
         [0122]     The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings, in which:  
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0123]      FIGS. 1A, 1B , and  1 C are schematic, sectional illustrations of a heart, showing the placement of electrodes therein, in accordance with preferred embodments of the present invention;  
         [0124]      FIG. 2  is a schematic block diagram of a control unit, which generates signals to be applied to the electrodes shown in  FIGS. 1A, 1B , and/or  1 C, in accordance with a preferred embodiment of the present invention; and  
         [0125]      FIGS. 3, 4 , and  5  are graphs showing experimental results from the application of an ETC signal to an animal heart, in accordance with a preferred embodiment of the present invention.  
     
    
     DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS  
       [0126]      FIG. 1A  is a schematic illustration of cardiac control apparatus  18 , which applies electrical energy to improve the performance of the heart  20  of a patient in accordance with a preferred embodiment of the present invention. Apparatus  18  preferably comprises an implantable or external control unit  90 , which applies an ETC signal through a set of one or more electrodes  98  to the heart. (For clarity, connections between control unit  90  and the various electrodes are not shown).  
         [0127]     Preferably, a catheter  68  is used to convey a screw electrode  65 , or other type of electrode, through the right ventricle  30  to a site on the interventricular septum  22  to which the electrode is attached. Alternatively or additionally, a catheter  66  conveys an electrode  69  through the right ventricle to be fixed to the septum, and/or conveys an electrode  67  into the right ventricle, where it is in electrical contact with electrodes  65  and  69  through the blood in the right ventricle. In a preferred embodiment one or more electrodes are placed at or adjacent to the intersection of the septum and the right ventricular free wall.  
         [0128]     Preferably, at least some of the electrodes have a coating applied thereto which increases the electrodes&#39; capacitance. A preferred coating comprises iridium oxide (IROX). Alternatively or additionally, at least some of the electrodes comprise coils, a mesh, or other means for increasing the effective application area of the ETC signal.  
         [0129]     As described hereinbelow, control unit  90  drives one or more of the electrodes to apply an ETC signal to the septum, so as to modify an aspect of the heart&#39;s contractility. For example, the signal may be applied so as to increase or decrease contractility of the right ventricle, the left ventricle, or the septum. Optionally, the control unit is implanted in the patient&#39;s body, and a metal case of the control unit serves as a return electrode for current driven through the electrodes in right ventricle  30 .  
         [0130]     Preferably, aspects of ETC signal application are performed in accordance with techniques described in the above-referenced U.S. patent application Ser. Nos. 09/101,723 and 09/254,900. Typically, the ETC signal is applied subsequent to an artificial pacing pulse, as described hereinbelow. Alternatively, the ETC signal is applied responsive to natural electrical activity of the heart, for example, after a designated delay following a detected activation of the atrium. For these applications, it is preferable to use apparatus and methods described in Israel Patent Application 129,257, entitled “Trigger-based regulation of excitable tissue control in the heart,” which is assigned to the assignee of the present invention and is incorporated herein by reference.  
         [0131]     Control unit  90  is optionally coupled to one or more local sense electrodes  74 , which are placed in the right ventricle or elsewhere on or in the heart. Local sense electrodes  74  preferably convey electrical signals to the control unit responsive to cardiac electric activity. Alternatively or additionally, one or more of electrodes  98  and any other electrodes coupled to control unit  90  may also serve as sense electrodes. Optionally, one or more mechanical sensors  70  (e.g., accelerometers, force transducers, strain gauges, or pressure gauges), coupled to the control unit, are placed on the right ventricle or elsewhere on the heart. Alternatively or additionally, one or more supplemental sensors  72  (e.g., blood pressure, thoracic electrical impedance, pH, SvO2, pCO2 or pO2 sensors) are coupled to the control unit and are placed on or in the heart or elsewhere on or in the patient&#39;s body. The control unit modifies the energy applied through electrodes  98  responsive to signals from sensors  70  and  72  and local sense electrodes  74 , as described hereinbelow.  
         [0132]     The number of electrodes and sensors, as well as the positions thereof, are shown in  FIG. 1A  by way of example, and other sites on heart  20  or in a vicinity thereof are appropriate for placement of some of the electrodes and sensors in other applications of the present invention.  
         [0133]     Preferably, control unit  90  is implanted in the patient in a manner similar to that used to implant pacemakers or defibrillators known in the art, such that after an initial calibration period, described hereinbelow, the unit is generally able to automatically modify the ETC signal it applies to the heart as needed, so as to maintain a desired level of performance. In many applications, standard pacing, cardioversion, and defibrillation capabilities are additionally incorporated into apparatus  18 .  
         [0134]      FIGS. 1B and 1C  are schematic illustrations of other preferred configurations of cardiac control apparatus  18 , in accordance with respective preferred embodiments of the present invention.  FIG. 1B  shows a catheter  166 , which conveys a plurality of electrodes  165 ,  167 , and  169  to respective sites on the right ventricular septum, while  FIG. 1C  shows a catheter  266 , which conveys a different arrangement of electrodes  265 ,  267 ,  269 , and  271  to the septum. In another preferred embodiment (not shown), a catheter passes a basket electrode into the right ventricle, so as to apply the ETC signal to the septum as well as to other right ventricular sites. Preferably, but not necessarily, all of the electrodes shown in  FIGS. 1A, 1B , and  1 C are independently controlled by control unit  90 .  
         [0135]      FIG. 2  is a schematic block diagram of control unit  90 , in accordance with a preferred embodiment of the present invention. Mechanical sensors  70 , supplemental sensors  72 , local sense electrodes  74 , and electrodes  98  are preferably coupled to provide feedback signals to a cardiac function analysis block  80  of control unit  90 . The feedback signals generally provide information about various aspects of the heart&#39;s performance to block  80 , which analyzes the signals and actuates control unit  90  to modify the electrical energy applied to the heart responsive to the analysis. Preferably, the ETC signal is adjusted by the control unit responsive to the feedback signals in order to yield a desired response, e.g., a predetermined blood pressure, blood oxygen level, cardiac output and/or cardiac electrical or motion profile.  
         [0136]     Preferably, block  80  conveys results of its analysis to a “parameter search and tuning” block  84  of control unit  90 , which iteratively modifies characteristics of the electrical energy applied to the heart in order to attain a desired response. Preferably, operating parameters of block  84  are entered by a human operator of the control unit using operator controls  71 , which typically comprise a keyboard or mouse (not shown) coupled to the control unit. Block  84  typically utilizes multivariate optimiization and control methods known in the art in order to cause one or more of the aforementioned mechanical, electrical, chemical and/or other measured parameters to converge to desired values.  
         [0137]     In general, each one of electrodes  98  may convey a particular waveform to heart  20 , differing in certain aspects from the waveforms applied by the other electrodes. The particular waveform to be applied by each electrode is determined by control unit  90 , preferably under the control of the operator. Aspects of the waveforms which are set by the control unit, and may differ from electrode to electrode, typically include parameters such as time shifts between application of waveforms at different electrodes, waveform shapes, amplitudes, DC offsets, durations, and duty cycles. For example, although the waveforms applied to some or all of electrodes  98  usually comprise a biphasic square wave signal following a natural or applied pacing pulse, other waveforms, such as a sinusoid, a series of monophasic square waves, or a waveform including an exponentially-varying characteristic, could be applied to other electrodes. Generally, the shape, magnitude, and timing of the waveforms are optimized for each patient, using suitable optimiton algorithms as are known in the art.  
         [0138]     For the purposes of this embodiment of the present invention, block  84  typically modifies a set of controllable parameters of the ETC signal, responsive to the measured parameters, in accordance with values in a look-up table and/or pre-programmed formulae stored in an electronic memory of control unit  90 . The controllable parameter may comprise, for example, ETC signal timing, magnitude and offset. Preferably, the controllable parameters are conveyed by block  84  to a signal generation block  86  of control unit  90 , which generates, responsive to the parameters, electrical signals that are applied by electrodes  98  to the heart. Block  86  preferably comprises amplifiers, isolation units, and other standard circuitry known in the art of electrical signal generation.  
         [0139]     In the initial calibration procedure, parameter search and tuning block  84  preferably modifies a characteristic (e.g., timing, magnitude, or shape) of the ETC signal applied through one of electrodes  98 , and then determines whether a predetermined cardiac functional response generally improves following the modification. For example, the electrode may be used to sense the duration of the refractory period of heart tissue to which the electrode is coupled, and block  84  may subsequently determine time points during the refractory period which are optimal for application of the ETC signal by that electrode to the tissue. In a series of similar calibration steps, block  84  repeatedly modifies characteristics of the energy applied through each of the electrodes, such that those modifications that improve the response are generally maintained, and modifications that cause it to worsen are typically eliminated or avoided.  
         [0140]     When apparatus  18  is calibrated in the presence of a physician, it is often desirable to have the patient perform increasing levels of exercise (e.g., walk on a treadmill), in order to derive a broader range of operating parameters, which are stored in control unit  90  and can be accessed responsive to signals from the sensors and electrodes coupled to the control unit. Preferably, the calibration procedure is subsequently performed by the physician at intermittent follow-up visits, and/or by unit  90  automatically during regular use of the apparatus (e,g., daily).  
         [0141]     Preferably, during the initial calibration procedure, the locations of one or more of electrodes  98  are varied while the ETC signal is applied therethrough, so as to determine optimum placement of the electrodes. Preferably, methods for measuring the heart&#39;s response to the applied signal include electrocardiography, echocardiography, and/or methods having as inputs the outputs of mechanical and supplemental sensors  70  and  72 . In subsequent steps, the electrode is moved over an area of the interventricular septum, and the response of the heart is measured. After the physician considers that a sufficient number of sites have been investigated, the electrode is returned to the site yielding the best response. Subsequently, other electrodes are moved according to the same protocol, so as to achieve substantially optimum placement of some or all of the electrodes.  
         [0142]     In a preferred embodiment, the ETC signal is applied in a vicinity of a site where standard pacing pulses are applied. Preferably, the ETC signal is applied through the same electrode as that through which the standard pacing pulse is applied, approximately 1-250 ms thereafter. Further preferably, the ETC signal is applied approximately 20-250 ms after the pacing pulse.  
         [0143]     Alternatively, the sinoatrial node generates the cardiac rhythm, substantially without artificial pacing. In such modes, local sense electrodes  74  and, optionally, some or all of electrodes  98 , convey electrical signals to control unit  90 , so as to enable parameter search and tuning block  84  to synchronize the electrical signals applied by electrodes  98  with the natural electrical activity of the heart. It will be understood that although electrodes  74  and  98  are shown for clarity of explanation as separate entities, a single set of electrodes may be used to perform both functions.  
         [0144]     In a preferred embodiment, the ETC signal is applied at one or more sites as a series of pulses, e.g., biphasic square pulses, typically having a frequency between about 50 and 100 Hz. The current applied during each pulse is preferably greater than 8 mA, and, firer preferably, greater than 10 mA.  
         [0145]     Most preferably, during calibration and during regular operation of control unit  90 , an arrhythmia detection block  82  of control unit  90  receives inputs from sensors  70  and  72  and electrodes  74  and  98 , and/or other electrodes and sensors (not shown), and evaluates these inputs to detect imminent or actual cardiac arrhythmia, e.g., an ectopic heartbeat, fibrillation, bradycardia or heart block. Preferably, block  82  employs techniques known in the art for detecting arrhythmias, so that parameter search and tuning block  84  can treat or terminate the arrhythmia by applying, for example, regular pacing pulses or defibrillation pulses.  
         [0146]      FIGS. 3, 4 , and  5  are graphs showing experimental results obtained during application of an ETC signal to a 30 kg anesthetized pig, in accordance with a preferred embodiment of the present invention. In this experiment, local sense electrodes comprised two stitch electrodes, which were placed at the mid-anterior wall of the left ventricle. The animal was paced in DDD mode at 120 beats per minute through an active fixation screw electrode, placed in the apical third of the right ventricular septum. At 20 ms following the onset of electrical activity as measured by the local sense electrodes, a biphasic electrical signal, composed of a 15 ms, +14 mA pulse immediately followed by a 15 ms, −14 mA pulse, was applied to the septum through the screw electrode implanted therein. In  FIG. 3 , results are shown following application of the ETC signal between the screw electrode implanted in the septum and a ring electrode in a vicinity thereof.  FIGS. 4 and 5  show results following application of the ETC signal between the screw electrode and a stitch electrode at the mid-anterior left ventricular free wall.  
         [0147]     In  FIG. 3 , an increase of approximately 5% in the measured d(LVP)/dt is seen to begin upon initiation of a 2 minute ETC signal application period. The dP/dt levels gradually return to baseline upon termation of the ETC signal.  FIGS. 4 and 5  show bipolar ETC application periods lasting over 3 and over 4 minutes, respectively, in which the measured dP/dt increased to approximately 20% above baseline, and remained at this level for the duration of signal application.  
         [0148]     It is believed that at least some of the results displayed in  FIGS. 3, 4 , and  5  derive from a change in contractility of the left ventricle induced by the application of the ETC signal to the interventricular septum.  
         [0149]     It is also believed that similar results can be obtained in humans, mutatis mutandis. It is further believed that these embodiments of the present invention can produce, at least to some extent, long-term effects which are likely to alleviate or cure aspects of some common cardiac pathologies, such as congestive heart failure (CHF). These effects are expected to derive from more effective use of the heart muscle, whereby systemic demands on the heart are reduced. Moreover, damage to other organs of the body is reduced, because of the increase in blood perfusion.  
         [0150]     It is believed that other signal application protocols would also be successfiul in enhancing cardiac performance, in combination with or in the absence of some of the stimulation and sensing protocols described hereinabove. In a preferred embodiment the ETC signal is applied at a plurality of sites on the interventricular septum, for example, on an anterior and a posterior aspect thereof. Alternatively or additionally, the ETC signal is applied generally simultaneously, or in alternation, at one or more of the following sites: the posterior septum, the anterior septum, the anterior wall of the right ventricle, the free wall of the right ventricle, and the posterior-inferior left ventricular free wall.  
         [0151]     Alternatively or additionally, the ETC signal is applied through the right ventricular septum so as to decrease regional contractility of the heart, preferably using techniques described in one or both of the above-referenced US patent applications. In particular, the ETC signal may be used to decrease septal contractility, which may be appropriate in treating conditions such as idiopathic hypertrophic subaortic stenosis (IHSS). It is believed that reduced septal contractility reduces functional subaortic stenosis, thereby improving left ventricular performance.  
         [0152]     In an embodiment, embodiments of the present invention are practiced using methods and apparatus described in US Patent Application Publication 2002/0055764 to Malonek et al., which is incorporated herein by reference.  
         [0153]     It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the the present invention includes both combinations and sub-combinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art which would occur to persons skilled in the art upon reading the foregoing description.