JP2003529389A - Remodeling of heart connections - Google Patents

Abstract

SUMMARY OF THE INVENTION The present invention is a method of treating a heart to remodel gap junctions, obtain remodeling of gap junctions, and / or alter the effective refractory period. Contacting the electrode pair with the epicardial surface of the heart, and contacting the electrode pair with a pacemaker to provide a periodic electrical signal to the epicardial surface via the electrode pair; The method provides a method wherein the signal is applied for a sufficient time and has properties sufficient to remodel the gap junction, obtain a remodeling of the gap junction, and / or alter the effective refractory period of the heart. The invention also provides an apparatus comprising a strip of electrode members having a plurality of connected pairs of electrodes mounted thereon in two rows.

Description

Detailed Description of the Invention

This application is US Provisional Application No. 60/11989 filed February 12, 1999.
It is a continuation-in-part application of No. 6, claiming its priority, and its content is
Incorporated herein by reference.

[0002]

FIELD OF THE INVENTION

This application relates to heart remodeling. More specifically, the present application relates to epicardial or endocardial pacing to induce electrical, mechanical, ion channel, and gap junction remodeling of the heart.

[0003]

BACKGROUND OF THE INVENTION

In this application, several documents are referenced by Arabic numerals in parentheses. Full citations for these and other references may be found at the end of the specification immediately preceding the claims. In order to more fully describe the state of the art to which this invention pertains, the entire disclosure content of these documents is incorporated into this application by way of reference.

Cardiac arrhythmias such as fibrillation are well known to those familiar with the heart. Localized or pervasive myocardial lesions can occur for any one of a variety of reasons, often resulting in repolarization and marked dispersal of refractoriness. as a result,
Under certain circumstances, the heart will either cease to undergo a normal series of depolarizations, or will result in an abnormal activation pattern and / or distribution of repolarizations. Abnormal impulses that occur at this time can cause electrical rupture and subsequent initiation of ventricular fibrillation.

By appropriately applying an electric shock to the heart,
It is known that all myocardial fibers can be restored to work in concert, ie the heart can be defibrillated. Defibrillation induced by electrical shock to the heart results in a steady onset of electrical excitement propagation by the simultaneous depolarization of all myocardial fibers that escape from the arrhythmogenic stage. Many defibrillators are known in the prior art for delivering defibrillation pulses after an arrhythmia has begun.

However, it has become clear that electrical defibrillation is not an ideal treatment for the problem of arrhythmia. First, it is often slow to act and does not provide a stimulatory signal if the arrhythmia is not at risk, even when implantable defibrillators are used. In addition, implantable defibrillators have been developed to remove existing ventricular fibrillation as quickly as possible, but they cannot defibrillate without detecting the actual defibrillation condition. Also, because defibrillation requires a strong electric shock, the operating time of the implantable defibrillator will be very limited. Moreover, such conventional defibrillators require some charging time prior to delivering the defibrillation shock, even after detection of the onset of defibrillation.

Determinants of myocardial conduction and repolarization include the properties of muscle cell size and arrangement, and gap junctions (specialized membranes that form low resistance pathways for carrying intercellular currents). (1,2). Gap junctions and their constituent proteins (connexins)
The changes in the amount and distribution of H2O3 have been demonstrated in various disease states (3-7), and experimental data indicate that such changes can lead to heterogeneous conduction delays (
It is strongly suggested that they are involved in the return to excitement (8, 9) (10). There is also increasing evidence to support the concept of myocardial electrophysiological remodeling induced by tachyarrhythmias and by pacing (11, 12). Pacing-induced changes in the activation pathway cause changes in the T-wave that last longer than the return to sinus rhythm (13-16), and are commonly referred to as "cardiac memory".
“Mory)” (13, 17). If the connection between cells with low resistance is the basis of electrical tension, and that electrical tension current controls the time course of repolarization voltage near myocytes (18), the gap junction Conjugate remodeling may be involved in the mechanism of cardiac memory. Changes in conduction and repolarization that occur in altered activation appear to be crucial to the pathophysiology of arrhythmias,
Both would be facilitated by changes in electrical tension that could be associated with gap junction remodeling.

[0008]

[Outline of the Invention]

It is an object of the present invention to provide an apparatus and method for remodeling the heart.

It is also an object of the present invention to provide a device and method for pacing the epicardium or endocardium to induce electrical, mechanical, ion channel, and gap junction remodeling of the heart. Is.

It is a further object of the invention to provide an apparatus and method for providing a multi-point stimulus to an active heart for an extended period of time and obtaining a multi-point recording from the active heart.

It is an object of the present invention to provide a device and method for continuously pacing the heart to maintain antiarrhythmic effects and also alter contraction patterns to induce gap junctions and ion channel remodeling. Is the further purpose of.

One aspect of the present invention is a method of treating the heart to remodel gap junctions by contacting a plurality of coupled electrode pairs with the epicardial surface of the heart. Contacting the electrode pair with a pacemaker and applying a periodic electrical signal to the epicardial surface through the electrode pair, the signal being applied for a sufficient time and of the heart. Methods are provided that have sufficient properties to remodel gap junctions.

According to another aspect of the invention, a device for treating a heart to obtain gap junction remodeling, the device being in contact with the epicardial surface of the heart, the electrode being coupled via an electrode pair. Provided is a device comprising a substrate having a plurality of electrode pairs connected to carry a periodic pacemaker electrical signal to the adventitia surface to remodel the gap junctions of the heart.

Another aspect of the invention is a method of treating a heart to alter the effective refractory period, comprising contacting a plurality of coupled electrode pairs with the epicardial surface of the heart, Connecting the pair to a pacemaker and applying an electrical signal to the epicardial surface, the signal being applied for a sufficient time and having a property sufficient to change the effective refractory period of the heart. A method of having is provided.

Another aspect of the present invention is a device for treating a heart to change the effective refractory period, the device being in contact with the epicardial surface of the heart and through an electrode pair said epicardial surface. An apparatus is provided that includes a substrate having a plurality of electrode pairs connected thereto for transmitting a periodic pacemaker electrical signal to the heart to change the effective refractory period of the heart.

According to another aspect of the invention, a method of treating a heart to induce remodeling of ion channels, comprising contacting a plurality of coupled electrode pairs with the epicardial surface of the heart. And connecting the electrode pair to a pacemaker to provide a periodic electrical signal to the epicardial surface, the signal being provided for a sufficient time and remodeling of the ion channel in the heart. A method having sufficient properties to induce

Yet another aspect of the present invention is a device for treating a heart to induce remodeling of ion channels, the device being in contact with the epicardial surface of the heart, and through the electrode pair. Provided is a device comprising a substrate having a plurality of electrode pairs connected to conduct a periodic pacemaker electrical signal to the adventitia surface to induce ion channel remodeling in the heart.

These and other objects of the invention will be described in the accompanying drawings, the following detailed description,
And will be apparent from the appended claims.

[0019]

Detailed Description of the Invention

The present invention is a method of treating a heart to remodel gap junctions by contacting a plurality of connected electrode pairs with the epicardial surface of the heart and contacting the electrode pairs with a pacemaker. Applying a periodic electrical signal to the epicardial surface via the electrode pair, the signal being applied for a sufficient time and sufficient to remodel the gap junctions of the heart. A method having characteristics is provided.

The contacting step may include contacting a strip-shaped electrode member having a plurality of coupled electrode pairs mounted thereon.

The strip electrode member may be composed of a strip of medical polyurethane. The size of the strip is about 7 cm x 1 cm.

The plurality of connected electrode pairs are arranged in two columns so that one electrode of each pair is in one column and the other electrode of each pair is in the other column. Good. Preferably, each electrode of the electrode pair is separated from each other by about 2 mm and each electrode pair is separated from the closest electrode pair by about 5 mm.

[0023]   The electrodes may be composed of platinum and may consist of substantially unalloyed platinum.

The contacting step may comprise sewing a substrate piece containing a plurality of connected electrode pairs to the epicardial surface of the heart. The contacting step may comprise placing a transvenous catheter containing a plurality of coupled electrode pairs in the epicardial vein. The contacting step may comprise placing an electrode within the ventricle to activate the endocardium.

The present invention is an apparatus for treating a heart to obtain gap junction remodeling, which comprises contacting the epicardial surface of the heart, and periodically cycling the epicardial surface via electrode pairs. Also provided is a device with a substrate having a plurality of electrode pairs connected to carry a different pacemaker electrical signal to remodel the gap junctions of the heart.

The base material may include contacting a strip-shaped electrode member having a plurality of coupled electrode pairs mounted thereon. The electrode member may comprise medical grade polyurethane.

The electrode pairs may be arranged in two rows, with one electrode of each pair in one row and the other electrode of each pair in the other row. One electrode of the pair is preferably about 2 mm from the other electrode of the pair, and each electrode pair is preferably about 5 mm from the closest electrode pair.

The electrodes are preferably composed of platinum, more preferably substantially unalloyed platinum. Each electrode is preferably connected to an insulated stainless steel wire.

According to another aspect of the invention, a method of treating a heart to alter the effective refractory period, comprising contacting a plurality of coupled electrode pairs with an epicardial surface of the heart, Connecting the pair of electrodes to a pacemaker and applying an electrical signal to the epicardial surface, the signal being applied for a sufficient time and sufficient to change the effective refractory period of the heart. A method having characteristics is provided.

Another aspect of the present invention is a device for treating a heart to change the effective refractory period, the device being in contact with the epicardial surface of the heart and through the electrode pair said epicardial surface. An apparatus is provided that includes a substrate having a plurality of electrode pairs connected thereto for transmitting a periodic pacemaker electrical signal to the heart to change the effective refractory period of the heart.

Yet another aspect of the invention is a method of treating a heart to induce remodeling of ion channels, comprising contacting a plurality of coupled electrode pairs with an epicardial surface of the heart. Connecting the electrode pair to a pacemaker to apply a periodic electrical signal to the epicardial surface, the signal being applied for a sufficient time and remodeling of the ion channel in the heart. Methods are provided that have sufficient properties to induce.

The present invention is a device for treating a heart to induce remodeling of ion channels, which is contacted with the epicardial surface of the heart and is cycled to the epicardial surface via electrode pairs. Also provided is a device comprising a substrate having a plurality of electrode pairs coupled to carry a typical pacemaker electrical signal to induce ion channel remodeling in the heart.

Propagation of action potentials from cell to cell depends on a number of structural properties of the myocardium (24). These structural myocardial transmission determinants include the size and arrangement of the constituent myocytes, the number of cells with which each cell is in contact (typically about 10 (in normal mammalian ventricles). 23, 5)), as well as the distribution of gap junctions (1), which are specialized membranes that form low resistance pathways for carrying intercellular currents. As a major determinant in myocardial transmission, alterations in the gap junctional conjugation affect conduction and are directly involved in promoting the development of recurrent excitatory arrhythmias (25, 1).
0, 26, 27).

There is increasing experimental evidence for a role in changing both action potential (11) and functional morphology of myocardial structure in the development of excitatory recurrent arrhythmias (25, 1).
0, 24). However, electrophysiological remodeling not only plays a role in causing the development of excitatory recurrent arrhythmias, but may also be a direct consequence of tachyarrhythmias, and that this remodeling seems to perpetuate the tendency of arrhythmias. It has recently been revealed that it can act on (11). This phenomenon has been demonstrated in the atria of animal models of both atrial fibrillation (11) and ultrafast atrial pacing (28,29), and the expression "atrial fibrillation produces atrial fibrillation" was created. (11). An explanation for this self-proliferating tachyarrhythmia-induced atrial remodeling was whatever resulted in the tachyarrhythmia first, resulting from the rapid stimulation of atrial cardiomyocytes. It has been suggested that remodeling is triggered and constitutes part of the myopathic process induced by tachycardia.

The results of our experimental studies of the ventricles of the inventors have shown that altering the activation pattern of the myocardium causes a remodeling of that myocardial gap junctional configuration. Importantly, this finding cannot be attributed to tachycardia-induced muscle disease, as pacing was slow. Moreover, we previously reported a study of microregional hemodynamics and cell capacitance in this model, which reports that myocardial ischemia, hypertrophy, or congestive ventricular disease is responsible for the role. Are excluded (15, 19). Remodeling of Cx43 gap junctions occurs differently in different layers and different regions of the LV wall, most prominent in the epicardial layer near the pacing site.

There have been numerous reports that changes in the order of activation of the ventricles cause changes in the electrophysiological function of the myocardium, and the clinical manifestation of such a phenomenon is cardiac memory (during sinus rhythm). ECG T-wave, paced QRS complex or arrhythmic QRS
Presents a vector that approaches the vector of the complex) (13, 14, 17).
This phenomenon has been probed in the paced ventricle of this canine model, resulting from action potential changes that occur differently within, within, and within the left ventricular wall (15). These changes in action potentials result from changes in a subset of ion channels (19) and require the synthesis of new proteins (15). The results of this study indicate that changes in the action potential of each cell may be determined in part by the mode of electrical coupling of each cell. Therefore,
Changes in coupling play a role in the development of cardiac memory not only by giving rise to locally differential control of depolarized wavefront patterns and velocities, but also by changing electrotonic currents during repolarization. Can be fulfilled. Computer model studies have shown that progressive decoupling of myocytes in the heart reduces the electrotonic currents, resulting in differences in intrinsic action potential characteristics between adjacent cells, layers of the ventricular wall, It has been shown to reveal differences in action potential characteristics that exist between adjacent cells, layers of the ventricular wall, and different regions of the ventricle, thereby altering normal heterogeneity (27, 28). . Indeed, it was previously demonstrated by the present inventors that the heterogeneity of repolarization across the myocardium is altered in the setting of cardiac memory (15).

A small but consistent and significant activation change, together with the pacing-induced induction of cardiac memory, is important in elucidating the possible physiological consequences of altered connexin 43 gap junctional organization. Is. First, during ventricular pacing, activation remained unchanged for the LV sites that were relatively close to the pacing electrodes and were activated most quickly, but for the last activated RV site, Activation was delayed. Second, during atrial pacing, activation did not change for the earliest activated site, but for the last activated site, the LV basal, the activation was not. The conversion was delayed. In other words, in either setting, the site of slowest conduction during regulation showed delayed activation. One possible cause of the altered activation is the remodeling of the gap junction organization that occurred in these animals.

Such local gap junction remodeling can not only promote the changes seen in normal cardiac impulse conduction and repolarization, but also have important implications for understanding excitatory recurrent arrhythmias. You can Changes in the structure of gap junctions have been demonstrated in fibrillating mammalian atria (31, 32), and disruption of specific gap junction patterns causes excitability in the epicardial border zone of a model for treating canine infarction. We have shown that it appears to define the inducibility and location of the recursive circuit (10).
The results of this study raise the possibility that gap junctional remodeling may be the result of an abnormal activation pattern during arrhythmias. Furthermore, these findings show that even abnormal conduction pathways during sinus rhythm caused by local structural and functional changes in pathological myocardium such as the presence of infarction are associated with the underlying development of arrhythmia. It raises a very interesting possibility that it may lead to a local remodeling of the coupling of gap junctions that may be central. In other words, just as it was shown for the atrium that "fibrillation produces fibrillation," changes in the activation pattern of the ventricular myocardium result in a distribution of factors that structurally determine myocardial conduction. There is a structural basis for the proposal to sustain the development of arrhythmias by causing changes in

One aspect of the present invention relates to providing an apparatus and method that allows for multi-point stimulation of an active heart for extended periods of time to obtain multi-point recordings from the active heart. In other words, the system is myocardial, that is, by passing an electrical current, arranged to make a strengthening and stable contact at selected points on the inner or outer surface of the contracting, moving heart. It must contain a plurality of electrical contact points with suitable properties that can be used for stimulating or for recording its electrical activity by measuring the potential difference. These contact points are connected to a stimulating current or voltage recording unit via flexible insulated leads. All of these must form a two-dimensionally aligned high density circuit.

In order to make contact points with electrical conductors, there are currently two fundamentally different silicon chip-microelectronics technologies (hereinafter “chips”) and printed circuit technologies (hereinafter “prints”). The technology is widely used. The former is widely used to build essentially all types of modern electronic microchips such as microprocessors, while the latter is mainly used for various electrical components (conductors, conductors, It is used as a substrate for connecting resistors, capacitors, etc. and as an electronically active device (transistor, processor, etc.).

From the viewpoint of the present invention, the main features and differences between the two techniques are as follows.

The chip structure is arranged around the silicon. Since silicon has the same mechanical properties as glass, it is not flexible and has the mechanical limit of being easily cracked when thin. In contrast, the print structure is placed around a plastic, such as polyimide, which is extremely flexible and does not break even in the form of thin films.

The substrate is cut into units by etching in the case of chips and by laser light in the case of printing. Therefore, this step in printing is more expensive.

Standard chip technology allows for smaller and denser circuitry, but about 5
The limit of the printing technology of μ is not a problem in our application.

[0045]   At present, the integration of the active elements of the circuit must rely on chip technology.

To meet the above requirements, and in light of the above characteristics of the two technologies, the use of flexible prints is the optimal choice. The print is about 0.0
2 glued together to hold a piece of conductive metal sandwiched between them to form a flexible compound sheet with a thickness of 3 to 0.3 mm.
It can be made from two thin sheets of electrically insulating and biocompatible plastic material. One such preferred embodiment would be two polyimide sheets that are extremely strong, biocompatible, and tend to adhere well to living cells. The conductive metal strip can be made from any metal used in such circuits. It can be, for example, aluminum if its exposed parts are coated with a suitable conductive element such as gold or platinum. Such plating technique is common in this industry. Contact points are created by drilling holes in the plastic at desired locations. Such metal exposure is made, for example, by a laser beam.
The exposed area not only forms a suitable connector to the electronic activation unit, but also serves as a contact site with the myocardium.

The overall design of the circuits and contacts is not particularly limited, and is usually made by a mask created by a computer program and lithography, and provided on a sheet of fixed paper (stationary paper) size. The sheet can be cut into virtually any shape by means of a laser beam.

In principle, chip technology makes it possible to construct circuits which practically contain such thin films of silicon so that they are flexible. There may be other chip technologies that appear to make the chip flexible enough. Such a circuit would have the advantage of being able to contain active elements on the board, for example the first amplification stage.

[0049]

[Experiment]

Electrical Measurements in a Dog Model: Male or female crossbreed dogs weighing 22-27 kg were intravenously administered 6 mg / kg propofol and then anesthetized by inhaling 92% isoflurane. Under aseptic conditions, make an incision in the chest and place the heart in a pericardial cradle.
It was made to float in e). Two groups of dogs were prepared.

In Group 1 (7 dogs), a Medtoronic continuous pacing lead (model 6971) was attached to the epicardium of the anterior left ventricle. The lead wire was connected to a Medtronic MINIX 8340 pulse generator placed in the subcutaneous sac. No other leads were attached to minimize handling and measurement of the heart for subsequent histological examination (see below).

The second group (5 dogs) was prepared as above, but with different measurements. Here, a Medtronic pacemaker is implanted in the epicardium of the posterior basal left ventricle, with bipolar surface electrodes in the following areas of the epicardium: right atrial limb, left ventricular posterior wall 2 cm away from the pacemaker, anterior basal, And the right ventricle free wall
Sewn on. In this way, the inventors were able to pace the atria or ventricles and to measure the activation of the heart during ventricular or atrial pacing. To make further measurements, these animals were used only in studies of cardiac activation and repolarization, not in studies involving histology and immunohistochemistry.

In both groups, the incision was closed and the animals were allowed to recover for 2-3 weeks, during which time they were trained to lie gently on their right side for ECG recording. Subsequently, 3 weeks of ventricular pacing was initiated at a rate of 10-15% above the sinus rate of each animal (
VVO mode, speed of 110-120 bpm; amplitude, 3.3-5 V; pulse width,
0.35-. 05 mg). By monitoring for 24 hours on randomly selected days, we confirmed that the fixation was reliable for at least 75% of the time.

Cardiac hemodynamics, myocardial blood flow, and ventricular myocyte capacitance, which are indicative of cell size, have previously been shown in this model to be unaffected by pacing. (15, 19). The sinus rhythm of 5 non-operated dogs housed under the same conditions served as controls. ECG baselines were recorded and ECGs were recorded every 2-3 days with the animals lying gently on their right side during the 3 week study period.

Ventricular activation and repolarization were investigated as follows. As mentioned before (15)
, In addition to recording the anterior surface vector of the heart, the deflection of the first lead of the local electrogram as the interval between the stimulation artifact (during ventricular pacing) or the onset of the QRS complex (during atrial pacing) Activation time was measured until maximum. The interval between activation and recovery was measured from the steepest deflection of the local electrogram to the maximum peak of the first induction of the last limb of the T wave (20, 21).

Tissue Handling: Three weeks after ventricular pacing, the last ECG was recorded from Group 1 animals during atrial and ventricular pacing. 30 mg / kg of pentobarbital (IV
), The dogs were anesthetized, the heart was removed and weighed. Anterior left ventricular wall (1-2 cm from pacing site) and posterior LV wall (away from pacing site)
Then, a transmural LV sample was cut out. All specimens were divided into epimyocardial (epi), mid-cardiac (mid), and endocardial (endo) layers and snap frozen in liquid nitrogen.

Connexin immunohistochemistry: Frozen sections of the samples were made in cryostat at -20 ° C to obtain random 10 μm tissue sections and slides coated with poly-L-lysine. Place on top, store at -20 ° C and fix in methanol at -20 ° C for 5 minutes. All histological samples were subjected to standard histological staining and light microscopy to confirm preservation, cell structure and orientation and were photographed. Connexin immunohistochemistry was performed on the upper, middle, and inner myocardial layers.

The antibody used to study the distribution of gap junctional connexin 43 in the heart was
IgG ₁ (Chemicon International) produced in mice against a synthetic peptide corresponding to positions 252 to 270 of rat native connexin.
al Inc. )Met. To label connexin 40, rabbit anti-rat antibody (against amino acid residues 254-268) was used as both crude serum and purified form. Nichola at Imperial College in London
sJ. Further details on the antibody, courtesy of Professor Sevens, have been described elsewhere (22).

Antibodies raised against mouse immunoglobulin (when labeling connexin 43) and rabbit immunoglobulin (when labeling connexin 40) (Che
micon International Inc. ) Fluorescent dye C bound to
y3 (peak absorption wavelength 550 nm, peak fluorescence wavelength 570 nm) was used appropriately for these studies.

Immunolabeling Protocol: Immobilization and blocking of slides were followed by incubation with first a primary connexin antibody followed by an appropriate Cy3 conjugated secondary antibody. For connexin 43 immunolabeling, the primary antibody was diluted 1: 1000 and used with 1% BSA for 1 hour at room temperature. In the case of connexin 40 immunolabeling, it was concluded that no detectable connexin 40 label was expressed in either control or paced canine ventricular myocytes using various conditions (results below. reference)
.

Image Acquisition and Analysis: Immunolabeled sections were examined using a Leica TCS 4D laser scanning confocal microscope running software called SCANware where digital images are stored on 250 Mb MO discs.

Western blotting of connexin 43: Whole tissue homogenates were prepared from frozen tissue samples to give a final concentration of 0.5 μg / μL in sample buffer. (Using 4.5% stacker) 1
3.0 μg of total protein from each sample was separated by polyacrylamide gel electrophoresis (Biorad) on a 2.5% gel. The gel was developed at 60V until the dye front passed through the stacker, then at 150V. The gel was electrophoretically transferred onto a polyvinylidene fluoride membrane at a constant voltage of 30V. Transcription was assessed by Ponceau S (Sigma). Dilution buffer (TBS / 0.2% Tween20 (Merck) / 1
% BSA) for 30 min, after blocking the membrane, connexin 4
Incubated with primary antibody to 3 (used for immunohistochemistry, supra) and diluted 1: 1000 in dilution buffer for 1 hour. After washing, the membranes were incubated with alkaline phosphate conjugated anti-mouse secondary antibody (Pierce) and diluted 1: 2500 with dilution buffer for 1 hour. After washing, the membrane was incubated with alkaline phosphate buffer (0.1 M Tris pH 9.5, 0.1 M MgCl ₂ ) for 5 minutes before freshly prepared substrate solution (Pro
Incubation with Mega Corporation). After quantifying band intensities by densitometry, co-developed actin bands on Coomassie stained gels were used to correct all values for the loaded proteins.

Statistical Analysis: To study activation of the heart, the time of flight of impulses to various sites on the ventricles was recorded using QS on the body surface ECG as a reference point. Data were analyzed using repeated measures ANOVA by Bonferroni's test, where f values allowed. The connexin quantification result by Western of the sample group is,
The unpaired two-tailed t-test was used for comparison, and the duration of ECG QRS for each animal was compared by the paired t-test. A p-value of 0.05 was considered significant in all studies.

<Results> Occurrence of electrophysiological changes: FIG. 1 shows that atrial pacing immediately before the start of ventricular pacing (day 1), immediately after atrial pacing (day 1), and after returning to atrial pacing. 1 hour later (21st
Fig. 6 is an anterior T-wave vector electrocardiogram of six dogs and one dog in (Sun). 21
By day one, T waves during atrial pacing followed the paced QRS complex. ECG scale = 1 mV and 50 mm / sec. Vector scale = 0.5m
V.

FIG. 1 is a representative experiment from a second group of dogs during atrial pacing (
Day 1), and 1 hour after the start of ventricular pacing (Day 1), and 1 hour after the end of 21 days of ventricular pacing, the ECG and anterior T-wave vectors are shown. Atrial paced T-wave generation and its vector appeared to track the ventricular paced QRS complex at day 21. The ECG characteristics and cardiac T-wave vector characteristics for Group 1 and Group 2 animals are shown in Table 1. As previously described (15), there were no significant changes in heart rate, PR interval, QRS duration, or QT interval in either group. Also, as previously described, as shown in Figure 1, there was a significant change in the T-wave vector, which exhibited an angle and amplitude that followed the angle and amplitude of the paced QRS complex. There is.

Of particular importance, however, are changes that occur in the duration of ventricular paced QRS. This was significantly increased in both groups (Table 1). Thus, the first group of animals that were paced from the anterior left ventricle and then used in the connexin study and the second group of animals that were paced from the posterior left ventricle and were measured to examine their electrograms were both: Complementary changes in the T-wave and its vector, and pacing over 21 days showed a similar extension to the paced QRS complex. As shown in Table 1 below, no prolongation of QRS was observed when activated via the AV node during sinus rhythm (Group 1) or atrial pacing (Group 2).

[0066]

[Table 1] Figure 2 shows control, 1 hour atrial pacing intervals (7th, 14th and 21st days) (
FIG. 9 is a graph showing activation times during panel A) and during ventricular pacing (panel B). In panel A, there is no significant change in activation time for the two earliest activated sites (RV and LV lower). In contrast, at the site of final activation (basal LV), the activation time is extended during this protocol. Similarly, the two earliest activated sites, here the lower LV and basal LV, show no change in activation time during ventricular pacing (Panel B), but are activated last. The activated region (RV) shows an extended activation time during this protocol. Symbols are p <. It has shown that it is 05.

FIG. 3 shows that during the control period one hour between atrial pacing (7th, 14th and 21st).
FIG. 5 is a graph showing activation and recovery intervals during days (panel A) and during ventricular pacing (panel B). In both panels, there are no significant changes in ARI at any of the sites studied.

Only in the second group were local electrogram measurements taken to more clearly define the changes that occur during activation and repolarization. 2A (
21 during atrial pacing) and 2B (during ventricular pacing)
No significant changes have occurred over the day. On the other hand, sites with slow activation (L
In V-basal atrial pacing, anterior RV free wall during LV posterior pacing), there is a significant prolongation of activation time. During atrial (FIG. 3A) or ventricular (FIG. 3B) pacing, the activation-recovery interval of Group 2 remained unchanged during the 21 day period. This result is similar to that seen for the QT interval (see Table 1).

Gap Junction Remodeling: Overview of Heart and Myocardium Hearts removed from paced animals are minimally scarred, with minimal scarring and fibrosis confined exclusively to the pacemaker lead-out site. The left ventricular wall just outside the pacing site was normal in appearance with no apparent edema, necrosis, or scars. Standard light microscopy revealed normal appearance of myocardium and no difference in myocardium in either the paced or control groups.

Connexin 43 Immunolabeling: These studies demonstrate that the only cardiac measurement is a single derivation of anterior left ventricular pacing.
Performed on groups of animals.

Control animals : By optimizing the labeling protocol, a clear, consistent, uniform Cx43 with high signal / background ratio was observed in all specimens.
A label was obtained (Fig. 4). The previously described distribution pattern of gap junctions in mammalian ventricular myocardium (23, 3, 5) was confirmed in the epicardial and endopericardial layers of control specimens. That is, with a cluster of Cx43, gap junctions are present along the longitudinal direction of the cells, with intercalated discs being most prominent at the ends of adjacent myocytes.
It was predominantly localized in the area of the smaller plate, all oriented transverse to the longitudinal axis of the cell. Therefore, when the myocardium was cut parallel to the vertical axis (Fig. 4), the clusters appeared as transverse bands at the adjacent portions between cells.

Pacing Animals : In contrast to this normal distribution pattern, the myocardial adventitia layer of pacing animals
It had varying degrees of aberrant Cx43 immunolabel distribution patterns. The clusters of labels tended to be scattered in rows arranged vertically along the longitudinal axis of the cells, with fewer discontinuous clusters arranged horizontally. A representative image is shown in FIG. To be able to summarize this finding for all groups of animals, a simple optional scoring system was used. 1 for each sample, depending on the label distribution observed by the blinded operator
We devised a grade that gives a score of -10. A score of "1" was given for the extreme distribution of connexins, where the labeling was exclusively confined to the normal lateral clusters, clusters of cell flanks (Fig. 4A), score "10". Showed that there was significantly less label in the immediate vicinity and that the label was distributed in the tandem along the myocytes (FIG. 4B).

These semi-quantitative data are summarized in Table 2. The paced dog epicardium showed a clear change in label distribution I in contrast to the middle and inner pericardial layers compared to controls (FIG. 4). Due to the semi-quantitative nature of these data, we did not attempt to perform statistical analysis, but this is the mean endocardial score in Table 2 (control vs.
Pacing, 3.0 vs. Backed by 7.0).

[0074]

[Table 2] FIG. 4 shows the epicardial muscle layer of the anterior left ventricle wall (about 1 cm from the pacing site) obtained from control animals without pacing (top panel) and Group I animals pacing for 21 days (bottom panel). 2 are two confocal micrographs immunolabeled with connexin 43 showing the effect of long-term pacing on the gap junctional remodeling of E. coli. Both micrographs are longitudinally sectioned myocardium with the longitudinal axis of the constituent cells running horizontally. In the upper panel, laterally-disposed clusters of connexin 43-labels confined to the intercalating plate of the transverse cell abutment are characteristic of normal ventricular myocardium (
In visual grade, score 2-results and see Table 2). The lower panel is an example showing an unusual pattern of Connexi 43 label distribution, with a significant proportion of the label extending in clusters along the longitudinal border of myocytes (score 8). In the memory setting, the gap junction stains do not cluster at the ends of muscle cells, but rather at their lateral margins. This represents a significant redistribution of the location of gap junctions with no change in the reference protein (connexin 4
0, results not shown here) (see refs. 37, 38).

Quantitative Western Blotting of Connexin 43: Relative Cx43 expression values (normalized to loaded actin) in the three myocardium of the paced and control samples (both near and far from the pacing site). Are shown) in Table 3. Between the layers of tissue,
Or between samples obtained from anterior or posterior LV walls obtained from control animals,
There were no significant differences in Cx43 expression. However, when comparing the paced and control animals, the control sample (107 ± 43.3; p = 0.031
), Cx43 in paced (61.7 ± 18.4) epicardium
Was significantly reduced. Expression of Cx43 showed no significant reduction in the myocardial intimal layer adjacent to the pacing site compared to controls (82.8 ± 30.2 v).
s 109.2 ± 21.0; p = 1.101). The LV wall of paced dogs after leaving the pacing site showed no significant difference in Cx43 expression compared to controls.

[0076]

[Table 3] Connexin 40 immunolabeling: Despite the use of appropriate positive controls, no CX40 labeling was detectable in ventricular myocytes from control or pacing groups.

Electrodes, Results, and Pacing Modalities The following is a discussion of electrodes and preliminary results with them, and general modalities of pacing for inducing electrical, mechanical, and gap junction remodeling. Is the description of.

Electrodes (FIG. 5) As shown in FIG. 5, the electrodes can be in multiple or variable ones spaced 5 mm apart.
． 7 cm x 1 cm medical polyurethane (Biospan) with a 2 mm unalloyed platinum electrode pair (each member of this pair is 2 mm away from its counterpart).
It is a strip. In this way, the electrodes have one electrode of the pair in one row,
The other electrode is lined up in the other row to form two rows. The electrodes are linked or connected to each other as shown in the figure. Each electrode has an electric wire. The line is
30 gauge stainless steel consisting of multiple cords coated with medical grade polyurethane. This array can be driven by any standard implantable pacemaker device so that all electrodes or any subset of electrodes can contribute to the wavefront being activated at the same time. Signals from standard pacemakers have certain signal characteristics (ie voltage, current, frequency) that have been shown to give the desired results. Similarly, other signals can be used, as described herein, provided they also provide the desired results. The electrode piece may be sewn onto the epicardial surface or, if repositioned on a transvenous catheter, placed in the epicardial vein via the coronary sinus or activated endocardium. Can be placed in the ventricle to We performed experiments on remodeling induced using both whole rows or point source stimuli from each dipole pair.

Results: We use changes in the ECG T-wave as a general indicator of remodeling. This is the "golden standard" of cardiac memory (a special form of remodeling induced by our pacing protocol), as it is easy to record from the surface of the body and can be read as-is. 13, 17, 33).

Point Source Stimulation: FIG. 6 is a series of representative examples of the effect of point source stimulation on the accumulation of T-wave changes in ECG and vector electrocardiogram. Pacing was continued for 21 days and interrupted for 1 hour on days 7, 14 and 21. The ECG T-wave gradually exhibits a vector of paced QRS complexes. The changes in the T vector become even clearer when the vector electrocardiogram recording in the lower panel is examined. Here, panel A is the control, panel B represents ventricular pacing, and panel C shows the vector shift seen during sinus rhythm, the T-wave vector at control, days 14 and 21. Panel D is a return to sinus rhythm on day 21 (Reference 1).
5).

As shown in FIG. 6, pacing the anterior left ventricle of an anesthetized dog from a point source produces T-wave changes on the ECG that have memory characteristics (ie, T as the stimulation is repeated). The wave changes increase and the decay from the peak extends as the pacing period repeats) (15,34).

FIG. 7 is a series of two graphs quantifying changes in pacing-induced sinus rhythm T vector amplitudes (left) during pacing of 16 dogs for 35 days. , Shows that major changes occur by day 12 and clearly reach a plateau by day 22. On the right is T-wave recovery after pacing is stopped. When the pacing duration was 21-25 days, the recovery was rapid with almost complete recovery in one week. In contrast, after 42 to 52 days of pacing, no significant recovery occurred within a month (see reference 15).

As shown on the left of FIG. 7, the effect of long-term pacing on conscious dogs is to maximally induce T-wave changes on day 21 (15). This then continues for different periods of time, depending on the time the heart was first paced (Fig. 7-right) (15,34). These changes, as demonstrated using standard hemodynamic and microsphere techniques, occur without significant changes in ventricular hemodynamics or myocardial flow. Furthermore, based on the measurement of cell capacitance,
There is no evidence to support hypertrophy (19).

[0084]

[Table 4] As shown in Table 4, pacing a conscious dog through the posterior left ventricle for 21 days induces a change in the T-wave on the ECG that is characteristic of memory. The changes that occur in activation are shown in Figure 8 (35).

FIG. 8 shows reference QRS to left ventricle (LV) apex, LV fundus, and right ventricle (RV).
3 is two graphs showing the activation time measured up to the bipolar epicardial electrode part in FIG. From the posterior LV, activation time is recorded during 21-day point source pacing followed by atrial pacing to stimulate sinus rhythm (left) or ventricular pacing (right). During atrial pacing, activation to the last activated sites (ie, LV apical and basal) is significantly delayed. During ventricular pacing, activation to the last activated site (RV in this case) is delayed again.

During atrial pacing, there is a delay in activation to the site of final activation (ie, left ventricular and apical) to mimic sinus rhythm. In contrast, during ventricular pacing, the last activated site, the lateral right ventricle, is delayed in this case. In other words, the delay in normal physiological activation that would be expected as a result of changes in the impulse start site is unchanged by pacing to induce cardiac memory. Of great importance in the light of this, significant changes in repolarization and effective refractory period occur as shown in FIG. 9 (35, 36).

FIG. 9 shows the recovery interval (A) at the same site and the same time point as FIG.
5 is a graph showing changes in RI, reflecting the duration of local repolarization) and the effective refractory period (ERP). Depending on the site, the ARI (and thus repolarization) may be long or short. However, the ERP was long in all cases, indicating that significant remodeling had occurred. ERP
The / ARI ratio increases at each site, indicating better protection against the propagation of extra systoles.

The most important aspect of FIG. 9 was effective, as revealed by local recording of the activation-recovery interval, regardless of whether the duration of repolarization was shortened or prolonged. It means that the refractory period becomes longer. There is greater protection at each site against the propagation of incomplete depolarizations compared to previous protections, in other words,
The overall result is that it has a superantiarrhythmic effect.

FIG. 10 shows QRS duration, QT interval duration, effective refractory period (ERP),
And Figure 3 is a series of three graphs showing the effect of 21-day posterior LV pacing on ERP / QT ratio. Controls and recordings after 21 days of pacing to induce cardiac memory. A slight extension of the QRS complex is seen during ventricular pacing but not atrial pacing. The QT interval, which reflects total repolarization measured from the body surface, increases during both types of pacing and ERP is significantly prolonged. Importantly, the ERP / QT ratio was significantly increased, indicating better protection against the propagation of extrasystoles.

A summary of changes in QRS and QT intervals recorded by ECG and effective refractory period is given in
It is shown in FIG. There is a small but significant prolongation of the QRS complex during ventricular pacing but not during atrial pacing. More importantly,
During both atrial and ventricular pacing, the QT interval is extended, similar to the effective refractory period during ventricular pacing. The most significant aspect of refractory and prolonging repolarization is that the former change is greater than the latter, as the ERP / QT ratio increases. All of these results indicate that under conditions in which arrhythmias are most likely to be propagated, the pacing treatments taken are very likely to prevent the arrhythmias from developing or persisting.

FIG. 11 is a series of graphs showing the effect of long-term pacing on action potential and ion channel remodeling. The upper panel shows epicardial action potentials recorded from control dogs and chronically paced dogs at a pacing cycle length of 650 ms. The first phase notch (arrow) is more prominent under the "memory" condition, the plateau is higher and the duration of the action potential is longer.
This is in perfect agreement with the change in QT interval reported in FIG. The remaining panels are
Ito (Ion channel involved in the first phase notch). Middle left panel shows It from single epicardial myocytes from control (upper) and memory (lower) animals.
The current recorded for o is shown. In contrast, the current is more negatively activated (
-20 mV), +10 mV, and has a higher amplitude. The right panel is a graph showing the average of the results obtained from all experiments examining channel conductivity. Greater conductance (reflecting current) in controls than in memory
Is found over a wide range of voltages. The difference is about 1/3. The lower panel is K
Figure 3 shows v4.3 messenger RNA, a genetic determinant of Ito current in dog and human hearts. On the left are the results obtained from 3 controls and 3 memory animals, showing a decrease in Kv4.3 ("Cyc" refers to the reference gene cyclophilin). On the right, the results are quantified and the K present in memory.
v4.3 is about 1/3 less than the control, similar to the results seen with the current in the middle panel itself (see reference 19).

FIG. 11 shows action potentials and their first-phase notches, changes in I _to (ion currents that cause action potential notches), and Kv4.3 messenger RNAs (I in dog and human hearts). is understood to be the genetic determinant of _to ). In the upper panel, the isolated cells show not only the same prolongation of action potentials as described above for local changes in activation-recovery intervals in normal heart, but also in the magnitude of phase 1 notch. Shows a decrease. In the middle panel, the magnitude of I _to causing the notch is reduced by 1/3. In addition, very importantly, the activation voltage for current shifts from about −22 mV to −5 mV and the time constant for recovery from inactivation increases more than 20-fold from the control 27 ms. Finally, as shown in the lower panel, the message level for Kv4.3 is reduced by 1/3. Thus, the overall flow of information is completely internally coordinated, from action potentials to ionic currents to molecular messages (19), indicating that ion channel remodeling is occurring.

FIG. 4 represents the remodeling of gap junctions induced by 21 days of pacing. The upper panel is the control and the lower panel is the same site of the paced animal. The overall gap junction distribution has changed, with a clear lateral shift. By measuring the expression of connexin 43 in epicardial fascia using quantitative western blotting, 10 days of control within a 3 cm radius of the pacemaker after 21 days of VVO pacing (37, 38).
It became clear that it decreased from 7 ± 43 to 62 ± 18 (P <0.05, n = 12).

Array stimulation: Figure 12 shows that using the above row, three anesthetized dogs were ineffective after 1 hour of pacing the left ventricular anterior septum. The measured value of the response period (ERP) is shown. The results show that the ERP is increased by 8-12% (top), and a significant prolongation (bottom) can occur at each of the three reference sites measured.

FIG. 12 shows that an electrode array was placed on the anterior septum of three anesthetized dogs that had been ventricular pacing for 1 hour each and then 60 minutes pacing twice with 30 minutes intervening atrial pacing. It represents changes in the effective refractory period when used. Even after these relatively short pacing periods, the effective refractory period at each site is significantly prolonged (8% in the left ventricle and right ventricle, and 12% in the left ventricle apex). In other words, the refractoriness is extended at three widely distributed sites in the heart.

[0096]

[References]

[Brief description of drawings]

[Figure 1]   FIG. 1 is a derived electrocardiogram and an anterior T-wave vector electrocardiogram of six dogs.

[Fig. 2]   FIG. 2 is a graph showing activation time.

[Figure 3]   FIG. 3 is a graph showing activation-recovery time.

FIG. 4 shows two confocal microscopes of the epicardial layer of the anterior left ventricle wall immunolabeled for connexin 43 obtained from unpaced control animals and Group I animals paced for 21 days. It is an image.

[Figure 5]   FIG. 5 is a drawing of an electrode array of the present invention.

FIG. 6 shows an electrocardiogram and a vector electrocardiogram of the effect of point source stimulation on the accumulation of T-wave changes for a representative sample.

FIG. 7 is two graphs showing quantification of pacing-induced changes in sinus rhythm T vector amplitude in animals and recovery of T-waves after pacing is stopped.

FIG. 8 is two graphs showing activation times measured from the reference QRS to the left ventricular apex, left ventricular basal, and right ventricular bipolar epicardial electrode sites.

FIG. 9 is a graph showing changes in activation recovery interval and effective refractory period at the same site and at the same time point as in FIG. 8.

FIG. 10 shows DRS duration, QT interval duration, effective refractory period (ERP),
And shows the effect of pacing on the posterior LV for 21 days on ERP / QT ratio 3
It is a series of two graphs.

FIG. 11 is a series of graphs showing the effect of long-term pacing on action potential and ion channel remodeling.

FIG. 12 shows the effective refractory period (ERP) obtained after pacing twice to the anterior septum of the left ventricle for 1 hour using the above row for 3 anesthetized dogs. ) Shows the measured value.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61N 1/39 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, EE, ES, F , GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA , UG, UZ, VN, YU, ZA, ZW (71) Applicants Peters, Nicholas S. England, W. 4.2 Q-Quex, London, Paxton Road 78 (71) Applicants Parthi, Yoram Israel, 34404 Haifa, Ruth Street 51 (72) Inventor Rosen, Michael Earl, USA 10028 New York, East 80 Sixth Street 25, Apartment 14 Sea (72) Inventor Peters, Nicholas S. England, 4-2 Quex, London, Paxton Road, London 78 (72) Inventor Parti, Yoram Israel, 34404 Haifa, Ruth Street 51 F-term (Reference) 4C053 CC01 CC03 KK02 KK08

Claims (57)

[Claims] 1. A method of treating a heart to remodel gap junctions, comprising contacting a plurality of coupled electrode pairs with an epicardial surface of the heart, the electrode pairs contacting a pacemaker. And applying a periodic electrical signal to the epicardial surface via the electrode pair, the signal being applied for a sufficient time and sufficient to remodel the gap junctions of the heart. With different properties. 2. The method of claim 1, wherein the contacting step comprises contacting a strip electrode member having a plurality of coupled electrode pairs mounted thereon. 3. The method of claim 2, wherein the strip electrode member comprises a strip of medical grade polyurethane. 4. The method of claim 3, wherein the strip has a size of about 7 cm × 1 cm. 5. The method of claim 1, wherein the contacting step comprises contacting a plurality of coupled electrode pairs with the epicardial surface of the heart. A method wherein the pairs are arranged in two rows, with one electrode of each pair in one row and the other electrode of each pair in the other row. 6. The electrodes of the electrode pair are separated from each other by about 2 mm, and the electrode pairs are
The method of claim 5, wherein the method is about 5 mm from the closest electrode pair. 7. The method of claim 1, wherein the electrode comprises platinum. 8. The method of claim 7, wherein the electrode comprises substantially unalloyed platinum. 9. The method of claim 1, wherein the contacting step comprises sewing a substrate piece containing a plurality of connected electrode pairs to an epicardial surface of the heart. 10. The method of claim 1, wherein the contacting step comprises placing a transvenous catheter containing a plurality of coupled electrode pairs in an epicardial vein. 11. The method of claim 1, wherein the contacting step comprises placing an electrode in the ventricle to activate the endocardium. 12. A device for treating a heart to obtain gap junction remodeling, wherein the device is contacted with the epicardial surface of the heart and is periodically pacemaker to the epicardial surface via electrode pairs. A device comprising a substrate having a plurality of electrode pairs connected to carry an electrical signal to remodel the gap junctions of the heart. 13. The apparatus according to claim 12, further comprising a strip-shaped electrode member having a plurality of coupled electrode pairs mounted thereon. 14. The apparatus according to claim 13, wherein the electrode member is composed of medical grade polyurethane. 15. The apparatus of claim 12, wherein the electrode pairs are arranged in two rows, one electrode of each pair in one row and the other electrode of each pair in the other row. . 16. One electrode of the pair is approximately 2 mm from the other electrode of the pair.
16. The apparatus of claim 15, spaced apart, wherein each electrode pair is separated from the closest electrode pair by about 5 mm. 17. The device of claim 12, wherein the electrodes are composed of platinum. 18. The device of claim 17, wherein the electrode comprises substantially unalloyed platinum. 19. The apparatus of claim 12, wherein each electrode is connected to an insulated stainless steel wire. 20. A method of treating a heart to alter the effective refractory period, comprising contacting a plurality of coupled electrode pairs with an epicardial surface of the heart and connecting the electrode pairs to a pacemaker. And applying an electrical signal to the epicardial surface, the signal being applied for a sufficient time and having properties sufficient to change the effective refractory period of the heart. 21. The method of claim 20, wherein the contacting step comprises contacting a strip electrode member having a plurality of coupled electrode pairs mounted thereon. 22. The method of claim 21, wherein the strip electrode member comprises a strip of medical grade polyurethane. 23. The method of claim 22, wherein the strip size is about 7 cm x 1 cm. 24. The method of claim 20, wherein the contacting step comprises contacting a plurality of coupled electrode pairs with the epicardial surface of the heart. The method wherein the pairs are arranged in two rows, with one electrode of each pair in one row and the other electrode of each pair in the other row. 25. The method of claim 24, wherein each electrode of the pair of electrodes is separated from each other by about 2 mm and each pair of electrodes is separated from the closest pair of electrodes by about 5 mm. 26. The method of claim 20, wherein the electrode comprises platinum. 27. The method of claim 26, wherein the electrode comprises substantially unalloyed platinum. 28. The method of claim 20, wherein the contacting step comprises sewing a substrate piece containing a plurality of coupled electrode pairs to the epicardial surface of the heart. 29. The method of claim 20, wherein said contacting step comprises placing a transvenous catheter containing a plurality of electrode pairs connected in an epicardial vein. 30. The method of claim 20, wherein the contacting step comprises placing an electrode within the ventricle to activate the endocardium. 31. A device for treating a heart to alter the effective refractory period, the device being in contact with the epicardial surface of the heart, the pacemaker electricity being periodically applied to the epicardial surface via electrode pairs. An apparatus comprising a substrate having a plurality of electrode pairs coupled thereto for transmitting a signal to alter the effective refractory period of the heart. 32. The device according to claim 31, further comprising a strip-shaped electrode member having a plurality of coupled electrode pairs stacked thereon. 33. The device of claim 32, wherein the electrode member is comprised of medical grade polyurethane. 34. The at least two electrode pairs are arranged in two rows, with one electrode of each pair in one row and the other electrode of each pair in the other row. Equipment. 35. One electrode of the pair is approximately 2 mm from the other electrode of the pair.
35. The device of claim 34, wherein each electrode pair is spaced apart and is about 5 mm from the closest electrode pair. 36. The device of claim 31, wherein the electrodes are composed of platinum. 37. The device of claim 36, wherein the electrode comprises substantially unalloyed platinum. 38. The device of claim 31, wherein each electrode is connected to an insulated stainless steel wire. 39. A method of treating a heart to induce ion channel remodeling, comprising contacting a plurality of interconnected electrode pairs with an epicardial surface of the heart, the electrode pairs being adapted to a pacemaker. Connecting and applying a periodic electrical signal to the epicardial surface, the signal being applied for a sufficient time and having a property sufficient to induce remodeling of ion channels in the heart. A method having. 40. The method of claim 39, wherein the contacting step comprises contacting a strip electrode member having a plurality of coupled electrode pairs mounted thereon. 41. The method of claim 40, wherein the strip electrode member comprises a strip of medical grade polyurethane. 42. The method of claim 41, wherein the strips are about 7 cm × 1 cm in size. 43. The method of claim 39, wherein the contacting step comprises contacting a plurality of coupled electrode pairs with the epicardial surface of the heart. The method wherein the pairs are arranged in two rows, with one electrode of each pair in one row and the other electrode of each pair in the other row. 44. The method of claim 43, wherein each electrode of the electrode pair is separated from each other by about 2 mm and each electrode pair is separated from the closest electrode pair by about 5 mm. 45. The method of claim 39, wherein the electrode comprises platinum. 46. The method of claim 45, wherein the electrode comprises substantially unalloyed platinum. 47. The method of claim 39, wherein the contacting step comprises sewing a substrate piece containing a plurality of coupled electrode pairs to an epicardial surface of the heart. 48. The method of claim 39, wherein said contacting step comprises placing a transvenous catheter containing a plurality of electrode pairs connected in an epicardial vein. 49. The method of claim 39, wherein the contacting step comprises placing an electrode in the ventricle to activate the endocardium. 50. A device for treating a heart to induce remodeling of ion channels, wherein the device is contacted with the epicardial surface of the heart and is cyclical to the epicardial surface via electrode pairs. A device comprising a substrate having a plurality of electrode pairs connected to conduct a pacemaker electrical signal to induce remodeling of ion channels in the heart. 51. The device according to claim 50, further comprising a strip-shaped electrode member having a plurality of coupled electrode pairs stacked thereon. 52. The device of claim 51, wherein the electrode member is comprised of medical grade polyurethane. 53. The apparatus of claim 50, wherein the electrode pairs are arranged in two rows, one electrode of each pair in one row and the other electrode of each pair in the other row. . 54. One electrode of the pair is approximately 2 mm from the other electrode of the pair.
54. The device of claim 53, wherein each electrode pair is spaced apart and is about 5 mm from the closest electrode pair. 55. The device of claim 50, wherein the electrodes are composed of platinum. 56. The device of claim 55, wherein the electrode comprises substantially unalloyed platinum. 57. The device of claim 50, wherein each electrode is connected to an insulated stainless steel wire.