WO2000047276A1 - Cardiac junctional remodeling - Google Patents
Cardiac junctional remodeling Download PDFInfo
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- WO2000047276A1 WO2000047276A1 PCT/US2000/003640 US0003640W WO0047276A1 WO 2000047276 A1 WO2000047276 A1 WO 2000047276A1 US 0003640 W US0003640 W US 0003640W WO 0047276 A1 WO0047276 A1 WO 0047276A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/362—Heart stimulators
- A61N1/365—Heart stimulators controlled by a physiological parameter, e.g. heart potential
- A61N1/368—Heart stimulators controlled by a physiological parameter, e.g. heart potential comprising more than one electrode co-operating with different heart regions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/02—Details
- A61N1/04—Electrodes
- A61N1/05—Electrodes for implantation or insertion into the body, e.g. heart electrode
- A61N1/0587—Epicardial electrode systems; Endocardial electrodes piercing the pericardium
Definitions
- This application is directed to cardiac remodeling. More particularly, this application is directed to pacing of the epicardium or endocardium to induce cardiac electrical, mechanical, ion channel and gap junctional remodeling.
- Arrhythmias of the heart such as fibrillation
- fibrillation are well known to those familiar with the heart.
- Localized or diffuse lesions of the myocardium which may result from any one of various reasons, often lead to a pronounced dispersion of repolarization and refractoriness.
- the heart does not experience a normal sequential depolarization but, rather, there results an abnormal activation pattern and/or dispersion of repolarization.
- An abnormal impulse occurring during this period can lead to electrical fragmentation, and consequent initiation of ventricular fibrillation. It is known that the proper application of an electrical shock to the heart can change a fibrillating heart back to synchronous action of all myocardial fibers; that is, the heart can be defibrillated.
- Defibrillation induced by electrical shock of the heart results in a regular development of propagation of electrical excitation by means of simultaneous depolarization of all myocardial fibers that have gone out of step to cause the arrhythmia.
- Many defibrillation devices are known in the prior art for providing a defibrillation pulse after the arrhythmia has commenced .
- the determinants of myocardial conduction and repolarization include the dimensions and packing geometry of the myocytes, and the properties of the gap junction which are the membrane specializations that form the low resistance pathways for the flow of intercellular current.
- (1,2) Changes in quantity and distribution of gap junctions and their constituent proteins, connexins, have been demonstrated in various disease states (3-7) and experimental data indicate that such changes may cause heterogeneous slowing of conduction (8,9) and are strongly implicated in reentry (10) .
- Pacing-induced alterations in activation pathways cause changes in the T wave that long outlast the return to sinus rhythm (13-16), and are generally referred to as "cardiac memory" (13,17).
- cardiac memory 13,17
- low resistance connections between cells are the basis for electrotonus
- electronic current flow modulates the voltage-time course of repolarization of nearby myocytes (18)
- remodeling of gap-junctional coupling may be implicated in the mechanism of cardiac memory. Changes in conduction and repolarization that occur in circumstances of altered activation may be critical to the pathophysiology of arrhythmias, and both would be facilitated by altered electrotonus that might accompany gap junctional remodeling.
- One aspect of the invention provides a method of treating a heart to remodel gap junctions, comprising contacting linked multiple electrode pairs to an epicardial surface of a heart, and connecting the electrode pairs to a pacemaker to apply periodic electrical signals to the epicardial surface through said electrode pairs, said signals being applied for a sufficient time and having characteristics sufficient to remodel gap junctions in the heart.
- a device for treating a heart to obtain gap junctional remodeling, comprising a substrate having linked multiple electrode pairs for contacting an epicardial surface of a heart and for delivering periodic pacemaker electrical signals to the epicardial surface through said electrode pairs, to remodel gap junctions in the heart.
- Another aspect of the invention is a method of treating a heart to alter the effective refractory period, comprising contacting linked multiple electrode pairs to an epicardial surface of a heart, and connecting the electrode pairs to a pacemaker to apply electrical signals to the epicardial surface, said signals being applied for a sufficient time and having characteristics sufficient to alter the effective refractory period of the heart .
- Another aspect of the invention provides a device for treating a heart to alter the effective refractory period, comprising a substrate having linked multiple electrode pairs for contacting an epicardial surface of a heart and for delivering periodic pacemaker electrical signals to the epicardial surface through said electrode pairs, to alter the effective refractory period in the heart.
- a method for treating a heart to induce ion channel remodeling comprising contacting linked multiple electrode pairs to an epicardial surface of a heart, and connecting the electrode pairs to a pacemaker to apply periodic electrical signals to the epicardial surface, said signals being applied for a sufficient time and having characteristics sufficient to induce ion channel remodeling in the heart.
- Yet another aspect of the invention provides a device for treating a heart to induce ion channel remodeling, comprising a substrate having linked multiple electrode pairs for contacting an epicardial surface of a heart and for delivering periodic pacemaker electrical signals to the epicardial surface through said electrode pairs, to induce ion channel remodeling in the heart.
- Figure 1 is a six lead electrocardiogram and frontal plane T wave vectrocardiogram of a dog
- Figure 2 is a graph showing activation times
- Figure 3 is a graph showing activation-recovery times
- Figure 4 comprises two confocal micrographs of the epimyocardial layer of the anterior left ventricular wall immunolabelled for connexin 43, from an unpaced control animal and a Group I animal paced for 21 days;
- FIG. 5 is a drawing of an electrode array according to the invention.
- Figure 6 shows electrocardiograms and vectrocardiograms of representative samples of effects of point source stimulation on accumulation of T wave changes
- Figure 7 comprise two graphs showing quantification of pacing-induced changes in sinus rhythm T vectoramplitude in animals, and the recovery of the T wave following cessation of pacing;
- Figure 8 is two graphs showing activation time measured from reference QRS to bipolar epicardial electrode sites at left ventricular apex, left ventricular base and right ventricle;
- Figure 9 is a graph showing changes in activation recovery intervals and effective refractory periods at the same sites and the same times as in Figure 8;
- Figure 10 is a series of three graphs showing the effect of 21 days of posterolateral LV pacing on the QRS duration, QT interval duration, effective refractory period (ERP) and ERP/QT ratio;
- Figure 11 is a series of graphs showing the effects of chronic pacing on action potential and ion channel remodeling;
- Figure 12 show effective refractory period (ERP) measurements made following two one hour periods of left ventricular anteroseptal pacing using the array in three anesthetized dogs .
- ERP effective refractory period
- the invention provides a method of treating a heart to remodel gap junctions, comprising contacting linked multiple electrode pairs to an epicardial surface of a heart, and connecting the electrode pairs to a pacemaker to apply periodic electrical signals to the epicardial surface through said electrode pairs, said signals being applied for a sufficient time and having characteristics sufficient to remodel gap junctions in the heart.
- the step of contacting may comprise contacting a strip electrode material having linked multiple electrode pairs mounted thereon.
- the strip electrode material may comprise a strip of medical grade polyurethane, wherein the strip is about 7cm x 1cm in dimension.
- the linked multiple electrode pairs may be arranged in two columns with one electrode in each pair in one column, and the other electrode in each pair in the other column.
- each electrode in the electrode pair is about 2mm from each other, and wherein each electrode pair is about 5mm from its closest electrode pair.
- the electrodes may comprise platinum, and may even consist essentially of unalloyed platinum.
- the step of contacting may comprise sewing a substrate strip containing linked multiple electrode pairs to an epicardial surface of the heart.
- the step of contacting may comprise locating a transvenous catheter containing linked multiple electrode pairs into an epicardial vein.
- the step of contacting may comprise placing electrodes into heart ventricles for endocardial activation.
- the invention also provides a device for treating a heart to obtain gap junctional remodeling, comprising a substrate having linked multiple electrode pairs for contacting an epicardial surface of a heart and for delivering periodic pacemaker electrical signals to the epicardial surface through said electrode pairs, to remodel gap junctions in the heart .
- the substrate may comprise a strip of electrode material having mounted thereon the linked multiple electrode pairs.
- the electrode material may comprise medical grade polyurethane.
- the electrode pairs may be arranged in two columns with one electrode in each pair in one column, and the other electrode in each pair in the other column.
- one electrode in the pair is about 2mm from the other electrode in the pair, and each electrode pair is about 5mm from its closest electrode pair.
- the electrodes are preferably comprised of platinum, and more preferably consist essentially of unalloyed platinum. Each electrode is preferably connected to an insulated stainless steel wire.
- a method of treating a heart to alter the effective refractory period comprising contacting linked multiple electrode pairs to an epicardial surface of a heart, and connecting the electrode pairs to a pacemaker to apply electrical signals to the epicardial surface, said signals being applied for a sufficient time and having characteristics sufficient to alter the effective refractory period of the heart.
- Another aspect of the invention provides a device for treating a heart to alter the effective refractory period, comprising a substrate having linked multiple electrode pairs for contacting an epicardial surface of a heart and for delivering periodic pacemaker electrical signals to the epicardial surface through said electrode pairs, to alter the effective refractory period in the heart .
- a yet further aspect of the invention provides a method of treating a heart to induce ion channel remodeling, comprising contacting linked multiple electrode pairs to an epicardial surface of a heart, and connecting the electrode pairs to a pacemaker to apply periodic electrical signals to the epicardial surface, said signals being applied for a sufficient time and having characteristics sufficient to induce ion channel remodeling in the heart.
- the invention also provides a device for treating a heart to induce ion channel remodeling, comprising a substrate having linked multiple electrode pairs for contacting an epicardial surface of a heart and for delivering periodic pacemaker electrical signals to the epicardial surface through said electrode pairs, to induce ion channel remodeling in the heart .
- Propagation of the action potential from cell to cell is dependent on a number of architectural characteristics of the myocardium.
- These architectural determinants of myocardial conduction include the dimensions and packing geometry of the constituent myocytes, the number of cells with which each cell makes contact (typically about 10 in the normal mammalian ventricle (23,5)), and the distribution of the gap junctions which are the membrane specializations that form the low resistance pathway for the flow of intercellular current (1) .
- As a principal determinant of myocardial conduction alteration in the organization of gap-junctional coupling affects conduction and is directly implicated in promoting reentrant arrhythmogenesis . (25,10,26,27)
- gap-junctional organization that occurred in these animals.
- Such localized gap-junctional remodeling may not only facilitate the changes seen in the conduction and repolarization of the normal cardiac impulse, but has important implications for understanding reentrant arrhythmias.
- Changes in gap-junctional organization have been demonstrated in the fibrillating mammalian atrium (31,32), and we have shown that a specific pattern of gap-junctional disorganization appears to define the inducibility and location of the reentrant circuit in the epicardial border zone of the model of healing canine infarct (10) .
- the results of the present study raise the possibility that gap-junctional remodeling may be a consequence of the abnormal activation pattern during the arrhythmia.
- An aspect of the present invention concerns providing an apparatus and method to enable long-term, multi-point stimulation of as well as multi -point recording from a functioning heart.
- the system has to include multiple electrical contact points of suitable properties that can be used to stimulate the heart muscle by passing current, or record its electric activity by measuring potential differences, positioned such that they make firm and stable contact at selected points on the internal or external surface of a hearing, i.e., contracting and moving heart .
- These contact points are to be connected via flexible insulated leads to the stimulating current or potential recording units. All of this has to form a cwo-dimensional array of high density circuitry.
- Chip silicon chip - microelectronics technology
- Print printed circuit technology
- the first is in wide use in construction of practically all types of modern electronic micro-chips, such as microprocessors, while the second is mainly used as a base for connecting between the various electric components (conductors, resistors, capacitors, etc.) and electronic active elements (transistors, processors, etc . )
- Chip construction is based around silicon which has the mechanical properties of glass and therefore has mechanical limitations: it is not flexible and if thin tends to break easily.
- Prints construction is based around plastics such as polyimid which are very flexible and do not break when in the form of thin films.
- the cutting of the base material to individual units is done by etching in Chips and laser beams in Prints. This makes the process, more expensive for Prints.
- the Prints can be made of two thin electrically-insulating and bio-compatible plastic material sheets glued together so as to be holding in between them conductive metal strips that are sandwiched to form a compound flexible sheet, about 0.03-0.3 mm in thickness.
- One such preferred embodiment would be two polyimid sheets which are very strong, bio-compatible and to which living cells tend to adhere well.
- the conducting metal strips can be made from any metal used in such circuits. For example, aluminum, provided that their exposed sections are coated with a suitable conducting element such as gold, platinum, etc. Such plating is also standard in the industry.
- the contact points are made by perforating the plastic at the desired locations. Such exposure of the metal is made, for example, by laser beams. The exposed areas are to serve as heart muscle contacts as well as to form suitable connectors to the electronic activating units.
- the overall geometry of the circuit and contacts is practically unlimited and is usually made by means of masks generated by computer programs and lithography and implicated on sheets of stationary paper sizes.
- the sheets can be cut into practically any shapes by laser beams.
- Chip technology can allow the building of circuits which practically contain such a thin layer of silicone so as to be flexible. There may be other Chip technologies that would make the Chip sufficiently flexible. Such circuits would have the advantage that they can contain active elements- on board, for example, the first amplification stage.
- Mongrel dogs of either sex weighing 22 to 27 kg were anaesthetized with propofol 6 mg/kg IV, followed by inhalation of isoflurane 92%) .
- the chest was opened and the heart suspended in a pericardial cradle. Two groups of dogs were prepared.
- a Medtronic permanent pacing lead (model 6917) was attached to the epicardium of the anterolateral left ventricle. The lead was connected to a Medtronic MINIX 8340 pulse generator that was placed in a subcutaneous pocket. No other leads were attached to minimize manipulation and instrumentation of the hearts for subsequent histological examination (see below) .
- Ventricular activation and repolarization were studied as follows: in addition to recording cardiac frontal plane vectors, as previously described (15) , activation times were measured as the interval between the stimulus artifact
- ECGs were recorded from Group I animals during atrial pacing and ventricular pacing. These dogs were anaesthetized with pentobarbital, 30 mg/kg, IV, and the heart removed and weighed.
- Transmural LV samples were excised from the anterior left ventricular wall, 1 to 2 cm from the pacing site, and from the posterior LV wall, distant from the pacing site. All specimens were divided into epimyocardial (epi) , midmyocardial (mid) and endomyocardial (endo) layers, and immediately snap frozen in liquid nitrogen.
- Frozen sectioning of the samples was carried out in a cryostat at -20°C, producing 10 ⁇ m tissue sections of random orientation, which were picked up on slides coated with poly-L-lysine, stored at -20°C, and fixed in methanol for 5 minutes at -20°C. Standard histological staining and light microscopy was carried out on all tissue samples to confirm preservation, cell structure and orientation, and for photography. Connexin immunohistochemistry was carried out on epi-, mid-, and endomyocardial layers. The antibody used for the localization of cardiac gap-junctional connexin43 was IgGj .
- the fluorochrome Cy3 (peak absorption wavelength 550 nm, peak emission wavelength 570 nm) was used for these studies, conjugated to antibodies (Chemicon International Inc.) raised against immunoglobulin from mouse (for connexin43 labeling) and rabbit (for connexin40 labeling) as appropriate.
- Connexin43 Immunolabelling the primary antibody was used at a dilution of 1;1000, with 1% BSA, for 1 hour at room temperature.
- Connexin40 Immunolabelling a range of conditions was used, leading to the conclusion that no detectable connexin40 labeling was expressed in either the control or paced canine ventricular myocytes (see Results below) .
- Immunolabelled sections were examined using a Leica TCS 4D laser scanning confocal microscope running on SCANware software with the digitized images stored on 250Mb magneto-optical disks.
- Total tissue homogenates were prepared from the frozen tissue samples to give a solution of final concentration 0.5 ⁇ g/ ⁇ l in sample buffer. 3.0 ⁇ g of total protein from each sample were resolved by polyacrylamide gel electrophoresis (BioRad) on a 12.5% gel (with a 4.5% stacker) . The gel was run at 60V until the dye front was through the stacker and then at 150V. The gel was electrophoretically transferred onto a polyvinylidene fluoride membrane at constant voltage 30V. Transfer was assessed by Ponceau S (Sigma) .
- the membrane was blocked in the dilution buffer (TBS/0.2% Tween20 (Merck) /l% blot qualified BSA) for 30 minutes, followed by incubation with the primary antibody for connexin43 (as used for immunohistochemistry, above), diluted 1:1000 in dilution buffer for one hour. After washing, the membrane was incubated with the secondary alkaline phosphates conjugated anti-mouse antibody (Pierce), diluted 1:2500 with dilution buffer, for one hour. After washing, the membrane was incubated with alkaline phosphate buffer (0.1M Tris pH 9.5, 0.1M MgCl 2 ) for 5 minutes, followed by incubation with freshly prepared substrate solution (Promega Corporation) . Following densitometric quantification of band intensity, all values were corrected for protein loading using the actin band on a coomassie stained gel run in parallel .
- TBS/0.2% Tween20 (Merck) /l% blot qualified BSA diluted 1:1000 in
- Figure 1 is a six lead electrocardiogram and frontal plane T wave vectrocardiogram of one dog on day 1 during atrial pacing just before, and then shortly after, initiating ventricular pacing, and on day 21, one hour after the return to atrial pacing. By day 21 the T wave during atrial pacing has tracked the paced QRS complex.
- ECG calibrations 1 mV and 50 mm/sec.
- the vector calibration 0.5 mV.
- Figure 1 is a representative experiment from a Group II dog, demonstrating the ECG and the frontal plane T wave vector during atrial pacing and one hour after initiating ventricular pacing on day 1, and during atrial pacing an hour after the end of 21 days of ventricular pacing.
- the evolution of the atrially-paced T wave and its vector are such that at 21 days it has tracked the ventricularly-paced
- QRS complex The characteristics of the ECG and of cardiac T wave vectors for Group I and II animals are shown in Table 1. No significant changes occurred in the heart rate, P-R interval, QRS duration or QT interval in either group, as has been previously described (15) . Also, as previously described, there are significant changes in the T wave vector, which, as demonstrated in Figure 1, assumes an angle and amplitude that track those of the paced QRS complex.
- Figure 2 is a graph showing activation times during control and on days 7, 14, and 21 during the 1 hour interludes of atrial pacing (Panel A) and during the ventricular pacing, itself (Panel B) .
- panel A for the two sites activated earliest (RV and LV inferior) there is no significant change in activation time.
- LV base site activated last
- RV ventricular pacing
- the two sites activated earliest show no change in activation time
- RV area activated latest
- the symbol indicates P ⁇ .05 cf control.
- Figure 3 is a graph showing activation-recovery intervals during control and on days 7, 14, and 21 during the 1 hour interludes of atrial pacing (Panel A) and during the ventricular pacing, itself (Panel B) . In both panels there is no significant change in ARI at any of the sites studied.
- the removed hearts from the paced animals appeared grossly normal, with minimal scarring and fibrosis limited exclusively to the pacemaker lead site.
- the left ventricular wall outside the immediate vicinity of the pacing site appeared normal, with no obvious edema, necrosis or scarring.
- Standard light microscopy revealed normal myocardial appearance and no differences between any of the myocardial layers in the paced or control groups.
- Paced Animals By contrast with this normal pattern of distribution, the epimyocardial layer of the paced animals had, to a variable extent, an abnormal pattern of distribution of Cx43 Immunolabelling.
- the clusters of label tended to be strewn along the long axis of the cells, in longitudinally oriented arrays, with fewer discrete transversely orientated clusters. Representative images are shown in Figure 4. To be able to summarize this finding for the entire groups of animals, a simple, arbitrary scoring system was used. A scale was devised with a score of 1 to 10 given to each individual sample depending upon the label distribution observed by a blinded operator.
- a score of "1" was given to an extreme distribution of connexin organization with labeling confined exclusively to the normal, transversely orientated clusters at cell abutments ( Figure 4A) , and a score of "10” represented a distribution of labeling within longitudinal arrays along the myocyte, with markedly diminished labeling at the end-on abutments ( Figure 4B) .
- Figure 4 comprises two confocal micrographs which show the effects of chronic pacing on gap junctional remodeling of the epimyocardial layer of the anterior left ventricular wall ( ⁇ lcm from pacing site) immunolabelled for connexin43, from an unpaced control animal (Upper panel) and from a Group I animal paced for 21 days (Lower panel) . Both micrographs are longitudinally sectioned myocardium, with the long axis of the constituent cells running horizontally. The transversely oriented clusters of connexin43 label confined to the intercalated disks at the transverse cell abutments in Upper
- Lower Panel is an illustrative example of the abnormal pattern of connexin43 label distribution, with a significant proportion of the label spread in clusters along the longitudinal borders of the myocytes (Score 8) .
- Score 8 the gap junctional staining, rather than concentrating at the ends of the myocytes is distributed along their lateral margins as well . This represents a significant redistribution of gap junctional location, and occurred in the absence of change is a reference protein (connexin 40, results not shown here) (see refs. 37, 38) .
- the posterior LV wall, distant from the pacing site, in the paced dogs showed no significant differences in Cx43 expression compared with controls .
- the following is a description of the electrode and of preliminary results using it, as well as the general modality of pacing to induce electrical, mechanical and gap junctional remodeling.
- the electrode is a 7 cm x 1 cm medical grade polyurethane (Biospan) strip having a plurality or multiplicity of 1.2 mm unalloyed platinum electrode pairs (each member of a pair spaced 2 mm from its mate) with the pairs spaced at 5 mm intervals.
- the electrodes are thus arranged in two columns with one electrode of the pair in one column, and the other electrode in the other column.
- the electrodes are linked or connected together as shown.
- Each electrode has an electrode wire.
- the wires are 30 gauge multi-stranded stainless steel covered with medical grade polyurethane .
- the array may be driven by any standard implantable pacemaker device, such that all electrodes or any subset of electrodes can contribute to a simultaneously activating wavefront .
- the signals from a standard pacemaker has certain signal characteristics (i.e. voltage, current, frequency) which has been shown to produce the desired results. Other signals can be used, provided they also produce the results desired, as described herein.
- the electrode strip can be sewn to the epicardial surface or, if re-arrayed on a transvenous catheter, placed into an epicardial vein via the coronary sinus or placed into the ventricles for endocardial activation. We have done experiments regarding the remodeling induced using both the entire array, or using point source stimulation from individual bipolar pairs. Results :
- the general indicator of remodeling that we use is a change in the electrocardiographic T wave. This is readily recordable from the body surface, requires no interventions in order to read it, and is recognized as the "gold standard” for cardiac memory (13, 17, 33), which is the specialized form of remodeling our pacing protocols induce.
- FIG. 6 is a series of representative examples of effects of point source stimulation on accumulation of T wave changes on ECG and vectrocardiogram. Pacing was continued for 21 days and discontinued for an hour on days 7, 14, and 21. The T wave on ECG gradually assumes the ventor of the paced QRS complex. The T vector change is better appreciated on the vectorcardiographic records in the lower panels.
- panel A is a control
- B represents ventricular pacing
- C is an enlargement of the T wave vectors at control and days 14 and 21 showing the shift in vector as seen during sinus rhythm
- panel D is the return to sinus rhythm on day 21 (see ref . 15) .
- pacing of anesthetized dogs from a point source on the anterior left ventricle gives rise to an altered T wave on ECG that has the characteristics of memory (that is, with repeated stimulation the T wave change is increased and its decay from peak is more protracted with repeated periods of pacing) (15, 34).
- Figure 7 is a series of two graphs showing quantification of pacing-induced changes in sinus rhythm T vector amplitude in 16 dogs during 3 ⁇ > days of pacing (left) , demonstrating the major change to occur by 12 and the plateau fully evident by 22 days.
- On the right is recovery of the T wave following cessation of pacing.
- pacing was 21-25 days in duration, recovery was rapid, and largely complete in a week.
- 42-52 days of pacing significant recovery had not occurred by one month (see ref . 15) .
- Figure 8 is two graphs which show activation time measured from reference QRS to bipolar epicardial electrode sites at left ventricular (LV) apex, LV base and right ventricle (RV) . Following 21 days of point source pacing from posterolateral LV, activation time is recorded during atrial pacing (left) to simulate sinus rhythm, or ventricular pacing (right) . During atrial pacing, there is significant delay of activation to the latest sites activated (i.e. LV apex and base) . During ventricular pacing, the delay in activation is again to the latest site, in this case, the RV.
- LV left ventricular
- RV right ventricle
- Figure 9 is a graph showing changes in activation-recovery intervals (ARI, reflecting duraction of local repolarization) and effective refractory periods (ERP) at the same sites and the same times as in Figure 8.
- ARI activation-recovery intervals
- ERP effective refractory periods
- Figure 10 is a series of three graphs showing the effect of 21 days of posterolateral LV pacing on the QRS duration, QT interval duration, effective refractory period (ERP) and ERP/QT ratio. Recordings are during control and after 21 days of pacing to induce cardiac memory. A slight prolongation in the QRS complex is seen during ventricular pacing, but not during atrial pacing. The QT interval, reflecting net repolarization measured from the body surface is increased during both types of pacing, and the ERP is prolonged significantly. Importantly, the ERP/QT ratio increases significantly indicating a greater protection against the propagation of premature beats.
- FIG. 10 A summary of the QRS and QT interval and effective refractory period changes as recorded on ECG is provided in Figure 10.
- pacing there is a small but significant prolongation of the QRS complex.
- the QT interval is prolonged as is the effective refractory period during ventricular pacing.
- the most critical aspect of the prolongation in refractoriness and repolarization is that the change in the former is greater than the latter, such that the ratio, ERP/QT increases.
- the pacing intervention performed is most likely to prevent it from either expressing or sustaining itself.
- Figure 11 is a series of graphs showing the effects of chronic pacing on action potential and ion channel remodeling.
- the Upper panel at a pacing cycle length of 650 msec, shows epicardial action potentials recorded from control and chronically paced dogs.
- Figure 11 demonstrates changes in the action potential and its phase 1 notch; I t0/ the ion current responsible for the action potential notch; and the messenger RNA for Kv4.3 , understood to be the genetic determinant of I to in canine and human heart.
- the isolated cells show the same action potential prolongation described above for regional changes in activation-recovery intervals in the intact heart as well as a reduction in magnitude of the phase 1 notch.
- I to which is responsible for the notch, decreases in magnitude by 1/3.
- the activation voltage for the current moves from about -22mV to -5mV and the time constant for recovery from inactivation increases over 20-fold from a control of 27 ms .
- the message levels for Kv4.3 are reduced by 1/3.
- the entire trail of information is completely internally consistent, from action potential to ion current to molecular message (19) and indicates that ion channel remodeling has occurred.
- Figure 4 demonstrates gap junctional remodeling induced by 21 days of pacing.
- the upper panel is a control, and the lower panel is the same region from an animal that was paced.
- the entire gap junctional distribution has changed, with lateralization clearly visualized.
- Figure 12 shows effective refractory period (ERP) measurements made following two one hour periods of left ventricular anteroseptal pacing using the array in three anesthetized dogs. The results show that there is an 8-12% increase in the ERP (upper) , with significant prolongation demonstrable at each of the three reference sites measured (lower) .
- ERP effective refractory period
- Figure 12 demonstrates the changes seen in effective refractory period using the electrode array in the anteroseptal position in 3 anesthetized dogs paced for two 60 minute periods with a 30 minute respite of atrial pacing after each hour of ventricular pacing. Even after these relatively brief pacing periods there is a significant prolongation in effective refractory period at each site (8% each at left ventricular base and right ventricle and 12 % at left ventricular apex) . In other words, at three widely dispersed sites in the heart, refractoriness is prolonged.
- Wit AL, Janse MJ Basic mechanisms of arrhythmias, in The Ventricular Arrhythmias of Ischemia and Infarction . New
- Van-Der-Velden-Huub -M-W Van-Kempen-Marj an-J-A; Wij f f els-Maurits-C-E-F; Van-Zijverden-Maaike ; Groenewegen-W- Antoinette; Allessie-Maurits-A; Jongsma-Habo-J: Altered pattern of connexin40 distribution in persistent atrial fibrillation in the goat. Journal -of-Cardiovascular- Electrophysiology. June, 1998 ; 9 (6) 595-607.
Abstract
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Application Number | Priority Date | Filing Date | Title |
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CA002360177A CA2360177A1 (en) | 1999-02-12 | 2000-02-11 | Cardiac junctional remodeling |
JP2000598225A JP2003529389A (en) | 1999-02-12 | 2000-02-11 | Remodeling of heart connections |
AU28799/00A AU2879900A (en) | 1999-02-12 | 2000-02-11 | Cardiac junctional remodeling |
EP00907275A EP1159031A1 (en) | 1999-02-12 | 2000-02-11 | Cardiac junctional remodeling |
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US11989699P | 1999-02-12 | 1999-02-12 | |
US60/119,896 | 1999-02-12 |
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WO2000047276A9 WO2000047276A9 (en) | 2001-11-01 |
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EP (1) | EP1159031A1 (en) |
JP (1) | JP2003529389A (en) |
AU (1) | AU2879900A (en) |
CA (1) | CA2360177A1 (en) |
WO (1) | WO2000047276A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2453601A (en) * | 2007-10-12 | 2009-04-15 | Cardio Logic Innovations Ltd | Cardiac ablation catheter with flexible targetable electrode array |
CN105726015A (en) * | 2016-01-29 | 2016-07-06 | 武汉朗迪远程医疗科技有限公司 | Intelligent analysis and learning method for electrocardiogram data |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8644927B2 (en) | 2009-04-21 | 2014-02-04 | Incube Labs, Llc | Apparatus and method for the detection and treatment of atrial fibrillation |
CN111657874A (en) * | 2012-03-02 | 2020-09-15 | 皇家飞利浦有限公司 | Apparatus and method for visualizing a conduction tract of a heart |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5800464A (en) * | 1996-10-03 | 1998-09-01 | Medtronic, Inc. | System for providing hyperpolarization of cardiac to enhance cardiac function |
-
2000
- 2000-02-11 AU AU28799/00A patent/AU2879900A/en not_active Abandoned
- 2000-02-11 JP JP2000598225A patent/JP2003529389A/en not_active Withdrawn
- 2000-02-11 CA CA002360177A patent/CA2360177A1/en not_active Abandoned
- 2000-02-11 EP EP00907275A patent/EP1159031A1/en not_active Withdrawn
- 2000-02-11 WO PCT/US2000/003640 patent/WO2000047276A1/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5800464A (en) * | 1996-10-03 | 1998-09-01 | Medtronic, Inc. | System for providing hyperpolarization of cardiac to enhance cardiac function |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2453601A (en) * | 2007-10-12 | 2009-04-15 | Cardio Logic Innovations Ltd | Cardiac ablation catheter with flexible targetable electrode array |
GB2453601B (en) * | 2007-10-12 | 2010-07-21 | Cardio Logic Innovations Ltd | Radio frequency catheter for the ablation of body tissues |
CN105726015A (en) * | 2016-01-29 | 2016-07-06 | 武汉朗迪远程医疗科技有限公司 | Intelligent analysis and learning method for electrocardiogram data |
Also Published As
Publication number | Publication date |
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CA2360177A1 (en) | 2000-08-17 |
AU2879900A (en) | 2000-08-29 |
WO2000047276A9 (en) | 2001-11-01 |
EP1159031A1 (en) | 2001-12-05 |
JP2003529389A (en) | 2003-10-07 |
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