CN100518697C - Control of cardiac arrhythmias by modification of neuronal conduction within fat pads of the heart - Google Patents

Abstract

To control cardiac arrhythmias, various conduction-modifying agents include biopolymers, fibroblasts, neurotoxins, and growth factors are introduced either epicardially or endocardially to the fat pads in proximity to the ganglia therein. Any desired technique may be used for injection , including injection from a catheter inserted percutaneously, or direct injection through the epicardial during open heart surgery. Preferably the patient's heart is beating throughout the injection.

Description

Control arrhythmia by neuronic conduction in the adjusting heart fat pad

The inventor

Nicholas Peters is the British citizen who lives in the London.

Mark Maciejewski is a United States citizen of living in Edina city, Minn..

The related application of cross reference

The application requires following priority: the U.S. Provisional Patent Application No.60/519 that on November 13rd, 2003 submitted to, 588 (" the Method to ControlVentricular Rate " of people such as Peters invention), the U.S. Provisional Patent Application No.60/523 that on November 20th, 2003 submitted to, 848 (" the Method to Cure Atrial Fibrillationby Modifying Local Autonomic Supply " of people such as Peters invention), the U.S. Provisional Patent Application No.60/550 that on March 3rd, 2004 submitted to, 185 (" the Treatment ofCardiac Arrhythmias " of people such as Peters invention), and the U.S. Provisional Patent Application No.60/550 of submission on March 4th, 2004,076 (" the Treatment of CardiacArrhythmias with Neurotoxins " of people such as Peters invention), the full content of above-mentioned patent application is incorporated this paper at this into way of reference.

Technical field

The present invention relates to a kind of processing, more particularly, the present invention relates to control arrhythmia by neuronic conduction in the adjusting heart fat pad to the medical conditions relevant with heart.

Background technology

Autonomic nervous system (ANS) is divided into the sympathetic nervous system parasympathetic nervous system of unifying.Sympathetic nervous system makes Heartbeat rate quickening, ventricular systole enhancing, skeletal muscle vasodilation, skin and visceral vessel contraction, blood sugar level raise, and promote sweating, make pupil to scatter, make visceral motility and gastric juice secretory activity to be suppressed.Parasympathetic nervous system is more active when rest, and generally speaking it has anabolic effect.For example, parasympathetic nervous system makes that Heartbeat rate slows down, contracted pupil, gastric secretion increase, and intestinal motive force is strengthened.

Neural control to heart depends on the active degree of sympathetic neuron and parasympathetic neuron and the reciprocal action between autonomic these two branches.As McGuirt, A.S. at Am.J.Physiol.272 (Heart Circ.Physiol.41), 1997, disclosed in the article of delivering on the H2525-H2533 " Autonomic interactions for control of atrial rate aremaintained after SA nodal parasympathectomy ": in order to control the partial function of heart, leading between the autonomic nerve synapse of heart (autonomic projection), particularly at the target site of end-organ (antrum (SA) knot for example, the constriction of chamber (AV) knot and atrium and ventricle) locates, the interaction of joint preceding (pre-junctional) and joint back (post-junctional) all occurs.The cardiac nerve joint comprises parasympathetic nervous, sympathetic nerve and afferent neuron.In normal physiological processes, cardiac conduction is to be transmitted to another cell from a cell, is transmitted to the AV knot from the SA knot, and is transmitted to ventricle from the atrium.

Arrhythmia is each chamber of heart and the abnormal conditions that other structure took place.Referring to Steinberg, Jonathan S. is at Journal of the American College ofCardiology, Vol.43, No.6, the article of delivering on 2004 " Postoperative AtrialFibrillation:A Billion-Dollar Problem ", auricular fibrillation (" AF ") is the highest perpetual arrhythmia of a kind of frequency of disease development, particularly the old people, have the patient of organic heart disease and just from the patient of coronary bypass grafting (" CABG ") surgery recovery easily the morbidity.For example, in being the patient of operation on heart, AF can take place in the patient up to 50%.The patient who suffers from chronic AF have Symptomatic tachycardia or cardiac output low, the risk probability that thromboembolic complication and accident take place is 5% to 10%.

In order to recover sinus rhythm, use the cardioversion method to treat AF usually, wherein can use the cardioversion method separately or cardioversion method and arrhythmia therapy are combined treatment AF.It is reported, adopt this class therapy after, relapse rate is up to 75%.The patient that pharmacologic therapy suffers from AF to the overwhelming majority has side effect.The conventional method of the treatment AF that other is more general all concentrates on by surgical method or uses various forms of energy to eliminate conduction, so that the atrium district that separates electricity isolates, thereby melts (destruction) abnormal conduction path.

Ablation is to intervene and stop up the abnormal conduction path and treatment technology commonly used in order to form conduction block devastatingly, otherwise the abnormal conduction path can disturb normal Cardiac cycle.The design idea that forms the system and method that the typical ablation techniques of conduction block uses is: kill the tissue that the tissue that causes ARR source of disease place or unusual cascade pathway are gone up on the way.Usually destroy cell in the pathway with high temperature action, cold service or chemical action.Be suitable for producing pyritous kind of energy and comprise radio-frequency current, ultrasound wave, microwave and laser energy.In addition, use cryotherapy can produce low temperature.The example of chemical ablation art is that destructive ethanol is transported in the heart tissue.Though when forming conduction block by the above-mentioned various technology of use, observed significant advantage and successful curative effect, every kind of method all has certain disadvantageous consequence.For example, according to observations, ablative high temperature or other cause downright bad mode can cause cicatrix, form thrombosis, (collagen) shrinks to make collagen, and dark tissue is caused disadvantageous structural damage.

Therefore, need under situation about heart tissue not being melted, control arrhythmia.

Summary of the invention

One embodiment of the invention are a kind of ARR systems that control in patient's heart, and this system comprises heart induction system (cardiac delivery system) and the conduction-modifying agent medicine source that links to each other with this heart induction system.This conduction-modifying agent is effective for the neuron conduction of regulating in the neuroganglion.This heart induction system comprises distal portions, and this distal portions is transported to conduction-modifying agent near the neuroganglion of at least one heart fat pad from the medicine source.

Another embodiment of the invention is a kind of ARR system that controls in patient's heart, and this system comprises heart induction system and the conduction-modifying agent medicine source that links to each other with this heart induction system.This conduction-modifying agent is effectively for the neuron conduction of regulating in the neuroganglion, and comprises various ingredients.This medicine source comprises a plurality of individual components, each component is contained in respectively individually in each parts in medicine source.The heart induction system comprises distal portions and a plurality of independently transfer passage, this distal portions has and a plurality of each component of conduction-modifying agent is transported to the passage of the end of distal portions, and each passage of the distal portions of heart induction system is that fluid is communicated with each parts in medicine source respectively by each transfer passage.

Another embodiment of the invention is a kind of entry needle, this entry needle comprises distal portions and a plurality of independently transfer passage, this distal portions has a plurality of passages that extend to the entry needle end, and each passage and the transfer passage of the distal portions of this heart induction system is that fluid is communicated with.

Another embodiment of the invention is a kind of ARR method of controlling in patient's heart, and this method may further comprise the steps: detect arrhythmia; Prepare the conduction-modifying agent medicine source of the neuron conduction in effective adjusting neuroganglion; The conduction-modifying agent of effective therapeutic dose near the medicine source is transported at least one neuroganglion the heart fat pad.

Description of drawings

Fig. 1 is the sketch map from the vagal preganglionic neuron of neck to the nervous pathway of the sinuatrial node of heart.

Fig. 2 is illustrated in the sinuatrial node fat pad that a Fibrin Glue (fibrin glue) is expelled to dog class subjects after a period of time the figure as a result in this time domain.

Fig. 3 is the sketch map of the used tube injection system of one pack system conduction-modifying agent.

Fig. 4 is the transverse cross-sectional view of conduit, and wherein entry needle is slidably mounted in single cavity (lumen shaft) of catheter main body.

Fig. 5 is the transverse cross-sectional view with conduit of three inner chambers, and entry needle is installed in one of them inner chamber slidably.

Fig. 6 is the transverse cross-sectional view with conduit of four inner chambers, and entry needle, backguy and two leads are installed in these four inner chambers slidably.

Fig. 7 is the sketch map of the used exemplary catheter injecting systems of bi-component conduction-modifying agent.

Fig. 8 is the transverse cross-sectional view with conduit of two inner chambers, in these two inner chambers entry needle is installed slidably respectively.

Fig. 9 is the sketch map of the used exemplary injection system of injection bi-component conduction-modifying agent.

Figure 10 is the sketch map of the used another kind of exemplary injection system of injection bi-component conduction-modifying agent.

Figure 11 illustrates a kind of entry needle, and its main body separates to form well-separated inner chamber with sept.

Figure 12 illustrates a kind of entry needle, forms two well-separated inner chambers in its main body.

Figure 13 illustrates a kind of entry needle, is surrounded with second inside subject to form well-separated inner chamber in its main body.

Figure 14 is illustrated in the injection Fibrin Glue time domain before the figure that stimulates the SN fat pad that sinus rhythm is exerted an influence.

Figure 15 illustrates in the time domain that follows closely after the injection Fibrin Glue figure that stimulates the SN fat pad that sinus rhythm is exerted an influence.

Figure 16 is illustrated in the injection Fibrin Glue time domain before the figure that stimulates the AVN fat pad that auricular pacemaking is exerted an influence.

Figure 17 illustrates in the time domain that follows closely after the injection Fibrin Glue figure that stimulates the AVN fat pad that auricular pacemaking is exerted an influence.

Figure 18 is illustrated in the injection Fibrin Glue time domain before the figure that stimulates the AVN fat pad that auricular fibrillation is exerted an influence.

Figure 19 illustrates in the time domain that follows closely after the injection Fibrin Glue figure that stimulates the AVN fat pad that auricular fibrillation is exerted an influence.

The detailed Description Of The Invention that comprises preferred forms

The crucial therapy of two kinds of widely used alternative treatment auricular fibrillations (" AF ") is rhythm of the heart control and Heartbeat rate control.For rhythm of the heart control therapy, the target of treatment is to recover and to keep sinus rhythm.Pulmonary vein and atrium have abundant autonomic nerve, mainly carry out the autonomic nerve domination by the joint of the cardiac nerve in the fat pad of each sharp outline in the pericardium district, and wherein part autonomic nerve and pulmonary vein are adjacent.Control and intervention to autonomic nerve for a long time is considered to significantly to change the method that AF brings out and continue threshold value, and in the past, this method has been used to set up proper A F model experimentally.

The data that clinical trial produced of isolating strategy based on pulmonary vein (PV) show: need not reach fully and isolate, just might obtain clinical success.Above-mentioned observed result shows: this test has not only reached the effect of isolation AF triggering factors (trigger), also reaches the effect that changes the substrate (substrate) that AF takes place by the autonomic nerve domination is disappeared.May back one effect be the major decision sexual factor of this therapy success.

Many research worker are reported: to the intervention that experimentizes of the autonomic ganglion of heart, can change the probability of AF morbidity, and AF has successfully been eliminated in some early stage clinical researches, these are studied some position (in these positions, stimulation produces measurable variation in autonomic nervous tension) as target, melt at the pulmonary vein opening part, shown position in the autonomic nerve domination that is positioned at cardiac nerve joint downstream.We believe: the pathogeny of AF depends on local dysautonomia (dysautonomia), therefore can be by autonomic nerve domination function being carried out specific change or supplying with by interrupting autonomic nerve, perhaps carry out specific change or interrupt autonomic nerve supplying with by autonomic nerve being arranged function on this rank of the autonomic ganglion in fat pad, handle triggering factors and the substrate of AF.

We have found that: to the AF triggering factors particularly the treatment of substrate can conduct and carry out by regulating in the heart neuron of various visceral pericardium fat pads.The most noticeable neuroganglion is in following three kinds of visceral pericardium fat pads: being preferably upper right atrium and sinuatrial node provides the right pulmonary vein of nerve fiber (" RPV ") fat pad; Postcava-left atrium (" IVC-LA ") fat pad of nerve fiber is provided for AV interface and two atrium; And the 3rd fat pad (" SVC-AO " fat pad) between superior vena cava and aorta.The SVC-AO fat pad provides efferent fiber for all RPV and IVC-LA fat pad, and provides additional fiber for two atrium.Because above-mentioned fat pad is accessibility and clear and legible, so they are noticeable especially, yet other fat pad also is fit to.In above-mentioned three kinds of fat pads, preferred especially RPV fat pad and IVC-LA fat pad, this is because they also have the cause of the efferent fiber that comes from the SVC-AO fat pad.

Various conduction-modifying agents comprise various biopolymers (for example Fibrin Glue and alginate), various cell (for example fibroblast (comprise allogeneic or from body)), various neurotoxin (for example A type Botulinum toxin) and various somatomedin (for example fibroblast growth factor).In any required mode conduction-modifying agent is introduced the fat pad from visceral pericardium or endocardium, preferably injected, perhaps in open heart surgery, by the visceral pericardium direct injection by the conduit that inserts via skin.Preferably in whole injection process, patient's heart is beaten always.

For example, conduction-modifying agent can be by the Fibrinogen precursor of 1 to 1 (1:1) and the formed Fibrin Glue of mixture of thrombin precursor.Be preferably with dual pathways entry needle or entry needle independently, Fibrinogen and thrombin are transported to target position on the anatomy respectively with non-blended form, mix thereby the target position place on this anatomy produces, rather than in induction system or outside the target position on the described anatomy, produce mixing.The suitable dose that produces positive clinical effectiveness is that the fibrin of a 1ml is expelled to target position place on the anatomy, but this dosage also can change along with the required curative effect that will reach.

For example, conduction-modifying agent can be the fibroblast of injecting heart of patient.Fibroblast can be injected in bovine serum albumin (" the BSA ") solution or in any other suitable carriers solution compatible with human tissue.The volume of injection solution can change in the volume range of about 5ml at the about 0.1ml of per injection, and the fibroblast of per injection reaches 1,000 ten thousand to 100,000,000.In same therapeutic treatment process or in different therapeutic treatment processes, can be transported to same anatomical location place to the fibroblast of multiple injection.For example, can at first be transported to treatment position to one " agent " fibroblast, and specify suitable " waiting for and the observation " phase to estimate clinical efficacy.Then,, then can be expelled to extra fibroblast substantially identical anatomical location place,, thereby produce required clinical effectiveness with the increase predose if see fit.Can be expelled to identical substantially anatomical location place to the fibroblast of nearly 50 injections or more times injection, to produce required clinical effectiveness.

Can use the cell of other type, condition is that their (for example fibroblast) and heart cells can form enough gaps and are connected and form required conduction block.The cell delivery of having a talk again, cell can be to be cultivated by patient's oneself cell (for example autogenous cell) to form, and also can be cell in vitro (for example cells that obtains from modulated cell culture).

In one of the heart induction system concrete exemplary embodiment, treat arrhythmia by conduction-modifying agent being transported in one or more heart fat pad.A kind of medicine source of conduction-modifying agent is provided.The heart induction system is connected with this medicine source, thereby the conduction-modifying agent of certain volume is transported to desired location the heart fat pad from the medicine source.

In an exemplary endocardium embodiment of heart induction system, comprise a kind of cardiac conduction navigation system that is used to discern medicine source and/or ARR position.Can make in any suitable manner (for example by apply electromagnetic energy or by detecting the current potential in the tissue) to implement the location.Material source contains the conduction-modifying agent preparation.Use conduit that this conduction-modifying agent is transported to and comprise in the innerv fat pad relevant,, thereby reduce or eliminate arrhythmia with the conduction in the adjusting neuroganglion with arrhythmia.Conduit is suitable for injecting in fat pad.

In another exemplary of heart induction system, material source is the preparation of a kind of bi-component (or multicomponent) conduction-modifying agent precursor, a kind of conduit also is provided, be used for conduction-modifying agent is transported to and contain the innerv fat pad relevant with arrhythmia, with the conduction in the adjusting neuroganglion, thereby reduce or eliminate arrhythmia.Every kind of precursor uses independent syringe, and syringe links to each other with branch components, and next branch components links to each other with multiple channel duct again.Independently passage begins to extend from each syringe, arrives the end of conduit by branch components.When depressing the piston of syringe, precursor is delivered by autonomous channel separately, and by after the opening of conduit, mixes near the neural nodal plexus in fat pad immediately.Conduit is suitable for injecting in fat pad, and its end is near neural nodal plexus.

In an exemplary of the assemble method for the treatment of irregular heart pulse system, selection can be transported to delivery conduit in the heart tissue (for example fat pad) to the conduction-modifying agent preparation.This delivery conduit is inserted in the heart tissue, and this conduit also links to each other with conduction-modifying agent medicine source.

In a kind of variation of this assemble method, delivery conduit also comprises syringe, by delivery conduit conduction-modifying agent is expelled in the required fat pad.

Be used for comprising heart induction system and conduction-modifying agent medicine source in another exemplary of the ARR system of patient's interior therapeutic, this medicine source links to each other with the heart induction system.The heart induction system is suitable for conduction-modifying agent is transported to the fat pad relevant with patient's heart basically from the medicine source.The heart induction system can be the membrane type visceral pericardium formula or intracardiac, and conduction-modifying agent can directly be carried by induction system in the open heart surgery process, perhaps can carry with penetrating carrying method via skin.Specifically, according to the more suitably variation of apparatus and method, can carry by transthoracic minimum intrusion technology respectively, perhaps intravascular (for example by coronary sinus or septal perforation device) is carried.

In a kind of variation of native system, the heart induction system comprises also and is suitable for the contact element that fully contacts with fat pad that when contact element fully contacted with fat pad, the heart induction system was transported to conduction-modifying agent in the contact element.

In the another kind of native system changed, the heart induction system comprised many entry needles with above-mentioned contact element co-operate.Described many entry needles are inserted in the fat pad by the heart induction system and are run through fat pad basically, thereby are expelled to fibroblast in the fat pad fully and run through fat pad, to regulate the neuroganglion conduction.

It should be understood that and to expect: use according to the used conduction-modifying agent of various cell therapy schemes as herein described, other various schemes and mode can also be arranged.By the research patent document, above-mentioned other scheme and mode are conspicuous for the person of ordinary skill of the art.

Available various material is as conduction-modifying agent.A kind of this class material is a compositions, and said composition comprises the pedestal (scaffold) from Fibrin Glue or other biopolymer reagent, and this pedestal and fibroblast and/or neurotoxin and/or somatomedin combine.Can choose wantonly and make said composition only comprise (1) biological agent from pedestal, (2) fibroblast, (3) neurotoxin, (4) somatomedin or (5) any other retardance or the conduction in the weakening fat pad neuroganglion of Fibrin Glue or other biopolymer medicament.

In one embodiment, conduction-modifying agent comprises from the body fibroblast.Fibroblast is the cell of non-conduction type, also secretes the collagen as electrical insulator.Come from the biopsy of patient skin from the body fibroblast, through injecting and/or transplant after the propagation.In another embodiment, this mechanocyte is taken from the patient, and prepares in a kind of mode that makes it to be suitable for to be transported to the heart desired area.Above-mentioned preparation is connected with suitable delivery conduit.

In the neuroganglion of heart fat pad, conduct the mechanism of adjusting

Mammiferous heart has the various and neural relevant ganglionic set that is called as neural nodal plexus.Neuroganglion contains neuron in many joints, and wherein major part is a multipolar neuron, is one pole or bipolar neuron but part is also arranged.Have been found that in human heart joint heart visceral ganglion and relevant nerve thereof mainly are included in the visceral pericardium fat, they form the neural nodal plexus in five atrium and five ventricular ganglion clumps in visceral pericardium fat.As Armour, people such as J.Andrew are at The Anatomical Record, Vol.247,1997, disclosed in the article of delivering on the pp.289-298 " Gross and Microscopic Anatomy of the Human Intrinsic CardiacNervous System ": the neural nodal plexus in atrium (" AGP ") is positioned on the upper surface of right atrium (upper right AGP), on the upper surface of left atrium (upper left AGP), on the rear surface of right atrium (right back AGP), (AGP in left back) (right back AGP and left back middle AGP are fused to together in the centre) gone up on the back middle surface of left atrium after they extend in the atrial septum forward, and the following and lateral surface (back left exterior AGP) in left back atrium; And the fat that ventricular ganglion clump (" VGP ") can be arranged in around aortic root (has the right side, before, a left side, the aortic root VGP of back composition), left and right sides starting point coronarius (the neural nodal plexus that is positioned at the starting point of left coronary artery extends to ramus descendens anterior arteriae coronariae sinistrae and the starting point (anterior descending branch VGP) of circling round and propping up), the starting point of posterior descending coronary artery (posterior descending branch VGP), the starting point (blunt edge props up VGP) of propping up with right coronary artery sharp-edged Zhi Xianglin (right sharp-edged props up VGP) and left coronary artery blunt edge.Neuron also can be arranged in the position beyond the above-mentioned position, mainly is the fat that is arranged in other large-scale coronary arterial tree spot correlation.

Though other fat pad also can be received treatment according to mechanism as herein described, the most noticeable is three kinds of visceral pericardium fat pads.They are postcava-left atrium (" the IVC-LA ") fat pads that are preferably upper right atrium and sinuatrial node and provide right pulmonary vein (" the RPV ") fat pad of nerve fiber, nerve fiber is provided for AV interface and two atrium; And for all RPV and IVC-LA fat pad provide efferent fiber, and provide superior vena cava-aorta (" SVC-AO ") fat pad of additional fiber for two atrium.

In neural nodal plexus, taking place on the function between the neuron on the position (being called as synapse) of contact, impulsion is transmitted to another neuron from a neuron.Though it is electrical synapse that the part synapse is arranged among the central nervous system, the conduction between the neuron is normally undertaken by the chemical neurotransmitter that axon ends discharged of excitatory cells or presynaptic cell.Neurotransmitter is crossed synaptic space and is spread, with the postsynaptic cell film on receptors bind, the electricity in the postsynaptic cell is changed exerting an influence thus.

One class conduction-modifying agent is injectable biopolymer, for example Fibrin Glue and alginate.Biopolymer becomes semirigid pedestal (scaffold) after injection, form fibrin matrix, and we think that this fibrin matrix can make the conduction of impulse in the synapse mechanically be interrupted.Fibrin self is an electrical insulator, and therefore in any electrical synapse that may exist, fibrin is expected to be used for suppress conduction.

A kind of typical fibers albumen substrate has noticeable performance, makes it to be particularly conducive in being in coronary bypass grafting (" CABG ") operation, the convalescent patient of other cardiac surgery procedure to control AF.As Steinberg, Jonathan S. is at Journal of the AmericanCollege of Cardiology, Vol.43, No.6, March 17,2004, described in the article of delivering on the pp.1001-1003 " Editorial Comment:Postoperative Atrial Fibrillation, ABillion Dollar Problem ": AF is coronary bypass grafting (" CABG ") operation most common complication.AF is frequently outbreak repeatedly in initial two to four days after operation.Fa Zuo partly cause is the weakness that is pre-existing in the atrium on the electrophysiology repeatedly, but may have the other factors that works in a large number, and preoperative electrical anomaly and textural anomaly, postoperative fibrillation (profibrillatory) factor that causes.As Cummings, Jennifer E. is at Journal of the American College of Cardiology, Vol.43,2004, report in the article of delivering on the pp.994-1000 " Preservation of the anterior fat padparadoxically decreases the incidence of postoperative atrial fibrillation inhumans ": the common measure of fat pad is arrhythogenic reason before extracing in the CABG process, may be owing to upset the equilibrated cause of sympathetic nerve and parasympathetic nervous regulating action.Steinberg also proposes: the innerv heterogeneous damage in atrium (heterogeneous loss) that is caused by fat pad before extracing, can increase the weight of heterogeneous intractable (heterogeneity of refractoriness), this is extremely important for impelling as turning back of AF mechanism, and is the crucial deciding factor of AF.If like this, then can bring a large amount of problems.This class problem is: whether denervation (denervation) is more effective than keeping innervation completely.Another this class problem is: when extracing fat pad, whether can produce serious harmful effect to function or other autonomic nerve cardiac response of sinuatrial node or AV knot.

Noticeable performance is: the typical fibers albumen substrate was only kept 7 days to 10 days, then this albumen substrate begins degraded, and this performance makes the typical fibers albumen substrate be particularly conducive to control AF outbreak in being in coronary bypass grafting (" CABG ") operation, the convalescent patient of other cardiac surgery procedure.Therefore, the conduction regulating action of typical fibers albumen substrate is temporary transient, and in the critical period after operation or operation, can be used for reaching denervation completely, restore funcitons subsequently is to avoid any adverse effect by irreversible denervation was caused completely.Even extractd the SVC-AO fat pad, remaining RPV fat pad and IVC-LA fat pad also can be handled with biopolymer, to reach denervation completely, restore funcitons in remaining RPV fat pad and IVC-LA fat pad subsequently in the critical period after operation or operation.

Fig. 1 is the sketch map of simplifying, and preganglionic neuron 110 from neck vagus nerve 120 is shown to the nervous pathway 100 of sinuatrial node 160.In RPV or sinuatrial node fat pad 140, preganglionic neuron 110 and postganglionic neuron 150 are got in touch by neuroganglion synapse 130.Postganglionic neuron 150 links to each other with sinuatrial node 160.

Fig. 2 is curve Figure 200, is illustrated in the time domain interior result of sinuatrial node fat pad 140 (Fig. 1) after middle a period of time who Fibrin Glue is expelled to dog class subjects.Time domain is traced the contrasting data that line 210,220,230 and 240 is represented sinus rhythm reaction, and is respectively the signal of ECG, right atrium RA, right ventricle RV and blood pressure BP before applying electricity irritation in about 4 weeks behind the injection fibrin mixture, to neck vagus nerve 120.Time domain is traced line 250 to 280 and is illustrated electricity irritation is applied to the physiological reactions same as described above that neck vagus nerve 120 back is produced.Trace line 250 to 280 and lump together the interval time lengthening that demonstrates between the cardiomotility, thereby the animal Heartbeat rate obviously slows down.We believe: the fibrin gel matrix is heavily absorbed, and makes the 120 suffered electricity irritation of neck vagus nerve come into force and causes parasympathetic nervous reaction, and the animal Heartbeat rate is slowed down.

Another kind of conduction-modifying agent is injectable fibroblast preparation.Fibroblast is a kind of connective tissue cell that forms fibrous tissue in vivo.We believe: when near the neural nodal plexus that fibroblast is injected fat pad, fibroblast move into synapse near, and the conduction of getting excited in the synapse is mechanically interrupted.Fibroblast is an electrical insulator, and in any electrical synapse that may exist, fibroblast is expected to be used for suppress conduction.And this effect is sustainable.

Another kind of conduction-modifying agent is injectable fibroblast growth factor (" FGF ") preparation.Fibroblast growth factor is a cytokine family, and it works to intravital fibroblast and makes it propagation.Most of cell of various organs (comprising nervous system and heart) all has the receptor of FGF in the body, therefore is subjected to its biological Effect easily.In addition, fibroblast growth factor can link and the formation binding molecule with various biopolymers.Suitable biopolymer comprises polysaccharide and mucosa-adhesive agent (muco-adhesive).FGF is a kind of small protein, when being heated or place acid, and degeneration easily.When FGF was combined, protein was more stable.In order to keep the required effect of GF on ad-hoc location, combination can also make FGF controlledly carry out from the dispose procedure of carrier.

Another kind of conduction-modifying agent is injectable neurotoxin preparation.Available neurotoxin comprises that (for example A type Botulinum toxin can be the California, USA Irvine city Allergan company that is positioned at that derives to Botulinum toxin, and commodity are by name

The neurotoxin complex of purification).Another kind of is that Botulinum toxin known in the field is the Type B Botulinum toxin.We believe: when near the neural nodal plexus that it is expelled in the fat pad time, and the conduction that Botulinum toxin can interrupt getting excited in the synapse.This effect is temporary, and neuron generally recovered in about 3 to 6 months.

The method of arrhythmia being treated according to mechanism as herein described is owing to be to form conduction block in the innervation of fat pad, thus non-ablation techniques that is considered to be highly profitable or MIN ablation techniques.Other forms the used routine techniques (for example specific routine operation excision and conventional energy ablation art) of heart block and has many other side effect and shortcoming, when a kind of required therapy that does not have above-mentioned side effect and a shortcoming was provided, this programme had great advantage.This programme has been avoided the high temperature and collagen contraction and other the substantive cicatrix that are produced by ablation energy delivery form.In addition, the defective of most ablation techniques is also to want control energy to carry and the coverage in target site or target site tissue in addition.For example, most RF energy ablation equipment and technology can cause carbonization, and this is relevant with the required high-temperature gradient of the conduction block that forms saturating wall.Observe through regular meeting when using most conventional energy ablation technology: energy unnecessarily is distributed in the surrounding tissue, and this programme has also been avoided this situation.

Because main fat pad all is easy to discern and neural nodal plexus wherein enters easily, so the method ratio of arrhythmia being treated according to mechanism as herein described is easier to implement.In addition, when conduction-modifying agent was applied to fat pad, effective therapeutic dose of conduction-modifying agent was important when it is applied to other cardiac structure.Effectively therapeutic dose is general inessential be because: the conduction-modifying agent of most of types (comprising fibroblast, neurotoxin, somatomedin and biopolymer) has scatter by the fat in the fat pad (comprise the part that must reach required effect therein that innervates, and do not have effect or the very little other parts of effect therein).In addition, fibroblast increases in vivo and spreads and spreads all over target tissue.

The technology of preparing of part conduction-modifying agent

Can use fibroblast to regulate conduction in the heart fat pad neuroganglion.Fibroblast is relevant with the healing tissue usually.By activation, cell changes activatory phenotype into.The corresponding biological function that resting stage, cell had fundamental difference in activatory phenotype and the normal structure.Above-mentioned cell phenotype (coming from collaborative gene expression) is regulated and control by cytokine, somatomedin and downstream nuclear target.Even this cell also can be survived and breed under low-oxygen environment.Fibroblast resting stage in the normal structure mainly is responsible for coming the transition cell epimatrix with steady statue.

Fibroblast is transplanted and is used for fibroblast is transported in the neural nodal plexus along the ARR path of fat pad.Fibroblastic person's character will be filled in-house space exactly.When being expelled to fibroblast in the fat pad, fibroblast is filled the space in the fat pad, but is controlled so as on gene level: in case they begin to assemble, then stop propagation and breeding.

Fibroblast is very favorable for forming conduction block by cell therapy.A particularly advantageous aspect is: when fibroblast was converted into myotube, they need not will experience as the skeleton sarcoplast from breeding the conversion stage to mature cell.Therefore, compare with skeletal muscle, fibroblast has the excited phenotype of uniformity more.In addition, the electrophysiological characteristics between all fibroblasts is quite consistent, and is considered to the retardance conduction effectively.

A kind of exemplary fibrocellular method that is prepared into is: use patient oneself intravital from body fibroblast (for example fibroblast that is obtained by skin samples), subsequently with its suitably preparation (for example in cultivation/preparation test kit) and be transplanted to target site place in the heart tissue structure, with conduction along arrhythmia path delay heart tissue, thereby the conduction disturbance in the treatment heart (for example, auricular fibrillation, ventricular tachycardia and/or ventricular arrhythmia and CHF).Fibroblast has the ability of retardance or change/transformation cardiac conduction path.

Skin flbroblast is enhanced to the migration of PDGF, the gathering of the synthetic and netted collagen of the gathering of enhancing collagen and MMP.The formation of this collagen stroma is added and is lacked the gap conjugated protein in the fibroblast, has formed the isolated probability of electromechanical.Formerly suffers from the overall shortage of having observed conductivity in patient's the cardiac muscle of myocardial infarction in the fibroblast migration area.

Fibroblast can carry out biopsy, separation, cultivation propagation from many tissues in the body (lung, the heart, skin), and uses or do not use polymer support or skeleton to inject, transplant conveyings, transplanting etc. and be introduced in the zone that needs to regulate conduction or isolation arrhythmia path in the heart.Fibroblastic preparation can mainly comprise a kind of material or only comprise a kind of combination of material or comprise the combination of multiple material.For example, comprise fibroblastic preparation and may comprise other material (for example fluid or other substrate), to be provided at the cell in the whole preparation, as the cell medium that is suitable for injection (for example particularly injecting) by the conveyor chamber of delivery conduit.In a concrete example, fibroblast can with bio-polymer material (Fibrin Glue for example, himself can obtain like this: two kinds of precursor materials are formed Fibrin Glue through mixing) combination, when this bio-polymer material was transported in the heart desired location place with cell, this bio-polymer material is auxiliary to form conduction block.In this compositions, collagen wherein or preparation (precursor or analog or the derivant that comprise collagen) also are useful.

Can use biopolymer to regulate conduction in the heart fat pad neuroganglion.Biopolymer is transported to neural nodal plexus along the arrhythmia path in the fat pad.It has been generally acknowledged that polymer is the chain that a plurality of unit or " monomer chain link " constitute.For example, Fibrin Glue comprise polymerization fibrin monomer because its composition is a biotic component, so also be counted as the illustrative example of biopolymer in this article.Thrombin in the test kit is initiator or catalyst, fibrinogenase is separated be cracked into fibrin.Then monomer polymerization is become fibrin colloid or glue.Available Fibrin Glue is TISSEAL ^TM(deriving from the Baxter Healthcare company in Illinois, America Chicago city).Sierra DH is at J.Biomater Appl., vol.7,1993, disclosed other example of Fibrin Glue in the article of delivering on the pp.309-52 " Fibrin sealant adhesive systems:areview of their chemistry; material properties and clinical applications ", incorporated its full content into this paper with way of reference at this.

Biopolymer can use separately or use with other combination of materials.In a useful combination, the preparation of fibroblast and biopolymer is transported in the heart tissue structure to form conduction block herein.This biopolymer makes and is transported to fibroblastic persistence (retention) enhancing that will form the conduction block position, and helps to form conduction block.With provide in the material of remarkable advantage during fibroblastic cell therapy is used in combination, an instantiation is a Fibrin Glue.

Fibroblast growth factor (" FGF ") can be used for regulating the conduction of the neuroganglion of heart fat pad.The protein short chain (being commonly called polypeptide) that somatomedin (" GF ") normally is attached to the cell surface receptor position and directly target cell is played a role.This process is passed through cell proliferation and/or cell differentiation usually.Usually, somatomedin works at cellular level, to repair damaged cells, to strengthen cell proliferation, keep the best-of-breed functionality of target organ and aged tissue is restored.

Fibroblast growth factor is meant intravital fibroblast played a role and makes it the proliferating cells factor family.Have 23 FGF superfamily members, they and at least four kinds of distinct cell surface receptor reciprocal actions.Derive from the R﹠amp that is positioned at Minneapolis city, Minn.; The multiple material of D Systems company (comprises R﹠amp; The catalogue of D Systems company calendar year 2001: Fibroblast Growth Factors, 2001 (http://www.rndsystems.com/asp/g_SiteBuilder.asp? BodyID=308); And R﹠amp; D Systems company catalogue in 1996: Fibroblast Growth Factors 9,1996 (http://www.rndsystems.com/asp/g_sitebuilder.asp? bBodyOnly=1﹠amp; BodyId=199)) in fibroblast growth factor is further described in detail, all right with reference to following document: Gospodarowicz Denis, Fibroblast growth factof:chemicalstructure and biologic function, Clinical Orthopedics and Related Research, Number 257, August 1990, pp.231-248.

Can use the conduction in the neurotoxin adjusting heart fat pad neuroganglion.The example of an available neurotoxin is a Botulinum toxin, and this toxin is to produce and can resist in several virtuous neurotoxin of proteolytic enzyme digest any one by bacillus botulinus.The product information of Allergan company issue in 2004: Botox:mechanism of action ( Http:// www.botox.com/site/professionals/product info/mechanism_of a Ction.asp) disclosed the botulinal mechanism of action of A type.In essence, A type Botulinum toxin is by making the SNAP-25 cracking to stop the release of acetylcholine, and SNAP-25 is a kind of cytoplasmic protein matter that is positioned on the cell membrane, and is that the above-mentioned mediator of release is necessary.

Various material as herein described (for example Fibrin Glue and related agents thereof, analog and derivant) is especially effectively also useful.But, in special-purpose, also can use other suitable material with above-mentioned certain material combinations or as its succedaneum.One concrete aspect in, Fibrin Glue or relevant biopolymer medicament have wherein been described in this article, in this case, particularly with regulate neuroganglion in the relevant situation of conduction under, also expectation use collagen or its precursor or analog or derivant.In addition, under the situation that comprises collagen in this way, also precursor or the analog or the derivant of collagen used in expectation, for example: the structure that is formed collagen in vivo by metabolism or change; Or finally can form the combined material of collagen; Or thereby molecular structure and collagen do not have the required purposes (for example, with respect to this function remove or change non-functional groups) and collagen on all four material of its activity of essential distinction with respect to this paper expection.Can organize collagen and this class precursor thereof or analog or derivant to this and call " collagen agent ".Similarly, the precursor that other " medicament " (biological example polymer doses, Fibrin Glue medicament, neurotoxin medicament and somatomedin medicament) can also comprise the precursor that actual end product, their quilt are carried separately or their quilt is carried together or carry in collaborative mode is to form final material.

Though the present invention makes conduction block in heart, and heart tissue is melted, but it should be understood that, for example " do not melt basically ", " being essentially non-ablative " and the term of similar meaning be meant that the dominant mechanism of effect is not to make ablation of tissue, and most being organized in carries the position of material not melt.But what should consider is that any material that is transported in the tissue all can cause some relevant cell death.For example, injection pressure or or even the piercing process of pin itself all can kill some cell, but this is not the dominant mechanism that obtains conduction block.Similar aspect is: possible all material all can have certain toxicity to all cells to a certain extent.

But if do not make ablation of tissue basically when material is transferred, and under the situation that material exists with this conveying capacity, heart cell generally can both be survived, and then to be considered to heart cell in this article be non-ablative to this class material basically.

It is also contemplated that: the cell delivery of being implemented according to the present invention, can cause the cell mortality in the heart germinal cell in having implemented the tissue district that carries under certain conditions, perhaps make this germinal cell apoptosis subsequently, but the transplanted cell of this germinal cell replaces.The result of this situation remains useful, because this structure remains tissue to cell, we think that this result is better than the result of the cicatrix damage zone that traditional ablation techniques causes.

In addition, provide significant advantage although be used for the various aspects of the present invention of non-ablative conduction block, yet other embodiment also can comprise the mode of melting (mode that the conveying of cell or Fibrin Glue and ablation are combined for example, the two or carry out simultaneously or carry out successively).

Conduction-modifying agent is transported to method in the fat pad

Can make ins all sorts of ways is transported to conduction-modifying agent in the neuroganglion of fat pad.Suitable method has been described: the U.S. Patent application No.10/329 of December in 2002 application on the 23rd in following document, 295 (Randall J.Lee and Mark Maciejewski, System andMethod for Forming a Non-Ablative Cardiac Condition Block), on November 20th, 2003, the disclosed world disclosed No.WO 03/094855 A1 (Randall J.Lee and Mark Maciejewski, System and Method for Treating Cardiac Arrhythmiaswith Fibroblast Cells); The U.S. Patent application No.10/349 of application on January 21st, 2003,323 (RandallJ.Lee, System and Method for Forming aNon-Ablative Cardiac Conduction Block), and on November 20th, 2003 open No.WO 03/095016 A1 in the disclosed world, the full content of these patent documentations is incorporated this paper at this into way of reference.

Fig. 3 is the sketch map of the used tube injection system 300 of exemplary one pack system conduction-modifying agent.The tube injection system comprises delivery conduit 330, and delivery conduit 330 is its near-ends with connector 340 and the pipe 350 of syringe 310 links to each other, its far-end has entry needle 320 prolate body.Inner chamber extends through delivery conduit 330.Entry needle 320 extends beyond the far-end of delivery conduit 330 and extends in the tissue, thereby medicament is transported to the tissue from syringe 310.Entry needle 320 can be relatively fixed on the delivery conduit 330, and is perhaps movable in the axial direction.Entry needle 320 can adopt various form, comprises the spiral form of straight pinnacle type and hollow, to help in the target site grappling.

The performance of delivery conduit 330 can change significantly according to the operation that will implement.Fig. 4 is the transverse cross-sectional view of conduit 400, and wherein entry needle 420 is slidably mounted in single cavity in the catheter main body 410.Fig. 5 is the transverse cross-sectional view of conduit 500, and wherein, entry needle 520 is slidably mounted in the inner chamber of catheter main body 510.Have other inner chamber 530 and 540 in the catheter main body 510, can have various function according to the above-mentioned inner chamber of concrete needs.Fig. 6 is the transverse cross-sectional view with conduit 600 of four inner chambers.Be installed with slidably in one of them inner chamber in 630, one inner chambers of entry needle backguy 640 is installed slidably, two remaining inner chambers are installed with lead 620 and 650, and for example, above-mentioned lead can be connected to localizing electrode (mapping electrode).Localizing electrode is the part of navigation system, and described navigation system is used for the correct position of test material injection, particularly under situation about being expelled to from heart inside (endocardium) the fat pad.The heart location is well-known, Pappone, people such as Carlo are at Circulation 109, r7-r14, a localized example of heart described in the article of delivering on 2004 " Pulmonary vein denervationenhances long-term benefit after circumferential ablation for paroxysmalatrial fibrillation ", and the full content of this article is incorporated this paper at this into way of reference.

It should be understood that the conduit variant shown in conduit system shown in Figure 3 300 and Fig. 4 to 6 only is exemplary.Can use various multi-form conduit systems and conduit that conduction-modifying agent is carried and is expelled in the fat pad.

Fig. 7 is the sketch map of the used tube injection system 700 of exemplary bi-component conduction-modifying agent.The tube injection system comprises delivery conduit 750, and delivery conduit 750 is its near-ends by connector 760 and syringe 720 and 710 separately prolate bodys that pipe 770 links to each other with 780, its far-end has entry needle 730 and 740 respectively.Entry needle 730 and 740 extends beyond the far-end of delivery conduit 750 and extends in the tissue, thereby medicament is transported to the tissue from syringe 710 and 720. Entry needle 730 and 740 can be fixing, perhaps movable in the axial direction with respect to delivery conduit 750.

Tube injection system 700 is particularly suitable for wherein, and component is the bi-component conduction-modifying agent of precursor biopolymer (for example Fibrin Glue).When Fibrinogen mixes with thrombin under the condition that calcium ion exists, will form fibrin, fibrin is the necessary fibrous proteins of blood clotting.Under special-purpose, need mix in systemic specific region Fibrinogen and thrombin in (fat pad of (endocardium) in for example around the fat pad or heart of heart (visceral pericardium)).Usually, in most of such use, do not wish to make these two kinds of components they accurately will mixed the position in addition, position of injection.In tube injection system 700, bi-component keeps fully separately up to the far-end output from entry needle 730 and 740, so just do not exist make each component in tube injection system 700 or in the injection site in addition the polymeric chance in any other position.

Fig. 8 is the transverse cross-sectional view of the conduit 800 that is suitable for of tube injection system 700.Conduit 800 has two inner chambers in catheter main body 810, entry needle 820 and 830 wherein are installed respectively slidably.Entry needle 730 and 740 (Fig. 7) circulates by inner chamber with syringe 720 and 710.The Fibrin Glue precursor along distinct passage from separately injector current to entry needle separately, thereby precursor is mixed after only in being expelled to tissue.

It should be understood that conduit system shown in Figure 7 700 and conduit variant shown in Figure 8 only are exemplary.Can use various multi-form conduit systems and conduit that conduction-modifying agent is carried and is expelled in the fat pad.

Fig. 9 is the sketch map of an exemplary injection system, and this system is used at for example open heart surgery process injection bi-component conduction-modifying agent.Injecting systems shown in Figure 9 comprises that two syringes 940 and 960, two syringes can be shaped to single cell cube, also can be the independently syringe of clipping together with anchor clamps 950. Syringe 940 and 960 shown in the figure has the empty tube that matches with they pistons separately respectively.Perhaps, can connect together the piston of each empty tube, they just can be depressed simultaneously like this.The component 920 and 930 that entry needle parts 900 have dual pathways part 910 and are connected with 960 with syringe 940 respectively.Be conducted through separately branch 920 and 930, the passage separately in the admission passage part 910 from two kinds of components of conduction-modifying agents of syringe 940 and 960 outputs.Two kinds of components keep separating fully, up to far-end output from entry needle parts 900, so just do not exist make each component in syringe or in the injection site in addition the polymeric chance in any other position.

Figure 10 is the sketch map of another exemplary injection system, and this system is used at for example open heart surgery process injection bi-component conduction-modifying agent.Except that entry needle parts 1000 there are differences, injecting systems shown in Figure 10 was identical with the injecting systems of Fig. 9.The component 1020 and 1030 that entry needle parts 1000 have spiral helicine dual pathways part 1010 and link to each other with 960 with syringe 940 respectively.Be conducted through separately branch 1020 and 1030 from two kinds of components of conduction-modifying agents of syringe 940 and 960 outputs, separately passage in the admission passage part 1010.Two kinds of components keep separating fully, up to far-end output from entry needle parts 1000, so just do not exist make each component in syringe or in the injection site in addition the polymeric chance in any other position.

Enter in the tissue by linear movement guiding entry needle 900 (Fig. 9), and enter in the tissue tissue during entry needle 1000 is particularly suitable for moving (for example heart) by screw guiding entry needle 1000 (Figure 10).Preferably, have a passage through to their far-ends in entry needle 900 and the entry needle 1000.

Though Fig. 9 and injecting systems shown in Figure 10 are twin-channel, also any amount of autonomous channel can be set in the entry needle.In the multichannel entry needle independently passage precursor separately is directed to the far-end of entry needle.The far-end of entry needle be injected into systemic specific part (for example around heart or heart in fat pad) in.Left the far-end of entry needle by the material of being provided and delivered, in injected tissue, mix then, rather than in the internal mix of entry needle or syringe.What syringe can have any amount of empty tube and a respective numbers extends downwardly into the passage of far-end by empty tube.Can take the multichannel entry needle to handle respectively away from tube, perhaps can be fixed on the empty tube.In addition, tube injection system 300 (Fig. 3) and 700 (Fig. 7) can be provided with the single channel entry needle shown in multichannel entry needle rather than the figure.

Figure 11,12 and 13 only illustrates has more twin-channel possibility methods in the entry needle.Figure 11 illustrates the entry needle 1100 with main body 1110, and main body 1110 is spaced apart thing 1140 separately to form well-separated inner chamber 1120 and 1130.Figure 12 illustrates the entry needle 1200 with main body 1210, has formed two well-separated inner chambers 1220 and 1230 in the main body 1210.Figure 13 illustrates the entry needle 1300 with main body 1310, and main body 1310 is interior around second inside subject 1340, to form well-separated inner chamber 1320 and 1330.Though inner chamber shown in the figure and entry needle are circular, they also can be oval-shaped or any other required shapes.

It should be understood that tube injection system as herein described and injecting systems only are exemplary,, can use other suitable substitute in order to reach two kinds of precursor materials of conveying and to make it to mix to form the purpose of injected medicament.For example, the precursor material of some type can perhaps just mix before being connected to delivery conduit in (for example near the mixing chamber duct coupler) just mixing before the far-end output of entry needle.In addition, can use more than one conveying equipment in two kinds of materials being carried each; For example, can use two well-separated entry needles each from two kinds of precursor materials of medicine source conveying separately, this medicine source is positioned at outside the patient body.

Experimental example

Operation is prepared as follows: two adult mongrels (body weight be 23 to 30kg) are implemented premedicate with penthiobarbital (20mg/kg) from intravenous injection, intubate is also used respiratory organ (Narkomed 2 types, derive from the NorthAmerican Drager company that is positioned at Pennsylvania, America Telford city) feed the room air that has replenished oxygen as required, to keep normal arterial blood gas.Make whole experiment keep anesthesia with 1% to 2% isoflurane then.Lose with additional spontaneous liquid with 100 to 200mL/ hour speed venoclysis normal saline solution.In whole research process, the standard ecg leads of continuous monitoring body surface (I, П, Ш).Intermittently detect arterial blood gas and regulate respiratory organ to correct any Developmental and Metabolic Disorder.Monitor rectal temperature with transrectal probe, and make the body temperature of Canis familiaris L. remain 36 to 37 ℃ with electric warming pad under the Canis familiaris L. health and operating room lamp.

Carry out the right common femoral artery intubate and insert the catheter pressure sensor (can derive from the Millar company that is positioned at Texas, USA Houston city) that micromanometer is housed the top, this pressure transducer advances near the thoracic aorta the aortic valve, with the blood pressure of monitoring whole body.After opening the thoracic cavity, found the pericardium support to support heart by median sternotomy.The quadrupole plate electrode of Ag-AgCl of customization is sewn onto the high position of right atrium and right ventricle, is used for bipolar pace-making and record.Re-using similar bipolar plate electrode stimulates two visceral pericardium fat pads that contain the parasympathetic nervous path, and this parasympathetic nervous is selectivity domination sinuatrial node (SN) and AVN respectively.The SN fat pad is positioned at the junction in right pulmonary vein (RPV)-atrium.The AVN fat pad is positioned at the junction of postcava and left atrium (IVC-LA).All signals (surface ECG, right atrium and ventricular electrogram, arteriotony) amplification, filtering, digitized also are presented on the monitoring system (Prucka Engineering company) continuously.In addition, these signals and correction signal be recorded in simultaneously tape (Vetter Digital, 4000A) on, use Axoscope (AxonInstrument company) and user software program to carry out computer analysis afterwards.

Research approach is as follows.Research divides 2 stages, the observation period after initial acute operation (acute surgery) and 4 weeks recover.In initial acute operation, we detect vagal effect by transmitting electricity irritation to fat pad.Electricity irritation with 20Hz (interval of 50ms), persistent period be 0.2 to 0.5ms, amplitude is that 3 to 5mA rectangular pulse transmits.In last conceptual phase, except fat pad, we also are delivered to neck vagus nerve (when complete and after separation) to electricity irritation.In this case, each parameter of electricity irritation be 3,5 and 10Hz, persistent period be that 1ms, amplitude are 5mA.

When initial acute study, Fibrin Glue is injected in 2 fat pads.We use Quixil (binary mixture of a kind of thrombin and BAC), carry by the entry needle of dual pathways syringe and No. 23 (gauge), and two above-mentioned components are only mixed in fat pad.Entry needle is inserted under the fat pad epicardial surface 1 to 2mm.Is total amount that the Fibrin Glue of 1ml is transported in each fat pad.

Observe following effect.Before the injection Fibrin Glue, fat pad is subjected to the electricity irritation meeting and produces various observable effects.Figure 14 illustrates: before the injection Fibrin Glue, the sinuatrial node fat pad is subjected to the electricity irritation meeting and produces tangible chronotropic action; Interval 1410 and interval 1420, compared, can be observed and prolonged cycle time.Figure 16 is illustrated in before the injection Fibrin Glue equally, and AV knot fat pad is subjected to the electricity irritation meeting and produces tangible dromotropic effect; The relative timing of pulse 1610 and 1620 relatively, can be observed the RA-RV prolongation of interval.In addition, relatively interval 1810 and 1820 as seen: Figure 18 is illustrated in and brings out during the AF, and AV knot fat pad is upset and causes the ventricle rate of fighting obviously to slow down.But, after the injection Fibrin Glue, fat pad is carried out electricity irritation and do not observe above-mentioned effect at once.Compare Figure 15 and Figure 14 as seen, interval 1510 and 1520 shown in Figure 15, is equal substantially.Compare Figure 17 and Figure 16 as seen, pulse 1710 shown in Figure 17 and 1720 relative timing do not have to change substantially.Compare Figure 19 and Figure 18 as seen, interval 1910 and 1920 shown in Figure 19, is equal substantially.

After the injection 4 weeks the time,, also transmit vagal stimulation in addition first by the neck vagus nerve by identical scheme repeated experiments.After the cycle in 4 weeks, all vagus nerve effects have all occurred.

The invention that comprises implementation method and advantage that this paper provides is described, and is for illustrative purposes, rather than limits scope of the present invention that scope of the present invention is defined by the claims.By the research patent document, can change and change the disclosed embodiment of this paper, what one of ordinary skill in the art will appreciate that is: the various key elements of described embodiment have practical substitute and equivalent.Only otherwise depart from scope and spirit of the present invention, can carry out above-mentioned and other variation and change to the embodiment that this paper discloses.

Claims (22)

1. one kind is used in the ARR system of patient's heart control, and this system comprises:

The heart induction system; And

Neuron conduction-modifying agent medicine source, it links to each other with described heart induction system, described neuron conduction-modifying agent is essentially non-ablative to neuroganglion, and for regulate in the neuroganglion the neuron conduction effectively;

Wherein, described heart induction system comprises distal portions, and described distal portions is used for described neuron conduction-modifying agent is transported near the neuroganglion of at least one heart fat pad.

2. system according to claim 1, wherein, the described distal portions of described heart induction system comprises that at least one has terminal entry needle, and described end is used for the surface of described neuron conduction-modifying agent by described fat pad is expelled near the described neuroganglion.

3. system according to claim 2, wherein, described entry needle is straight.

4. system according to claim 2, wherein, described entry needle is spiral helicine.

5. system according to claim 1, wherein, described heart induction system comprises induction system in the heart.

6. system according to claim 1, wherein, described heart induction system comprises the endocardium system.

7. system according to claim 1, wherein, described heart induction system comprises the intravascular system, is used for described neuron conduction-modifying agent is transported to described fat pad by the blood vessel wall that links to each other with described heart.

8. system according to claim 1, wherein, described neuron conduction-modifying agent comprises fibroblast.

9. system according to claim 1, wherein, described neuron conduction-modifying agent comprises biopolymer.

10. system according to claim 9, wherein, described biopolymer is a Fibrin Glue.

11. system according to claim 9, wherein, described biopolymer is alginate.

12. system according to claim 1, wherein, described neuron conduction-modifying agent comprises neurotoxin.

13. system according to claim 12, wherein, described neurotoxin is an A type Botulinum toxin.

14. system according to claim 1, wherein, described neuron conduction-modifying agent comprises somatomedin.

15. system according to claim 14, wherein, described somatomedin is a fibroblast growth factor.

16. system according to claim 1, wherein, described heart induction system comprises:

At least one entry needle, it has and is used for described neuron conduction-modifying agent is expelled near the described neuroganglion far-end by described fat pad surface, and has near-end; And

Connector, the described proximal end that it places described entry needle is used to connect described entry needle and described medicine source.

17. system according to claim 1, wherein, described heart induction system comprises conduit, and described conduit comprises:

Prolate body, it has near-end and far-end;

At least one inner chamber, it runs through described prolate body between the near-end of the far-end of described prolate body and described prolate body;

At least one entry needle, it places the described far-end of described prolate body, and has the surface of described neuron conduction-modifying agent by described fat pad is expelled near the described neuroganglion end, and described entry needle is that fluid is communicated with described inner chamber; And

Connector, the described proximal end that it places described prolate body is used to connect described inner chamber and described medicine source.

18. system according to claim 17, described system also comprises:

Localizing electrode, it places the described far-end of described prolate body; And

Conductor, it runs through described prolate body between the near-end of the far-end of described prolate body and described prolate body.

19. system according to claim 1, described system also comprises:

Place the anchor of the described distal portions of described heart induction system, described anchor is used for the described distal anchor of described heart induction system is fixed on a certain position on the described fat pad, thereby when described anchor is anchored to described position, described neuron conduction-modifying agent is transported near the tissue district, described position.

20. system according to claim 1, wherein:

Described neuron conduction-modifying agent comprises various ingredients;

Described medicine source comprises a plurality of individual components, and described each component is contained in respectively in each individual components in described medicine source individually; And

Described heart induction system comprises a plurality of independently transfer passages, and each passage of the described distal portions of described heart induction system is communicated with each individual components fluid in described medicine source respectively by described each transfer passage.

21. system according to claim 20, wherein, described component comprises precursor biopolymer.

22. system according to claim 21, wherein, described component also comprises fibroblast, neurotoxin, somatomedin or its compositions.

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