WO2008043099A2 - systÈme de stimulation cardiaque hybride - Google Patents

systÈme de stimulation cardiaque hybride Download PDF

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Publication number
WO2008043099A2
WO2008043099A2 PCT/US2007/080718 US2007080718W WO2008043099A2 WO 2008043099 A2 WO2008043099 A2 WO 2008043099A2 US 2007080718 W US2007080718 W US 2007080718W WO 2008043099 A2 WO2008043099 A2 WO 2008043099A2
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WIPO (PCT)
Prior art keywords
pacing
imd
sensed
pacemaker
ventricular
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PCT/US2007/080718
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English (en)
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WO2008043099A3 (fr
Inventor
Orhan Soykan
Daniel C. Sigg
Timothy G. Laske
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Medtronic, Inc.
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Publication of WO2008043099A2 publication Critical patent/WO2008043099A2/fr
Publication of WO2008043099A3 publication Critical patent/WO2008043099A3/fr

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Classifications

    • 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
    • A61N1/3627—Heart stimulators for treating a mechanical deficiency of the heart, e.g. congestive heart failure or cardiomyopathy
    • 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
    • A61N1/3684—Heart stimulators controlled by a physiological parameter, e.g. heart potential comprising more than one electrode co-operating with different heart regions for stimulating the heart at multiple sites of the ventricle or the atrium
    • 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
    • A61N1/3684—Heart stimulators controlled by a physiological parameter, e.g. heart potential comprising more than one electrode co-operating with different heart regions for stimulating the heart at multiple sites of the ventricle or the atrium
    • A61N1/36842—Multi-site stimulation in the same chamber
    • 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
    • A61N1/3684—Heart stimulators controlled by a physiological parameter, e.g. heart potential comprising more than one electrode co-operating with different heart regions for stimulating the heart at multiple sites of the ventricle or the atrium
    • A61N1/36843—Bi-ventricular stimulation

Definitions

  • SA sinoatrial
  • AV atrioventricular
  • Bundle of His and Purkinje network which branches in many directions to facilitate simultaneous contraction of the left and right ventricles.
  • IMD implantable medical devices
  • IPG implantable pulse generators
  • ICD implantable cardioverter defibrillators
  • the IMD includes a can or device housing that is implanted subcutaneously with one or more leads extending to an appropriate location within, or external to, the heart.
  • the therapy is generated by circuitry within the device and is transmitted along the lead to an electrode in contact with heart tissue.
  • cardiovascular diseases and conditions such as coronary artery disease, high blood pressure (hypertension), heart attack, diabetes mellitus, cardiomyopathy, heart valve disease, infection of the heart values, congenital heart disease, can and often do lead to heart failure "HF” (sometimes known as congestive heart failure).
  • HF heart failure
  • heart failure While by itself heart failure is not considered a disease per se, heart failure is a serious, chronic, and complex condition in which the heart's pumping action is compromised. With heart failure, the heart is not operating efficiently and, therefore, must work harder. For example, the heart may pump more frequently to compensate for weaken pumping ability, or the size of its chambers may increase, especially the left ventricle. Hence, significant physical change occurs with heart failure and most notably, the enlargement and thinning of the left ventricle. While biventricular pacing of the heart can benefit HF patients, not all patients can receive optimal therapy as there are often difficulties in LV lead placement.
  • a hybrid pacing system achieves pacing by synchronized operation of a biological pacemaker ("biopacer”) implanted in the left ventricule of the heart and an implantable medical device for providing pacing stimuli to one or more other chambers of the heart.
  • biopacer biological pacemaker
  • the IMD synchronizes its operation to sensed signals representing pacing activity of the biopacer.
  • FIG. 1 is a diagram of a hybrid pacing system for providing biventricular pacing including a left ventricular biopacer and an IMD for providing electrical pacing to the right atrium and right ventricle.
  • FIG. 2 is a timing diagram illustrating operation of the hybrid system of FIG. 1 in which left ventricular pacing occurs prior to right ventricular pacing.
  • FIG. 3 is a flow chart illustrating operation of the IMD for the timing diagram of FIG. 2.
  • FIG. 4 shows a timing diagram for the hybrid system of FIG. 1 when right ventricular pacing precedes left ventricular pacing.
  • FIGS. 5A and 5B are flow charts illustrating operation of the IMD for the timing diagram of FIG. 4.
  • FIG. 6 is an illustration of a hybrid system in which a biopacer is implanted in the right ventricle, and a IMD provides pacing to the right atrium.
  • FIG. 7 shows a timing diagram for operation of the hybrid system of FIG. 6.
  • FIG. 8 shows a flow chart for the operation of the hybrid system of FIG. 6 according to the timing diagram of FIG. 7.
  • FIG. 9 shows an illustration of a hybrid system in which a biopacer is implanted in the right ventricle, and an IMD provides pacing to the right ventricle.
  • FIG. 10 shows a flow chart illustrating how a IPG can operate in concert with a biological pacemaker in the same cardiac chamber, as shown in FIG. 9.
  • LV leads are typically placed in the coronary vasculature via coronary sinus access.
  • optimal lead positioning for the LV lead cannot be achieved due to anatomical limitations, as the lead placement is restricted to coronary veins in which a lead can be securely positioned.
  • the coronary vasculature may not reach a particular anatomical position, or the position that can be reached may be surrounded by infarcted tissue so that stimulation delivered by the left side pacing lead will not provide the optimal benefit.
  • Placement of endocardial leads in the left ventricle is also avoided due to its potential for clot formation.
  • the hybrid pacing system described herein avoids the need to place a lead in the left ventricle while restoring relative timing of the two ventricles.
  • FIG. 1 shows the hybrid pacing system 10, which includes a biological pacemaker 12 also referred to herein as "biopacer” and an IMD 14 synchronized to provide biventriclar pacing to heart H.
  • the biopacer 12 is implanted in a wall of left ventricle LV.
  • the IMD 14 includes housing or can 16, header 18, atrial lead 20, and right ventricular lead 22.
  • Atrial lead 20 extends from header 18 to right atrium RA.
  • Electrode 24 carried at a distal end of atrial lead 20 contacts the wall of right atrium RA.
  • Right ventricular lead 22 includes distal fixation device 26, distal tip electrode 28, and ring electrode 30.
  • Biventricular pacing or cardiac resynchronization therapy is achieved by system 10 by pacing right atrium RA, right ventricle RV, and left ventricle LV.
  • IMD 14 provides pacing stimuli to right atrium RA and right ventricle RV.
  • IMD 14 includes, within housing 16, a power source such as a battery, power supply circuitry, sensing and signal processing circuitry, therapy delivery circuitry (which may include pacing as well as cardioversion/defibrillation circuitry), a microprocessor and associated memory, and telemetry circuitry.
  • Atrial stimulation is applied to right atrium RA through lead 20 and electrode 24.
  • Pacing stimulation for right ventricle RV is provided by electrical pulses applied by tip electrode 28 and ring electrode 30.
  • Pacing circuitry within housing 16 generates the pacing pulses delivered through leads 20 and 22 to right atrium RA and right ventricle RV. Electrodes 24, 28, and 30 are also used together with the sensing and signal processing circuitry to derive sense signals representing sensed electrical activity of heart H.
  • the biopacer 12 provides pacing for left ventricle LV.
  • Biopacer 12 can be formed using genetically engineered vectors or genetically engineered cells or unmodified pacemaker-like cells, which are implanted at a selected location in the wall of left ventricle LV.
  • a delivery tool such as a temporary lead or a catheter, is introduced through left atrium LA into left ventricle LV.
  • the delivery tool includes electrodes for sensing electrical activity and delivering pacing stimuli in order to determine the desired location for biopacer 12.
  • the genetically engineered viruses or cells are delivered to the myocardium at that location to form a new sinus node.
  • the genetically engineered cells or the unmodified pacemaker-like cells reach a state at which biopacer 12 is effective in providing pacing function for the left ventricle LV.
  • the pacing of left ventricle LV and right ventricle RV must be coordinated so that both ventricles contract with the proper timing. If the contractions are not synchronized, the contractions of ventricles LV and RV will cause the septal wall to deflect, and the pumping efficiency of heart H will be degraded.
  • FIGS. 2 and 3 illustrate the operation of system 10, and in particular, IMD 14 when pacing of left ventricle LV is required to occur prior to pacing of the right ventricle RV. This is the most common situation for patients requiring a resynchronization therapy.
  • FIG. 2 is a timing diagram showing the operation of system 10.
  • IMD 14 produces stimulation to the right atrium RA and the right ventricle RV, while biopacer 12 generates the LV pulse.
  • the vertical bars labeled as A and RV are either paced or sensed events.
  • FIG. 3 shows a flow chart illustrating the algorithm governing operation of
  • IMD 14 to provide the timing of pulses illustrated in FIG. 2.
  • IMD 14 sets timer ⁇ t to zero (step 42). IMD 14 then waits for an intrinsic A event to be sensed (step 44).
  • timer ⁇ t is again reset to zero (step 46).
  • timer ⁇ t reaches or exceeds the RV to A time (T RV - A )
  • IMD 14 delivers an atrial pacing pulse through lead 20 and electrode 24 to right atrium RA (step 48). Once right atrium RA has been paced, timer ⁇ t is set to zero (step 46).
  • IMD 14 then waits (step 50) for the LV event to be sensed.
  • the LV event is scheduled to occur before the RV event.
  • step 52 If the LV event is sensed either by RV electrodes 28 and 30 or by RA electrode 24 (step 52), timer ⁇ t is again reset to zero (step 54). IMD 14 then waits for the sensing of an intrinsic RV event by electrodes 28 and 30 (step 56). If the intrinsic RV event is sensed, IMD 14 returns to step 42 and resets timer ⁇ t to zero.
  • IMD 14 If an intrinsic RV event is not detected within the ventricle-to-ventricle time period (TJ L V-RV), IMD 14 generates a pulse which is delivered through lead 22 and electrodes 28 and 30 to pace right ventricle RV (step 58). Once the RV paced event has occurred, timer ⁇ t is reset to zero (step 42).
  • FIG. 3 also illustrates a situation where the LV event is not sensed within the
  • a to RV time (A A - RV )- If the LV event is not sensed, the RV pacing pulse is generated (step 58) and timer ⁇ t is reset to zero. The cycle then repeats as illustrated in FIG. 3.
  • IMD 14 synchronizes the pacing of both right atrium RA and right ventricle RV with respect to sensed LV events produced by biopacer 12. This synchronizes biopacer 12 and IMD 14 in order to provide cardiac ⁇ synchronization therapy.
  • IMD 14 reacts to sensed LV events, but cannot generate an LV pulse if an LV event is not sensed. IMD 14 may, however, log instances where the LV event is not sensed. That information can then be delivered by telemetry to inform a physician of the missing LV events. This information can then be used to determine whether biopacer 12 is functioning properly.
  • FIG. 4 shows a timing diagram in which the order of the RV and LV pulses is reversed from what is shown in FIG. 2. Once again, the LV pulse is generated by biopacer 12. IMD 14 produces the stimulation for right atrium RA and right ventricle RV. The vertical bars labeled A and RV in FIG. 4 represent either paced or sensed events.
  • FIGS. 5 A and 5B illustrate the operation of IMD 14 in a situation which cardiac resynchronization therapy requires that the RV pulse lead the LV pulse by a time TRV-LV-
  • FIG. 5 A shows the initialization of IMD 14 for the RV first pacing scheme.
  • IMD 14 initiates ADI pacing of right atrium RA and right ventricle RV (step 62).
  • IMD 14 paces right atrium RA, senses dual chambers (i.e., RA and RV), and inhibits pacing upon detection of intrinsic activation.
  • IMD 14 measures a time (T A - LV ) from an A event to an LV event (step 64). It then calculates an A to RV time (T A - RV ) based upon the measured A-LV time (T A - LV ), and the desired time between RV and LV events T RV - LV (step 66).
  • the initialization process shown in FIG. 5 A is performed periodically in order to maintain synchronization of IMD 14 with biopacer 12.
  • FIG. 5B illustrates operation of IMD 14 once initialization has occurred (step
  • Timer ⁇ t is set to zero (step 72), and IMD 14 waits for an intrinsic A event to occur (step 74).
  • IMD 14 has calculated during initialization the time from an A event to RV event (TA-RV)- Since the time from one atrial event to the next (T A - A ) is a known value, the time from an RV event to the next A event (T RV - A ) is also a known value.
  • IMD 14 will pace right atrium RA (step 76) if the timer ⁇ t equals or exceeds T RV - A - Timer ⁇ t is then set to zero (step 78). If an intrinsic A event is sensed before timer ⁇ t reaches T RV - A , the timer ⁇ t is set to zero (step 78).
  • IMD 14 then waits (step 80) until ⁇ t equals or exceeds T A -RV- At that point,
  • IMD 14 paces right ventricle RV (step 82). [0038] If a ventricular event is sensed representing either an LV pulse generated by biopacer 12 or an intrinsic RV event (step 84), this indicates that synchronization between biopacer 12 and IMD 14 is lost or not established. At step 86, IMD 14 returns to the initialization process shown in FIG. 5A to again measure the T A - LV time and recalculate the TA-RV time.
  • a loss of synchronization is also indicated if, during the waiting period (step
  • a Far Field R- Wave representing a ventricular event is sensed at RA electrode 24 (step 88). Since wait period 74 normally follows pacing right ventricle RV, it is expected that a Far Field R-Wave representing the LV event should be sensed at approximately the T RV - LV time following the RV pace event.
  • IMD 14 checks the value of timer ⁇ t when the Far Field R- Wave sense occurred to see whether the value of timer ⁇ t is between T MIN and TMAX- TMIN is the TRV-LV time minus the minimum tolerance of the T R V-LV time interval, while TMAX is TRV-LV plus the maximum tolerance on the timer interval.
  • IMD 14 continues to wait for an intrinsic A event or for the T RV - A interval to be reached so that a pacing pulse can be delivered to right atrium RA.
  • FIG. 6 shows hybrid system 100, which includes biopacer 102 and IMD 104.
  • biopacer 102 is shown implanted in a wall of right ventricle RV.
  • IMD 104 which includes housing 106, header 108, atrial lead 110, and atrial electrode 112, provides electrical pacing to right atrium RA. Operation of IMD 104 is synchronized with biopacer 102 by sensing ventricular events at electrode 112.
  • FIG. 7 shows a timing diagram for hybrid system 100.
  • IMD 104 generates stimulation to atrium RA, while biopacer 102 generates a ventricular pulse in right ventricle RV.
  • FIG. 8 shows a flow diagram for the algorithm used by IMD 104 in providing synchronized operation with biopacer 102.
  • the process starts (step 130) and IMD 104 waits (step 132) until the Far Field R- Wave is sensed by atrial electrode 112 (step 134).
  • timer ⁇ t is set to zero (step 136).
  • IMD 104 then waits (step 138) until the timer reaches or exceeds the ventricle-to-atrial time Tv-A- IMD 104 then paces right atrial RA with a pulse delivered through lead 110 and electrode 112.
  • IMD 104 again waits (step 132) for the next Far Field R- Wave to be sensed.
  • FIG. 6 shows biopacer 102 in right ventricle RV, it could also be placed in left ventricle LV, similar to what was shown in FIG. 1.
  • IMD 104 could provide pacing to left atrium LA, rather than right atrium RA.
  • the hybrid system shown in FIG. 6 minimizes the number of endocardial leads. In particular, it avoids the need for a ventricular lead extending through right atrium RA and into right ventricle RV.
  • FIG. 9 shows hybrid pacing system 200, which includes biopacer 202 and
  • IMD 204 Biopacer 202 is implanted in a wall of right ventricle RV.
  • IMD 204 includes housing or can 206, header 208, and right ventricular lead 212.
  • Right ventricular lead 212 includes distal fixation device 216, distal tip electrode 218, and ring electrode 220.
  • biopacer 202 can serve as a backup mechanism for pacing provided by IMD 204 to right ventricle RV.
  • IMD 204 can act as a backup for biopacer 202. In either case, operation of IMD 204 is coordinated with pacing activity of biopacer 202 by sensing pacing activity of biopacer 202.
  • FIG. 10 is a flow chart illustrating the coordinated operation of biopacer 202 and IMD 204.
  • the process starts (step 230) and IMD sets timer ⁇ T to zero (step 232), IMD 204 then waits (234) until an electrical signal is sensed or the minimum escape interval elapses.
  • the electrical signal sensed will typically be an R- wave.
  • timer ⁇ T is again set to zero (step 2326).
  • IMD 204 again waits (step 234). If timer exceeds a minimum escape interval, IMD 204 then paces the chamber (in this case right ventricle RV) (step 236). IMD 204 then returns to step 232 to reset timer ⁇ T to zero, and waits for the next electrical signal to be sensed (step 234).
  • FIG. 9 illustrates an embodiment in which biopacer 202 and pacing lead 212 are both located within right ventricle RV, the same concept can be used in other chambers, such as right atrium RA.
  • the flow chart shown in FIG. 10 would apply to that embodiment, with the electrical signal sensed being a P-wave rather than an R-wave.
  • hybrid pacing systems including coordinated operation of biopacers and IMDs are also possible.
  • biopacers may be implanted in more than one chamber, with a pacing lead from an IMD located in one of the chambers, or in a different chamber.
  • hybrid systems including multiple biopacers and multiple pacing leads can also be implemented.
  • hybrid pacing systems described in conjunction with the embodiments of FIG. 1 , FIG. 6, and FIG. 9 use electrical sensing of atrial and ventricular events
  • other types of sensors can also be used.
  • synchronization can also be based, at least in part, upon signals from an accelerometer or a pressure sensor.
  • the hybrid pacing system may also include transducers for providing sensory feedback to adjust the LV-RV or RV-LV timing.
  • the feedback can include signals representing dP/dt, absolute pressure, heart sounds, oxygen saturation, blood flow, wall motion and stroke volume measurements.
  • timing can be adjusted with external echocardiographic guidance or MRI guidance. These feedback inputs can be used to adjust the timing to maximize dP/dt, ejection fraction, stroke volume, or cardiac work as desired.
  • biologic pacing can be achieved by either introducing new pacing cells or altering the chemical structure of existing cells to create or modify a pacing or nodal function. Inducing automaticity in ventricular cells creates a biological pacemaker (biopacer) and the available approaches are many.
  • the biopacer can be formed using genetically engineered vectors, such as viral vectors and plasmid vectors.
  • a viral vector can be used to alter ionic currents to convert quiescent cells into cells with rhythmic depolarizations.
  • a vector is delivered to the myocardium, and the transfected cells become the new dominant pacemaker of the heart.
  • the biological pacemaker may also be formed using genetically engineered cells. In this approach, a cell may be modified genetically to induce automaticity. The genetically engineered cells are then delivered into the myocardium at a desired location to form a new cardiac pacemaker.
  • genetically unmodified cells of stem cell origin with a phenotype similar to a nodal cell can be utilized as a biological pacemaker.
  • biological pacemakers include transplantable biological materials, modified or unmodified, to perform pacemaking function similar to quiescent heart muscle cells.
  • the biological materials include, but are not limited to, cells, cell lines and other cellular compositions, vectors or cloning/expression vectors, DNA or RNA including oligos, expressed sequence tags and signal sequences, and proteins including recombinant proteins or proteins purified from biological samples and/or active fragments of proteins.
  • Other transplantable biological materials include siRNA, plasmids, engineered tissue, growth factors and differentiation inducing factors.
  • Examples of cell types that can be molecularly modified to perform pace making function include skeletal myoblasts, precursor cells, endothelial cells, differentiated or undifferentiated stem cells, undifferentiated contractile cells, fibroblasts and genetically engineered cells and components of cells, such as genetic material, or a chemoattractant to attract precursor cells as described specifically in US Published Patent Application No. 2006/0149184 at paragraphs [0007], [0029] and [0030] incorporated herein by reference.
  • Stem cells such as spoc cells, cardiomyocytes or their precursors, or mesenchymal stem cells are useful as biological materials as described in Example 3 of US Published Patent Application No.
  • Molecularly modified cells, including stem cells, altered to exhibit automaticity can be introduced into the left myocardium to form the biological pacemaker as disclosed in various publications including Potapova, L, et al., Human Mesenchymal Stem Cells as a Gene Delivery System to Create Cardiac Pacemakers, Circulation Research, 94:952-959 (2004) at page 953, paragraph 2, lines 4 to 17, pages 954 to 956, page 957, paragraph 4, lines 14 to 23, and page 958, lines 7 to 21, incorporated herein by reference.
  • Stem cells therapy includes differentiating stem cells into biological pacemakers as taught in US Published Patent Application No. 2005/0058633, paragraphs [0146] & [0147], incorporated herein by reference, and, in a publication by Choi, Y.H., et al., Cardiac Conduction Through Engineered Tissue, Am J. Pathol., 169: 72-85 (2006) at pages 75-81 incorporated herein by reference.
  • genes useful as biopacers include genes encoding dominant negative Kir2, HCN2 and ⁇ 2 adrenergic receptors, genes encoding channels including Pottasium channels (K+), sodium channels (Na+), T-type calcium channels, and genes encoding a channel or subunit thereof that produces funny current (I f ), polynucleotide sequences encoding Ikr (both subunits: ergl and MiRP),and Iks (both subunits: mink and KvLQTl), Connexins, especially connexin 43, and HCN 1-4 isoforms.
  • biopacers may be transplantable engineered tissue as disclosed in a publication by Choi, Y.H., et al., Cardiac Conduction Through Engineered Tissue, Am J. Pathol. 169:72-85 (2006) at pages 78 to 84, incorporated herein by reference.
  • Choi, et al. provide engineered tissue constructs, created from skeletal muscle-derived cells, in rat hearts, to create an alternative AV conduction pathway. These constructs exhibit sustained electrical coupling through persistent expression and function of gap junction proteins.
  • Papadaki, M., et al. disclose engineered cardiac tissue created from ventricular cardiac muscle cells, cultured in low-serum conditions, seeded onto polymer scaffolds coated with laminin.
  • transplantable biological materials are not always exclusive of one another, and a particular element of biological material may belong to more than one category.
  • the transplanted biological material need not be exclusively biological, but may include an inorganic or engineered material, such as a scaffold to hold biological material. As such, the invention is not limited to the particular materials listed herein.
  • Molecular modifications of the transplantable biological material for development of biological pacemakers may be made via gene transfer as disclosed in various publications including, but not limited to: Edelberg, J.M., et al., Enhancement of Murine Cardiac Chronotrophy by Molecular Transfer of Human b2 adrenergic Receptor cDNA, J. Clin Invest. 101 :337-343 (1998) at pages 338 to 340, incorporated herein by reference; Edelberg, J.
  • molecular modification of the transplantable biological material may be achieved by differentiation of stem cells into biopacers as taught in US Published Patent Application No. 2005/0058633, at paragraphs [0146] and [0147], incorporated herein by reference.
  • Different methodologies for placing the biological pacemaker in the heart can be applied. These methods include delivering nucleic acid/genes into cardiac cells by utilizing plasmid injections and viral constructs or implanting molecularly modified cells.
  • biological pacers can be formed by stem cell therapy.
  • Delivery of the biological pacemaker to the myocardial wall can be achieved by a catheter that is advanced into the ventricular cavity.
  • a catheter that is advanced into the ventricular cavity.
  • an electrophysiology mapping catheter one can first stimulate the left ventricle to locate the optimal location for the biopacer where the stimulation captures the left ventricle and causes the contraction of the left ventricle with the desired synchrony with the right ventricle. Afterwards, the same catheter is used to deliver the biological pacemaker to the same location on the left ventricular wall.
  • nucleic acid/genes to cardiac tissue are taught in US Patent No. 6,867,196, at Col. 13, line 21 through Col. 16, line 17, incorporated herein by reference, and published PCT Application No. WO 2005/028024 at paragraphs [0019]-[0049] incorporated herein by reference.
  • Example methods for delivery of DNA to the heart are taught in US patent No. 6,867,196.
  • nucleic acids combined with transfection reagents, plasmid DNA, or viruses are directly injected into coronary arteries and veins. This is a minimally invasive and clinically viable method for in vivo delivery system of naked nucleic acids.
  • PTCA percutaneous transluminal coronary angioplasty
  • double lumen balloon catheters are positioned into coronary veins from peripheral vessels and plasmid DNA solutions are injected under pressure to transfect cardiac muscle cells.
  • a third method uses an injection system that allows for automated regulation of injection speed and volume correlated to the pressure in the injected vessel.
  • Coronary angioplasty catheters are used to simultaneous inject fluids into the selected coronary bed and measure the intracoronary venous hydrostatic pressure during and after injection. For successful delivery of nucleic acid the permeability of a blood vessel needs to be increased. This is achieved by increasing the intravascular hydrostatic pressure.
  • Methods of increasing hydrostatic pressure include rapid (from 1 seconds to 30 minutes) injectionof nucleic acid in solution into the blood vessel, or obstructing the outflow of the injection solution from the tissue for a period of time sufficient to allow delivery of a nucleic acid. Furtherstill, rapid injection combined with obstructing the outflow can also be used as a method of increasing hydrostatic pressure.
  • Vectors are nucleic acids originating from a virus, a plasmid, or the cell of an organism into which another nucleic fragment of appropriate size can be integrated without loss of the vectors capacity for self-replication.
  • Vectors introduce nucleic acids into host cells, where it can be reproduced. Examples are plasmids, cosmids, and yeast artificial chromosomes. Vectors are often recombinant molecules containing nucleic acid sequences from several sources.
  • Vectors include viruses, for example adenovirus (an icosahedral (20- sided) virus that contains DNA and there are over 40 different adenovirus varieties, some of which cause respiratory disease), or retrovirus (any virus in the family Retroviridae that has RNA as its nucleic acid and uses the enzyme reverse transcriptase to copy its genome into the DNA and integrate into the host cell's chromosome).
  • viruses for example adenovirus (an icosahedral (20- sided) virus that contains DNA and there are over 40 different adenovirus varieties, some of which cause respiratory disease), or retrovirus (any virus in the family Retroviridae that has RNA as its nucleic acid and uses the enzyme reverse transcriptase to copy its genome into the DNA and integrate into the host cell's chromosome).
  • Vectors such as adenoviruses, adeno- associated viruses or non- viral vectors can be used to alter the electrophysiological properties of the cardiomyocytes in the left ventricle as disclosed in Miake, J., et al., Biological Pacemaker Created by Gene Transfer, Nature, 419: 132-133 (2002) at pages 132 to 133, incorporated herein by reference.
  • An adenoviral construct of mouse mHCN2 driven by a CMV promoter can be prepared as previously described. See, Qu, J., et al., HCN2 Overexpression In Newborn And Adult Ventricular Myocytes: Distinct Effects On Gating And Excitability, Circ. Res., 2001, 89:E8-E14.
  • a second adenoviral construct containing a mouse HCN2 gene harboring a point mutation, mE324A can be prepared as described previously. See, Bucchi, A., et al., Wild- Type and Mutant HCN Channels In A Tandem Biological Electronic Cardiac Pacemaker, Circulation., 2006, 114:992-999.
  • PROPHETIC EXAMPLE 2 Canine Studies
  • Implementation of the invention can be accomplished using four components, namely a biological pacing system, endocardial pacing leads, an electronic implantable pacemaker, and a software algorithm governing the operation of the pacemaker. This composite system is described in detail below.
  • a biological pacemaker can be formed by using a genetic vector.
  • an adenoviral construct of mouse hyperpolarization-activated, cyclic nucleotide-gated HCN2 (mHCN2, GenBank AF211837 - SEQ ID NO: 1) driven by the cytomegalovirus (CMV) promoter can be prepared by adhering to the good laboratory practices (GLP) procedures.
  • This construct of AdHCN2 can be purified through a plaque assay, amplified to a large stock, and harvested and titrated after CsCl banding for use in the clinical procedure.
  • the targeted titer for the AdHCN2 vector is between 3x10 11 ffu/mL and 4x10 11 ffu/mL (ffu: focus forming units).
  • ffu focus forming units
  • 2 XlO 10 to 3xlO 10 ffu of virus construct is needed, limiting the volume of the injection to less than 0.1 mL. Construct should be kept frozen at -8O 0 C until the injection procedure.
  • a right atrial (RA) and a right ventricular (RV) pacing lead such as Medtronic CapSure Z Novus models 5554 and 5054 can be placed into the right and left ventricles respectively.
  • a single VDD pacing lead such as Medtronic model 5038 can be used to access RA and RV simultaneously.
  • a left ventricular electrophysiology catheter such as Medtronic model
  • STABLEMAPR can be advanced into the left ventricular cavity. It is preferred to use a steerable delivery catheter, such as Medtronic Attain Deflectable Catheter, in addition to the electrophysiology catheter for the precise positioning of the electrophysiology catheter on the endocardial wall of the left ventricle.
  • a cardiac resyncronization therapy (CRT) device such as Medtronic InSync Sentry, can be used for the temporary pacing of the right atrium and right ventricle using the leads introduced earlier, and the left ventricle (LV) can be paced via the electrophysiology catheter.
  • CTR cardiac resyncronization therapy
  • LV left ventricle
  • Various pacing sites in the left ventricle and various LV-RV pacing delays can be tried to optimize the contraction of the ventricules and to restore the synchrony. The optimal LV pacing location and LV-RV delay can be noted.
  • a medical fluid delivery catheter such as the one described in US patent 7,274,966 can be advanced to the optimal pacing site in the left venctricle. Upto 0.1 mL of the AdHCN2 vector can be delivered to this site to establish the biological pacemaker on the LV wall. Afterwards, all catheters should be removed from the left ventricle, and a dual chamber pacing device, such as Medtronic EnPulse, should be implanted to pace the right atrium and the right ventricle. This pacemaker can be programmed to monitor any autonomous electrophysiological activity in the LV, and follow an algorithm that is similar to the ones shown on Figures 3, 5 or 8 of this application.
  • CCCATCCATC CCTGTGTGGG GTGAGGGTGG TTCAGGTGGA GGCGGGGCTC CCGCCCCCGC 3061 CCCTCCCCCG CAAGCAGAGG CTCCACCCCC GGCTCCGCCC TCCCTCGGGC TCGGCCGGCG

Abstract

Le système de stimulation cardiaque hybride selon l'invention comprend un stimulateur cardiaque biologique implanté et un dispositif médical implantable fournissant des stimuli en direction d'une ou plusieurs cavités du cœur. Le dispositif médical implantable détecte l'activité produite par le stimulateur cardiaque biologique et coordonne les stimuli qu'il envoie avec le rythme délivré par le stimulateur cardiaque biologique.
PCT/US2007/080718 2006-10-06 2007-10-08 systÈme de stimulation cardiaque hybride WO2008043099A2 (fr)

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WO2008140865A1 (fr) * 2007-05-08 2008-11-20 Cardiac Pacemakers, Inc. Procédé et système de contrôle d'une thérapie par stimulateur cardiaque

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US6867196B1 (en) 1995-12-13 2005-03-15 Mirus Bio Corporation Process for delivering nucleic acids to cardiac tissue
US20050058633A1 (en) 2001-10-22 2005-03-17 The Government Of The U.S.A. As Represented By The Secretary Of The Dept. Of Health & Human Services Stem cells that transform to beating cardiomyocytes
WO2005028024A1 (fr) 2003-09-15 2005-03-31 Medtronic, Inc. Acheminement de materiel genetique vers un site de stimulation
US7274966B2 (en) 2002-10-02 2007-09-25 Medtronic, Inc. Medical fluid delivery system

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US8013133B2 (en) * 2003-04-25 2011-09-06 Medtronic, Inc. Genetic modification of targeted regions of the cardiac conduction system
US20050021089A1 (en) * 2003-07-24 2005-01-27 Medtronic, Inc. Compositions and methods for treating cardiac dysfunction
US20060149184A1 (en) * 2005-01-06 2006-07-06 Orhan Soykan Myocardial stimulation
EP1909895A4 (fr) * 2005-07-21 2009-04-22 Univ Columbia Systeme de stimulation cardiaque en tandem

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Publication number Priority date Publication date Assignee Title
US6867196B1 (en) 1995-12-13 2005-03-15 Mirus Bio Corporation Process for delivering nucleic acids to cardiac tissue
US20050058633A1 (en) 2001-10-22 2005-03-17 The Government Of The U.S.A. As Represented By The Secretary Of The Dept. Of Health & Human Services Stem cells that transform to beating cardiomyocytes
US7274966B2 (en) 2002-10-02 2007-09-25 Medtronic, Inc. Medical fluid delivery system
WO2005028024A1 (fr) 2003-09-15 2005-03-31 Medtronic, Inc. Acheminement de materiel genetique vers un site de stimulation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008140865A1 (fr) * 2007-05-08 2008-11-20 Cardiac Pacemakers, Inc. Procédé et système de contrôle d'une thérapie par stimulateur cardiaque
US8224443B2 (en) 2007-05-08 2012-07-17 Cardiac Pacemakers, Inc. Method for controlling pacemaker therapy

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